Derivation Web

source_713609fb13f741f8

by researka:v2 · 2026-08-15 17:04:24.696339+04:00

{"publication_id": "28e44ab0-b228-4dba-8e70-b25bbc6c7ac8", "traces": [{"candidate_sources": [], "citation_support": [{"cited_as": "Farhat 2025", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "population": "not extracted", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "bundle_reference", "url": "https://doi.org/10.3390/nu17182974"}], "claim": "This paper synthesizes evidence on telomere measurement methods across the retained source corpus and high-confidence extracted claim set [bundle:5].", "claim_id": "claim_1"}, {"candidate_sources": [], "citation_support": [{"cited_as": "Farhat 2025", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "population": "not extracted", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "bundle_reference", "url": "https://doi.org/10.3390/nu17182974"}], "claim": "This paper synthesizes evidence on telomere measurement methods across the retained source corpus and high-confidence extracted claim set [bundle:5].", "claim_id": "claim_2"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "The geroscience hypothesis proposes that targeting fundamental aging biology, rather than individual diseases, could be a more efficient strategy to extend healthspan. Within this framework, telomere maintenance has been proposed as a key modifiable hallmark of aging. Interventions ranging from lifestyle modifications to pharmacological agents are being investigated for their potential to influence telomere dynamics. This variability underscores the complexity of telomere biology and suggests that broad lifestyle-based interventions may have modest or context-dependent effects on telomere length, necessitating a more targeted approach.", "claim_id": "claim_3"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "The human randomized controlled trial (RCT) landscape for telomere-focused interventions is characterized by diverse study designs, populations, and endpoints, leading to a mixed and sometimes contradictory evidence base. Many trials are mechanistic or biomarker-focused, assessing TL change as a primary or secondary endpoint without clinical outcomes. This diversity of trial contexts and populations makes it difficult to synthesize a unified narrative about the efficacy of interventions aimed at modifying telomere length.", "claim_id": "claim_4"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "This synthesis aims to contribute by systematically examining the tensions between mechanistic plausibility and clinical evidence within the telomere measurement and intervention literature. A central challenge is the separation of clinical from mechanistic evidence, as findings from different outcome domains cannot be directly compared. The review will therefore weight the evidence by separating these layers: mapping the landscape of human RCTs that have directly measured telomere length change, examining the observational associations with longevity and specific diseases, and evaluating the mechanistic studies that inform biological plausibility. The goal is to identify where the evidence is consistent, where it is contradictory, and where the most significant gaps remain, particularly concerning the functional consequences of modifying telomere length and the boundary conditions for any potential clinical benefit.", "claim_id": "claim_5"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "Risk-of-bias honesty note: No populated per-source public appraisal ratings are reported in this artifact. Risk-of-bias language is therefore descriptive of source design and directness, not a claim that formal framework-specific scoring was completed.", "claim_id": "claim_6"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.", "claim_id": "claim_7"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "A source was coded as direct only when it tested the topic itself against a clinically proximate outcome in the relevant population. Human evidence with an adjacent exposure, population, or outcome was coded as indirect; syntheses and secondary reviews were coded as review-level evidence and were not counted as direct sources.", "claim_id": "claim_8"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "Risk-of-bias framework assignment follows study design (risk-of-bias appraisal for RCTs, non-randomized-study appraisal for non-randomised studies, review-quality appraisal for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.", "claim_id": "claim_9"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, frailty, immune and inflammation, longevity, mortality and survival, muscle function); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.", "claim_id": "claim_10"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Evidence domain | Corpus slice | Direction profile | Directness | Main limitation |", "claim_id": "claim_11"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Contextual Adjacent Evidence | n=25; claims=319 | positive=1, negative=2, null=2, mixed=1, unclear=19 (n=25) | 17 direct; 5 indirect; 3 review | limited corpus depth in this outcome class |", "claim_id": "claim_12"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Cardiometabolic | n=4; claims=30 | positive=0, negative=0, null=0, mixed=0, unclear=4 (n=4) | 3 direct; 1 review | limited corpus depth in this outcome class |", "claim_id": "claim_13"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Immune and Inflammation | n=4; claims=72 | positive=0, negative=0, null=2, mixed=0, unclear=2 (n=4) | 2 direct; 1 indirect; 1 review | limited corpus depth in this outcome class |", "claim_id": "claim_14"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Longevity | n=2; claims=44 | positive=1, negative=0, null=0, mixed=0, unclear=1 (n=2) | 1 direct; 1 review | limited corpus depth in this outcome class |", "claim_id": "claim_15"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Animal/Preclinical Context | n=1; claims=11 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 mechanistic | single-source slice; hypothesis-generating |", "claim_id": "claim_16"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Deficiency Prevalence | n=1; claims=14 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 indirect | single-source slice; hypothesis-generating |", "claim_id": "claim_17"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Frailty | n=1; claims=10 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 indirect | single-source slice; hypothesis-generating |", "claim_id": "claim_18"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Mortality and Survival | n=1; claims=13 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 indirect | single-source slice; hypothesis-generating |", "claim_id": "claim_19"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "| Telomere Measurement Methods / Muscle Function | n=1; claims=7 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 review | single-source slice; hypothesis-generating |", "claim_id": "claim_20"}, {"candidate_sources": [], "citation_support": [{"cited_as": "Ribeiro 2021", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "population": "not extracted", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "bundle_reference", "url": "https://doi.org/10.3390/ijerph182111274"}], "claim": "Ribeiro 2021 [bundle:1] (Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in; representative statistic p ≤ 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).", "claim_id": "claim_21"}, {"candidate_sources": [], "citation_support": [{"cited_as": "Jaeger 2024", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "population": "not extracted", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "bundle_reference", "url": "https://doi.org/10.3390/nu16172963"}], "claim": "Jaeger 