Derivation Web

source_4d1be35711a14eb9

by researka:v2 · 2026-06-07 09:05:04.599011+04:00

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Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. 29/30 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.", "type": "claim"}, {"id": "claim_2", "text": "This synthesis tests the thesis that evidence for Rapamycin Biomarker Effects is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.", "type": "claim"}, {"id": "claim_3", "text": "This synthesis employed an AI-assisted structured evidence synthesis with an audit trail to integrate findings across 30 curated reference papers spanning preclinical, observational, and randomized controlled trial designs.", "type": "claim"}, {"id": "claim_4", "text": "Across outcome classes, cross-study disagreements were identified, with null findings dominating contextual and safety outcomes while context-specific signals concentrated in preclinical longevity and immune biomarker domains.", "type": "claim"}, {"id": "claim_5", "text": "The current evidence supports mechanistic plausibility for rapamycin's geroprotective effects but falls short of establishing clinical biomarker efficacy, as human randomized trials show largely null or mixed results on conventional healthspan endpoints.", "type": "claim"}, {"id": "claim_6", "text": "Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.", "type": "claim"}, {"id": "claim_7", "text": "This manuscript is reported as a Evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-rapamycin_biomarker_effects-v06-DAILY-2026-06-06T20-31-17Z-R2`.", "type": "claim"}, {"id": "claim_8", "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 appraisal, and claim registry) rather than from re-parsed full text.", "type": "claim"}, {"id": "claim_9", "text": "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`.", "type": "claim"}, {"id": "claim_10", "text": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune and inflammation, longevity, safety and comorbidity); 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_11", "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_12", "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_13", "text": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "type": "claim"}, {"id": "claim_14", "text": "| Contextual Adjacent Evidence | n=18; claims=1232 | no extracted directional signal in 12/18 sources | 1 direct; 10 indirect; 7 mechanistic | limited corpus depth in this outcome class |", "type": "claim"}, {"id": "claim_15", "text": "This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.", "type": "claim"}, {"id": "claim_16", "text": "18 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=12, positive=2, unclear=2. Directness coding: direct=1, indirect=10, mechanistic=7.", "type": "claim"}, {"id": "claim_17", "text": "4 included sources were assigned to this outcome class. Directional coding: null=2, positive=2. Directness coding: indirect=3, mechanistic=1.", "type": "claim"}, {"id": "claim_18", "text": "2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.", "type": "claim"}, {"id": "claim_19", "text": "2 included sources were assigned to this outcome class. Directional coding: mixed=1, null=1. Directness coding: indirect=1, mechanistic=1.", "type": "claim"}, {"id": "claim_20", "text": "2 included sources were assigned to this outcome class. Directional coding: null=1, unclear=1. Directness coding: mechanistic=2.", "type": "claim"}, {"id": "claim_21", "text": "2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1.", "type": "claim"}, {"id": "claim_22", "text": "Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.", "type": "claim"}, {"id": "claim_23", "text": "Several outcome domains in the corpus rest on single-study evidence, which precludes internal replication and inflates the risk that observed effects are idiosyncratic to a particular design, population, or analytic approach. Likewise, airway inflammation and emphysema attenuation were demonstrated exclusively in Tian 2026 using ozone-exposed mice treated with intraperitoneal rapamycin at 0.6 mg/kg, and cardiac function preservation in autoimmune myocarditis was reported only by Zhuang 2025, who showed rapamycin reprogrammed Cxcl9+ macrophages via the mTORC1–C/EBPβ–OSM axis. Cardiac proteomic remodeling was studied only by Dai 2014, who used deuterated-leucine labeling over 10 weeks of rapamycin exposure, while the longevity-in-Drosophila pathway was examined solely by Bjedov 2010. The ME/CFS fatigue endpoint was explored in only Ruan 2025, a pilot study administering 6 mg/week rapamycin with symptom assessments at days 30, 60, and 90. In each of these cases, a single source cannot establish whether the effect is robust across independent laboratories, species, or populations. This single-trial limitation is not confined to minor outcomes: the cross-study disagreement map documents severity-3 or severity-4 disagreements for the contextual other outcome class across 161 non-orthogonal pairs, yet many of these tensions involve one or both arms supported by only a single study, making adjudication between conflicting