{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "mTOR Hyperactivation as Aging Driver", "entry_form": "phenomenon", "gradeable_restatement": "Persistent mTOR hyperactivation is the central rate-limiting integrator of organismal aging, and reducing mTOR activity is the dominant mechanism for extending lifespan and healthspan.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, baseline disease, diet, dose and timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "mTOR Hyperactivation as Aging Driver", "central_claim": "Persistent mTOR hyperactivation is the central rate-limiting integrator of organismal aging, and reducing mTOR activity is the dominant mechanism for extending lifespan and healthspan.", "proposed_mechanism": "Persistent mTOR hyperactivation is the central rate-limiting integrator of organismal aging, and reducing mTOR activity is the dominant mechanism for extending lifespan and healthspan.", "claimed_scope": "Persistent mTOR hyperactivation is the central rate-limiting integrator of organismal aging, and reducing mTOR activity is the dominant mechanism for extending lifespan and healthspan.", "claimed_level": [ "initiation", "progression" ], "is_conjunctive": true, "conjunctive_note": "Use the index primary-subclaim rule with SC2 as the explicit central-driver gate. SC1 lifespan benefit is not substituted for SC2 primacy. Normal aging is distinguished from developmental slowing, cancer suppression and treatment of selected diseases." }, "rubric_routing": { "primary_rubric": "06-metabolism-aging.md", "secondary_rubrics": [], "index_notes_applied": [ "Use the index primary-subclaim rule with SC2 as the explicit central-driver gate. SC1 lifespan benefit is not substituted for SC2 primacy. Normal aging is distinguished from developmental slowing, cancer suppression and treatment of selected diseases." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Reducing mTOR signalling extends lifespan or healthspan across experimentally assessed species.", "subclaim_type": "application", "scope": "normal experimental aging across species and mammalian backgrounds", "claimed_scope": "normal experimental aging across species and mammalian backgrounds", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Late-life rapamycin, genetic narrowing, dose/sex/background and functional outcomes", "hsef_level": "Η", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Independent TOR/S6K genetics, adult pharmacology, conserved model-system effects and replicated heterogeneous-mouse dose/site/sex survival results support the constrained experimental modulation claim. This is not a human-life claim or a claim that every function improves." }, { "id": "SC2", "statement": "mTOR is the central rate-limiting integrator of organismal aging rather than one of several causal modulators.", "subclaim_type": "primacy", "scope": "normal organismal aging, including mammalian systems; human generalization separate", "claimed_scope": "normal organismal aging, including mammalian systems; human generalization separate", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Specific pathway mediation, temporal necessity/sufficiency and alternatives including combinations", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "There is no scope-matched discriminator showing that persistent mTOR hyperactivation is the central necessary rate-limiting integrator of normal mammalian aging. Signaling heterogeneity, harmful inhibition contexts and additional benefit from MEK targeting favor a network." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "Use the index primary-subclaim rule with SC2 as the explicit central-driver gate. SC1 lifespan benefit is not substituted for SC2 primacy. Normal aging is distinguished from developmental slowing, cancer suppression and treatment of selected diseases.", "primary_subclaim_id": "SC2", "aggregation_derivation": "The preregistered primary-subclaim gate is SC2, yielding Γ. The strong experimental-benefit sensitivity is Η. A weaker primacy score must not erase the cross-species causal modulation evidence or be interpreted as refuting mTOR biology.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Multifactorial nutrient-sensitive network", "core_claim": "mTORC1 is one potent controllable node with interacting parallel processes.", "explains_what_nominal_does_not": "mTORC1 is one potent controllable node with interacting parallel processes.", "strongest_supporting_evidence": [ "Convergent genetics and drug survival effects, combined MEK benefit and tissue-specific responses." ], "strongest_contradictory_evidence": [ "Additivity alone does not establish fully independent pathways." ], "hsef_level_for_this_model": "Η", "rationale": "Convergent genetics and drug survival effects, combined MEK benefit and tissue-specific responses. Additivity alone does not establish fully independent pathways." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Pleiotropic nutrient sensing", "core_claim": "Autophagy translation immune and metabolic effects jointly influence outcomes.", "explains_what_nominal_does_not": "Autophagy translation immune and metabolic effects jointly influence outcomes.", "strongest_supporting_evidence": [ "Epistasis and mediator perturbations support defined branches." ], "strongest_contradictory_evidence": [ "No single mediator is shown necessary across all organisms and endpoints." ], "hsef_level_for_this_model": "Ζ", "rationale": "Epistasis and mediator perturbations support defined branches. No single mediator is shown necessary across all organisms and endpoints." }, { "rank_in_tournament": 3, "model_id": "M5", "is_nominal": false, "name": "Disease and immune protection", "core_claim": "Cancer delay and organ-specific protection explain part of survival benefit.", "explains_what_nominal_does_not": "Cancer delay and organ-specific protection explain part of survival benefit.", "strongest_supporting_evidence": [ "Tumour-prone and clinical immune studies show relevant disease effects." ], "strongest_contradictory_evidence": [ "This alone does not explain all non-neoplastic functional benefits." ], "hsef_level_for_this_model": "Ε", "rationale": "Tumour-prone and clinical immune studies show relevant disease effects. This alone does not explain all non-neoplastic functional benefits." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "ROS and damage mediation", "core_claim": "mTOR changes survival partly through oxidative damage and proteostasis.", "explains_what_nominal_does_not": "mTOR changes survival partly through oxidative damage and proteostasis.", "strongest_supporting_evidence": [ "Liver marker changes and autophagy contrasts are compatible." ], "strongest_contradictory_evidence": [ "Marker changes do not establish survival mediation." ], "hsef_level_for_this_model": "Γ", "rationale": "Liver marker changes and autophagy contrasts are compatible. Marker changes do not establish survival mediation." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Central hyperfunction bottleneck", "core_claim": "Persistent mTOR hyperactivation is the dominant autonomous aging integrator.", "explains_what_nominal_does_not": "Persistent mTOR hyperactivation is the dominant autonomous aging integrator.", "strongest_supporting_evidence": [ "Strong intervention potency and cellular geroconversion favor this possibility." ], "strongest_contradictory_evidence": [ "Heterogeneous signaling and contextual inhibition harms leave central primacy unproved." ], "hsef_level_for_this_model": "Γ", "rationale": "Strong intervention potency and cellular geroconversion favor this possibility. Heterogeneous signaling and contextual inhibition harms leave central primacy unproved." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Adult selective normalization of measured excess mTORC1, with a drug-resistant rescue and independently engaged comparator pathways, distinguishes one potent node from a necessary rate-limiting bottleneck.", "study_separating_rank1_from_rank2": "Adult selective normalization of measured excess mTORC1, with a drug-resistant rescue and independently engaged comparator pathways, distinguishes one potent node from a necessary rate-limiting bottleneck.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "19587680", "title": "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.", "citation": "Harrison DE, Strong R, Sharp ZD et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. 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The mTOR pathway is necessary for survival of mice with short telomeres. Nature communications. 2020.", "doi": "10.1038/s41467-020-14962-1", "pmcid": "PMC7054554", "url": "https://pubmed.ncbi.nlm.nih.gov/32127537/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32127537/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID32127537", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nature cell biology. 2015.", "doi": "10.1038/ncb3195", "pmcid": "PMC4691706", "url": "https://pubmed.ncbi.nlm.nih.gov/26147250/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26147250/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33824512" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26147250", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia. Nature communications. 2020.", "doi": "10.1038/s41467-020-18140-1", "pmcid": "PMC7481251", "url": "https://pubmed.ncbi.nlm.nih.gov/32908143/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32908143/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID32908143", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging cell. 2016.", "doi": "10.1111/acel.12425", "pmcid": "PMC4717274", "url": "https://pubmed.ncbi.nlm.nih.gov/26695882/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26695882/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26695882", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse tissues sexes backgrounds", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Age-related signaling is heterogeneous rather than uniformly elevated", "what_it_does_not_show": "Does not exclude transient or cell-specific hyperactivation", "confounders_present": [ "Does not exclude transient or cell-specific hyperactivation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "32289154", "title": "Endothelial mTOR maintains hematopoiesis during aging.", "citation": "Ramalingam P, Poulos MG, Gutkin MC et al. Endothelial mTOR maintains hematopoiesis during aging. The Journal of experimental medicine. 