{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Intermittent low-dose oral rapamycin improves physical function in otherwise healthy adults aged 50 and older.", "entry_form": "claim", "gradeable_restatement": "Intermittent low-dose oral rapamycin improves physical function in otherwise healthy adults aged 50 and older.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Age, baseline clinical health, sedentary/exercise status, formulation, dose/schedule, comparator and functional horizon fixed before results", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Rapamycin and Human Healthspan", "central_claim": "Intermittent low-dose oral rapamycin improves physical function in otherwise healthy adults aged 50 and older.", "proposed_mechanism": "Intermittent low-dose oral rapamycin improves physical function in otherwise healthy adults aged 50 and older.", "claimed_scope": "Otherwise healthy or clinically stable adults aged 50 andolder; intermittent low-dose oral rapamycin,12–104 weeks; prespecified objective physical function or functional scale contrasted with placebo", "claimed_level": [ "response" ], "is_conjunctive": false, "conjunctive_note": "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint." }, "rubric_routing": { "primary_rubric": "06-metabolism-aging.md", "secondary_rubrics": [], "index_notes_applied": [ "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint." ], "rubric_fit_note": "Frozen metabolism/aging rubric 06 fits the mechanism, with an explicit phenotype adaptation for SC2: objective physical performance and prespecified functional scales are the registered healthspan analogue, without requiring a human lifespan RCT to test this narrower claim. Biomarkers, lean mass, symptoms, tissue phenotypes, infection incidence and survival retain distinct outcomes. Literal caps govern transfer to the claimed clinical scope; animal causal effects are not downgraded merely because they fail to prove humans. Senolytic equivalence is evaluated separately." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Intermittent rapamycin engages mTOR-related biology in older adults.", "subclaim_type": "mechanism", "scope": "Oral intermittent dose, age and baseline health fixed", "claimed_scope": "Oral intermittent dose, age and baseline health fixed", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Controlled pharmacodynamic measures", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "mTOR-related action is biologically well supported in models and human tissues, and older-person clinical experiments show selected molecular responses. The direct intermittent healthy-older-adult target-to-function link remains unestablished. Drug concentration is exposure and senescence markers are intermediate evidence. Γ concerns this clinical mechanistic bridge; it does not deny that rapamycin inhibits mTOR.", "rubric_adaptation": "mTOR-related molecular response does not prove functional benefit; a measured drug concentration is exposure, not target-specific engagement or aging reversal." }, { "id": "SC2", "statement": "Intermittent rapamycin improves physical function against placebo.", "subclaim_type": "sufficiency", "scope": "Otherwise healthy adults aged at least 50; objective function and prespecified functional scales; 12-104 weeks", "claimed_scope": "Otherwise healthy adults aged at least 50; objective function and prespecified functional scales; 12-104 weeks", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Controlled human functional-outcome trials", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "The direct 13-week weekly 6 mg RAPA-EX trial has a negative-direction ITT chair-stand null and prespecified sensitivity contrasts showing attenuation. PEARL has a primary visceral-fat null, secondary female lean mass/pain signals, surveys outside specified endpoints and WOMAC null. No positive same-scope physical-function crossing was verified. Γ preserves partial support without declaring every dose ineffective.", "rubric_adaptation": "Prespecified physical performance/function over 12–104 weeks is the healthspan analogue. A valid clinically relevant natural instrument can qualify, but animal lifespan or lean mass alone cannot substitute." }, { "id": "SC3", "statement": "Immune markers or animal lifespan establish slower human aging.", "subclaim_type": "generalization", "scope": "Human disease trajectory and survival distinct from biomarkers and animal systems", "claimed_scope": "Human disease trajectory and survival distinct from biomarkers and animal systems", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Human clinical healthspan or survival outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Genuine animal survival/function and specific human immune clinical effects are retained, with phase III infection and model-context nulls. They do not establish a slower whole-human aging trajectory or survival. Evidence for biological activity cannot replace clinical scope matching.", "rubric_adaptation": "Restricted immune clinical benefit and model survival must not be relabeled global slowing of human aging; acknowledge organismal positives while testing translation." }, { "id": "SC4", "statement": "Senolytic combinations reproduce established rapamycin healthspan benefit in humans.", "subclaim_type": "generalization", "scope": "Agent, baseline