Derivation Web

source_f99e5335e3334d1d

by researka:v2 · 2026-06-21 23:11:13.519142+04:00

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The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.", "type": "claim"}, {"id": "claim_4", "text": "The conclusion is that Alpha-klotho remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.", "type": "claim"}, {"id": "claim_5", "text": "This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two.", "type": "claim"}, {"id": "claim_6", "text": "The geroscience hypothesis holds that targeting the biology of aging itself, rather than each chronic disease in isolation, may produce larger and more synchronized gains in late-life health, and the hypothesis has motivated a wave of drug-repurposing and novel-development programs aimed at candidate longevity proteins. Klotho sits prominently in that landscape, and the question of whether soluble klotho should be considered a druggable target, a biomarker, an exerkine, or all three has been debated. The intervention logic differs by strategy: observational associations between klotho levels and outcomes are being treated as a rationale for prospective supplementation studies, while exercise-induced changes in circulating klotho are being framed as a non-pharmacologic pathway to engage the same biology. The repurposing case is supported by small open-label human work such as Adema 2018, a prospective single-center case-control pilot examining exogenous growth hormone administration and circulating α-klotho in healthy and chronic kidney disease subjects, and by preclinical high-intensity interval and aerobic training studies in CKD models (Rokhsati 2026). Each of these lines of evidence is mechanistically plausible, and the question of whether they converge on a clinically meaningful klotho axis remains uncertain.", "type": "claim"}, {"id": "claim_7", "text": "Klotho is best understood as a longevity protein with two principal isoforms — membrane-bound and soluble (s-Klotho/α-Klotho) — that act as obligate co-receptors for fibroblast growth factor-23 and as circulating effectors on multiple organ systems. The mechanism has been linked to mineral metabolism, vascular calcification, muscle and bone homeostasis, and central nervous system function, and the question of which of these pathways is most clinically actionable has driven the design of recent human studies. From a regulatory and clinical-history standpoint, klotho has reached the clinic primarily as a biomarker: in chronic kidney disease, lower circulating α-klotho has been associated with adverse kidney outcomes (Liu 2019) and with cardiovascular parameters (Kim 2018), and an inverse correlation with arterial calcification has been reported (Wungu 2024). Serum klotho has also been studied as an early risk-predictive biomarker in settings such as acute kidney injury following acute myocardial infarction (Pei 2023) and in sepsis-associated AKI (Pei 2022), and in cardiometabolic and sex-stratified NHANES analyses (Zeng 2025; Zuo 2025; Zhang 2026). Access to klotho-related research reagents has historically been heterogeneous, and the question of whether interlaboratory assay variability is itself a source of clinical heterogeneity has been raised (Correa 2022). The current picture, then, is that klotho is at once a well-characterized longevity protein and a candidate whose therapeutic access remains limited, and the question of how to move from biomarker to intervention has not yet been answered.", "type": "claim"}, {"id": "claim_8", "text": "Additional corpus sources included animal/preclinical evidence; the human randomized trial landscape for klotho is sparse and, where it exists, heavily indirect. Direct supplementation trials of recombinant soluble klotho in older adults are not represented in the curated reference bundle, and the bulk of the clinical evidence is therefore drawn from observational cohorts and meta-analyses of those cohorts. Population heterogeneity is striking: studies range from preterm infants with bronchopulmonary dysplasia (Batlahally 2020) to middle-aged adults with obesity (Ariadel-Cobo 2026) to nursing-home residents (Sanz 2021), to pediatric chronic kidney disease (Lindblad 2017), to hemodialysis patients (Nowak 2014), and to community-dwelling mid-to-older adults drawn from NHANES and similar surveys (Zeng 2025; Zhuang 2025; Zuo 2025; Zhang 2026). Endpoints span the canonical safety comorbidity, cardiometabolic, muscle function, frailty, longevity, and immune classes, and within frailty, Sanz 2021 reported associations between low serum klotho and worse cognition, psychological components of frailty, dependence, and falls, while Guldan 2026 meta-analyzed circulating α-klotho against multidimensional aging and frailty outcomes. The exercise-as-exerkine evidence base is anchored by Oliveira 2026 and Correa 2022, and the question of whether non-pharmacologic klotho engagement produces sustained, clinically meaningful change has been proposed but remains uncertain. The practical consequence is that the klotho human evidence base is best characterized as a constellation of indirect signals rather than a series of confirmatory trials.", "type": "claim"}, {"id": "claim_9", "text": "Several unresolved questions complicate any attempt to translate the klotho signal into clinical recommendations. The first is mechanism-to-function translation: the question of whether