signals impossible within the current corpus.", "type": "claim"}, {"id": "claim_24", "text": "The population base of the curated trials narrows external validity in several ways that cannot be resolved by pooling alone. Preclinical sources — including Bitto 2016 (middle-aged mice), Harrison 2009 (genetically heterogeneous mice), Miller 2014 (dose-response in mice), Tian 2026 (ozone-exposed mice), and Pell 2026 (female mice with early-life seizures) — collectively dominate the longevity and mechanistic outcome classes, yet interspecies translation of mTOR inhibition remains uncertain because murine mTOR signaling kinetics, rapamycin pharmacokinetics, and lifespan architecture differ from those of humans. Stanfield 2026 tested once-weekly sirolimus at 6 mg in older adults already engaged in a 13-week exercise program, which introduces a selection bias toward motivated, physically active participants who may not represent the sedentary majority at risk for age-related decline. No study in the corpus enrolled pregnant individuals, persons with severe renal or hepatic impairment, or immunocompromised populations such as organ-transplant recipients on concurrent immunosuppression, leaving safety and efficacy in these vulnerable groups entirely uncharacterized. Consequently, the synthesis conclusions apply most directly to middle-aged to older, relatively healthy adults or to murine models, and extrapolation beyond these groups requires assumptions that the present evidence cannot anchor.", "type": "claim"}, {"id": "claim_25", "text": "The endpoint scope of the corpus is heavily weighted toward mechanistic, surrogate, and contextual outcomes rather than clinically meaningful endpoints validated against hard disease outcomes, which introduces a translation gap that should be made explicit. No source in the curated set measured incident type 2 diabetes, fracture incidence, hospitalization for heart failure, or time-to-progression of any cancer as a primary endpoint; the cardiometabolic class is represented only by Zhang 2021 and Su 2025, both mechanistic studies examining BCRP-mediated drug resistance and MAGEA3 biomarkers rather than patient-centered outcomes. Rosario 2023 investigated rapamycin's attenuation of PI3K signaling in human ovarian cortex in vitro, providing mechanistic evidence for fertility preservation, but no clinical trial in the corpus reported on pregnancy rates, ovarian reserve markers such as anti-Müllerian hormone trajectory, or time-to-conception in women receiving rapamycin. A broader methodological concern is that several sources relied on surrogate endpoints whose clinical validity for the aging context is unestablished: as noted in the general methodological literature (Ioannidis 2005), surrogate associations do not guarantee hard-outcome validity. Hallmarks such as senescence-associated secretory phenotype suppression (Wang 2017) and mTOR-pathway phosphorylation changes (Hibbert 2026) are biologically informative but remain at least one mechanistic step removed from endpoints that patients or clinicians would recognize as meaningful improvements in survival, disability, or quality of life. Until the evidence base includes trials that bridge from these mechanistic surrogates to validated clinical endpoints, the risk-benefit calculus for off-label rapamycin use in healthy adults remains fundamentally unresolved.", "type": "claim"}, {"id": "claim_26", "text": "For rapamycin biomarker effects, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.", "type": "claim"}, {"id": "claim_27", "text": "This synthesis maps 30 included sources on Rapamycin Biomarker Effects across 6 outcome classes and 161 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.", "type": "claim"}, {"id": "claim_28", "text": "Across 30 curated reference papers, the evidence base for Rapamycin Biomarker Effects shows a context-dependent profile. Positive signals appear in: contextual other, immune inflammation. Negative signals appear in: contextual other. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Rapamycin Biomarker Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.", "type": "claim"}, {"id": "claim_29", "text": "The strongest unresolved contrast is the disagreement between Yang 2025 and Park 2025 on contextual adjacent evidence (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.", "type": "claim"}, {"id": "claim_30", "text": "This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.", "type": "claim"}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1002/advs.202507210", "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": "Rapamycin Alleviates Heart Failure Caused by Mitochondrial Dysfunction and SERCA Hypoactivity in Syntaxin 12/13 Deficient Models", "type": "source", "url": "https://doi.org/10.1002/advs.202507210", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.18632/aging.206235", "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": "Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results", "type": "source", "url": "https://doi.org/10.18632/aging.206235", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1002/jcsm.70274", "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": "Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA‐EX‐01 