disease and functional outcome specified before treatment", "claimed_scope": "Agent, baseline disease and functional outcome specified before treatment", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Independent controlled senolytic clinical trials", "hsef_level": "Α", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Senolytic trials concern different mechanisms, agents and diseases. No direct experiment shows reproduction of an already established intermittent-rapamycin healthy-human functional benefit. This comparative equivalence is narrative at Α; it does not grade every senolytic intervention.", "rubric_adaptation": "Clinical senolytic trials retain their own diagnoses, agents and outcomes; equivalence to rapamycin requires direct matched evidence and an established comparator benefit." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint.", "primary_subclaim_id": "SC2", "aggregation_derivation": "Preregistered primary-subclaim aggregation returns SC2 Γ. Strong preclinical biology and selected exploratory human signals coexist with a directly relevant negative-direction functional primary null. Markers, body composition and other-indication clinical results do not identify sustained physical-function benefit for the registered regimen and population. This scores the stated positive proposition without a preset verdict or safety recommendation.", "aggregation_alternatives": { "weakest_link_would_return": "Α", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered full-scope gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M3", "is_nominal": false, "name": "Animal regimen and context determine real benefit", "core_claim": "Rapamycin causes lifespan and selected health/function benefits in defined model contexts; translation to intermittent human function remains separate.", "explains_what_nominal_does_not": "Rapamycin causes lifespan and selected health/function benefits in defined model contexts; translation to intermittent human function remains separate.", "strongest_supporting_evidence": [ "Late-life heterogeneous mice 19587680 and C57BL/6 function/survival 23682161 are positive; nfκb1 healthspan without lifespan 30468013 maps an outcome boundary." ], "strongest_contradictory_evidence": [ "Direct human functional trial 41985884 lacks benefit; sex, genetic, exercise, metabolic and formulation differences constrain transfer." ], "hsef_level_for_this_model": "Ε", "rationale": "Late-life heterogeneous mice 19587680 and C57BL/6 function/survival 23682161 are positive; nfκb1 healthspan without lifespan 30468013 maps an outcome boundary. Direct human functional trial 41985884 lacks benefit; sex, genetic, exercise, metabolic and formulation differences constrain transfer." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Target and immune effects differ from generalized healthspan", "core_claim": "Defined mTOR interventions can change immune phenotypes or specific infection risk without establishing healthy-human physical benefit.", "explains_what_nominal_does_not": "Defined mTOR interventions can change immune phenotypes or specific infection risk without establishing healthy-human physical benefit.", "strongest_supporting_evidence": [ "Vaccine 25540326 and phase 2a infection 29997249 positives preserve actual clinical and biological action." ], "strongest_contradictory_evidence": [ "Phase III 33977284 illness null despite antiviral genes and daily older 29408453 function null prevent a uniform slow-human-aging inference." ], "hsef_level_for_this_model": "Δ", "rationale": "Vaccine 25540326 and phase 2a infection 29997249 positives preserve actual clinical and biological action. Phase III 33977284 illness null despite antiviral genes and daily older 29408453 function null prevent a uniform slow-human-aging inference." }, { "rank_in_tournament": 3, "model_id": "M1", "is_nominal": true, "name": "Intermittent mTOR modulation improves older-human function", "core_claim": "Weekly low-dose oral rapamycin causes sustained physical-function improvement in otherwise healthy older adults.", "explains_what_nominal_does_not": "Weekly low-dose oral rapamycin causes sustained physical-function improvement in otherwise healthy older adults.", "strongest_supporting_evidence": [ "Rat 26997106 and mouse 23682161 function, plus PEARL female composition/pain signals, provide plausibility and exploratory clinical support." ], "strongest_contradictory_evidence": [ "Direct RAPA-EX primary is not positive; PEARL function questionnaires are null or not designated endpoints. A positive clinical functional crossing is unverified." ], "hsef_level_for_this_model": "Γ", "rationale": "Rat 26997106 and mouse 23682161 function, plus PEARL female composition/pain signals, provide plausibility and exploratory clinical support. Direct RAPA-EX primary is not positive; PEARL function questionnaires are null or not designated endpoints. A positive clinical functional crossing is unverified." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Senolytics have separate clinical scope", "core_claim": "Senescent-cell targeting may benefit defined conditions through another mechanism, without reproducing an established rapamycin benefit.", "explains_what_nominal_does_not": "Senescent-cell targeting may benefit defined conditions through another mechanism, without reproducing an established rapamycin benefit.", "strongest_supporting_evidence": [ "Open-label IPF 30616998 function, human kidney 31542391 markers and controlled mouse 29988130 effects justify further testing." ], "strongest_contradictory_evidence": [ "Controlled IPF 36857968 functional null, postmenopausal 38956196 primary null and acute kidney-injury 40573218 negative prevent generic healthy-function or equivalence claims." ], "hsef_level_for_this_model": "Γ", "rationale": "Open-label IPF 30616998 function, human kidney 31542391 markers and controlled mouse 29988130 effects justify further testing. Controlled IPF 36857968 functional null, postmenopausal 38956196 primary null and acute kidney-injury 40573218 negative prevent generic healthy-function or equivalence claims." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. RAPA-EX 41985884 randomizes weekly 6 mg within matched exercise and tests ITT chair-standing, prespecified functional outcomes and sensitivity analyses. It directly tests added function, while PEARL mostly measures composition and exploratory surveys. RTB101 33977284 separately demonstrates that gene activation need not generate clinical illness reduction.", "study_separating_rank1_from_rank2": "RAPA-EX 41985884 randomizes weekly 6 mg within matched exercise and tests ITT chair-standing, prespecified functional outcomes and sensitivity analyses. It directly tests added function, while PEARL mostly measures composition and exploratory surveys. RTB101 33977284 separately demonstrates that gene activation need not generate clinical illness reduction.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "41985884", "title": "Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA-EX-01 Randomised, Double-Blind, Placebo-Controlled Trial.", "citation": "Stanfield B, Leroux B, Kaeberlein M et al. Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA-EX-01 Randomised, Double-Blind, Placebo-Controlled Trial. Journal of cachexia, sarcopenia and muscle. 2026.", "doi": "10.1002/jcsm.70274", "pmcid": "PMC13082878", "url": "https://pubmed.ncbi.nlm.nih.gov/41985884/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41985884/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "ACTRN12624000790549", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph8, 1:Methods:paragraph9, 1:Methods:paragraph10, 1:Methods:paragraph11, 1:Methods:paragraph14, 1:Methods:paragraph15, 1:Methods:paragraph16, 1:Methods:paragraph17, 2:Results:paragraph3, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph7, 2:Results:paragraph9, 2:Results:paragraph10, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph16. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Forty sedentary adults aged 65–85 randomized to commercial Rapamune 6 mg weekly or matched placebo plus identical exercise for 13 weeks had primary ITT chair-stand difference −2.13 (CI −4.61 to 0.34, P = 0.089);prespecifiedCC/PPcontrasts favored placebo.", "what_it_does_not_show": "Exploratory, powered only for large effects; no multiplicity adjustment. Direct primary result is negative-direction null, not definitive universal harm. AEcounts99versus63 yield IRR 1.57 (CI 0.86–2.87, P = 0.14);one possibly related pneumonia after a single dose. Secondary functional outcomes also lack benefit.", "confounders_present": [ "Exploratory, powered only for large effects; no multiplicity adjustment. Direct primary result is negative-direction null, not definitive universal harm. AEcounts99versus63 yield IRR 1.57 (CI 0.86–2.87, P = 0.14);one possibly related pneumonia after a single dose. Secondary functional outcomes also lack 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": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 2, "pmid": "26997106", "title": "Rapamycin increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats.", "citation": "Xue QL, Yang H, Li HF et al. Rapamycin increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats. Aging. 2016.", "doi": "10.18632/aging.100929", "pmcid": "PMC4925827", "url": "https://pubmed.ncbi.nlm.nih.gov/26997106/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26997106/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID26997106", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Six-month dietaryrapamycin in 28 old low-capacity-runner rats improvedgrip andattenuatedrunningdecline withsex differences.", "what_it_does_not_show": "Highdailyanimaldose andselectedriskbackground, notweeklyhealthyhuman. Baselineimprovement notnecessarilybetween-groupcontrast onallreportedmetrics; male MRDchange nonsignificant. Physicalpositive retainedwithoutclinicaltransfer.", "confounders_present": [ "Highdailyanimaldose andselectedriskbackground, notweeklyhealthyhuman. Baselineimprovement notnecessarilybetween-groupcontrast onallreportedmetrics; male MRDchange nonsignificant. Physicalpositive retainedwithoutclinicaltransfer." ], "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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 3, "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": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NCT02874924", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2, 1:Methods:paragraph3, 1:Methods:paragraph4, 1:Methods:paragraph10, 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph3, 2:Results:paragraph5, 2:Results:paragraph6, 2:Results:paragraph8, 2:Results:paragraph9, 2:Results:paragraph10. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Actual older-person pilot enrolled 28 in two phases, 25 completed ≥8 weeks; daily 1 mg commercial drug for planned 16 or 8 weeks produced no handgrip/walk/cognition benefit and several erythrocyte declines.", "what_it_does_not_show": "Daily schedule is a regimen boundary. TREG within-arm P = 0.008 but between-arm P = 0.13 does not establish immune superiority; short small screened sample cannot establish long-term safety. Unchangedfunction is not proven equivalence or weekly-regimen inefficacy.", "confounders_present": [ "Daily schedule is a regimen boundary. TREG within-arm P = 0.008 but between-arm P = 0.13 does not establish immune superiority; short small screened sample cannot establish long-term safety. Unchangedfunction is not proven equivalence or weekly-regimen inefficacy." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 4, "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": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID29997249", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "264 elderly subjects randomized low-dose BEZ235/RAD001 combination for 6 weeks hadreportedone-yearinfection reduction(P = 0.001),antiviralexpression andvaccineresponse improvement.", "what_it_does_not_show": "Different TORC1 agents, shortexposure andspecificinfectionendpoint; notweekly rapamycinphysicalfunction orhumansurvival. Self-reportinfection ascertainment andlater phase IIIboundary mustbechecked.", "confounders_present": [ "Different TORC1 agents, shortexposure andspecificinfectionendpoint; notweekly rapamycinphysicalfunction orhumansurvival. Self-reportinfection ascertainment andlater phase IIIboundary mustbechecked." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 5, "pmid": "27341957", "title": "Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate.", "citation": "Lelegren M, Liu Y, Ross C et al. Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiology of aging & age related diseases. 2016.", "doi": "10.3402/pba.v6.31793", "pmcid": "PMC4920937", "url": "https://pubmed.ncbi.nlm.nih.gov/27341957/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27341957/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID27341957", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Marmosetrapamycintissueanalysis reportsselectiveproteostasis/autophagychanges:muscle/adiposeautophagy+,livernot; proteasomeexpression+,activityunchanged.", "what_it_does_not_show": "Modeltissuebiomarkers andpriorpilotoverlap; notlifespan orhumanfunction. Tissue-specificnulls preventuniformautophagyassertion; nonhumanprimate doesnotautomaticallytranslate.", "confounders_present": [ "Modeltissuebiomarkers andpriorpilotoverlap; notlifespan orhumanfunction. Tissue-specificnulls preventuniformautophagyassertion; nonhumanprimate doesnotautomaticallytranslate." ], "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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 6, "pmid": "38956196", "title": "Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.", "citation": "Farr JN, Atkinson EJ, Achenbach SJ et al. Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial. Nature medicine. 2024.", "doi": "10.1038/s41591-024-03096-2", "pmcid": "PMC11705617", "url": "https://pubmed.ncbi.nlm.nih.gov/38956196/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38956196/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NCT04313634", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Sixty postmenopausal women randomizedintermittent D+Q had primary 20 week CTx null; P1NP early secondary positives not maintained 20 weeks; exploratoryhigh-p16 subsetradius BMDpositive.", "what_it_does_not_show": "Biomarkers/BMDnotfractureorphysicalfunction; subgroupmustbeprospectivelydefined/replicated, notselectedresponders. Primarynullcannotbeoverriddenbyexploration; differentmechanism notrapamycinequivalence.", "confounders_present": [ "Biomarkers/BMDnotfractureorphysicalfunction; subgroupmustbeprospectivelydefined/replicated, notselectedresponders. Primarynullcannotbeoverriddenbyexploration; differentmechanism notrapamycinequivalence." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 7, "pmid": "30616998", "title": "Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.", "citation": "Justice JN, Nambiar AM, Tchkonia T et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019.", "doi": "10.1016/j.ebiom.2018.12.052", "pmcid": "PMC6412088", "url": "https://pubmed.ncbi.nlm.nih.gov/30616998/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30616998/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NCT02874989-openlabel-cohort", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal model", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Heterogeneousmousehigherdietarydose extendsmedianlifespan 23% male 26% female, maximallifespanalso; sex/dose effects andmetabolicdistinctionfromdietrestriction.", "what_it_does_not_show": "Animaldietarylifespanvaliditynotregisteredclinicalphysicalfunction. ITPdose-study/histologyfamily mayoverlap 22587563;replicationdoesnotbyitselfcreateindependentcausalclasses.", "confounders_present": [ "Animaldietarylifespanvaliditynotregisteredclinicalphysicalfunction. 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Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. The Journal of physiology. 