higher circulating klotho is causally protective, merely a marker of preserved renal and metabolic function, or, in some contexts, a stress-induced alarm signal (as suggested by the paradoxical mortality association in Paradoxical Prognostic Role 2026) is unresolved. The second is the tradeoff between observational and interventional evidence: the 5% preclinical lifespan extension typical of metformin-style anti-aging studies (Anisimov 2008) provides a reference point, but the question of whether soluble klotho can produce comparable human effects has not been tested. A third uncertainty is population specificity — whether the signal is strongest in chronic kidney disease, in frail older adults, in midlife adults with cardiometabolic risk, or in children and adolescents (Allwsh 2026) — and the literature is not yet sufficient to discriminate these. Duration and dose-response are essentially unmapped for any klotho-directed intervention, and the question of whether acute and chronic exercise protocols (Oliveira 2026; Castillo 2024) and pharmacologic agents such as SGLT2 inhibitors (Mora-Fernandez 2022) and statins/angiotensin-receptor blockers (Janic 2019) share a common dose-response surface is open. Finally, the boundary conditions under which klotho is associated with benefit, harm, or null effect on the same outcome — such as the disagreement between Nong 2025 and Charoenngam 2020 on longevity in different populations — remain to be established.", "type": "claim"}, {"id": "claim_10", "text": "The contribution of this synthesis is to surface the cross-outcome tensions, weight the structured evidence by directness and design, and keep the clinical and mechanistic literatures in separate but explicit conversation. Across cross-study disagreements identified in the curated reference bundle, the dominant pattern is that positive signals cluster in muscle function and selected safety comorbidity contexts — for example, exercise-induced increases in s-Klotho (Oliveira 2026; Correa 2022) and the protective association of higher α-Klotho with frailty (Guldan 2026) — while negative signals appear in other safety comorbidity and deficiency prevalence contexts, exemplified by the inverse relationship between serum klotho and magnesium depletion (Zhuang 2025) and the paradoxical adverse prognostic signal in post-myocardial infarction (Paradoxical Prognostic Role 2026). Null findings are the modal category, especially in vascular calcification (Liu 2021; Fan 2024) and in several hard-outcome meta-analyses of chronic kidney disease (Edmonston 2024). Where the field appears to disagree most sharply, the disagreement is between prognostic directions rather than between statistical significances, and this synthesis makes those cross-source disagreements explicit. Throughout, the distinction between surrogate-endpoint association and hard-outcome validity (Ioannidis 2005) is preserved, and the question of whether the klotho anti-aging case as currently constituted is sufficient to justify dedicated human supplementation trials is left open, as the evidence suggests, but does not yet confirm, a clinically actionable role.", "type": "claim"}, {"id": "claim_11", "text": "Geroscience frames aging not as a single organ-by-organ decline but as a coordinated set of molecular and cellular processes whose modulation could compress morbidity and extend healthspan (Sanz 2021). The hallmarks of aging — mitochondrial dysfunction, cellular senescence, stem-cell exhaustion, and altered intercellular communication — have become a heuristic for prioritizing candidate interventions, because targeting a hallmark should, in principle, modify multiple age-related diseases at once (Guldan 2026). Within this framework, klotho has attracted attention as a putative longevity protein whose decline in mammals accompanies the appearance of a syndrome resembling accelerated aging, and whose overexpression extends lifespan in preclinical models (Gan 2026). The regulatory implications of a geroprotective claim are substantial: any intervention that targets aging biology itself, rather than a specific disease, must demonstrate multi-system benefit and acceptable safety, and the klotho literature has so far produced mostly surrogate-endpoint and biomarker evidence rather than hard clinical outcomes (Ioannidis 2005). The case for klotho thus sits at the boundary between mechanistic plausibility and clinical proof, and a rigorous synthesis must weigh preclinical signal against human evidence quality.", "type": "claim"}, {"id": "claim_12", "text": "The clinical-trial landscape for klotho is sparse and dominated by surrogate-endpoint studies in renal, cardiometabolic, and pediatric populations rather than by large hard-outcome trials (Edmonston 2024). One quasi-mechanistic signal in patients with diabetic kidney disease came from a clinical-and-experimental study of SGLT2 inhibitors, which raised serum Klotho (P < 0.001) while DPP4 inhibitors did not, even though both reduced HbA1c comparably (Mora-Fernandez 2022). Together these trials suggest that klotho is modifiable by existing drugs, exercise, and possibly low-dose pharmacologic combinations, but they do not yet establish hard-outcome efficacy.", "type": "claim"}, {"id": "claim_13", "text": "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.", "type": "claim"}, {"id": "claim_14", "text": "Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 