2020.", "doi": "10.1084/jem.20191212", "pmcid": "PMC7971143", "url": "https://pubmed.ncbi.nlm.nih.gov/32289154/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32289154/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID32289154", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse endothelial niche", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Reduced endothelial mTOR disrupts aged hematopoietic support", "what_it_does_not_show": "Does not generalize all tissues", "confounders_present": [ "Does not generalize all tissues" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "23734717", "title": "Late-life rapamycin treatment reverses age-related heart dysfunction.", "citation": "Flynn JM, O'Leary MN, Zambataro CA et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging cell. 2013.", "doi": "10.1111/acel.12109", "pmcid": "PMC4098908", "url": "https://pubmed.ncbi.nlm.nih.gov/23734717/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23734717/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "Old-heart rapamycin program", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "old female mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Late short rapamycin improves cardiac function", "what_it_does_not_show": "Does not demonstrate whole-life or human benefit", "confounders_present": [ "Does not demonstrate whole-life or human benefit" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "31570569", "title": "A triple drug combination targeting components of the nutrient-sensing network maximizes longevity.", "citation": "Castillo-Quan JI, Tain LS, Kinghorn KJ et al. A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "doi": "10.1073/pnas.1913212116", "pmcid": "PMC6800352", "url": "https://pubmed.ncbi.nlm.nih.gov/31570569/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31570569/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31570569", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "flies", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Multiple pathway drugs combine for lifespan benefit", "what_it_does_not_show": "Does not prove complete pathway independence", "confounders_present": [ "Does not prove complete pathway independence" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "33742521", "title": "Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol.", "citation": "Shen Z, Hinson A, Miller RA et al. Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol. Aging cell. 2021.", "doi": "10.1111/acel.13345", "pmcid": "PMC8135077", "url": "https://pubmed.ncbi.nlm.nih.gov/33742521/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33742521/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33742521", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse tissue translation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Translation programs track geroprotective manipulations", "what_it_does_not_show": "Does not test organismal lifespan mediation in this report", "confounders_present": [ "Does not test organismal lifespan mediation in this report" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "26872208", "title": "Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts.", "citation": "Chiao YA, Kolwicz SC, Basisty N et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging. 2016.", "doi": "10.18632/aging.100881", "pmcid": "PMC4789585", "url": "https://pubmed.ncbi.nlm.nih.gov/26872208/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26872208/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "Old-heart rapamycin program", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "old mouse heart", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Autophagy and energetics change with distinct timing during functional benefit", "what_it_does_not_show": "Does not isolate one necessary universal mediator", "confounders_present": [ "Does not isolate one necessary universal mediator" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 11, "pmid": "31761958", "title": "Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial.", "citation": "Chung CL, Lawrence I, Hoffman M et al. Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. GeroScience. 2019.", "doi": "10.1007/s11357-019-00113-y", "pmcid": "PMC6925069", "url": "https://pubmed.ncbi.nlm.nih.gov/31761958/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31761958/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31761958", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human topical skin trial", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Local skin markers and appearance improve with large attrition", "what_it_does_not_show": "Does not establish systemic human healthspan", "confounders_present": [ "Does not establish systemic human healthspan" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "26809496", "title": "Rapamycin Attenuates Age-associated Changes in Tibialis Anterior Tendon Viscoelastic Properties.", "citation": "Zaseck LW, Miller RA, Brooks SV et al. Rapamycin Attenuates Age-associated Changes in Tibialis Anterior Tendon Viscoelastic Properties. The journals of gerontology. Series A, Biological sciences and medical sciences. 2016.", "doi": "10.1093/gerona/glv307", "pmcid": "PMC4906327", "url": "https://pubmed.ncbi.nlm.nih.gov/26809496/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26809496/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26809496", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy. 2020.", "doi": "10.1080/15548627.2019.1704117", "pmcid": "PMC8386626", "url": "https://pubmed.ncbi.nlm.nih.gov/31884871/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31884871/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31884871", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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Duration of rapamycin treatment has differential effects on metabolism in mice. Cell metabolism. 2013.", "doi": "10.1016/j.cmet.2013.02.008", "pmcid": "PMC3658445", "url": "https://pubmed.ncbi.nlm.nih.gov/23473038/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23473038/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23473038", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse rapamycin timing", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Metabolic effects vary with treatment duration", "what_it_does_not_show": "Does not directly establish survival mediation", "confounders_present": [ "Does not directly establish survival mediation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "26923601", "title": "C. elegans S6K Mutants Require a Creatine-Kinase-like Effector for Lifespan Extension.", "citation": "McQuary PR, Liao CY, Chang JT et al. C. elegans S6K Mutants Require a Creatine-Kinase-like Effector for Lifespan Extension. Cell reports. 2016.", "doi": "10.1016/j.celrep.2016.02.012", "pmcid": "PMC4823261", "url": "https://pubmed.ncbi.nlm.nih.gov/26923601/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26923601/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26923601", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging cell. 2014.", "doi": "10.1111/acel.12194", "pmcid": "PMC4032600", "url": "https://pubmed.ncbi.nlm.nih.gov/24341993/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24341993/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "ITP dose cohort, shared platform", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph6. 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Rapamycin rejuvenates oral health in aging mice. eLife. 2020.", "doi": "10.7554/eLife.54318", "pmcid": "PMC7220376", "url": "https://pubmed.ncbi.nlm.nih.gov/32342860/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32342860/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID32342860", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "aged mouse periodontal tissue", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Short rapamycin improves bone inflammation and microbiome measures", "what_it_does_not_show": "Does not demonstrate systemic lifespan mediation", "confounders_present": [ "Does not demonstrate systemic lifespan mediation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "23657975", "title": "Assessment of mitochondrial biogenesis and mTORC1 signaling during chronic rapamycin feeding in male and female mice.", "citation": "Drake JC, Peelor FF, Biela LM et al. Assessment of mitochondrial biogenesis and mTORC1 signaling during chronic rapamycin feeding in male and female mice. The journals of gerontology. Series A, Biological sciences and medical sciences. 2013.", "doi": "10.1093/gerona/glt047", "pmcid": "PMC3814233", "url": "https://pubmed.ncbi.nlm.nih.gov/23657975/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23657975/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23657975", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "UM-HET3 tissue protein synthesis", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TOR and synthesis responses differ by tissue and sex", "what_it_does_not_show": "Does not test lifespan mediation", "confounders_present": [ "Does not test lifespan mediation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "31823466", "title": "Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment.", "citation": "Quarles E, Basisty N, Chiao YA et al. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging cell. 2020.", "doi": "10.1111/acel.13086", "pmcid": "PMC6996961", "url": "https://pubmed.ncbi.nlm.nih.gov/31823466/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31823466/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "Old-heart persistence program", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "old mouse heart follow-up", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Functional benefits persist after drug withdrawal", "what_it_does_not_show": "Does not establish whole-body or human persistence", "confounders_present": [ "Does not establish whole-body or human persistence" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "26472877", "title": "Sex-specific Tradeoffs With Growth and Fitness Following Life-span Extension by Rapamycin in an Outcrossing Nematode, Caenorhabditis remanei.", "citation": "Lind MI, Zwoinska MK, Meurling S et al. Sex-specific Tradeoffs With Growth and Fitness Following Life-span Extension by Rapamycin in an Outcrossing Nematode, Caenorhabditis remanei. The journals of gerontology. Series A, Biological sciences and medical sciences. 