2009.", "doi": "10.1113/jphysiol.2008.163816", "pmcid": "PMC2678224", "url": "https://pubmed.ncbi.nlm.nih.gov/19188252/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19188252/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID19188252", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Acutehumanrapamycin beforecontractionblocks ~40% earlymuscleproteinsynthesisincrease andselectedmTORC1/ERKpathwayresponses.", "what_it_does_not_show": "Acuteanabolicphysiology notweekly≥50 longtermfunctionalharm; age/dose mustnotbeassumedfromabstract. Itmotivatestiminginteractionchecks, notproofallintermittentregimensabolishadaptation.", "confounders_present": [ "Acuteanabolicphysiology notweekly≥50 longtermfunctionalharm; age/dose mustnotbeassumedfromabstract. 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Aging cell. 2016.", "doi": "10.1111/acel.12405", "pmcid": "PMC4717280", "url": "https://pubmed.ncbi.nlm.nih.gov/26463117/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26463117/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID26463117", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal model", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Mousealternative schedulesandrapalogs reduceglucose/pyruvate/immune sideeffectsthanchronicrapamycin whileinhibitingmTORC1.", "what_it_does_not_show": "Comparativesafety-windowmechanism nothumanfunctionalbenefit, absenceofallrisk orlifespanqualifier; youngshortexperimentandmTORC1/2 specificitycontext retained.", "confounders_present": [ "Comparativesafety-windowmechanism nothumanfunctionalbenefit, absenceofallrisk orlifespanqualifier; youngshortexperimentandmTORC1/2 specificitycontext retained." ], "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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 60, "verified": 60, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Biomarker change without functional/phenotypic change caps at Γ.", "specific_trigger": "mTOR-related action is biologically well supported in models and human tissues, and older-person clinical experiments show selected molecular responses. The direct intermittent healthy-older-adult target-to-function link remains unestablished. Drug concentration is exposure and senescence markers are intermediate evidence. Γ concerns this clinical mechanistic bridge; it does not deny that rapamycin inhibits mTOR.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Intermittent low-dose oral rapamycin improves physical function in otherwise healthy adults aged 50 and older.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "A valid model lifespan or functional effect can cross causal thresholds within its species/background. Human physical-function inference requires matching clinical outcomes. Complementary preclinical evidence is assessed as a set, without repeatedly capping its weakest component; its actual scope still differs from the clinical claim. Composition, pain and immune outcomes cannot replace the registered endpoint. A well-designed negative study earns no positive Δ crossing.", "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": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "ROS, NAD, mitochondrial, senescence and immune markers alone cannot establish the registered functional benefit. Model single-species/strain limits govern human translation, while actual cross-species/background positives retain their restricted scope. Human functional primary nulls do not become positive causal crossings; secondary signals cannot silently replace endpoints." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "mTOR-related action is biologically well supported in models and human tissues, and older-person clinical experiments show selected molecular responses. The direct intermittent healthy-older-adult target-to-function link remains unestablished. Drug concentration is exposure and senescence markers are intermediate evidence. Γ concerns this clinical mechanistic bridge; it does not deny that rapamycin inhibits mTOR.", "ceiling_from_boundary_check": "Γ" }, { "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": "", "gamma_hard_rules_triggered": [ "ROS, NAD, mitochondrial, senescence and immune markers alone cannot establish the registered functional benefit. Model single-species/strain limits govern human translation, while actual cross-species/background positives retain their restricted scope. Human functional primary nulls do not become positive causal crossings; secondary signals cannot silently replace endpoints." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "The direct 13-week weekly 6 mg RAPA-EX trial has a negative-direction ITT chair-stand null and prespecified sensitivity contrasts showing attenuation. PEARL has a primary visceral-fat null, secondary female lean mass/pain signals, surveys outside specified endpoints and WOMAC null. No positive same-scope physical-function crossing was verified. Γ preserves partial support without declaring every dose ineffective.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "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": "", "gamma_hard_rules_triggered": [ "ROS, NAD, mitochondrial, senescence and immune markers alone cannot establish the registered functional benefit. Model single-species/strain limits govern human translation, while actual cross-species/background positives retain their restricted scope. Human functional primary nulls do not become positive causal crossings; secondary signals cannot silently replace endpoints." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Genuine animal survival/function and specific human immune clinical effects are retained, with phase III infection and model-context nulls. They do not establish a slower whole-human aging trajectory or survival. Evidence for biological activity cannot replace clinical scope matching.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "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": "", "gamma_hard_rules_triggered": [ "ROS, NAD, mitochondrial, senescence and immune markers alone cannot establish the registered functional benefit. Model single-species/strain limits govern human translation, while actual cross-species/background positives retain their restricted scope. Human functional primary nulls do not become positive causal crossings; secondary signals cannot silently replace endpoints." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Senolytic trials concern different mechanisms, agents and diseases. No direct experiment shows reproduction of an already established intermittent-rapamycin healthy-human functional benefit. This comparative equivalence is narrative at Α; it does not grade every senolytic intervention.", "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": "no", "supporting_evidence": [], "what_would_cross_it": "Prespecified intermittent older-human target-specific pharmacodynamics, with dose/time/assay controls and clinical phenotype linkage tested separately." }, { "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": [], "what_would_cross_it": "Registered 12–104 week randomized or independently valid natural-experiment evidence in the prespecified population, with clinically meaningful objective function or functional scales, verified exposure, balanced exercise and complete missing-data/benefit-harm reporting." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Independent controlled human clinical aging-trajectory or hard healthspan/survival effects; immune/animal-marker mediation must be tested rather than assumed." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Controlled agent- and disease-specific senolytic functional benefit plus direct comparative evidence; do not assume an established rapamycin reference benefit." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": "RAPA-EX has a direct functional primary null; PEARL visceral fat/WOMAC and older daily rapamycin function are null. RTB101 phase III clinical illness is null despite antiviral gene responses. Mouse 30468013 improves healthspan without lifespan/inflammation benefit. Controlled IPF senolytic function and acute kidney-injury experiments provide additional context limits.", "note": "Dose, formulation, sex, exercise, baseline disease, species and endpoint boundaries were examined. No positive intermittent healthy-human physical-function effect is yet mapped across adults. Robust model lifespan/health effects retain their causal status in their actual contexts; translation uncertainty is not a downgrade of those observations." }, "falsification_patterns_met": [ { "pattern": "Pathway manipulation changes markers but not the registered phenotype", "evidence": "PEARL composition/survey signals coexist with WOMAC null; RTB101 antiviral genes coexist with phase III illness null. These are phenotype/scope distinctions, not healthy-human functional confirmation.", "downgrade_applied": false }, { "pattern": "Relevant intervention does not improve function", "evidence": "RAPA-EX primary negative-direction null and sensitivity attenuation do not confirm added weekly 6 mg benefit; the small trial and regimen limits prevent universal absence or harm conclusions.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Confirmation by biomarker", "where": "Lean mass, immune genes, p21,DNA clocks orautophagy becomeclinicalfunction/humansurvival proof." }, { "pitfall": "Selective generalization", "where": "Mouse/dog/cell, topicalskin, dailytransplantdose orspecificinfectionresultsbecomehealthyweeklyolder-humanbenefit." }, { "pitfall": "Missing-control interpretation", "where": "Within-arm SF36/TREG significance is mistaken for between-group benefit; open-label D+Qfunctionbecomescontrolledtherapy." }, { "pitfall": "Negative field-valid perturbation read as a crossed threshold", "where": "Direct RAPA-EX andsenolyticfunctionalnulls arecounted aspositivecausal units." }, { "pitfall": "Mechanism conflation", "where": "mTOR senomorphic, senolyticclearance andsenescentcellmarkers aretreatedasoneclinicalintervention." }, { "pitfall": "Scope may not be defined by the outcome", "where": "Smallfemale 10 mg PEARLsignal orposthocp16 senolyticresponders redefineenrolledclinicalscopeafterresults." } ], "causal_tally_audit": { "tally_claimed_by_document": 0, "tally_after_audit": 0, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 29, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "No positive qualifying same-scopehealthy-humanintermittentphysicalfunctionunitisclaimed.", "Stronganimalphenotypes/specificimmuneclinicalpositivesretainscope; notallbiologicalresultsaretreatedasbiomarkers.", "Directnulls/sensitivitynegativesareinformativebutnotpositivecrossings; smalltrialsdonotproveuniversalabsence.", "Protocol/review/punctum/comment/correctionrecordsdo