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.", "type": "claim"}, {"id": "claim_15", "text": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, muscle function, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.", "type": "claim"}, {"id": "claim_16", "text": "Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.", "type": "claim"}, {"id": "claim_17", "text": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "type": "claim"}, {"id": "claim_18", "text": "| Contextual Adjacent Evidence | n=14; claims=637 | no extracted directional signal in 5/14 sources | 9 indirect; 5 review | limited corpus depth in this outcome class |", "type": "claim"}, {"id": "claim_19", "text": "Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.", "type": "claim"}, {"id": "claim_20", "text": "Contextual Adjacent Evidence: n=14; claims=637; no extracted directional signal in 5/14 sources | directness: 9 indirect; 5 review; main limitation: no direct clinical anchor.", "type": "claim"}, {"id": "claim_21", "text": "The cardiometabolic evidence base for klotho centers on two complementary study types. Together, these sources provide both a cross-sectional association map and an intervention-based read on whether Klotho can be pharmacologically mobilized in a high-risk cardiometabolic population.", "type": "claim"}, {"id": "claim_22", "text": "In the Mora-Fernandez 2022 review, both DPP4 inhibitors and SGLT2 inhibitors reduced HbA1c similarly, but only SGLT2 inhibitors decreased eGFR decline, albuminuria, and urinary TNF-alpha while increasing serum Klotho (P < 0.001). Per the evidence synthesis, the two sources converge on Klotho as a measurable biomarker that tracks renal and vascular injury cross-sectionally and can be upregulated by an intervention that simultaneously improves hard renal endpoints.", "type": "claim"}, {"id": "claim_23", "text": "Mechanistically, the renal and vascular findings align: Klotho is highly expressed in the kidney, and its soluble form is shed into circulation where it interfaces with FGF-23 signaling and phosphate-calcium handling, both directly implicated in vascular calcification. The concordance across an observational cohort and an intervention-based review supports Klotho as both a marker of cardiometabolic-renal injury and a candidate mediator of SGLT2 inhibitor renoprotection.", "type": "claim"}, {"id": "claim_24", "text": "The Mora-Fernandez 2022 review, by contrast, reports a clearly negative-direction effect for the SGLT2 inhibitor arm (decreased eGFR decline, albuminuria, urinary TNF-alpha) coupled with a positive Klotho response (P < 0.001).", "type": "claim"}, {"id": "claim_25", "text": "Mechanistically, these cohort and cross-sectional observations are consistent with klotho's known biology as a circulating anti-aging protein co-expressed with renal tubular function and vascular integrity. By contrast, Zeng 2025 frames higher klotho as a downstream correlate of cardiovascular-health behaviors (LE8 score), supporting the interpretation that klotho concentrations track cardiometabolic and renal reserve rather than functioning as a unidirectional risk marker. Pei 2022 sits within the sepsis-AKI biomarker literature, where the early-prediction endpoint is mechanistically distinct from the deficiency-prevalence framing used by the other studies.", "type": "claim"}, {"id": "claim_26", "text": "The Zhuang 2025 negative signal also partially conflicts with the null findings of Pei 2022 and the null CRIC findings in Edmonston 2024 (HRs crossing unity for survival, heart-failure hospitalization, and atherosclerotic cardiovascular events).", "type": "claim"}, {"id": "claim_27", "text": "Finally, Wang 2026 reports that higher serum klotho was associated with increased odds of thrombocytopenia in middle-aged and older adults, introducing a positive-direction signal on a different deficiency-prevalence endpoint that does not align with the predominantly negative direction seen in Zhuang 2025 and Zhang 2026.", "type": "claim"}, {"id": "claim_28", "text": "The frailty evidence base for klotho is anchored by Sanz 2021, an observational cohort study conducted in frail and sarcopenic adults that examined serum klotho concentrations in relation to multiple frailty-domain endpoints [Sanz 2021]. The endpoint framework spans cognitive, functional, psychological, and falls-related domains, allowing a within-study comparison of how a single klotho measure tracks several Fried-style frailty components simultaneously [Sanz 2021]. This observational, single-cohort design — rather than a randomized intervention — frames the entire frailty subsection as indirect rather than as a clinical RCT [Sanz 2021].", "type": "claim"}, {"id": "claim_29", "text": "Within-corpus tension in the frailty class is constrained by the single-source composition of the supplied evidence: Sanz 2021 is the only frailty-domain source, so there is no second author-year with which to surface a direct disagreement on direction, population, or endpoint [Sanz 2021]. The cross-study disagreement map for this corpus contains no same-outcome non-orthogonal pairs, which means any apparent disagreement must be discussed in cross-domain terms rather than within the frailty subsection itself [Sanz 2021]. Readers should therefore treat the frailty signal as a single-source, internally consistent positive finding whose generalizability — across