2024 [bundle:4] (A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized; representative statistic p = 0.01; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).", "claim_id": "claim_22"}, {"candidate_sources": [], "citation_support": [{"cited_as": "Salvador 2016", "directness": "direct", "doi": "10.1089/rej.2015.1793", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the low dose of TA-65 (250 U) significantly increased TL over the 12 months period (530 ± 180 bp; p = 0.005), whereas subjects in the placebo group significantly lost TL (290 ± 100 bp; p = 0.01). The high dose of TA-65 (1000 U) showed a trend of improvements in TL compared with that of the placebo group; however, the improvements did not reach statistical significance. TL changes in the low-dose group were similar for both median and 20th percentile TLs. The findings suggest that TA-65 can lengthen telomeres in a statistically and possibly clinically significant manner.", "excerpt": "Subjects taking the low dose of TA-65 (250 U) significantly increased TL over the 12 months period (530 ± 180 bp; p = 0.005), whereas subjects in the placebo group significantly lost TL (290 ± 100 bp; p = 0.01). The high dose of TA-65 (1000 U) showed a trend of improvements in TL compared with that of the placebo group; however, the improvements did not reach statistical significance. TL changes in the low-dose group were similar for both median and 20th percentile TLs. The findings suggest that TA-65 can lengthen telomeres in a statistically and possibly clinically significant manner. Keywords: : telomere length, TA-65, Astragalus , telomerase, randomized, placebo controlled trial T A -65 was discovered as a chemically defined small molecule activator of telomerase in the year 2000 from an empirical screen of natural product extracts from traditional Chinese medicines. 1 , 2 (Patent number: US7846904). Since that time, there have been research and observational studies on TA-65 in humans and animal models supporting improvements in biomarkers of aging, including immune, cardiovascular, metabolic, bone, and inflammatory markers, without significant signs of toxicity. 2–4 The formulation (TA-65MD) is manufactured under the regulations of current good manufacturing practice (cGMP); it is designated as GRAS (generally recognized as safe) for use in a medical food and is sold as a dietary supplement by the company TA Sciences. Interest in TA-65 as a telomerase activator is largely driven by the potential health benefit of telomere maintenance. Without telomerase, telomeres gradually shorten with each cell division due to the “end replication problem,” oxidative stress, and other natural DNA processing at chromosome ends, ultimately triggering cell senescence, that is, the loss of cell replication capacity and ensuing tissue degeneration when telomeres become critically short. 5 There is abundant evidence that telomerase activation can help maintain and/or lengthen telomeres 6–8 and in some cases restore tissue and organ function that has been compromised by critical telomere shortening. 9 However, to date, there have been no blinded, placebo controlled human studies of TA-65. This report provides the first evidence from a randomized, double blind, placebo controlled study that dietary supplementation with TA-65 has the ability to lengthen telomeres and potentially improve health outcomes in humans, with no observed safety concerns. Cytomegalovirus (CMV) infects the majority of the population worldwide asymptomatically. Seventy to eighty percent of individuals by the age of 50 are infected with CMV. CMV has been implicated in decreased T-cell immunity, associated immunosenescence, and decrease in the T-cell receptor repertoire, causing clonal expansion of senescent CD8 + CD28 − T cells with a proinflammatory profile. 10 Recent studies also suggest that CMV infections are associated with increased mortality in the elderly and are a potential factor in the development of cardiovascular disease among immuno-compromised individuals. 11 , 12 Here we investigated whether TA-65 can alleviate telomere attrition in CMV + subjects, to support our previous observational study finding that TA-65 appears to preferentially lengthen critically short telomeres in CMV + subjects. 1 This study is aimed at understanding telomere length (TL) changes in CMV + subjects taking the telomerase activator TA-65 in comparison with the placebo group. In a previous observational study, subjects taking TA-65 along with other supplements showed improvements from baseline in health biomarkers, especially in CMV + subjects. 1 Since the subjects were blind to their CMV status while taking TA-65, it is unlikely that the positive effects of TA-65 were due to a placebo effect. To confirm that there was in fact no significant placebo effect, this study was designed to be randomized, double blind, and placebo controlled. We tested a cohort of CMV + subjects for the effect of TA-65 on TL. The TLs were measured using HT Q-FISH with automation to handle a large number of human samples and to improve consistency. The cross-sectional analysis of TL at baseline indicates a decline of 50 ± 21 bp/year, which is higher than in some studies, but consistent with other published data. 5 , 16 , 17 The rate of telomere loss has been reported to be exacerbated in CMV + individuals, 18 which may also contribute to the relatively high rate of change in the cross-sectional analysis. The rate of loss reported in this study 18 was 94 ± 9 bp/year in CMV + subjects and 77 ± 9 bp/year in CMV − subjects. In this study, the placebo group had an average telomere attrition of 290 ± 100 bp/year ( p = 0.01), whereas the low-dose TA-65 (250 U) group had net increase of 530 ± 180 bp/year ( p = 0.005). Interestingly there were no statistically significant changes in TL in the high-dose TA-65 (1000 U) group. Loss of 290 bp/year in the placebo group is indeed large, but a large loss is to be expected in a group that is 100% CMV + and consists of older individuals aged >60 years. The accelerated attrition is supported by: (1) CMV infection that causes significant shortening of TL in the age group of >60 years 18 and (2) CMV seropositivity increases the oligoclonal expansion of the immune cells with age. 19 Although variation in the rate of TL loss over time cannot be ruled out, there are limited studies on TLs in CMV subjects. In the previous observational study, 1 the subjects who took a very low starting dose of 5–10 mg/day of unformulated TA-65 ( i.e. , active ingredient alone) had no significant change in TL. In this study, with an improvement in formulation (TA-65MD) to enhance bioavailability, the TA-65 250 U (with 8 mg of active ingredient) increased TL, whereas TA-65 1000 U (with 3", "population": "not extracted", "source_id": "source_34", "study": "A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo Controlled Study", "support_kind": "bundle_reference", "url": "https://doi.org/10.1089/rej.2015.1793"}], "claim": "Salvador 2016 [bundle:34] (A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo; representative statistic p = 0.005; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).", "claim_id": "claim_23"}, {"candidate_sources": [], "citation_support": [{"cited_as": "Sindi 2020", "directness": "direct", "doi": "10.1093/gerona/glaa279", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Between September 7, 2009 and November 24, 2011, 2654 individuals were screened and 1260 were randomly assigned to the intensive intervention group ( n = 631) or control group ( n = 629). The full trial profile has been previously described ( 17 ). There were no significant differences in baseline characteristics between intervention and control groups