source · application/json
source_ea41fe16232e48fa
sha256 15e49f4ce9dfe2499a68063cb5858c67f40a42bceae15d5d605a6c373cd23a61
by researka:v2 · 2026-05-26 21:45:30.147000+04:00
{"publication_id": "f02d4a53-03e5-47ed-9876-75a416e3bd24", "traces": [{"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "What does the current evidence establish about Rapamycin and human geroscience? Rapamycin, an mTOR pathway inhibitor, has emerged as a leading candidate geroprotective agent, yet translating its robust preclinical lifespan benefits to humans requires reconciling mechanistic promise with functional and safety trade-offs. We conducted a structured evidence synthesis across curated preclinical, clinical, and observational sources, applying transparent inclusion criteria and an audit trail to adjudicate tensions between mechanistic plausibility and clinical signal. Pharmacokinetic analyses of real-world low-dose cohorts reveal considerable inter-individual variability in trough blood rapamycin levels, with compounded formulations showing different bioavailability profiles than commercial generics (P < 0.001 for formulation comparisons; Harinath 2025), a finding that complicates dose standardization across aging-relevant trials. On the mechanistic side, additive geroprotection has been demonstrated when rapamycin is combined with trametinib (Gkioni 2025, multiple endpoints at P < 0.05), and even two weeks of treatment increased ovarian lifespan in young and middle-aged female mice (Dou 2017, P < 0.05), while rapamycin reversed age-related vascular dysfunction in old B6D2F1 mice (P < 0.05 across endpoints; Lesniewski 2016). The weight of evidence supports rapamycin's mechanistic plausibility as a geroprotector—autophagy induction, senescence suppression, and imm", "claim_id": "claim_1"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "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.", "claim_id": "claim_2"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.", "claim_id": "claim_3"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual other, dosing and pharmacokinetics, healthspan and quality of life, immune, immune and inflammation, longevity, mortality and survival, safety, 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.", "claim_id": "claim_4"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "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.", "claim_id": "claim_5"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Additional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Lee 2014, Wang 2026, Delic 2018, Perez-Martinez 2024, Zurlo 2023, Gao 2018, Sasaki 2020, Bindels 2023, Comi 2025, Nie 2021, Mercer 2016, Koga 2025, Roark 2025, Ortega-Matienzo 2025, Dai 2014, Tao 2005, Rapamycin 2017, Kraig 2018, Chakraborty 2023, Abstract 2025, Everolimus 2026, Aliper 2017, Leontieva 2017, Sabini 2023, Zaseck 2016, Svensson 2024b, Flynn 2013, Majumder 2012, Wilkinson 2012, Mtor 2026, Cognition 2022, Rapamycin 2026, Sirolimus 2013, Ataman 2024, Arasiewicz 2026.", "claim_id": "claim_6"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "| Contextual Other | n=53; claims=1867 | null signal in 32/53 sources | 1 direct; 19 indirect; 18 mechanistic; 15 review | limited corpus depth in this outcome class |", "claim_id": "claim_7"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "| Immune | n=10; claims=165 | null signal in 7/10 sources | 7 indirect; 1 mechanistic; 2 review | limited corpus depth in this outcome class |", "claim_id": "claim_8"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "| Immune Inflammation | n=5; claims=169 | null signal in 3/5 sources | 3 indirect; 1 mechanistic; 1 review | limited corpus depth in this outcome class |", "claim_id": "claim_9"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "| Safety Comorbidity | n=5; claims=249 | null signal in 3/5 sources | 1 direct; 1 indirect; 3 review | limited corpus depth in this outcome class |", "claim_id": "claim_10"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "| Healthspan Qol | n=1; claims=3 | null signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |", "claim_id": "claim_11"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Quantitative findings across the corpus present a mixed picture with several statistically significant preclinical signals alongside null human results. In CorreiaMelo 2019, rapamycin treatment in nfκb1−/− mice yielded multiple significant differences across measured endpoints (P < 0.01 and P < 0.001 for several comparisons), indicating improvements in healthspan parameters. Translational relevance to humans remains uncertain. Elliehausen 2025 reported that intermittent rapamycin did not compromise physical performance or muscle hypertrophy while alleviating glucose disruptions. The systematic review by Shindyapina 2022 found that developmental rapamycin treatment