settings, assays, and frailty instruments — remains an open empirical question pending additional sources [Sanz 2021].", "type": "claim"}, {"id": "claim_30", "text": "Four sources in the curated bundle address longevity directly, and they converge on the conclusion that the klotho–mortality relationship is context-dependent rather than unidirectional. The Nong 2025 finding frames elevated Klotho as a marker of survival benefit in the cancer-survivor setting, although the U-shape simultaneously implicates very high circulating concentrations as potentially adverse. Charoenngam 2020, a systematic review and meta-analysis, reached the opposite pole, showing that chronic kidney disease (CKD) patients with lower circulating soluble Klotho had a significantly increased risk of all-cause mortality (Charoenngam 2020), positioning low Klotho as the risk-bearing pole in the renal population.", "type": "claim"}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1007/s11255-025-04475-5", "effect": "not extracted", "endpoint": "not extracted", "id": "source_1", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Association of serum Klotho and fibroblast growth factor-23 levels with vascular calcification severity in patients with chronic kidney disease: an observational cohort study", "type": "source", "url": "https://doi.org/10.1007/s11255-025-04475-5", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1007/s13105-026-01182-2", "effect": "not extracted", "endpoint": "not extracted", "id": "source_2", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Effects of acute, subacute, and chronic exercise on plasma s-Klotho levels: a systematic review and meta-analysis", "type": "source", "url": "https://doi.org/10.1007/s13105-026-01182-2", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1038/s41598-024-56377-8", "effect": "not extracted", "endpoint": "not extracted", "id": "source_3", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Role of klotho and fibroblast growth factor 23 in arterial calcification, thickness, and stiffness: a meta-analysis of observational studies", "type": "source", "url": "https://doi.org/10.1038/s41598-024-56377-8", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41598-020-69296-1", "effect": "not extracted", "endpoint": "not extracted", "id": "source_4", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants", "type": "source", "url": "https://doi.org/10.1038/s41598-020-69296-1", "year": 2020}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1007/s00223-026-01537-3", "effect": "not extracted", "endpoint": "not extracted", "id": "source_5", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Circulating α-Klotho and Multidimensional Aging and Frailty Outcomes: A Systematic Review and Meta-Analysis from the European Renal Association CKD-MBD Working Group", "type": "source", "url": "https://doi.org/10.1007/s00223-026-01537-3", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/ijms27041983", "effect": "not extracted", "endpoint": "not extracted", "id": "source_6", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Associations Between Klotho/FGF-Related Protein Expression in Peripheral Blood Mononuclear Cells, Inflammation, and Muscle Function in Middle-Aged Adults with Obesity: A Pilot Study", "type": "source", "url": "https://doi.org/10.3390/ijms27041983", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3390/ijms26051915", "effect": "not extracted", "endpoint": "not extracted", "id": "source_7", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Influence of Klotho Protein Levels in Obesity and Sarcopenia: A Systematic Review", "type": "source", "url": "https://doi.org/10.3390/ijms26051915", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1002/agm2.70005", "effect": "not extracted", "endpoint": "not extracted", "id": "source_8", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Interaction Effect of Estimated Pulse Wave Velocity and Serum Klotho Level on Chronic Kidney Disease", "type": "source", "url": "https://doi.org/10.1002/agm2.70005", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1155/2023/8244545", "effect": "not extracted", "endpoint": "not extracted", "id": "source_9", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "α -Klotho: An Early Risk-Predictive Biomarker for Acute Kidney Injury in Patients with Acute Myocardial 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"not appraised in public sidecar", "study": "Anti-aging protein α-Klotho is potential for reducing comorbidity risk of cardiometabolic diseases in vulnerable populations and enhancing long-term prognosis", "type": "source", "url": "https://doi.org/10.1038/s41598-025-01580-4", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.jnha.2025.100618", "effect": "not extracted", "endpoint": "not extracted", "id": "source_18", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Serum klotho is inversely associated with girth in older women but is not associated with falls or musculoskeletal measures in either sex", "type": "source", "url": "https://doi.org/10.1016/j.jnha.2025.100618", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1038/s41598-022-22123-1", "effect": "not extracted", "endpoint": "not extracted", "id": "source_19", 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"not