in the LTL subpopulation ( Table 1 ). The LTL subpopulation ( n = 756) had a higher education level ( p = .039), lower systolic blood pressure ( p = .003), and better cognitive performance on the total NTB ( p = .001), executive functioning ( p", "excerpt": "Between September 7, 2009 and November 24, 2011, 2654 individuals were screened and 1260 were randomly assigned to the intensive intervention group ( n = 631) or control group ( n = 629). The full trial profile has been previously described ( 17 ). There were no significant differences in baseline characteristics between intervention and control groups in the LTL subpopulation ( Table 1 ). The LTL subpopulation ( n = 756) had a higher education level ( p = .039), lower systolic blood pressure ( p = .003), and better cognitive performance on the total NTB ( p = .001), executive functioning ( p ≤ .001), and processing speed ( p = .035) domains compared with the rest of the FINGER participants ( n = 504; Supplementary Table S1 ). Baseline Characteristics of Participants in the FINGER LTL Exploratory Substudy Notes: FINGER = Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability; NTB = Neuropsychological Test Battery. Values are means ± SD unless otherwise specified. Differences between intervention and control groups were analyzed with chi-square and t tests as appropriate. *Scores on the NTB total score, executive functioning, processing speed, memory, and long-term memory are mean values of z -scores of the cognitive tests included in each cognitive outcome. Higher scores indicate better performance. Mean relative LTL ( SD ) at baseline was 1.075 (0.325) for participants aged 60–70 years and 1.042 (0.338) for participants aged 70–77 years. Because there is no “general reference scale” for the size of change in relative LTL values over time, and LTL decreases with age, these mean baseline values per age decade are provided as reference. FINGER is so far the largest clinical trial investigating the effects of a multidomain lifestyle intervention on change in LTL and the first to relate the change in LTL to change in cognition in older adults at risk for dementia from the general population. Overall, LTL change during 2 years was not significantly different between the intervention and control groups.", "population": "not extracted", "source_id": "source_7", "study": "Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline: A Randomized Clinical Trial", "support_kind": "bundle_reference", "url": "https://doi.org/10.1093/gerona/glaa279"}], "claim": "Sindi 2020 [bundle:7] (Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline: A Randomized Clinical Trial; representative statistic p = .039; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).", "claim_id": "claim_24"}, {"candidate_sources": [], "citation_support": [{"cited_as": "Kalstad 2019", "directness": "direct", "doi": "10.1186/s12877-019-1383-9", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "[ 21 ] demonstrated a significant reduced shortening with higher baseline levels of eicoapentaenoic acid (EPA) and docosahexaenoic acid (DHA) over a period of 6 years in a CVD population [ 21 ]. Reduced shortening of telomeres was also reported with decreasing n-6/n-3 ratio in a supplementation study in a healthy middle-aged population [ 22 ]. The aim of the present study was to further explore the relationship between LTL and selected commonly studied LCPUFAs and diet in elderly survivors of myocardial infarction (MI). In addition, any associations of LTL with risk cardiovascular risk", "excerpt": "[ 21 ] demonstrated a significant reduced shortening with higher baseline levels of eicoapentaenoic acid (EPA) and docosahexaenoic acid (DHA) over a period of 6 years in a CVD population [ 21 ]. Reduced shortening of telomeres was also reported with decreasing n-6/n-3 ratio in a supplementation study in a healthy middle-aged population [ 22 ]. The aim of the present study was to further explore the relationship between LTL and selected commonly studied LCPUFAs and diet in elderly survivors of myocardial infarction (MI). In addition, any associations of LTL with risk cardiovascular risk factors, MI characteristics and markers of myocardial injury and dysfunction were explored. Baseline characteristics of the patient cohort ( n = 299) are presented in Table 1 .The median age of was 75 (72, 78) years. Males comprised 70.2% of the population. All patients were of Caucasian ethnicity. Other cardiovascular risk factors were prevalent, with 60.9% diagnosed with hypertension or used anti-hypertensive medications, 47.8% diagnosed with hyperlipidemia or on lipid-lowering agents and 23.1% were diagnosed with diabetes mellitus. Pre-existing coronary artery disease was reported in 45.2% of patients prior to the index MI. A total of 40 patients (13.4%) had diagnosis of heart failure, either preexisting or diagnosed during or after the index hospitalization. LVEF < 50% was recorded in 52 patients (32.1% of 162). NSTEMIs constituted 68.6% of cases and STEMIs the remaining 31.4%. Table 1 Characteristics of the study cohort. Data are presented as number (%) or median values (25, 75 percentiles) Age (years)(range) 75 (70,82) Males 210 (70.2) BMI (kg/m 2 ) 25.6 (23.8, 28.3) Systolic BP (mmHg) 140 (125, 151) Diastolic BP (mmHg) 74 (67, 80) Current smokers 41 (13.7) Previous hyperlipidemia 156 (47.8) Previous hypertension 182 (60.9) Diabetes mellitus 69 (23.1) Previous chronic kidney disease 1 15 (5.1) Previous heart failure 16 (5.4) Previous coronary artery disease 135 (45.2) Previous ischaemic stroke 21 (7.0) NSTEMI/STEMI 68.6 / 31.4 (205 / 94) 3-vessel disease 2 61 (21.3) Maximum Troponin T (ng/L) 700 (153, 2500) NT-proBNP (ng/L) 634 (279, 1374) LVEF < 50% 3 52 (32.1) Taking n-3 FA supplement 135 (45.2) BMI Body Mass Index; NSTEMI Non-ST-segment elevation myocardial infarction; STEMI ST-segment elevation myocardial infarction; NT-proBNP N-terminal pro-Brain natriuretic peptide; LVEF Left ventricle ejection fraction; FA fatty acids 1 creatinine > 150 μmol/L 2 of n = 286 with angiography 3 of n = 162 with echocardiography The findings in this study of telomere lengths in elderly patients with a recent MI were predominantly neutral. A weak, but significant correlation between serum levels of linoleic acid and LTL, and a borderline relationship between LTL and dietary habits were found, whereas no significant relation to conventional cardiovascular risk factors or features of MI could be demonstrated. Previous studies investigating the associations between LCPUFAs and LTL have shown that these fatty acids affect telomere attrition rate. However, in accordance with our findings no associations on a cross-sectional level have been demonstrated. Farzaneh-Far et al. found that the higher quartiles of serum EPA+ DHA were associated with reduced telomere shortening over 6 years in patients with coronary heart disease [ 21 ]. A decreasing n-6/n-3 ratio was associated with reduced shortening in a 4 months intervention study on healthy, sedentary overweight middle-aged and older individuals [ 22 ].", "population": "not extracted", "source_id": "source_36", "study": "Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients", "support_kind": "bundle_reference", "url": "https://doi.org/10.1186/s12877-019-1383-9"}], "claim": "Kalstad 2019 [bundle:36] (Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and; 8 extracted claim(s); receipt-level direction is the coded finding; outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1).", "claim_id": "claim_25"}, {"candidate_sources": [], "citation_support": [{"cited_as": "Su 2025", "directness": "review", "doi": "10.1007/s10565-025-10115-6", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "TA-65 supplementation induced moderate telomere