notpadprimarycount." ] }, "steelman": { "case_one_rung_higher": "One rung above Δ: late-life model benefits across backgrounds, plausible target biology and PEARL female lean mass/pain signals support a real possibility of human benefit. A different dose, training schedule or longer horizon could work. Those hypotheses motivate testing; they do not turn the observed functional primary null into a positive.", "case_one_rung_lower": "One rung below Β: the healthy-human physical-function proposition lacks a demonstrated positive from its closest controlled tests, and user surveys are confounded. An endpoint-only reading could hold the positive inference to association.", "which_rejected": "Δ is not granted because no positive same-scope functional perturbation was verified. Animal, immune and composition outcomes do not substitute for physical function. Β understates deliberate mechanistic intervention support and exploratory clinical signals, but Γ is not a clinical-benefit recommendation. Direct negative evidence remains explicit.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: A registered multicenter 52–104 week placebo-controlled trial of verified commercial-equivalent intermittent doses in otherwise healthy adults aged 50 or older, with balanced exercise strata, objective function as primary and prospective dose/exposure/sex analyses, followed by independent replication." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Multiple independent studies with some replication (three-site heterogeneous-mouse lifespan work, repeated ITP dose studies), but the registered healthy-human functional question rests on one 40-participant exploratory trial plus one decentralized trial with compounded-formulation exposure uncertainty, so methodological heterogeneity keeps the band at Moderate. Confidence reflects evidence density and reproducibility, not reviewer access or correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered primary-subclaim aggregation returns SC2 Γ. Strong preclinical biology and selected exploratory human signals coexist with a directly relevant negative-direction functional primary null. Markers, body composition and other-indication clinical results do not identify sustained physical-function benefit for the registered regimen and population. This scores the stated positive proposition without a preset verdict or safety recommendation." }, "role_of_mechanism": { "classification": "epiphenomenon", "derivation_step_matched": 2, "derivation": "Causal dependency of improved healthy-older-human physical function on weekly rapamycin is not established in either direction. This is an endpoint-specific evidence classification; it does not assert mTOR inactivity. Model and immune causal effects retain their own scopes.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "PEARL and RAPA-EX have completed original outcome reports through 2026. Their older protocols are not evidence that they remain underway. No additional currently active healthy-human functional trial was verified in this bounded assessment; preclinical work alone does not demonstrate a clinical causal test underway.", "justification": "PEARL and RAPA-EX have completed original outcome reports through 2026. Their older protocols are not evidence that they remain underway. No additional currently active healthy-human functional trial was verified in this bounded assessment; preclinical work alone does not demonstrate a clinical causal test underway." }, "stability": { "value": "Stable", "trigger": "A registered positive functional result in a new dose or context would alter the grade; no specific currently pending healthy-human functional result was verified at the examined access depth.", "justification": "A registered positive functional result in a new dose or context would alter the grade; no specific currently pending healthy-human functional result was verified at the examined access depth." }, "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": "none assigned", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": true, "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": "A registered multicenter 52–104 week placebo-controlled trial of verified commercial-equivalent intermittent doses in otherwise healthy adults aged 50 or older, with balanced exercise strata, objective function as primary and prospective dose/exposure/sex analyses, followed by independent replication.", "readout": "Prespecified chair-standing, walking capacity, strength and validated functional response; falls/disability secondary; lean mass, immune/p21 and clock markers separate intermediate outcomes", "critical_control": "Verified formulation and exposure, target engagement, prespecified baseline health/activity and sex/dose strata, balanced exercise/contact, blinded assessors, ITT missing-data handling and complete infection/metabolic/wound adverse-event capture", "supporting_result": "Clinically meaningful function improves versus placebo across a prespecified context with supported target specificity and an acceptable benefit-harm profile", "falsifying_result": "Precise unchanged or worse function despite appropriate exposure and target effect, or composition change without primary functional benefit; adverse-event shifts constrain the regimen" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Independent positive healthy-older-human functional evidence with registered endpoints and longer follow-up.