extracted", "id": "source_21", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers", "type": "source", "url": "https://doi.org/10.1177/13872877251326199", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1097/MD.0000000000043471", "effect": "not extracted", "endpoint": "not extracted", "id": "source_22", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Circulating Klotho and mortality patterns among US cancer survivors: A cohort study", "type": "source", "url": "https://doi.org/10.1097/MD.0000000000043471", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s12933-026-03150-y", "effect": "not extracted", "endpoint": "not 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"directness": "review-level", "doi": "10.1038/s41598-024-54812-4", "effect": "not extracted", "endpoint": "not extracted", "id": "source_27", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis", "type": "source", "url": "https://doi.org/10.1038/s41598-024-54812-4", "year": 2024}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3389/fphys.2021.711904", "effect": "not extracted", "endpoint": "not extracted", "id": "source_28", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Correlation Between Soluble Klotho and Vascular Calcification in Chronic Kidney Disease: A Meta-Analysis and Systematic Review", "type": "source", "url": "https://doi.org/10.3389/fphys.2021.711904", "year": 2021}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/jcm15072727", "effect": "not extracted", "endpoint": "not extracted", "id": "source_29", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Association of Increased Cardio-Ankle Vascular Index (CAVI) with Echocardiographically Impaired Diastolic Dysfunction and Low Klotho Levels in Kidney Transplant Patients", "type": "source", "url": "https://doi.org/10.3390/jcm15072727", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.4239/wjd.v16.i1.98714", "effect": "not extracted", "endpoint": "not extracted", "id": "source_30", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Risk factors for developing osteoporosis in diabetic kidney disease and its 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"population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Low levels of circulating anti-ageing hormone Klotho predict the onset and progression of diabetic retinopathy", "type": "source", "url": "https://doi.org/10.1177/1479164120970901", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s12944-025-02541-6", "effect": "not extracted", "endpoint": "not extracted", "id": "source_33", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Central adiposity and α-klotho: inflammatory mechanisms underlying aging biomarkers related to body roundness index", "type": "source", "url": "https://doi.org/10.1186/s12944-025-02541-6", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3389/fendo.2022.902765", "effect": "not extracted", "endpoint": "not extracted", "id": "source_34", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Relationship of Soluble Klotho and Early Stage of Diabetic Nephropathy: A Systematic Review and Meta-Analysis", "type": "source", "url": "https://doi.org/10.3389/fendo.2022.902765", "year": 2022}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1053/j.ajkd.2024.02.008", "effect": "not extracted", "endpoint": "not extracted", "id": "source_35", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.", "type": "source", "url": "https://doi.org/10.1053/j.ajkd.2024.02.008", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/ijms26030902", "effect": "not extracted", "endpoint": "not extracted", "id": "source_36", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Preeclampsia as a Study Model for Aging: The Klotho Gene Paradigm", "type": "source", "url": "https://doi.org/10.3390/ijms26030902", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1016/j.biopha.2022.113677", "effect": "not extracted", "endpoint": "not extracted", "id": "source_37", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.", "type": "source", "url": "https://doi.org/10.1016/j.biopha.2022.113677", "year": 2022}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1161/circ.152.suppl_3.4365476", "effect": "not extracted", "endpoint": "not extracted", "id": "source_38", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Abstract 4365476: The Klotho Protein Reduces Vascular Calcification via Suppressing GPX4-mediated Ferroptosis in Vascular Smooth Muscle Cells", "type": "source", "url": "https://doi.org/10.1161/circ.152.suppl_3.4365476", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/ijms26178551", "effect": "not extracted", "endpoint": "not extracted", "id": "source_39", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "The Anti-Inflammatory Actions of Soluble Klotho in Brain Aging and Its Main Associated Diseases", "type": "source", "url": "https://doi.org/10.3390/ijms26178551", "year": 2025}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1007/s11255-020-02510-1", "effect": "not extracted", "endpoint": "not 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"directness": "review-level", "doi": "10.1177/13872877261422411", "effect": "not extracted", "endpoint": "not extracted", "id": "source_42", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Age-related alterations in plasma biomarkers of relevance to Alzheimer's disease are attenuated in KLOTHO KL-VS heterozygotes", "type": "source", "url": "https://doi.org/10.1177/13872877261422411", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1097/md.0000000000048281", "effect": "not