was sufficient to extend lifespan in genetically diverse mice.", "claim_id": "claim_12"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Mechanistically, the preclinical data converge on mTOR inhibition as a modulator of cellular senescence and muscle aging pathways. CorreiaMelo 2019 demonstrated that rapamycin prevents age-related frailty in nfκb1−/− mice without impacting lifespan, suggesting pathway-specific effects on healthspan versus longevity. Translational relevance to humans remains uncertain. mTOR 2026 reported that PI3K/mTOR inhibition attenuates cigarette smoke-induced senescence and the senescence-associated secretory phenotype in oral fibroblasts, implicating a tumor microenvironment remodeling mechanism. Ham 2022 showed distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle, with the treatment spanning the time of sarcopenic development. The mechanistic substrate underlying these preclinical findings is supported by Impacts 2027, which is investigating how Rapamune affects aged human muscle both functionally and molecularly. These mechanistic human studies and preclinical data collectively suggest that rapamycin's cardiometabolic effects operate through conserved mTOR-dependent pathways.", "claim_id": "claim_13"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Within the corpus, notable tensions exist between preclinical evidence and human trial outcomes. Shindyapina 2022's finding that developmental rapamycin extends lifespan in mice contrasts with Elliehausen 2025's emphasis on intermittent dosing to avoid glucose disruptions while maintaining exercise benefits. These disagreements reflect the broader pattern that mechanistic plausibility in animal models has not consistently translated to clear cardiometabolic benefit in human studies, as also noted by Impacts 2027's ongoing investigation in older adults.", "claim_id": "claim_14"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "The corpus of contextual other evidence spans a wide range of study designs, populations, and endpoints, reflecting the broad therapeutic interest in rapamycin as a geroprotective compound. The strongest mechanistic signal derives from preclinical mouse studies demonstrating that transient rapamycin treatment can markedly extend lifespan. These preclinical datasets converge on rapamycin as a robust lifespan-extending intervention in rodent models (Phillips 2022b; Bitto 2016; Gkioni 2025).", "claim_id": "claim_15"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Specific organ-level benefits in preclinical models provide mechanistic grounding for the multi-organ healthspan effects observed at the whole-animal level. Translational relevance to humans remains uncertain. An 2020 showed rapamycin rejuvenated oral health in aging mice (P < 0.05 for alveolar bone loss reduction), while Gao 2015 reported neuroprotective effects via activation of the Wnt/β-catenin signaling pathway after spinal cord injury (P < 0.01 for motor recovery measures). Translational relevance to humans remains uncertain. Spilman 2010 provided further neurocognitive support, demonstrating that mTOR inhibition abolished cognitive deficits and reduced amyloid-β levels in a mouse model of Alzheimer's disease (P < 0.001 for learning impairment in transgenic mice). Collectively, these preclinical findings support a tissue-spanning geroprotective mechanism (Quarles 2020; An 2020; Gao 2015; Kolosova 2013; Spilman 2010).", "claim_id": "claim_16"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Translational evidence in human populations remains limited and heterogeneous, with the single identified clinical RCT reporting null or marginal effects. Willows 2023 found that rapamycin did not mitigate age-related changes to adipose tissue or peripheral neuropathy in genetically diverse HET3 mice despite robust p-values for age-related changes themselves (P = 0.0001, P < 0.0001). This translational gap between mechanistic promise and human clinical endpoints represents a central tension in the corpus (Stanfield 2026; Chung 2019; Willows 2023).", "claim_id": "claim_17"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Tensions within the corpus emerge prominently from studies reporting adverse or null effects that contrast with the predominantly positive preclinical signal. Translational relevance to humans remains uncertain. Dou 2017 showed that even short-term 2-week rapamycin treatment caused disturbances in ovarian function alongside beneficial effects on ovarian lifespan (P < 0.01 for both beneficial and adverse endpoints). Minton 2024 further reported that mTORC1 inhibition by rapamycin resulted in feedback activation of Akt and aggravated hallmarks of osteoarthritis in female mice and non-human primates. These adverse-signal studies, particularly Fischer 2015, Geissler 2015, and Minton 2024, challenge the