elongation (SMD = 0.47, 95% CI: 0.31–0.62; p < 0.00001), with amplified effects in adults > 60 years (SMD = 0.63 vs. 0.36; p = 0.03). Industry-funded trials reported inflated efficacy (SMD = 0.63 vs. 0.40; p = 0.03). Critically, telomere elongation did not translate to functional improvements in frailty (SMD = 0.09, p = 0.15) or inflammation (CRP/IL-6 SMD = − 0.11, p = 0.07), revealing a telomere-function disconnect. Safety analysis (n = 487) identified mild gastrointestinal toxicity (12.4% incidence; nausea: 7.1%, abdominal discomfort: 5.3%)", "excerpt": "TA-65 supplementation induced moderate telomere elongation (SMD = 0.47, 95% CI: 0.31–0.62; p < 0.00001), with amplified effects in adults > 60 years (SMD = 0.63 vs. 0.36; p = 0.03). Industry-funded trials reported inflated efficacy (SMD = 0.63 vs. 0.40; p = 0.03). Critically, telomere elongation did not translate to functional improvements in frailty (SMD = 0.09, p = 0.15) or inflammation (CRP/IL-6 SMD = − 0.11, p = 0.07), revealing a telomere-function disconnect. Safety analysis (n = 487) identified mild gastrointestinal toxicity (12.4% incidence; nausea: 7.1%, abdominal discomfort: 5.3%) but no severe adverse events (e.g., oncogenesis) over 12 months. Dose–response relationships (10–50 mg/day) and measurement-method variations were non-significant (p > 0.05). While TA-65 demonstrates telomerase-activating efficacy, particularly in older adults, its failure to improve functional aging metrics underscores limitations of unimodal biomarker targeting. The absence of dose-dependent toxicity or short-term oncogenic risk is notable, yet long-term carcinogenic potential remains unaddressed. Rigorous, independent trials must evaluate TA-65’s chronic toxicity, telomere-independent mechanisms, and utility within multidimensional aging frameworks. Clinical application may consider older adults with immunosenescence, incorporating safety surveillance for gastrointestinal and oncological endpoints. This graphical abstract summarizes the design, key findings, and conclusion of our meta-analysis on TA-65's effects on telomere length and functional aging outcomes. The online version contains supplementary material available at 10.1007/s10565-025-10115-6. Keywords: TA-65, Telomere paradox, Biomarker-function disconnect, Translational gerontology, Industry bias, Anti-aging pharmacology Telomere attrition represents a fundamental pillar of cellular aging, driving genomic instability, senescence, and systemic functional decline across organ systems (Ly et al. 2018 ; Martínez and Blasco 2015 ; De Rosa and Opresko 2023 ). Shortened leukocyte telomere length (LTL) is consistently linked to age-associated pathologies—from cardiovascular disease to neurodegeneration—imposing staggering societal burdens in aging populations worldwide (Lu and Pickett 2022 ; Cheng et al. 2021 ; Haycock et al. 2017 ; Guo et al. 2022 ). While telomerase activation offers a promising strategy to counteract this process, its paradoxical role in carcinogenesis poses critical safety concerns: constitutive telomerase upregulation may fuel malignant transformation, as evidenced by TERT promoter mutations in diverse cancers (Shim et al. 2024 ; Gao and Pickett 2022 ; Tsoukalas et al. 2019 ). This delicate balance between anti-aging efficacy and oncogenic risk underscores the urgent need for toxicologically informed evaluations of telomerase-targeting compounds. TA-65® ( cycloastragenol ), a small-molecule telomerase activator derived from Astragalus membranaceus, exemplifies this translational challenge. Preclinical studies demonstrate its capacity to elongate telomeres and improve metabolic parameters in aging models (Fernandez et al. 2018 ; Liu et al. 2017 ; Bawamia et al. 2023 ; Bernardes de Jesus et al. 2011 ). However, the mechanism underlying telomere elongation remains uncertain. While TA-65 is proposed to act as a telomerase activator, the evidence in humans is inconsistent (13), and its effects may alternatively involve a redistribution of immune cell populations toward naïve cells with inherently longer telomeres, rather than direct telomerase activation (Salvador et al. 2016 ; Muscari et al. 2023 ). These discrepancies stem from methodological heterogeneity, commercial bias (78% industry funding) (Huang et al. 2024 ), and insufficient attention to tissue-specific bioavailability and off-target effects. Crucially, the absence of integrated analyses reconciling molecular efficacy, functional outcomes, and toxicological risks hinders evidence-based clinical translation (Table S1 ). Our study addresses these gaps through the first systematic meta-analysis quantitatively dissecting TA-65’s dual roles in cellular aging and toxicity. Leveraging PRISMA-guided methodology across 8 randomized trials (n = 750), we integrate three innovative dimensions: (1) simultaneous assessment of telomere dynamics and functional aging metrics (frailty, inflammation), (2) toxicological profiling of dose-dependent adverse events and oncogenic risks, and (3) rigorous bias adjustment for commercial funding confounders. By employing GRADE evidence grading and meta-regression, we establish a biologically stratified risk–benefit framework—enabling identification of responsive subpopulations while mitigating safety hazards. This approach transcends prior reviews through its mechanistic focus on the telomere-function disconnect and proactive safety surveillance protocol. Throughout this paper, 'telomere length' refers to LTL unless otherwise specified. The societal imperative for this work is unequivocal: with global populations aging rapidly, ineffective or unsafe \"anti-aging\" interventions exacerbate healthcare costs and erode public trust. Our findings provide urgently needed evidence to guide regulatory policies, clinical practice, and future research—prioritizing independent validation of TA-65’s long-term safety, multidimensional aging endpoints, and tailored implementation for high-risk geriatric cohorts. By resolving the tension between TA-65’s molecular promise and its functional-toxicological realities, this work redefines standards for evaluating aging therapeutics in the precision medicine era. The aim of this systematic review is to evaluate the effects of TA-65 on LTL, functional outcomes, and inflammatory markers in adults aged ≥ 40 years, using PICOS criteria: Participants (adults ≥ 40 years), Intervention (TA-65 monotherapy), Comparison (placebo or no treatment), Outcomes (telomere length, functional metrics, inflammation), and Study design (RCTs and observational studies). Several primary limitations temper the interpretation of our findings. First, methodological heterogeneity in telomere measurement techniques (e.g., qPCR vs. Southern blot) may obscure true effect sizes, though our subgroup analyses suggested this was not a major source of bias. Second, the median follow-up of 12 months precludes a robust assessment of long-term oncological risks—a critical gap given telomerase's dual role in aging and carcinogenesis. and Third, several important subgroup analyses (e.g., by age and funding source) were conducted post-hoc rather than being pre-specified in our PROSPERO protocol. While these analyses provide valuable exploratory insights into potential sources of heterogeneity, their findings should be interpreted as hypothesis-generating and require confirmation in future pre-specified studies. Fourth, a key methodological concern is that none of the included studies controlled for or reported changes in immune cell distribution (e.g., the ratio of naïve to memory T-cells). As shifts in leukocyte subsets can significantly influence the average telomere length measured in bulk samples, the observed telomere elongation attributed to TA-65 could be partially confounded