extracted", "endpoint": "not extracted", "id": "source_43", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Association between serum Klotho and thrombocytopenia in middle-aged and older adults: A cross-sectional study based on NHANES.", "type": "source", "url": "https://doi.org/10.1097/md.0000000000048281", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s12882-019-1297-y", "effect": "not extracted", "endpoint": "not extracted", "id": "source_44", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study", "type": "source", "url": "https://doi.org/10.1186/s12882-019-1297-y", "year": 2019}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s12882-018-1114-z", "effect": "not extracted", "endpoint": "not extracted", "id": "source_45", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study", "type": "source", "url": "https://doi.org/10.1186/s12882-018-1114-z", "year": 2018}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1007/s00467-017-3766-5", "effect": "not extracted", "endpoint": "not extracted", "id": "source_46", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study", "type": "source", "url": "https://doi.org/10.1007/s00467-017-3766-5", "year": 2017}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1155/2018/9481475", "effect": "not extracted", "endpoint": "not extracted", "id": "source_47", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Correlation 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"The Prognostic Role of Klotho in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis", "type": "source", "url": "https://doi.org/10.1155/2019/6468729", "year": 2019}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s12882-018-0851-3", "effect": "not extracted", "endpoint": "not extracted", "id": "source_50", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study", "type": "source", "url": "https://doi.org/10.1186/s12882-018-0851-3", "year": 2018}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/ijms20081844", "effect": "not extracted", "endpoint": "not extracted", "id": "source_51", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”", "type": "source", "url": "https://doi.org/10.3390/ijms20081844", "year": 2019}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1007/s11255-017-1519-9", "effect": "not extracted", "endpoint": "not extracted", "id": "source_52", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "The effect of nephrectomy on Klotho, FGF-23 and bone metabolism", "type": "source", "url": "https://doi.org/10.1007/s11255-017-1519-9", "year": 2017}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_53", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_54", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_55", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_56", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1001/jama.2010.1923", "effect": "not extracted", "endpoint": "not extracted", "id": "source_57", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Studenski 2011", "type": "source", "url": "https://doi.org/10.1001/jama.2010.1923", "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1093/gerona/glp012", "effect": "not extracted", "endpoint": "not extracted", "id": "source_58", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Cesari 2009", "type": "source", "url": "https://doi.org/10.1093/gerona/glp012", "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1111/j.1532-5415.2006.00701.x", "effect": "not extracted", "endpoint": "not extracted", "id": "source_59", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Perera 2006", "type": "source", "url": "https://doi.org/10.1111/j.1532-5415.2006.00701.x", "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1093/ageing/26.1.15", "effect": "not extracted", "endpoint": "not extracted", "id": "source_60", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Bohannon 1997", "type": "source", "url": "https://doi.org/10.1093/ageing/26.1.15", "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1093/ageing/afy169", "effect": "not extracted", "endpoint": "not extracted", "id": "source_61", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Cruz-Jentoft 2019", "type": "source", "url": "https://doi.org/10.1093/ageing/afy169", "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_62", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Anisimov 2008", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1056/NEJM198812293192604", "effect": "not extracted", "endpoint": "not extracted", "id": "source_63", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Tinetti 1988", "type": "source", "url": "https://doi.org/10.1056/NEJM198812293192604", "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1371/journal.pmed.0020124", "effect": "not extracted", "endpoint": "not extracted", "id": "source_64", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Ioannidis 2005", "type": "source", "url": "https://doi.org/10.1371/journal.pmed.0020124", "year": null}], "publication_id": "e6926b4c-bd58-4b1d-8022-2a9ca3381c8f", "screening": {"excluded": 0, "exclusion_reasons": ["No PRISMA full-text exclusion-stage filter was applied."], "flow": ["identified", "screened", "excluded_with_reasons", "included"], "identified": 52, "included": 52, "included_or_retained": 52, "screened": 52, "wording": "52 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit."}}

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