2016.", "doi": "10.1093/gerona/glv174", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26472877/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26472877/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26472877", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "outcrossing nematodes", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Lifespan growth and fitness tradeoffs depend on sex and exposure timing", "what_it_does_not_show": "Does not generalize all ages or species", "confounders_present": [ "Does not generalize all ages or species" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 36, "pmid": "27498120", "title": "Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice.", "citation": "Martínez-Cisuelo V, Gómez J, García-Junceda I et al. Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice. Experimental gerontology. 2016.", "doi": "10.1016/j.exger.2016.08.002", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27498120/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27498120/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID27498120", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "middle-aged mouse liver", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Rapamycin reduces ROS and damage markers with autophagy changes", "what_it_does_not_show": "Does not show damage reduction mediates survival", "confounders_present": [ "Does not show damage reduction mediates survival" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "27919065", "title": "Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans.", "citation": "Heintz C, Doktor TK, Lanjuin A et al. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature. 2017.", "doi": "10.1038/nature20789", "pmcid": "PMC5361225", "url": "https://pubmed.ncbi.nlm.nih.gov/27919065/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27919065/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID28700577" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID27919065", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "worm splicing perturbations", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SFA1 is required for selected TOR and diet longevity effects", "what_it_does_not_show": "Not a universal mediator; linked erratum content unexamined", "confounders_present": [ "Not a universal mediator; linked erratum content unexamined" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 38, "pmid": "24655348", "title": "Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet.", "citation": "Leontieva OV, Paszkiewicz GM, Blagosklonny MV et al. Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Aging cell. 2014.", "doi": "10.1111/acel.12211", "pmcid": "PMC4326934", "url": "https://pubmed.ncbi.nlm.nih.gov/24655348/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24655348/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID24655348", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "high-fat obese male mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Weekly rapamycin improves survival to planned sacrifice", "what_it_does_not_show": "Disease context and censored follow-up are not natural maximum lifespan", "confounders_present": [ "Disease context and censored follow-up are not natural maximum lifespan" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "33796866", "title": "Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.", "citation": "Richardson NE, Konon EN, Schuster HS et al. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice. Nature aging. 2021.", "doi": "10.1038/s43587-020-00006-2", "pmcid": "PMC8009080", "url": "https://pubmed.ncbi.nlm.nih.gov/33796866/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33796866/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33796866", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "normal and progeroid mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "BCAA restriction has sex-specific survival and frailty effects", "what_it_does_not_show": "Does not isolate mTOR as dominant diet mediator", "confounders_present": [ "Does not isolate mTOR as dominant diet mediator" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "23117593", "title": "New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53-/- mice by delaying carcinogenesis.", "citation": "Comas M, Toshkov I, Kuropatwinski KK et al. New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53-/- mice by delaying carcinogenesis. Aging. 2012.", "doi": "10.18632/aging.100496", "pmcid": "PMC3517942", "url": "https://pubmed.ncbi.nlm.nih.gov/23117593/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23117593/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23117593", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "p53-null mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Rapatar delays cancer and increases survival", "what_it_does_not_show": "Does not distinguish general aging from engineered cancer rescue", "confounders_present": [ "Does not distinguish general aging from engineered cancer rescue" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "21212465", "title": "DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence.", "citation": "Leontieva OV, Blagosklonny MV et al. DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence. Aging. 2010.", "doi": "10.18632/aging.100265", "pmcid": "PMC3034181", "url": "https://pubmed.ncbi.nlm.nih.gov/21212465/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21212465/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID21212465", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "cultured human cells", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "mTOR reactivation influences senescence in arrested cells", "what_it_does_not_show": "In vitro geroconversion is not organismal aging primacy", "confounders_present": [ "In vitro geroconversion is not organismal aging primacy" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "33145977", "title": "Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.", "citation": "Strong R, Miller RA, Bogue M et al. Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects. Aging cell. 2020.", "doi": "10.1111/acel.13269", "pmcid": "PMC7681050", "url": "https://pubmed.ncbi.nlm.nih.gov/33145977/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33145977/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "ITP late-life cohort, shared platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "ITP heterogeneous late-life mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Late dose and intermittent regimens affect survival by sex", "what_it_does_not_show": "Food-source variation complicates comparisons; shared ITP platform", "confounders_present": [ "Food-source variation complicates comparisons; shared ITP platform" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "26546739", "title": "A novel autosomal recessive TERT T1129P mutation in a dyskeratosis congenita family leads to cellular senescence and loss of CD34+ hematopoietic stem cells not reversible by mTOR-inhibition.", "citation": "Stockklausner C, Raffel S, Klermund J et al. A novel autosomal recessive TERT T1129P mutation in a dyskeratosis congenita family leads to cellular senescence and loss of CD34+ hematopoietic stem cells not reversible by mTOR-inhibition. Aging. 2015.", "doi": "10.18632/aging.100835", "pmcid": "PMC4694062", "url": "https://pubmed.ncbi.nlm.nih.gov/26546739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26546739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26546739", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy. 2008.", "doi": "10.4161/auto.5618", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18219227/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18219227/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID18219227", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science (New York, N.Y.). 2005.", "doi": "10.1126/science.1115535", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16293764/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16293764/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID16293764", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Current biology : CB. 2004.", "doi": "10.1016/j.cub.2004.03.059", "pmcid": "PMC2754830", "url": "https://pubmed.ncbi.nlm.nih.gov/15186745/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15186745/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID15186745", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "fly TOR pathway genetics", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Multiple TOR manipulations extend life depending on nutrition", "what_it_does_not_show": "Does not establish uniform central rate limitation", "confounders_present": [ "Does not establish uniform central rate limitation" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "19797661", "title": "Ribosomal protein S6 kinase 1 signaling regulates mammalian life span.", "citation": "Selman C, Tullet JM, Wieser D et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science (New York, N.Y.). 2009.", "doi": "10.1126/science.1177221", "pmcid": "PMC4954603", "url": "https://pubmed.ncbi.nlm.nih.gov/19797661/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19797661/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "S6K1 mutant platform", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "S6K1 knockout mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Downstream genetic perturbation extends survival and selected functions", "what_it_does_not_show": "Developmental and sex boundaries remain; erratum details unexamined", "confounders_present": [ "Developmental and sex boundaries remain; erratum details unexamined" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "27083004", "title": "Evidence that hematopoietic stem cell function is preserved during aging in long-lived S6K1 mutant mice.", "citation": "Selman C, Sinclair A, Pedroni SM et al. Evidence that hematopoietic stem cell function is preserved during aging in long-lived S6K1 mutant mice. Oncotarget. 2016.", "doi": "10.18632/oncotarget.8729", "pmcid": "PMC5058654", "url": "https://pubmed.ncbi.nlm.nih.gov/27083004/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27083004/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "S6K1 mutant platform follow-up", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "S6K1 mouse HSC transplantation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Aged donor HSC engraftment is preserved", "what_it_does_not_show": "Shares mutant platform; no independent lifespan replication", "confounders_present": [ "Shares mutant platform; no independent lifespan replication" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "33977284", "title": "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials.", "citation": "Mannick JB, Teo G, Bernardo P et al. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. The lancet. Healthy longevity. 