by changes in cell population composition rather than true telomere elongation within individual cells. Fifth, observed funnel plot asymmetry (p = 0.02, Egger's test) suggests the potential for unpublished negative studies, which may inflate the overall efficacy estimate. Finally, our initial subgroup analysis of dosage was limited by an imbalanced distribution of studies, with only one trial in the highest dose category. However, we mitigated this concern by performing supplementary analyses, including meta-regression and an alternative binary split, which consistently reinforced the conclusion of a non-significant dose–response relationship. Future trials should prioritize the standardization of telomere quantification, extend safety monitoring beyond 5 years, adopt open-data practices to minimize publication bias, and pre-specify key subgroup hypotheses to allow for more confirmatory analyses (Table 4 ). GRADE evidence profile TA-65 epitomizes the challenges of translational gerontology: while it may elongate telomeres, the absence of functional improvements questions the utility of telomerase activation as a standalone anti-aging strategy and underscores the inadequacy of single-biomarker approaches. Industry sponsorship biases exacerbate the stark molecular-clinical dichotomy. Until robust longitudinal evidence emerges, TA-65 remains investigational. Clinicians should restrict use to older adults (> 60 years) with biomarker-confirmed immunosenescence, enforcing strict stopping rules due to the telomere-function disconnect.", "population": "not extracted", "source_id": "source_8", "study": "Effects of TA-65 on telomere length, functional outcomes, and inflammation: a systematic review and meta-analysis", "support_kind": "bundle_reference", "url": "https://doi.org/10.1007/s10565-025-10115-6"}], "claim": "Su 2025 [bundle:8] (Effects of TA-65 on telomere length, functional outcomes, and inflammation: a systematic review and meta-analysis; representative statistic p < 0.00001; source-level statistic reported; outcome=Biomarker/Adjacent Immune and Inflammation; direction=null; directness=review; tier=B1).", "claim_id": "claim_26"}, {"candidate_sources": [], "citation_support": [{"cited_as": "Nanda 2025", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "population": "not extracted", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "bundle_reference", "url": "https://doi.org/10.1007/s11357-025-01818-z"}], "claim": "Nanda 2025 [bundle:2] (Chronic inflammation mediates the relationship between physical activity and telomere length; 30 extracted claim(s); receipt-level direction is the coded finding; outcome=Biomarker/Adjacent Immune and Inflammation; direction=null; directness=indirect; tier=B2).", "claim_id": "claim_27"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "Liu 2025 [bundle:18] (representative non-significant statistic p>0.05; not treated as positive or negative directional support unless source direction is coded; outcome=Biomarker/Adjacent Frailty; direction=unclear; directness=indirect; tier=B2).", "claim_id": "claim_28"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "Thesis:** Across 40 curated reference papers, the evidence base for Telomere shows a context-dependent profile. Positive signals appear in: longevity, Contextual Adjacent Evidence. Negative signals appear in: Contextual Adjacent Evidence. Null findings dominate: immune inflammation, Contextual Adjacent Evidence. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Telomere broad aging-related case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile.", "claim_id": "claim_29"}, {"candidate_sources": [{"cited_as": "Ribeiro 2021", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/ijerph182111274", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women", "excerpt": "The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC ( p = 0.045), hip circumference ( p = 0.032), serum cholesterol ( p ≤ 0.001), and low-density lipoprotein ( p = 0.030). Whereas, the IAT decreased WC ( p = 0.014), waist-to-hip ratio ( p = 0.012), free androgen index (FAI) ( p = 0.037). WC ( p = 0.049) and body fat ( p = 0.015) increased in the non-training group while total cholesterol was reduced ( p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers. Polycystic ovary syndrome (PCOS) is a multifactorial heterogeneous endocrine disorder where the main characteristic behind this syndrome is chronic anovulation due to hyperandrogenism, a striking feature in this disease. However, the PCOS clinical expression varies and may include oligo-ovulation or anovulation and/or clinical or biochemical hyperandrogenism and evidence of polycystic ovaries [ 1 ]. Infertility and metabolic complications, such as dyslipidemia, hypertension, abnormal glucose metabolism, insulin resistance (IR), and obesity, are often present in PCOS [ 2 ], which increased the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [ 3 , 4 ]. This variability of phenotypes associated with PCOS depends on ethnicity and directly interferes with the prevalence of this syndrome, which affects between 5 and 16% of women of reproductive age [ 2 ]. Despite the genetic alterations related to PCOS [ 5 ], a strong environmental contribution is related to the development of the syndrome or even the worsening of the clinical conditions. The management of obesity with diet [ 6 ] or physical activity [ 7 , 8 ] has been suggested as a first-line treatment to improve related symptoms and infertility, a matter of concern in PCOS treatment [ 9 ]. This suggests an epigenetic component related to the pathogenesis of PCOS that affects gene expression, genomic stability, and telomere attrition [ 10 ]. Progressive telomere shortening is associated with loss of cellular proliferative capacity and premature reproductive aging, leading to chronic anovulation and infertility [ 11 ]. Several factors such as oxidative stress, inflammation, mitochondrial dysfunction, and hormonal alterations, as observed in PCOS, may accelerate telomere erosion [ 12 ]. On the other hand, increased levels of androgens in PCOS may be a protective factor improving telomerase activity [ 13 ] thereby not changing [ 7 , 14 ] or increasing telomere repeats [ 15 ]. These conflicting results were recently reported and are being continuously investigated [ 16 ]. It is well-known that regular practice of physical activity can improve metabolic complications and hyperandrogenism in women with PCOS, with implications in chronic anovulation and ultimately restoring fertility. Some studies have proposed that physical training could protect progressive shortening of telomeres, preventing premature aging [ 7 , 17 , 18 ]. Telomere shortening is associated with sedentarism, obesity, cardiometabolic risk factors, and oxidative stress, which leads to the development of many human diseases, in addition to a shorter life expectancy [ 19 , 20 ]. The intensity and interval training may have different effects on telomere biology. The aerobic physical exercise of moderate to high intensity improved metabolic and reproductive outcomes of PCOS women, reducing chronic anovulation, cardiometabolic risk, IR, and obesity-related indexes [ 21 ]. Larocca et al. (2010) [ 17 ] showed that the telomere length is more preserved in the physically active elderly compared to the inactive ones, and a positive correlation between telomeres and aerobic capacity was observed. Previously we reported that progressive resistance training (PRT) [ 7 , 8 ] had positive effects on hormonal and physical characteristics of women with PCOS, with no effects on telomere length specifically related to PCOS. However, the type of physical exercise and the intensity have different effects on metabolic rate, hormonal levels, body composition, and