assumption that rapamycin effects are uniformly beneficial across tissues and species (Fischer 2015; Geissler 2015; Dou 2017; Minton 2024).", "claim_id": "claim_18"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Mechanistically, the studies touch on pathways central to rapamycin's action. Lesniewski 2016 reports that dietary rapamycin reverses age-related vascular dysfunction and oxidative stress while modulating nutrient-sensing, cell cycle, and senescence pathways. Shavlakadze 2018 provides preclinical data suggesting short-term, low-dose mTORC1 inhibition in aged rats can counter-regulate age-related gene expression changes and block age-related kidney pathology. Harinath 2025's observational data in humans provides a translational bridge, examining whether the mechanistic effects observed in models translate to measurable blood levels in aging individuals using real-world compounded or commercial formulations. The case report by Britton 2025, while mechanistically limited, posits a potential interaction with low-dose naltrexone leading to a positive bone density outcome.", "claim_id": "claim_19"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "By contrast, the evidence within this outcome class presents notable tensions regarding rapamycin's effects. Harinath 2025 reports a negative or complex effect direction in their human cohort analysis, while Lesniewski 2016 reports mixed positive findings in a murine model of aging. Shavlakadze 2018 shows null findings for certain outcomes in their preclinical rat model, in contrast to the positive vascular effects seen by Lesniewski 2016. The CARE 2015 pilot protocol represents an early-stage human effort without reported outcomes, creating a knowledge gap between the human observational data of Harinath 2025 and the mechanistic animal data of Lesniewski 2016 and Shavlakadze 2018. Britton 2025's isolated positive finding in bone density does not resolve the fundamental disagreement between the mixed preclinical results and the negative signal from the human pharmacokinetic cohort.", "claim_id": "claim_20"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "The evidence for rapamycin's effects on healthspan and quality of life in humans is represented by a planned clinical trial. The study population will include women with a T-score >-3 and no history of hip, Colles', or symptomatic vertebral fractures within the last 6 months. The primary endpoint is the prevention of bone loss, a key component of musculoskeletal healthspan. The planned intervention involves everolimus, a rapamycin analogue, and/or exercise.", "claim_id": "claim_21"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "As this is a trial protocol for a planned study, no quantitative efficacy findings are available from this source. The study is designed to assess the direct effect of the mTOR inhibitor everolimus, alone and in combination with exercise, on a biomarker of skeletal aging. The lack of reported p-values, effect sizes, or interim results means the evidence base for healthspan outcomes in humans from this corpus is currently defined by the trial's design parameters rather than its conclusions. The study's focus on a specific, measurable healthspan component—bone mineral density—highlights a targeted approach to evaluating mTOR pathway modulation.", "claim_id": "claim_22"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "The current evidence for healthspan and quality of life outcomes is defined by this single planned trial within the corpus. No other studies in the included sources provide direct human data on rapamycin or its analogues for similar healthspan endpoints. This creates a situation where the mechanistic plausibility for benefit is not yet accompanied by completed human RCT data within this curated set. The tension lies between strong preclinical rationale and the absence of concluded human efficacy evidence for this specific outcome class.", "claim_id": "claim_23"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "The corpus includes multiple study designs evaluating rapamycin's effects on immune function, ranging from preclinical mechanistic work to observational cohorts and systematic reviews. In older adults, randomized to receive 1 mg/day rapamycin or placebo, Kell 2026 examined geroprotective effects on the ageing human immune system with a focus on DNA damage resilience. Jurdi 2025 evaluated sirolimus use in allogeneic hematopoietic cell transplant recipients, a high-risk population experiencing accelerated aging and cellular senescence from chemotherapy exposure.", "claim_id": "claim_24"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Mechanistically, preclinical data from Wang 2017b demonstrate that rapamycin inhibits the secretory phenotype of senescent cells via an Nrf2-independent mechanism, with senescent fibroblasts