2021.", "doi": "10.1016/S2666-7568(21)00062-3", "pmcid": "PMC8102040", "url": "https://pubmed.ncbi.nlm.nih.gov/33977284/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33977284/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "Distinct phase2b and phase3 trial cohorts", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph2, 1:Methods:paragraph4, 1:Methods:paragraph6, 1:Methods:paragraph8, 1:Methods:paragraph9, 1:Methods:paragraph10. 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Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. 2016.", "doi": "10.7554/eLife.16351", "pmcid": "PMC4996648", "url": "https://pubmed.ncbi.nlm.nih.gov/27549339/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27549339/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID27549339", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "middle-aged mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Transient rapamycin changes survival with sex and tumour-spectrum boundaries", "what_it_does_not_show": "Up-to-60% life expectancy is not universal full-life extension", "confounders_present": [ "Up-to-60% life expectancy is not universal full-life extension" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "23863708", "title": "Rapamycin extends murine lifespan but has limited effects on aging.", "citation": "Neff F, Flores-Dominguez D, Ryan DP et al. Rapamycin extends murine lifespan but has limited effects on aging. The Journal of clinical investigation. 2013.", "doi": "10.1172/JCI67674", "pmcid": "PMC3726163", "url": "https://pubmed.ncbi.nlm.nih.gov/23863708/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23863708/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23863708", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "male C57BL/6J aging phenotyping", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Survival improves but few age phenotypes improve; young controls reveal age-independent effects", "what_it_does_not_show": "Does not negate other mouse background or function benefits", "confounders_present": [ "Does not negate other mouse background or function benefits" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "31324799", "title": "A novel rapamycin analog is highly selective for mTORC1 in vivo.", "citation": "Schreiber KH, Arriola Apelo SI, Yu D et al. A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications. 2019.", "doi": "10.1038/s41467-019-11174-0", "pmcid": "PMC6642166", "url": "https://pubmed.ncbi.nlm.nih.gov/31324799/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31324799/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31324799", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cells and mice selective analog", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "DL001 separates mTORC1 inhibition from several metabolic side effects", "what_it_does_not_show": "Does not report lifespan benefit", "confounders_present": [ "Does not report lifespan benefit" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "40437307", "title": "The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.", "citation": "Gkioni L, Nespital T, Baghdadi M et al. The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan. Nature aging. 2025.", "doi": "10.1038/s43587-025-00876-4", "pmcid": "PMC12270913", "url": "https://pubmed.ncbi.nlm.nih.gov/40437307/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40437307/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "Hybrid mouse combination cohorts; some liver pathology previously published", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph12, 1:Results:paragraph14, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "male female hybrid mice", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "MEK inhibition adds survival benefit to intermittent rapamycin with separate engagement", "what_it_does_not_show": "Additivity does not prove perfect independence or preclude shared network centrality", "confounders_present": [ "Additivity does not prove perfect independence or preclude shared network centrality" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "29997249", "title": "TORC1 inhibition enhances immune function and reduces infections in the elderly.", "citation": "Mannick JB, Morris M, Hockey HP et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Science translational medicine. 2018.", "doi": "10.1126/scitranslmed.aaq1564", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29997249/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29997249/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29997249", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Strong", "system": "older-adult phase2a RCT", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Low-dose TORC1 combination reduces reported infections and improves immune endpoints", "what_it_does_not_show": "Does not establish general healthy-life extension", "confounders_present": [ "Does not establish general healthy-life extension" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "23994476", "title": "Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression.", "citation": "Wu JJ, Liu J, Chen EB et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell reports. 2013.", "doi": "10.1016/j.celrep.2013.07.030", "pmcid": "PMC3784301", "url": "https://pubmed.ncbi.nlm.nih.gov/23994476/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23994476/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23994476", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mTOR hypomorphic mice", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Genetic reduction extends survival with segmental functional preservation", "what_it_does_not_show": "Developmental manipulation and uneven organ effects do not prove central primacy", "confounders_present": [ "Developmental manipulation and uneven organ effects do not prove central primacy" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "28374166", "title": "A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs.", "citation": "Urfer SR, Kaeberlein TL, Mailheau S et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. GeroScience. 2017.", "doi": "10.1007/s11357-017-9972-z", "pmcid": "PMC5411365", "url": "https://pubmed.ncbi.nlm.nih.gov/28374166/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28374166/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID28374166", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "randomized companion dogs", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Short low-dose rapamycin suggests selected cardiac effects", "what_it_does_not_show": "Small short trial does not test lifespan", "confounders_present": [ "Small short trial does not test lifespan" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "20074526", "title": "Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster.", "citation": "Bjedov I, Toivonen JM, Kerr F et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell metabolism. 2010.", "doi": "10.1016/j.cmet.2009.11.010", "pmcid": "PMC2824086", "url": "https://pubmed.ncbi.nlm.nih.gov/20074526/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20074526/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID20074526", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "adult fruit flies", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Rapamycin longevity requires defined autophagy and translation pathways", "what_it_does_not_show": "Does not establish the same mediator across mammals", "confounders_present": [ "Does not establish the same mediator across mammals" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "29408453", "title": "A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.", "citation": "Kraig E, Linehan LA, Liang H et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Experimental gerontology. 2018.", "doi": "10.1016/j.exger.2017.12.026", "pmcid": "PMC5869166", "url": "https://pubmed.ncbi.nlm.nih.gov/29408453/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29408453/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29408453", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "older-adult pilot RCT", "decisive_perturbation": true, "endogenous": false, "direction": "null", "what_it_shows": "Short treatment leaves measured cognition performance and perceived health unchanged", "what_it_does_not_show": "Small safety pilot cannot exclude longer-term efficacy; enrollment wording requires body verification", "confounders_present": [ "Small safety pilot cannot exclude longer-term efficacy; enrollment wording requires body verification" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "39117797", "title": "Spermidine is essential for fasting-mediated autophagy and longevity.", "citation": "Hofer SJ, Daskalaki I, Bergmann M et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nature cell biology. 2024.", "doi": "10.1038/s41556-024-01468-x", "pmcid": "PMC11392816", "url": "https://pubmed.ncbi.nlm.nih.gov/39117797/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39117797/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID39117797", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "cross-species fasting polyamine experiments", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Polyamine and hypusination perturbation tests selected fasting longevity mechanisms", "what_it_does_not_show": "Human fasting markers are not human lifespan mediation; not exclusive mTOR proof", "confounders_present": [ "Human fasting markers are not human lifespan mediation; not exclusive mTOR proof" ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 62, "verified": 62, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Persistent mTOR hyperactivation is the central rate-limiting integrator of organismal aging, and reducing mTOR activity is the dominant mechanism for extending lifespan and healthspan.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Single-organ biomarkers and cell geroconversion cannot carry the primacy claim. Cross-species survival plus independent genetics allow Η for SC1 within mapped experimental contexts; broad human or universal-centrality extrapolation remains Γ. No manufactured one-species hard cap is applied to the whole corpus.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID19587680, PMID32908143, PMID23734717, PMID31570569, PMID26872208, PMID26809496, PMID29304191, PMID40188830, PMID22105852, PMID40441158, PMID25540326, PMID37939658, PMID30269951, PMID19240135, PMID29378959, PMID22587563, PMID32720643, PMID31884871, PMID23682161, PMID23473038, PMID26923601, PMID24341993, PMID32342860, PMID31823466, PMID26472877, PMID27919065, PMID24655348, PMID33796866, PMID23117593, PMID33145977, PMID18219227, PMID16293764, PMID15186745, PMID19797661, PMID27083004, PMID33977284, PMID27549339, PMID23863708, PMID31324799, PMID40437307, PMID29997249, PMID23994476, PMID28374166, PMID20074526, PMID29408453, PMID39117797", "gamma_hard_rules_triggered": [ "Human healthy-life extension is outside the experimentally mapped scope." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Independent TOR/S6K genetics, adult pharmacology, conserved model-system effects and replicated heterogeneous-mouse dose/site/sex survival results support the constrained experimental modulation claim. This is not a human-life claim or a claim that every function improves.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID19587680, PMID32127537, PMID26147250, PMID32908143, PMID26695882, PMID32289154, PMID31570569, PMID26872208, PMID40188830, PMID22105852, PMID40441158, PMID37939658, PMID30269951, PMID19240135, PMID29378959, PMID22587563, PMID32720643, PMID31884871, PMID22570137, PMID23682161, PMID23473038, PMID26923601, PMID24341993, PMID31823466, PMID26472877, PMID27919065, PMID33796866, PMID23117593, PMID21212465, PMID33145977, PMID26546739, PMID18219227, PMID16293764, PMID15186745, PMID19797661, PMID27083004, PMID33977284, PMID27549339, PMID23863708, PMID31324799, PMID40437307, PMID23994476, PMID20074526, PMID39117797", "gamma_hard_rules_triggered": [ "No literal one-species cap is imposed on this multispecies corpus. The primacy grade reflects the missing scope-matched necessity and bottleneck discriminator." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "There is no scope-matched discriminator showing that persistent mTOR hyperactivation is the central necessary rate-limiting integrator of normal mammalian aging. Signaling heterogeneity, harmful inhibition contexts and additional benefit from MEK targeting favor a network.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "yes", "supporting_evidence": [ "[1] Late-life rapamycin extends survival at three sites", "[4] Muscle mTORC1 activation and inhibition alter sarcopenic phenotypes", "[7] Late short rapamycin improves cardiac function", "[8] Multiple pathway drugs combine for lifespan benefit", "[10] Autophagy and energetics change with distinct timing during functional benefit", "[12] Rapamycin preserves selected aged tendon mechanics", "[13] RAD001 affects selected renal and other tissue pathology", "[14] Primary visceral-fat endpoint is null; selected secondary female lean-mass signal", "[15] Rapamycin impairs glucose handling and islet measures", "[16] Cholesterol-axis mTORC1 activation contributes to engineered aging phenotypes", "[17] Low-dose everolimus improves vaccination response", "[18] Isoleucine restriction improves frailty and survival with sex dependence", "[19] Drug combinations engage distinct network and lipid mechanisms", "[20] TORC2 survival effects reverse with food context and intake", "[23] Rapamycin extends control life but shortens GHRKO life with mTORC2 suppression", "[24] Multiple age-sensitive phenotypes improve while cataract and testis harms rise", "[25] Sex hormone and tissue perturbations uncouple metabolic health from survival", "[26] Cardiac TORC2 activation improves autophagy function and survival", "[28] Late rapamycin improves survival and selected functions", "[29] Metabolic effects vary with treatment duration", "[30] ARGK1 is a defined effector of S6K longevity with AMPK link", "[31] Dose and sex gradients replicate survival effects", "[32] Short rapamycin improves bone inflammation and microbiome measures", "[34] Functional benefits persist after drug withdrawal", "[35] Lifespan growth and fitness tradeoffs depend on sex and exposure timing", "[37] SFA1 is required for selected TOR and diet longevity effects", "[38] Weekly rapamycin improves survival to planned sacrifice", "[39] BCAA restriction has sex-specific survival and frailty effects", "[40] Rapatar delays cancer and increases survival", "[42] Late dose and intermittent regimens affect survival by sex", "[44] Autophagy loss blocks selected longevity pathways", "[45] TOR and Sch9 deletion extend replicative life with dietary epistasis", "[46] Multiple TOR manipulations extend life depending on nutrition", "[47] Downstream genetic perturbation extends survival and selected functions", "[48] Aged donor HSC engraftment is preserved", "[49] Phase2b pooled single-dose contrast positive after combination null; phase3 primary null despite IFN engagement", "[50] Transient rapamycin changes survival with sex and tumour-spectrum boundaries", "[51] Survival improves but few age phenotypes improve; young controls reveal age-independent effects", "[52] DL001 separates mTORC1 inhibition from several metabolic side effects", "[53] MEK inhibition adds survival benefit to intermittent rapamycin with separate engagement", "[54] Low-dose TORC1 combination reduces reported infections and improves immune endpoints", "[55] Genetic reduction extends survival with segmental functional preservation", "[56] Short low-dose rapamycin suggests selected cardiac effects", "[57] Rapamycin longevity requires defined autophagy and translation pathways", "[58] Short treatment leaves measured cognition performance and perceived health unchanged", "[59] Polyamine and hypusination perturbation tests selected fasting longevity mechanisms" ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "yes", "supporting_evidence": [ "[1] Late-life rapamycin extends survival at three sites", "[4] Muscle mTORC1 activation and inhibition alter sarcopenic phenotypes", "[7] Late short rapamycin improves cardiac function", "[8] Multiple pathway drugs combine for lifespan benefit", "[10] Autophagy and energetics change with distinct timing during functional benefit", "[12] Rapamycin preserves selected aged tendon mechanics", "[13] RAD001 affects selected renal and other tissue pathology", "[14] Primary visceral-fat endpoint is null; selected secondary female lean-mass signal", "[15] Rapamycin impairs glucose handling and islet measures", "[16] Cholesterol-axis mTORC1 activation contributes to engineered aging phenotypes", "[17] Low-dose everolimus improves vaccination response", "[18] Isoleucine restriction improves frailty and survival with sex dependence", "[19] Drug combinations engage distinct network and lipid mechanisms", "[20] TORC2 survival effects reverse with food context and intake", "[23] Rapamycin extends control life but shortens GHRKO life with mTORC2 suppression", "[24] Multiple age-sensitive phenotypes improve while cataract and testis harms rise", "[25] Sex hormone and tissue perturbations uncouple metabolic health from survival", "[26] Cardiac TORC2 activation improves autophagy function and survival", "[28] Late rapamycin improves survival and selected functions", "[29] Metabolic effects vary with treatment duration", "[30] ARGK1 is a defined effector of S6K longevity with AMPK link", "[31] Dose and sex gradients replicate survival effects", "[32] Short rapamycin improves bone inflammation and microbiome measures", "[34] Functional benefits persist after drug withdrawal", "[35] Lifespan growth and fitness tradeoffs depend on sex and exposure timing", "[37] SFA1 is required for selected TOR and diet longevity effects", "[38] Weekly rapamycin improves survival to planned sacrifice", "[39] BCAA restriction has sex-specific survival and frailty effects", "[40] Rapatar delays cancer and increases survival", "[42] Late dose and intermittent regimens affect survival by sex", "[44] Autophagy loss blocks selected longevity pathways", "[45] TOR and Sch9 deletion extend replicative life with dietary epistasis", "[46] Multiple TOR manipulations extend life depending on nutrition", "[47] Downstream genetic perturbation extends survival and selected functions", "[48] Aged donor HSC engraftment is preserved", "[49] Phase2b pooled single-dose contrast positive after combination null; phase3 primary null despite IFN engagement", "[50] Transient rapamycin changes survival with sex and tumour-spectrum boundaries", "[51] Survival improves but few age phenotypes improve; young controls reveal age-independent effects", "[52] DL001 separates mTORC1 inhibition from several metabolic side effects", "[53] MEK inhibition adds survival benefit to intermittent rapamycin with separate engagement", "[54] Low-dose TORC1 combination reduces reported infections and improves immune endpoints", "[55] Genetic reduction extends survival with segmental functional preservation", "[56] Short low-dose rapamycin suggests selected cardiac effects", "[57] Rapamycin longevity requires defined autophagy and translation pathways", "[58] Short treatment leaves measured cognition performance and perceived health unchanged", "[59] Polyamine and hypusination perturbation tests selected fasting longevity mechanisms" ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Reproducible intervention effects\n- Mechanistic narrowing\n- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts", "satisfied": "yes", "supporting_evidence": [ "[1] Late-life rapamycin extends survival at three sites", "[4] Muscle mTORC1 activation and inhibition alter sarcopenic phenotypes", "[7] Late short rapamycin improves cardiac function", "[8] Multiple pathway drugs combine for lifespan benefit", "[10] Autophagy and energetics change with distinct timing during functional benefit", "[12] Rapamycin preserves selected aged tendon mechanics", "[13] RAD001 affects selected renal and other tissue pathology", "[14] Primary visceral-fat endpoint is null; selected secondary female lean-mass signal", "[15] Rapamycin impairs glucose handling and islet measures", "[16] Cholesterol-axis mTORC1 activation contributes to engineered aging phenotypes", "[17] Low-dose everolimus improves vaccination response", "[18] Isoleucine restriction improves frailty and survival with sex dependence", "[19] Drug combinations engage distinct network and lipid mechanisms", "[20] TORC2 survival effects reverse with food context and intake", "[23] Rapamycin extends control life but shortens GHRKO life with mTORC2 suppression", "[24] Multiple age-sensitive phenotypes improve while cataract and testis harms rise", "[25] Sex hormone and tissue perturbations uncouple metabolic health from survival", "[26] Cardiac TORC2 activation improves autophagy function and survival", "[28] Late rapamycin improves survival and selected functions", "[29] Metabolic effects vary with treatment duration", "[30] ARGK1 is a defined effector of S6K longevity with AMPK link", "[31] Dose and sex gradients replicate survival effects", "[32] Short rapamycin improves bone inflammation and microbiome measures", "[34] Functional benefits persist after drug withdrawal", "[35] Lifespan growth and fitness tradeoffs