reproductive health in women with PCOS [ 8 , 22 , 23 ] that could interfere in telomere biology. The effects of supervised aerobic physical exercise on telomere length and its implication on inflammatory biomarkers, metabolic disturbance, and reproductive outcomes of PCOS were not investigated. Considering the importance of the practice of physical exercise in women with PCOS, we now investigate the effects of two aerobic physical training protocols, continuous (CAT) and intermittent (IAT), on telomere length and its correlation with metabolic, hormonal, and anthropometric parameters in women with PCOS. The flowchart of the study is illustrated in Figure 1 . According to the eligibility criteria, 126 participants were recruited. Of these 126, 16 were unable to reach the inclusion criteria for PCOS after initial evaluations, thus 110 women with PCOS started the physical training protocols. Of these, 23 did not finish the protocols and 87 participants completed the study: 28 in CAT, 29 in the IAT, and 30 in the CG groups. To adhere to the protocols and complete the study, the adherence was at least 90% of the training sessions. The physical, anthropometric and hormonal characteristics of the groups analyzed before and after the training or the observational period are presented in Table 1 . The age, diastolic and systolic blood pressure were not different between the studied groups. To characterize the PCOS, prolactin (CG = 16.6 ng/mL ± 9.1; CAT =17.4 ng/mL ± 12.7; IAT = 16.8 ng/mL ± 11.7), 17-OHP (CG = 106.0 uUI/mL ± 38.0; CAT = 98.0 uUI/mL ± 47.0; IAT = 86.0 uUI/mL ± 40.0), and TSH (CG = 2.38 ng/dL ± 1.18; CAT =1.76 ng/dL ± 0.67; IAT = 2.64 ng/dL ± 1.60) were measured. At baseline, the total testosterone level was higher in the CAT group (117 ± 50 ng/dL) when compared to the CG (86 ± 37 ng/dL), p = 0.01. The other variables analyzed were not different at the beginning of the training protocols. Serum levels of androstenedione, SHBG, estradiol, FSH, and LH did not change after aerobic physical training protocols (CAT and IAT) and the observational period in CG. The testosterone level decreased after CAT ( p ≤ 0.001) and IAT ( p = 0.019) and the FAI was reduced only in the IAT group ( p = 0.037). After the aerobic physical exercises or no training periods, no differences were observed in the anthropometric indices BMI and weight, or the metabolic parameters such as HDL, triglycerides, fasting glycemia and insulin and HOMA-IR. The lipidic profile as total cholesterol ( p ≤ 0.001) and LDL ( p = 0.030) was reduced after CAT.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_1", "study": "Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/ijerph182111274", "year": 2021}, {"cited_as": "Nanda 2025", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s11357-025-01818-z", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72", "excerpt": "1 Flow of study participants Table 1 Participant demographics Characteristic Female ( n = 44,836) Male ( n = 35,037) Total ( n = 79,873) Mean (SD) or n (%) Ethnicity (% white) 43,428 (96.86) 34,042 (97.16) 77,470 (96.99) Smoking status (% never smoked) 27,376 (61.06) 18,259 (52.11) 45,635 (57.13) Chronic diseases (% without) 32,293 (72.02) 22,646 (64.63) 54,939 (68.78) Baseline age (yrs) 56.18 (7.72) 57.35 (7.88) 56.69 (7.81) BMI 26.27 (4.84) 27.27 (4.00) 26.71 (4.52) Date difference from samples (yrs) 5.69 (1.07) 5.70 (1.07) 5.69 (1.07) Actigraph wear time (days) 6.70 (0.54) 6.73 (6.55) 6.72 (0.55) Townsend deprevation index −1.70 (2.81) −1.79 (2.81) −1.74 (2.81) Adjusted T.S ratio 0.85 (0.13) 0.82 (0.13) 0.84 (0.13) CRP (mg/L) 2.33 (3.93) 2.12 (3.85) 2.24 (3.89) MVPA (hrs/day) 0.59 (0.51) 0.83 (0.66) 0.70 (0.60) In the minimally adjusted regression models, time spent engaged in MVPA was positively associated with TL (β [95%CI] = 4.30e − 03 [2.94e − 03, 5.72e − 03], p = 9.34e − 10). Higher levels of MVPA were significantly associated with lower CRP concentrations (β [95%CI] = − 0.563 [− 0.584, − 0.543], p < 2e − 16). In a regression including MVPA and CRP, both were significant predictors of TL (β MVPA [95%CI] = 3.36e − 03 [1.95e − 03, 4.77e − 03], p MVPA = 3.12e − 06; β CRP [95%CI] = − 1.73e − 03 [− 2.20e − 03, − 1.27e − 03], p CRP = 3.51e − 13 respectively). In the minimally adjusted causal mediation analysis, CRP partially mediated the relationship between MVPA and TL, accounting for 22.46% [95%CI: 14.66%, 35.59%] of the total effect (β [95%CI] = 4.33e − 03 [2.92e − 03, 5.71e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 9.73e − 04 [7.07e − 04, 1.24e − 03], p < 2e − 16), and direct effect of MVPA on TL (β [95%CI] = 3.35e − 03 [1.92e − 03, 4.78e − 03], p < 2e − 16). When including all covariates in the fully adjusted model (see methods), there was a positive relationship between time spent engaged in MVPA and TL (β [95%CI] = 3.31e − 03 [1.87e − 03, 0.005], p = 6.77e − 06). MVPA was significantly associated with CRP (β [95%CI] = − 0.211 [− 0.23, − 0.19], p < 2e − 16). When both were included in the model, MVPA and CRP were significant predictors of TL (β MVPA [95%CI] = 3.03e − 03 [1.58e − 03, 4.47e − 03], p MVPA = 4.10e − 05; β CRP [95%CI] = − 1.36e − 03 [− 1.87e − 03, − 8.40e − 04], p CRP = 2.52e − 07 respectively). The association between MVPA and TL was significantly partially mediated by CRP (Fig. 2 ), with the overall proportion mediated accounting for 8.65% [95% CI: 4.77%, 16.0%] of the total effect (β [95%CI] = 3.31e − 03 [1.84e − 03, 4.75e − 03], p < 2e − 16). There was a significant indirect effect of MVPA on TL through CRP (β [95%CI] = 2.85e − 04 [1.73e − 04, 4.00e − 04], p < 2e − 16), and direct effect of MVPA on TL (β [95% CI] = 3.02e − 03 [1.56e − 03, 4.47e − 03], p = 2e − 04). In our sensitivity analysis including only participants > 60 years of age ( n = 47,658), female participants ( n = 44,836), and male participants ( n = 35,037) results did not dif", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_2", "study": "Chronic inflammation mediates the relationship between physical activity and telomere length", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s11357-025-01818-z", "year": 2025}, {"cited_as": "Chen 2026", "comparator": "not extracted", "directness": "indirect", "doi": "10.1007/s00415-025-13479-1", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "excerpt": "Conversely, longer LTL was associated with a 3.71-fold increased risk of multiple sclerosis (MS) (HR: 3.71, 95% CI 1.91–7.18, P < 0.001).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_3", "study": "Association between leukocyte telomere length and neurodegenerative diseases: a prospective cohort in the UK Biobank", "support_kind": "candidate_source_row", "url": "https://doi.org/10.1007/s00415-025-13479-1", "year": 2026}, {"cited_as": "Jaeger 2024", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu16172963", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated", "excerpt": "Subjects taking the Astragalus-based supplement exhibited significantly longer median TL ( p = 0.01) and short TL ( p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement’s intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging. Astragalus, a plant widely used in traditional Chinese medicine, has garnered significant attention for its potential to activate telomerase and extend telomere length, making it a promising natural nutritional supplement for promoting healthy aging. Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, thus maintaining genomic integrity during the cell cycle [ 1 ]. These structures consist of tandem repeats of the nucleotide sequence TTAGGG, associated with various regulatory proteins, including telomerase, the only enzyme capable of replicating telomeres [ 2 , 3 ]. In the absence of telomerase activity, which depends on the catalytic subunit telomerase reverse transcriptase (TERT), the ends of DNA are shortened by approximately 50 to 200 base pairs during each S phase of the cell cycle [ 4 ]. Cells that reach a critically low telomere length (TL) can no longer divide and thus undergo senescence or apoptosis [ 5 , 6 , 7 ]. Telomeres play a crucial role in preserving genome integrity by preventing chromosome ends from being recognized as DNA damage. During each cell replication cycle, genetic material is lost, but since telomeres do not contain coding sequences, there is no loss of genomic information. Without an effective telomere maintenance mechanism, cell division will ultimately lead to the formation of short telomeres. These short telomeres lose their protective function and are reported to the cell as damaged DNA, activating cellular senescence pathways such as p53 and pRb/p16 [ 8 ], which interrupt cellular proliferation and induce senescence or apoptosis, depending on the cell type involved. The Hayflick limit, the maximum number of divisions a cell can undergo [ 4 , 6 ], establishes a link between telomere length and cell lifespan. A decrease in TL, a marker of cellular aging, is associated with age and with aging-related diseases [ 1 , 5 , 9 ]. The rate of telomere shortening is influenced by environmental factors, including diet, physical activity, and lifestyle choices [ 10 , 11 , 12 ]. Astragalus contains active compounds such as astragaloside IV and cycloastragenol, which have been identified as potent telomerase activators. These compounds can compensate for replicative telomere erosion by activating telomerase, a specialized reverse transcriptase that uses a specific template RNA to extend the 3′ strand of chromosome ends. There are also telomerase-independent telomere-lengthening mechanisms based on homologous recombination events, known as ALT (alternative lengthening of telomeres) [ 13 ]. The average size of leukocyte telomeres at a given age results from three variables: inherited length, the rate of immune cell proliferation, and exposure to chronic oxidative stress. Chronic oxidative stress has been shown to be a major causal factor in telomere shortening and cellular senescence [ 14 ]. Average telomere size, which can be measured in peripheral blood leukocytes using various techniques, serves as a marker of biological age and chronic stress exposure under different physiological and pathological conditions [ 15 ]. In humans, telomere size decreases from about 10 kbp at birth to 4 kbp at 80 years of age, with a coding rate of a few dozen bases per year. The length of the telomeric sequence, which is shorter in men than in women, is linearly and inversely correlated with age and is largely genetically determined (70–80% heritability), exhibiting broad variability. A large longitudinal population-based cohort study on subjects aged 50 and older demonstrated that while telomere length declines with age, telomere size may vary over time [ 16 ]. The study found that TL shortened in 66.32% of the cohort, remained stable in 11.23%, and lengthened in 22.45% [ 16 ]. Women of the same age showed a lower within-individual leukocyte TL shortening rate than men [ 16 ]. Numerous studies have shown that telomere shortening in peripheral blood leukocytes is a risk factor for cardiovascular disease (atherosclerosis, early infarction, hypertension, vascular dementia), metabolic disorders (diabetes, obesity, insulin resistance), mental pathologies, infections, and cancer [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Mortality from infections or cardiovascular disease is three to eight times higher in individuals over 60 years of age, with the shortest telomeres compared to those with the longest telomeres [ 27 ]. This underscores the pivotal role of telomeres at the interface of molecular systems involved in aging, cell proliferation, tissue renewal, oxidative stress, inflammation, immune competence, and carcinogenesis [ 28 , 29 ]. Several potent telomerase activators have been brought to market in recent years, based on their proposed action on telomeres in vitro [ 3 , 30 ]. Astragalus, due to its potent telomerase-activating compounds, has shown benefits in vitro and in animal experiments [ 31 , 32 , 33 ], and early human trials have produced encouraging results [ 34 ]. We recently reported the benefits of an Astragalus extract containing astragaloside IV and cycloastragenol, a potent telomerase activator, in an open prospective preliminary study on telomere size and cardiovascular impact in healthy volunteers [ 35 ]. Encouraged by these results, we conducted a randomized, double-blind, controlled trial over six months to compare the effect of this Astragalus-based nutritional supplement versus a placebo on TL in 40 healthy volunteers. The purpose of this study is, then, to validate that a natural astragalus-based nutritional supplement lengthens telomeres in a middle-aged population thanks a randomized, double-blind, placebo-controlled study. Although the difference was not significant, the active-ingredient group decreased its physical activity during the study (from 4.4 ± 2.7 h/week at baseline to 3.3 ± 1.7 h/week at 6 months, p = 0.1), while the placebo group maintained stable physical activity over time (from 3.8 ± 2.4 h/week at baseline to 3.7 ± 2.4 h/week at M6). Recent reports have already shown promising results for several molecules belonging to the pharmaceutical class of telomerase activators [ 3 , 30 ]. Astragalus, a plant used in traditional Chinese medicine, is one of the most potent products in this pharmaceutical class. Astragalus and one of its derivatives (astragalosides) appear to be metabolized to cycloastragenol (CA), a telomerase activator [ 37 , 38 ]. Some products from Astragalus have shown benefits [ 31 , 32 , 33 ]. TA-65, an astragaloside IV, significantly increases telomerase activity 1.3 to 3.3-fold relative to controls in human T-cell cultures [ 39 ]. Our telomerase activator complex also contains hydroxytyrosol, which is known to inhibit oxidative stress and inflammation by enhancing the nuclear factor erythroid-2-related factor/heme-oxygenase 1 (Nrf2/HO-1) signaling pathway and inhibiting the mitogen-activated protein kinase/nuclear factor-kappa B (MAPK/NF-κB) signaling pathway [ 40 , 41 ]. So hydroxytyrosol can also have an influence on the final result. Another study involving a placebo containing olive fruit extract to demonstrate the effect of Astragalus extract could be interesting. The randomized, double-blind, placebo-controlled study showed that a natural Astragalus-based nutritional supplement lengthens telomeres in a middle-aged population. Our previous report had already highlighted a significant increase in short telomere length between baseline and M6 in all 10 subjects included [ 35 ], prompting us to proceed with this randomized, double-blind, placebo-controlled study. Indeed, the present longitudinal study confirmed a decline or a non-significant increase in both median and short telomere lengths in the placebo group, whereas the ASTCOQ02 group had a net increase in median telomere length of 271 kbp at 1 month, 472 kbp at 3 months, and 696 kbp at 6 months ( p = 0.01) and a net increase in average short telomere length of 244 kbp at 1 month, 650 kbp at 3 months, and 810 kbp at 6 months ( p = 0.004).", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_4", "study": "A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu16172963", "year": 2024}, {"cited_as": "Farhat 2025", "comparator": "not extracted", "directness": "direct", "doi": "10.3390/nu17182974", "effect": "not extracted", "endpoint": "not extracted", "evidence_span": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and", "excerpt": "Objective : To investigate the effects of pomegranate extract on telomere length and serum IGF-1 levels in older adults aged 55–70 years. Methods : Participants took part in a two-arm double-blind parallel trial, receiving either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6 and week 12, anthropometric measurements, blood pressure readings and blood samples were collected. Telomere length and serum IGF-1 levels were assessed. Results : A total of 72 participants completed the study. Analysis showed a significant effect of treatment and time on IGF-1 ((F 2,136 = 3.43, p = 0.04), with levels significantly increasing in the pomegranate extract group at week 12. No significant effects on telomere length were noted. Weight status, physical activity, age, gender and energy intake did not impact the outcomes. Conclusions : Pomegranate extract significantly increased IGF-1 levels and could exert a positive role on vascular ageing. Further research is needed to replicate these findings and confirm its long-term benefits. Extended studies are required to elucidate its potential to counteract telomere shortening. Keywords: pomegranate extract, polyphenols, ageing, telomere length, IGF-1 With the global population of older adults steadily increasing, there is a corresponding increase in age-related diseases and health challenges [ 1 ]. Ageing is a complex biological process influenced by genetic, environmental and lifestyle factors, and multiple factors are involved in the manifestation of ageing, including telomere shortening [ 2 ]. Telomeres are protective caps at the end of chromosomes that prevent their instability by shielding genetic material from degradation, preventing chromosomal end-to-end fusions and ensuring proper replication during cell division. As telomeres progressively shorten with each cell division, they contribute to cellular ageing and senescence [ 3 ]. It has been suggested that telomere length measurement could serve as a promising clinical tool for age-related diseases [ 4 ], and there is evidence showing an inverse association between telomere length and BMI [ 5 ], as well as between telomere length and blood pressure levels [ 6 ]. Evidence from cell research showed that oxidative stress can accelerate telomere shortening, thereby speeding the ageing process and contributing to age-related diseases [ 7 ]. Targeting oxidative stress could therefore potentially represent a therapeutic strategy to slow down the ageing process and age-related diseases. IGF-1 is a hormone increasingly recognised for its role in ageing and longevity, though its role remains controversial. Multiple studies suggest that IGF-1 is a biological marker of ageing, with lower concentrations associated with an increased risk of atherosclerosis, cardiovascular mortality and heart failure in older adults [ 8 , 9 ]. Findings from a review including both animal and human studies additionally highlight the role of IGF-1 in reducing oxidative stress, apoptosis and inflammatory signalling, suggesting a potential disease protective role in normal vascular ageing [ 10 , 11 , 12 ]. Although the exact mechanisms remain unclear, it is hypothesized that the effect may be mediated through the downregulation of tumour necrosis factor-alpha (TNF-α) in macrophages, an effect reported in humans [ 11 ]. However, IGF-1 has also been associated with negative effects on longevity, with proposed mechanisms including increased cellular proliferation and risk of tumour [ 13 ]. Some evidence suggests a complex interaction between IGF-1 and telomere length, proposing that elevated IGF-1 levels can independently predict longer telomere length. A study including 551 adults aged 65 years and older reported a significant association between higher IGF-1 and longer telomere length after adjusting for age, gender, disease status and BMI [ 14 ]. IGF-1 may reduce oxidative stress and inflammation [ 15 ], which are thought to be key mechanisms driving increased immune cell turnover and telomere shortening. Polyphenols, abundant in fruits and vegetables, are well-known for their antioxidant and anti-inflammatory properties and have garnered increasing interest for their potential anti-ageing effects. Limited human studies suggest that polyphenols may reduce telomere shortening, likely due to their antioxidant and anti-inflammatory activities [ 16 , 17 , 18 ]. Furthermore, polyphenols have been shown to upregulate IGF-1 in both animal and cell models [ 19 , 20 ]. Pomegranate extract (PE) has recently attracted particular attention due to its potent antioxidant properties and its potential as a sustainable option in the face of climate change [ 21 , 22 ]. An animal study demonstrated that administering pomegranate peel for two months enhanced telomerase reverse transcriptase expression, reduced oxidative stress and elevated IGF-1 levels in aged rats [ 23 ]. Given the limited studies, our study aimed to explore the effects of PE on telomere length and IGF-1 levels in older adults (55–70 years), with the goal of gaining insights into the mechanisms linking polyphenols to ageing and informing the need for longer-term studies. The study was conducted according to the guidelines laid down in the Declaration of Helsinki and received ethical approval from the Manchester Metropolitan University Faculty of Health and Education (reference number: 47627). Written informed consent was obtained from all participants before they joined the study. Recruitment occurred between December 2022 and June 2024. The study was registered with clinicaltrials.gov ( NCT05588479 ). The advertisement led to 355 individuals expressing interest, of whom 296 were assessed for eligibility and 86 met the eligibility criteria for participation. These participants were equally assigned to the PE and PL groups. Eight participants withdrew after their initial appointment, leaving 76 who completed the full intervention. In some cases (n = 4), challenges with blood collection during specific appointments resulted in incomplete data for certain participants. Consequently, 72 participants completed data from all three appointments and were included in the final analysis. The overall attrition rate was 11.6%. The CONSORT flow diagram has included in Figure 1 . Consort flow diagram. Abbreviations: PE: pomegranate extract; PL: placebo; HRT: hormone replacement therapy. The majority of participants were female (61%) and White British (83%). The mean age of the population is 61.22 (4.31) years, and the average BMI was 23.91 (3.25) kg/m 2 , with 65.28% belonging to the normal weight category.", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "source_id": "source_5", "study": "Effects of Pomegranate Extract on IGF-1 Levels and Telomere Length in Older Adults (55–70 Years): Findings from a Randomised Double-Blinded Controlled Trial", "support_kind": "candidate_source_row", "url": "https://doi.org/10.3390/nu17182974", "year": 2025}], "citation_support": [], "claim": "Threat 1: Several randomized controlled trials reporting telomere maintenance or lengthening also report concurrent improvements in cardiometabolic, hormonal, or inflammatory biomarkers, suggesting that the disconnect between elongation and function may be an artifact of short follow-up or underpowered functional endpoints rather than a true mechanistic disconnect. These findings appear consistent with a model in which the temporal horizon required for telomere elongation to manifest as functional improvement may exceed the 12- to 24-month windows most trials employ, and the evidence suggests that caloric restriction confers benefits through pathways that do not necessarily pass through measurable telomere length change.", "claim_id": "claim_30"}]}

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