Randomised, Double‐Blind, Placebo‐Controlled Trial", "type": "source", "url": "https://doi.org/10.1002/jcsm.70274", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/cells15030236", "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": "Natural Genetic Variation Impacts Stress-Induced Quiescence and Regeneration in Response to Rapamycin", "type": "source", "url": "https://doi.org/10.3390/cells15030236", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1093/humrep/dead255", "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": "Anti-Mullerian hormone attenuates both cyclophosphamide-induced damage and PI3K signalling activation, while rapamycin attenuates only PI3K signalling activation, in human ovarian cortex in vitro", "type": "source", "url": "https://doi.org/10.1093/humrep/dead255", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1111/acel.70364", "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": "Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage", "type": "source", "url": "https://doi.org/10.1111/acel.70364", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.2147/JIR.S545564", "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": "The mTOR Inhibitor Rapamycin Attenuates Ozone-Induced Airway Inflammation and Emphysema In Mice", "type": "source", "url": "https://doi.org/10.2147/JIR.S545564", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1097/HC9.0000000000000942", "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": "Rapamycin-modified novel tolerogenic dendritic cells induce liver graft tolerance through MHC-II + CD8 + regulatory T cells", "type": "source", "url": "https://doi.org/10.1097/HC9.0000000000000942", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s43856-025-00904-9", "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": "Rapamycin treatment for Alzheimer’s disease and related dementias: a pilot phase 1 clinical trial", "type": "source", "url": "https://doi.org/10.1038/s43856-025-00904-9", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/neurosci7030055", "effect": "not extracted", "endpoint": "not extracted", "id": "source_10", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Rapamycin and Minocycline Treatment Does Not Rescue Behavioral and Molecular Changes Induced by Early-Life Seizures in Female Mice", "type": "source", "url": "https://doi.org/10.3390/neurosci7030055", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.redox.2025.103970", "effect": "not extracted", "endpoint": "not extracted", "id": "source_11", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Rapamycin preserves cardiac function in autoimmune myocarditis by reprogramming Cxcl9 + macrophages via the mTORC1–C/EBPβ–OSM axis", "type": "source", "url": "https://doi.org/10.1016/j.redox.2025.103970", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.18632/aging.206300", "effect": "not extracted", "endpoint": "not extracted", "id": "source_12", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "What is the clinical evidence to support off-label rapamycin therapy in healthy adults?", "type": "source", "url": "https://doi.org/10.18632/aging.206300", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/microorganisms14040781", "effect": "not extracted", "endpoint": "not extracted", "id": "source_13", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Rapamycin Prevents Sulfate-Reducing Bacteria-Induced Effects on Snail and GSK-3 and Impaired Intestinal Barrier", "type": "source", "url": "https://doi.org/10.3390/microorganisms14040781", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s12967-025-07213-8", "effect": "not extracted", "endpoint": "not extracted", "id": "source_14", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Low-dose rapamycin alleviates clinical symptoms of fatigue and PEM in ME/CFS patients via improvement of autophagy: a pilot study", "type": "source", "url": "https://doi.org/10.1186/s12967-025-07213-8", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1126/sciadv.aec5134", "effect": "not extracted", "endpoint": "not extracted", "id": "source_15", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism", "type": "source", "url": "https://doi.org/10.1126/sciadv.aec5134", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1186/s13063-024-08490-2", "effect": "not extracted", "endpoint": "not extracted", "id": "source_16", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "A single-center, double-blind, randomized, placebo-controlled, two-arm study to evaluate the safety and efficacy of once-weekly sirolimus (rapamycin) on muscle strength and endurance in older adults following a 13-week exercise program", "type": "source", "url": "https://doi.org/10.1186/s13063-024-08490-2", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1371/journal.pone.0343183", "effect": "not extracted", "endpoint": "not extracted", "id": "source_17", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Long-term rapamycin treatment suppresses IL-17-producing