depend on sex and exposure timing", "[37] SFA1 is required for selected TOR and diet longevity effects", "[38] Weekly rapamycin improves survival to planned sacrifice", "[39] BCAA restriction has sex-specific survival and frailty effects", "[40] Rapatar delays cancer and increases survival", "[42] Late dose and intermittent regimens affect survival by sex", "[44] Autophagy loss blocks selected longevity pathways", "[45] TOR and Sch9 deletion extend replicative life with dietary epistasis", "[46] Multiple TOR manipulations extend life depending on nutrition", "[47] Downstream genetic perturbation extends survival and selected functions", "[48] Aged donor HSC engraftment is preserved", "[49] Phase2b pooled single-dose contrast positive after combination null; phase3 primary null despite IFN engagement", "[50] Transient rapamycin changes survival with sex and tumour-spectrum boundaries", "[51] Survival improves but few age phenotypes improve; young controls reveal age-independent effects", "[52] DL001 separates mTORC1 inhibition from several metabolic side effects", "[53] MEK inhibition adds survival benefit to intermittent rapamycin with separate engagement", "[54] Low-dose TORC1 combination reduces reported infections and improves immune endpoints", "[55] Genetic reduction extends survival with segmental functional preservation", "[56] Short low-dose rapamycin suggests selected cardiac effects", "[57] Rapamycin longevity requires defined autophagy and translation pathways", "[58] Short treatment leaves measured cognition performance and perceived health unchanged", "[59] Polyamine and hypusination perturbation tests selected fasting longevity mechanisms" ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Η", "requirement_quoted": "Requires:\n- Robust cross-context intervention evidence\n- Mechanistic specificity\n- Strong alignment of lifespan/healthspan outcomes", "satisfied": "yes", "supporting_evidence": [ "[1] Late-life rapamycin extends survival at three sites", "[4] Muscle mTORC1 activation and inhibition alter sarcopenic phenotypes", "[7] Late short rapamycin improves cardiac function", "[8] Multiple pathway drugs combine for lifespan benefit", "[10] Autophagy and energetics change with distinct timing during functional benefit", "[12] Rapamycin preserves selected aged tendon mechanics", "[13] RAD001 affects selected renal and other tissue pathology", "[14] Primary visceral-fat endpoint is null; selected secondary female lean-mass signal", "[15] Rapamycin impairs glucose handling and islet measures", "[16] Cholesterol-axis mTORC1 activation contributes to engineered aging phenotypes", "[17] Low-dose everolimus improves vaccination response", "[18] Isoleucine restriction improves frailty and survival with sex dependence", "[19] Drug combinations engage distinct network and lipid mechanisms", "[20] TORC2 survival effects reverse with food context and intake", "[23] Rapamycin extends control life but shortens GHRKO life with mTORC2 suppression", "[24] Multiple age-sensitive phenotypes improve while cataract and testis harms rise", "[25] Sex hormone and tissue perturbations uncouple metabolic health from survival", "[26] Cardiac TORC2 activation improves autophagy function and survival", "[28] Late rapamycin improves survival and selected functions", "[29] Metabolic effects vary with treatment duration", "[30] ARGK1 is a defined effector of S6K longevity with AMPK link", "[31] Dose and sex gradients replicate survival effects", "[32] Short rapamycin improves bone inflammation and microbiome measures", "[34] Functional benefits persist after drug withdrawal", "[35] Lifespan growth and fitness tradeoffs depend on sex and exposure timing", "[37] SFA1 is required for selected TOR and diet longevity effects", "[38] Weekly rapamycin improves survival to planned sacrifice", "[39] BCAA restriction has sex-specific survival and frailty effects", "[40] Rapatar delays cancer and increases survival", "[42] Late dose and intermittent regimens affect survival by sex", "[44] Autophagy loss blocks selected longevity pathways", "[45] TOR and Sch9 deletion extend replicative life with dietary epistasis", "[46] Multiple TOR manipulations extend life depending on nutrition", "[47] Downstream genetic perturbation extends survival and selected functions", "[48] Aged donor HSC engraftment is preserved", "[49] Phase2b pooled single-dose contrast positive after combination null; phase3 primary null despite IFN engagement", "[50] Transient rapamycin changes survival with sex and tumour-spectrum boundaries", "[51] Survival improves but few age phenotypes improve; young controls reveal age-independent effects", "[52] DL001 separates mTORC1 inhibition from several metabolic side effects", "[53] MEK inhibition adds survival benefit to intermittent rapamycin with separate engagement", "[54] Low-dose TORC1 combination reduces reported infections and improves immune endpoints", "[55] Genetic reduction extends survival with segmental functional preservation", "[56] Short low-dose rapamycin suggests selected cardiac effects", "[57] Rapamycin longevity requires defined autophagy and translation pathways", "[58] Short treatment leaves measured cognition performance and perceived health unchanged", "[59] Polyamine and hypusination perturbation tests selected fasting longevity mechanisms" ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Θ", "requirement_quoted": "Requires high reproducibility with minimal contextual contradiction.", "satisfied": "no", "supporting_evidence": [ "[1] Late-life rapamycin extends survival at three sites", "[4] Muscle mTORC1 activation and inhibition alter sarcopenic phenotypes", "[7] Late short rapamycin improves cardiac function", "[8] Multiple pathway drugs combine for lifespan benefit", "[10] Autophagy and energetics change with distinct timing during functional benefit", "[12] Rapamycin preserves selected aged tendon mechanics", "[13] RAD001 affects selected renal and other tissue pathology", "[14] Primary visceral-fat endpoint is null; selected secondary female lean-mass signal", "[15] Rapamycin impairs glucose handling and islet measures", "[16] Cholesterol-axis mTORC1 activation contributes to engineered aging phenotypes", "[17] Low-dose everolimus improves vaccination response", "[18] Isoleucine restriction improves frailty and survival with sex dependence", "[19] Drug combinations engage distinct network and lipid mechanisms", "[20] TORC2 survival effects reverse with food context and intake", "[23] Rapamycin extends control life but shortens GHRKO life with mTORC2 suppression", "[24] Multiple age-sensitive phenotypes improve while cataract and testis harms rise", "[25] Sex hormone and tissue perturbations uncouple metabolic health from survival", "[26] Cardiac TORC2 activation improves autophagy function and survival", "[28] Late rapamycin improves survival and selected functions", "[29] Metabolic effects vary with treatment duration", "[30] ARGK1 is a defined effector of S6K longevity with AMPK link", "[31] Dose and sex gradients replicate survival effects", "[32] Short rapamycin improves bone inflammation and microbiome measures", "[34] Functional benefits persist after drug withdrawal", "[35] Lifespan growth and fitness tradeoffs depend on sex and exposure timing", "[37] SFA1 is required for selected TOR and diet longevity effects", "[38] Weekly rapamycin improves survival to planned sacrifice", "[39] BCAA restriction has sex-specific survival and frailty effects", "[40] Rapatar delays cancer and increases survival", "[42] Late dose and intermittent regimens affect survival by sex", "[44] Autophagy loss blocks selected longevity pathways", "[45] TOR and Sch9 deletion extend replicative life with dietary epistasis", "[46] Multiple TOR manipulations extend life depending on nutrition", "[47] Downstream genetic perturbation extends survival and selected functions", "[48] Aged donor HSC engraftment is preserved", "[49] Phase2b pooled single-dose contrast positive after combination null; phase3 primary null despite IFN engagement", "[50] Transient rapamycin changes survival with sex and tumour-spectrum boundaries", "[51] Survival improves but few age phenotypes improve; young controls reveal age-independent effects", "[52] DL001 separates mTORC1 inhibition from several metabolic side effects", "[53] MEK inhibition adds survival benefit to intermittent rapamycin with separate engagement", "[54] Low-dose TORC1 combination reduces reported infections and improves immune endpoints", "[55] Genetic reduction extends survival with segmental functional preservation", "[56] Short low-dose rapamycin suggests selected cardiac effects", "[57] Rapamycin longevity requires defined autophagy and translation pathways", "[58] Short treatment leaves measured cognition performance and perceived health unchanged", "[59] Polyamine and hypusination perturbation tests selected fasting longevity mechanisms" ], "what_would_cross_it": "A broader generalization requires independent mammalian replication with complete functional trajectories and mediator rescue; human efficacy requires prespecified durable clinical outcomes." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [ "[1] Late-life rapamycin extends survival at three sites", "[2] Rapamycin and S6K loss shorten survival in Terc-null context", "[3] IL1A translation mediates a defined SASP effect with rescue", "[4] Muscle mTORC1 activation and inhibition alter sarcopenic phenotypes", "[5] Age-related signaling is heterogeneous rather than uniformly elevated", "[6] Reduced endothelial mTOR disrupts aged hematopoietic support", "[8] Multiple pathway drugs combine for lifespan benefit", "[10] Autophagy and energetics change with distinct timing during functional benefit", "[14] Primary visceral-fat endpoint is null; selected secondary female lean-mass signal", "[15] Rapamycin impairs glucose handling and islet measures", "[16] Cholesterol-axis mTORC1 activation contributes to engineered aging phenotypes", "[18] Isoleucine restriction improves frailty and survival with sex dependence", "[19] Drug combinations engage distinct network and lipid mechanisms", "[20] TORC2 survival effects reverse with food context and intake", "[23] Rapamycin extends control life but shortens GHRKO life with mTORC2 suppression", "[24] Multiple age-sensitive phenotypes improve while cataract and testis harms rise", "[25] Sex hormone and tissue perturbations uncouple metabolic health from survival", "[26] Cardiac TORC2 activation improves autophagy function and survival", "[27] Diet and rapamycin share TOR suppression yet differ physiologically", "[28] Late rapamycin improves survival and selected functions", "[29] Metabolic effects vary with treatment duration", "[30] ARGK1 is a defined effector of S6K longevity with AMPK link", "[31] Dose and sex gradients replicate survival effects", "[34] Functional benefits persist after drug withdrawal", "[35] Lifespan growth and fitness tradeoffs depend on sex and exposure timing", "[37] SFA1 is required for selected TOR and diet longevity effects", "[39] BCAA restriction has sex-specific survival and frailty effects", "[40] Rapatar delays cancer and increases survival", "[41] mTOR reactivation influences senescence in arrested cells", "[42] Late dose and intermittent regimens affect survival by sex", "[43] Rapamycin fails to rescue defective HSC function despite fibroblast benefit", "[44] Autophagy loss blocks selected longevity pathways", "[45] TOR and Sch9 deletion extend replicative life with dietary epistasis", "[46] Multiple TOR manipulations extend life depending on nutrition", "[47] Downstream genetic perturbation extends survival and selected functions", "[48] Aged donor HSC engraftment is preserved", "[49] Phase2b pooled single-dose contrast positive after combination null; phase3 primary null despite IFN engagement", "[50] Transient rapamycin changes survival with sex and tumour-spectrum boundaries", "[51] Survival improves but few age phenotypes improve; young controls reveal age-independent effects", "[52] DL001 separates mTORC1 inhibition from several metabolic side effects", "[53] MEK inhibition adds survival benefit to intermittent rapamycin with separate engagement", "[55] Genetic reduction extends survival with segmental functional preservation", "[57] Rapamycin longevity requires defined autophagy and translation pathways", "[59] Polyamine and hypusination perturbation tests selected fasting longevity mechanisms" ], "what_would_cross_it": "Selective adult normalization must prevent or strongly delay multisystem aging, establish necessity and timing, and occlude independently engaged alternative interventions with a credible rescue." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Young-versus-old phenotyping separates age-dependent from age-independent rapamycin effects.", "Terc-null and GHRKO contexts reverse the survival effect.", "TORC2 and endothelial signaling may be protective.", "Trametinib alone and in combination tests additional pathway leverage." ], "note": "Sex, dose, treatment age, genetic background, organ and TOR complex map substantial boundaries. Normal experimental animal benefit is distinct from engineered-lesion rescue, human tissue biomarkers and clinical healthy-life extension." }, "falsification_patterns_met": [ { "pattern": "Benefit is segmental or age-independent in some traits", "evidence": "Neff young controls, Wu organ-specific preservation and Baar signaling heterogeneity limit uniform rate claims.", "downgrade_applied": false }, { "pattern": "Additional pathway intervention retains benefit", "evidence": "Fly multi-drug and mouse trametinib/rapamycin additivity challenge exclusivity but do not prove perfect independence.", "downgrade_applied": false }, { "pattern": "Target engagement with clinical primary null", "evidence": "RTB101 phase3 IFN responses persist despite null symptomatic respiratory illness.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Intervention efficacy substituted for causal primacy", "where": "SC1 Η is kept separate from SC2 Γ." }, { "pitfall": "Lifespan equated with every healthspan domain", "where": "Metabolic harms, segmental phenotyping and tumor-spectrum shifts are retained." }, { "pitfall": "mTORC1 and mTORC2 conflated", "where": "Rictor, GHRKO and endothelial countercontexts are explicit." }, { "pitfall": "Provider meter treated as adjudication", "where": "Consensus prose rejects primacy while its meter favors yes; neither controls the score." }, { "pitfall": "Clinical secondary signals promoted over primary null", "where": "PEARL completer analysis, formulation and subgroup limits remain visible." } ], "causal_tally_audit": { "tally_claimed_by_document": 53, "tally_after_audit": 53, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "Δ for central primacy would require a discriminator matching the central bottleneck claim; survival efficacy alone tests a weaker claim. Θ for SC1 would require still broader independent necessary-pathway convergence and less residual endpoint/context ambiguity.", "case_one_rung_lower": "Β for primacy would ignore mechanistic perturbation support, while Ε for SC1 would understate convergent genetic, adult pharmacologic and cross-species survival evidence.", "which_rejected": "Retain Γ for registered centrality and Η for experimentally mapped modulation. Prespecify human clinical efficacy as a separate claim rather than infer it from vaccine response.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Independent-site factorial normal-aging mammalian trial of adult mTORC1 normalization, drug-resistant target rescue and orthogonal MEK/damage interventions, stratified by tissue activation measured before treatment." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "59 primary reports with 4 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered primary-subclaim gate is SC2, yielding Γ. The strong experimental-benefit sensitivity is Η. A weaker primacy score must not erase the cross-species causal modulation evidence or be interpreted as refuting mTOR biology." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Perturbation and rescue demonstrate causal effects, ruling out a solely downstream correlate under steps1–2. Uniform initiation, prevention and rate limitation are not established, and universal necessity is not shown under steps3–4. Defined persistent signaling can reinforce dysfunction; step5 applies.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Decisive work underway", "artifact": "The 2025 mouse combination and YTHDF1 studies and PEARL trial provide named active boundary tests; no unverified recruiting status is asserted.", "justification": "The 2025 mouse combination and YTHDF1 studies and PEARL trial provide named active boundary tests; no unverified recruiting status is asserted." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Independent-site factorial normal-aging mammalian trial of adult mTORC1 normalization, drug-resistant target rescue and orthogonal MEK/damage interventions, stratified by tissue activation measured before treatment.", "readout": "Prespecified survival and longitudinal multi-organ function, alongside target-specific signaling and time-resolved mediation", "critical_control": "Vehicle, young controls, rescue allele, equal exposure, TORC2 monitoring, background/sex replication, tumor adjudication and blinded outcomes", "supporting_result": "Normalization prevents multisystem decline and occludes independently engaged comparator benefits with rescue specificity", "falsifying_result": "Additional benefits persist after complete mTOR normalization or decline proceeds despite selective engagement" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Which normal-aging cell types actually develop excess mTORC1 signaling, when, and relative to injury rather than chronological age alone?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Which conserved mediators carry survival versus tissue-function effects, and can adult rescue isolate them?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "How much of survival benefit reflects cancer delay, demographic hazard changes or broader functional aging?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Can mTORC1-selective regimens preserve benefit while avoiding TORC2, metabolic and immune harm across sexes and backgrounds?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Can independent powered clinical trials show durable functional or disease benefit beyond biomarkers and exploratory subgroups?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Do combination effects remain after exposure matching, complete pathway engagement and shared-cohort accounting?", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-05", "reviewer": "Codex", "evidence_base_note": "59 primary reports; cutoff 2026-10-05; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Europe PMC; signed-in Consensus browser discovery and attempted indexed full-text extraction. Successful passages and failures are reconciled with original sections where available; see case reconciliation. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Η is assigned to the mapped experimental modulation claim because distinct genetics, adult pharmacology and multisite replication exclude different errors. It is withheld from centrality: human genetics, clinical immune endpoints and pathway epistasis do not establish central aging necessity, sufficiency or rate limitation. Θ–Ω would require stronger convergence and scope-matched necessity evidence." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Η is assigned to the mapped experimental modulation claim because distinct genetics, adult pharmacology and multisite replication exclude different errors. It is withheld from centrality: human genetics, clinical immune endpoints and pathway epistasis do not establish central aging necessity, sufficiency or rate limitation. Θ–Ω would require stronger convergence and scope-matched necessity evidence." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Η is assigned to the mapped experimental modulation claim because distinct genetics, adult pharmacology and multisite replication exclude different errors. It is withheld from centrality: human genetics, clinical immune endpoints and pathway epistasis do not establish central aging necessity, sufficiency or rate limitation. Θ–Ω would require stronger convergence and scope-matched necessity evidence." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Η is assigned to the mapped experimental modulation claim because distinct genetics, adult pharmacology and multisite replication exclude different errors. It is withheld from centrality: human genetics, clinical immune endpoints and pathway epistasis do not establish central aging necessity, sufficiency or rate limitation. Θ–Ω would require stronger convergence and scope-matched necessity evidence." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Η is assigned to the mapped experimental modulation claim because distinct genetics, adult pharmacology and multisite replication exclude different errors. It is withheld from centrality: human genetics, clinical immune endpoints and pathway epistasis do not establish central aging necessity, sufficiency or rate limitation. Θ–Ω would require stronger convergence and scope-matched necessity evidence." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 59, "claims_total": 62, "claims_verified": 62, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 59, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Late-life rapamycin extends survival at three sites Does not isolate aging rate from disease delay or prove primacy", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C2", "text": "Rapamycin and S6K loss shorten survival in Terc-null context Does not negate normal mouse benefit", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C3", "text": "IL1A translation mediates a defined SASP effect with rescue Does not establish organismal aging mediation; linked erratum unexamined", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C4", "text": "Muscle mTORC1 activation and inhibition alter sarcopenic phenotypes Does not establish all-organ rate limitation", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C5", "text": "Age-related signaling is heterogeneous rather than uniformly elevated Does not exclude transient or cell-specific hyperactivation", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C6", "text": "Reduced endothelial mTOR disrupts aged hematopoietic support Does not generalize all tissues", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C7", "text": "Late short rapamycin improves cardiac function Does not demonstrate whole-life or human benefit", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C8", "text": "Multiple pathway drugs combine for lifespan benefit Does not prove complete pathway independence", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C9", "text": "Translation programs track geroprotective manipulations Does not test organismal lifespan mediation in this report", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C10", "text": "Autophagy and energetics change with distinct timing during functional benefit Does not isolate one necessary universal mediator", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C11", "text": "Local skin markers and appearance improve with large attrition Does not establish systemic human healthspan", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C12", "text": "Rapamycin preserves selected aged tendon mechanics Does not show all functional domains", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C13", "text": "RAD001 affects selected renal and other tissue pathology Does not establish lifespan or centrality", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C14", "text": "Primary visceral-fat endpoint is null; selected secondary female lean-mass signal Completer analysis and broad exploratory outcomes do not prove human healthy-life extension", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS, 3:METHODS. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C15", "text": "Rapamycin impairs glucose handling and islet measures Does not negate survival benefit or establish all dosing schedules harmful", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C16", "text": "Cholesterol-axis mTORC1 activation contributes to engineered aging phenotypes Rescue of an engineered lesion is not proof of normal-aging primacy", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C17", "text": "Low-dose everolimus improves vaccination response Does not measure healthy lifespan", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C18", "text": "Isoleucine restriction improves frailty and survival with sex dependence Diet has multiple mediators; no exclusive mTOR mechanism", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C19", "text": "Drug combinations engage distinct network and lipid mechanisms Does not establish human benefit or independent pathways in mammals", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C20", "text": "TORC2 survival effects reverse with food context and intake Does not imply universal TORC2 inhibition benefit", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C21", "text": "AKG lifespan and metabolism change alongside AMPK and TOR signals Marker changes do not isolate mTOR mediation", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C22", "text": "TSC modulation links GH mutants to reduced mTORC1 signaling Does not test survival necessity in this report", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C23", "text": "Rapamycin extends control life but shortens GHRKO life with mTORC2 suppression Context boundary does not negate normal-aging rapamycin effects", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C24", "text": "Multiple age-sensitive phenotypes improve while cataract and testis harms rise Does not establish uniform aging-rate suppression", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C25", "text": "Sex hormone and tissue perturbations uncouple metabolic health from survival Does not establish universal effects outside mapped contexts", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C26", "text": "Cardiac TORC2 activation improves autophagy function and survival Does not resolve all organismal TORC2 effects", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C27", "text": "Diet and rapamycin share TOR suppression yet differ physiologically Does not quantify distinct lifespan mediators", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C28", "text": "Late rapamycin improves survival and selected functions Many metabolic and activity measures do not change", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C29", "text": "Metabolic effects vary with treatment duration Does not directly establish survival mediation", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C30", "text": "ARGK1 is a defined effector of S6K longevity with AMPK link Does not show a universal mammalian mediator", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C31", "text": "Dose and sex gradients replicate survival effects Gompertz slope estimates do not prove slowed demographic aging rate", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph6. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C32", "text": "Short rapamycin improves bone inflammation and microbiome measures Does not demonstrate systemic lifespan mediation", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C33", "text": "TOR and synthesis responses differ by tissue and sex Does not test lifespan mediation", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C34", "text": "Functional benefits persist after drug withdrawal Does not establish whole-body or human persistence", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C35", "text": "Lifespan growth and fitness tradeoffs depend on sex and exposure timing Does not generalize all ages or species", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C36", "text": "Rapamycin reduces ROS and damage markers with autophagy changes Does not show damage reduction mediates survival", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C37", "text": "SFA1 is required for selected TOR and diet longevity effects Not a universal mediator; linked erratum content unexamined", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C38", "text": "Weekly rapamycin improves survival to planned sacrifice Disease context and censored follow-up are not natural maximum lifespan", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C39", "text": "BCAA restriction has sex-specific survival and frailty effects Does not isolate mTOR as dominant diet mediator", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C40", "text": "Rapatar delays cancer and increases survival Does not distinguish general aging from engineered cancer rescue", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C41", "text": "mTOR reactivation influences senescence in arrested cells In vitro geroconversion is not organismal aging primacy", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C42", "text": "Late dose and intermittent regimens affect survival by sex Food-source variation complicates comparisons; shared ITP platform", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C43", "text": "Rapamycin fails to rescue defective HSC function despite fibroblast benefit Not a normal-aging human trial", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C44", "text": "Autophagy loss blocks selected longevity pathways Shared downstream requirement does not establish mTOR exclusivity", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C45", "text": "TOR and Sch9 deletion extend replicative life with dietary epistasis Yeast replicative life is not mammalian healthspan", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C46", "text": "Multiple TOR manipulations extend life depending on nutrition Does not establish uniform central rate limitation", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C47", "text": "Downstream genetic perturbation extends survival and selected functions Developmental and sex boundaries remain; erratum details unexamined", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C48", "text": "Aged donor HSC engraftment is preserved Shares mutant platform; no independent lifespan replication", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C49", "text": "Phase2b pooled single-dose contrast positive after combination null; phase3 primary null despite IFN engagement Endpoint and population changes limit direct comparison and neither trial measures healthy lifespan", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph2, 1:Methods:paragraph4, 1:Methods:paragraph6, 1:Methods:paragraph8, 1:Methods:paragraph9, 1:Methods:paragraph10. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C50", "text": "Transient rapamycin changes survival with sex and tumour-spectrum boundaries Up-to-60% life expectancy is not universal full-life extension", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C51", "text": "Survival improves but few age phenotypes improve; young controls reveal age-independent effects Does not negate other mouse background or function benefits", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C52", "text": "DL001 separates mTORC1 inhibition from several metabolic side effects Does not report lifespan benefit", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C53", "text": "MEK inhibition adds survival benefit to intermittent rapamycin with separate engagement Additivity does not prove perfect independence or preclude shared network centrality", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph12, 1:Results:paragraph14, 1:Results:paragraph15. 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