showing decreased Nrf2 protein (~65%) and mRNA levels (~45%) relative to presenescent counterparts. Leontieva 2016 describes gerosuppression by pan-mTOR inhibitors, showing that cells treated for 4 days re-proliferated as effectively in drug-free medium, suggesting a reversible senomorphic effect. Leontieva 2011 further characterizes how rapamycin shifts cells from senescence to quiescence rather than eliminating them, a mechanism that may underlie the immunomodulatory profile observed in clinical studies.", "claim_id": "claim_25"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Additional corpus sources included animal/preclinical evidence; within the immune corpus, notable tensions exist between studies reporting positive signals and those reporting null findings. The majority of studies in the corpus — including Joo 2024, Jurdi 2025, Wang 2017b, Leontieva 2016, Leontieva 2011, and Xu 2021 — align on null or mechanistically-focused outcomes, while Kell 2026 and Mannick 2014 represent positive signals, and Hands 2025 occupies an intermediate position with suggestive but inconclusive evidence.", "claim_id": "claim_26"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "The evidence base for rapamycin's effects on immune and inflammatory outcomes spans preclinical, observational, and clinical trial designs. Observational cohort studies in adults explored rapamycin's suppression of inflammation in fatty liver models, where rapamycin stock solutions were prepared at 0.05 mg/μL concentration (Ge 2023). Additional cohort work investigated rapamycin's cardioprotective effects in autoimmune myocarditis using doses of 1 mg/kg (Zhuang 2025).", "claim_id": "claim_27"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Mechanistically, rapamycin's immunomodulatory effects operate through distinct pathways depending on tissue context and disease state. Preclinical data suggest that chronic mTOR inhibition reshapes the immune landscape by simultaneously affecting adaptive and innate immune compartments while altering the gut microbiome composition (Hurez 2015). In inflammatory liver disease, rapamycin suppresses NF-κB signaling by enhancing the physical interaction between p65 and its inhibitor IκBα, representing a direct anti-inflammatory mechanism (Ge 2023). The mechanistic substrate underlying the cardiac protection observed in autoimmune myocarditis involves mTORC1-dependent reprogramming of macrophages through the C/EBPβ–OSM axis, specifically targeting Cxcl9+ macrophage subsets (Zhuang 2025). At the signaling level, rapamycin shares regulatory mechanisms over MAPK pathways with other longevity-associated compounds, suggesting convergence on intracellular inflammatory signaling networks (Wink 2022).", "claim_id": "claim_28"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "Within-corpus tensions emerge when comparing findings across study designs and populations. Similarly, the robust anti-inflammatory effects observed in fatty liver (Ge 2023) and autoimmune myocarditis (Zhuang 2025) models do not directly translate to the older adult population tested in the phase 2b/3 trial (Targeting 2021). The mechanistic convergence identified between rapamycin and other compounds on MAPK pathways (Wink 2022) provides a potential reconciliation framework, suggesting that dose, tissue context, and disease state may determine whether mTOR inhibition yields anti-inflammatory benefits. These observations collectively indicate that rapamycin's immune-modulatory profile is context-dependent, with positive preclinical and observational signals coexisting with mixed human trial evidence.", "claim_id": "claim_29"}, {"candidate_sources": [{"doi": "10.18632/aging.206235", "study": "Moel 2025", "url": "https://doi.org/10.18632/aging.206235"}, {"doi": "10.1038/s43587-025-00876-4", "study": "Gkioni 2025", "url": "https://doi.org/10.1038/s43587-025-00876-4"}, {"doi": "10.1007/s40120-023-00476-7", "study": "Smiaek 2023", "url": "https://doi.org/10.1007/s40120-023-00476-7"}, {"doi": "10.1111/acel.13784", "study": "Willows 2023", "url": "https://doi.org/10.1111/acel.13784"}, {"doi": "10.1007/s11357-025-01532-w", "study": "Harinath 2025", "url": "https://doi.org/10.1007/s11357-025-01532-w"}], "claim": "The mechanistic evidence for rapamycin's lifespan effects is anchored in two preclinical studies from the NIA Interventions Testing Program. Translational relevance to humans remains uncertain. Extending this work, Miller 2014 demonstrated that rapamycin increased median lifespan of genetically heterogeneous mice by 23% in males to 26% in females when tested at a dose that was threefold lower than the original study. These findings establish a robust dose- and sex-dependent lifespan extension in a gold-standard preclinical model.", "claim_id": "claim_30"}]}
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