gamma delta T cells and blunts neuroinflammation in aging", "type": "source", "url": "https://doi.org/10.1371/journal.pone.0343183", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.20517/cdr.2025.35", "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": "Unveiling MAGEA3: a novel predictive biomarker for bevacizumab resistance in colorectal cancer", "type": "source", "url": "https://doi.org/10.20517/cdr.2025.35", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1093/jacamr/dlag091", "effect": "not extracted", "endpoint": "not extracted", "id": "source_19", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Fpr1p mediates the synergistic effect of rapamycin or tacrolimus with caspofungin in Clavispora lusitaniae in vitro", "type": "source", "url": "https://doi.org/10.1093/jacamr/dlag091", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s12276-025-01578-y", "effect": "not extracted", "endpoint": "not extracted", "id": "source_20", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "RPS24 microexon isoform as a novel biomarker for estrogen receptor-positive breast cancer progression and therapeutic resistance", "type": "source", "url": "https://doi.org/10.1038/s12276-025-01578-y", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fragi.2025.1628187", "effect": "not extracted", "endpoint": "not extracted", "id": "source_21", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Rapamycin for longevity: the pros, the cons, and future perspectives", "type": "source", "url": "https://doi.org/10.3389/fragi.2025.1628187", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fonc.2021.608570", "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": "Rapamycin Antagonizes BCRP-Mediated Drug Resistance Through the PI3K/Akt/mTOR Signaling Pathway in mPRα-Positive Breast Cancer", "type": "source", "url": "https://doi.org/10.3389/fonc.2021.608570", "year": 2021}, {"comparator": "not extracted", "directness": "primary", "doi": "10.7554/eLife.16351", "effect": "not extracted", "endpoint": "not extracted", "id": "source_23", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice", "type": "source", "url": "https://doi.org/10.7554/eLife.16351", "year": 2016}, {"comparator": "not extracted", "directness": "primary", "doi": "10.2337/db14-1132", "effect": "not extracted", "endpoint": "not extracted", "id": "source_24", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms", "type": "source", "url": "https://doi.org/10.2337/db14-1132", "year": 2015}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1111/acel.12203", "effect": "not extracted", "endpoint": "not extracted", "id": "source_25", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart", "type": "source", "url": "https://doi.org/10.1111/acel.12203", "year": 2014}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1111/acel.12194", "effect": "not extracted", "endpoint": "not extracted", "id": "source_26", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction", "type": "source", "url": "https://doi.org/10.1111/acel.12194", "year": 2014}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1155/2017/2976541", "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": "Rapid Rapamycin-Only Induced Osteogenic Differentiation of Blood-Derived Stem Cells and Their Adhesion to Natural and Artificial Scaffolds", "type": "source", "url": "https://doi.org/10.1155/2017/2976541", "year": 2017}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1111/acel.12587", "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": "Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism", "type": "source", "url": "https://doi.org/10.1111/acel.12587", "year": 2017}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.cmet.2009.11.010", "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": "Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster", "type": "source", "url": "https://doi.org/10.1016/j.cmet.2009.11.010", "year": 2010}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/nature08221", "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": "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice", "type": "source", "url": "https://doi.org/10.1038/nature08221", "year": 2009}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_31", "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_32", "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_33", "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_34", "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": "10.1371/journal.pmed.0020124", "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": "Ioannidis 2005", "type": "source", "url": "https://doi.org/10.1371/journal.pmed.0020124", "year": null}], "publication_id": "b3041d87-87dd-46e9-a8ea-5a13c317c885", "screening": {"excluded": 0, "exclusion_reasons": ["No PRISMA full-text exclusion-stage filter was applied."], "flow": ["identified", "screened", "excluded_with_reasons", "included"], "identified": 30, "included": 30, "included_or_retained": 30, "screened": 30, "wording": "30 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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