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Drug timing relative to training and dose-specific anabolic/metabolic tradeoffs in a prespecified factorial experiment.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Compounded/commercial bioequivalence and measured target responses before interpreting nominal PEARL doses.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Multiplicity, small sex strata and missing-data interpretation of PEARL exploratory signals.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Human aging trajectory and survival separate from vaccine, antiviral genes, infection, mouse tumor delay and clocks.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Long-term and uncommon infection/metabolic/wound risks; selected surveys or short screened trials cannot establish universal safety.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Controlled senolytic disease/agent-specific functional evidence, target-cell identity and independent replication.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-13", "reviewer": "Codex", "evidence_base_note": "55 primary reports; literature cutoff 2026-10-13; source examination UTC date 2026-10-13; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite monthly limit was reached earlier in this session; no new Scite query or incoming citation-context audit is claimed for these cases. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs." }, "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": "These topic families were selected from an editorial traffic-priority list. Selection was visible; no blind calibration or predetermined clinical verdict was preregistered." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Exposure-specific genetics, natural instruments, multiple pharmacological classes and independent dose-response were considered. Randomized clinical designs are feasible and available, but no positive matching functional primary result was verified. Immune-agent/model-genetic experiments narrow biology without establishing independent healthy-human functional convergence. No human lifespan RCT is required to test the narrower registered function claim." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Exposure-specific genetics, natural instruments, multiple pharmacological classes and independent dose-response were considered. Randomized clinical designs are feasible and available, but no positive matching functional primary result was verified. Immune-agent/model-genetic experiments narrow biology without establishing independent healthy-human functional convergence. No human lifespan RCT is required to test the narrower registered function claim." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Exposure-specific genetics, natural instruments, multiple pharmacological classes and independent dose-response were considered. Randomized clinical designs are feasible and available, but no positive matching functional primary result was verified. Immune-agent/model-genetic experiments narrow biology without establishing independent healthy-human functional convergence. No human lifespan RCT is required to test the narrower registered function claim." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Exposure-specific genetics, natural instruments, multiple pharmacological classes and independent dose-response were considered. Randomized clinical designs are feasible and available, but no positive matching functional primary result was verified. Immune-agent/model-genetic experiments narrow biology without establishing independent healthy-human functional convergence. No human lifespan RCT is required to test the narrower registered function claim." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Exposure-specific genetics, natural instruments, multiple pharmacological classes and independent dose-response were considered. Randomized clinical designs are feasible and available, but no positive matching functional primary result was verified. Immune-agent/model-genetic experiments narrow biology without establishing independent healthy-human functional convergence. No human lifespan RCT is required to test the narrower registered function claim." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 55, "claims_total": 60, "claims_verified": 60, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 55, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Forty sedentary adults aged 65–85 randomized to commercial Rapamune 6 mg weekly or matched placebo plus identical exercise for 13 weeks had primary ITT chair-stand difference −2.13 (CI −4.61 to 0.34, P = 0.089);prespecifiedCC/PPcontrasts favored placebo. Exploratory, powered only for large effects; no multiplicity adjustment. Direct primary result is negative-direction null, not definitive universal harm. AEcounts99versus63 yield IRR 1.57 (CI 0.86–2.87, P = 0.14);one possibly related pneumonia after a single dose. Secondary functional outcomes also lack benefit.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph8, 1:Methods:paragraph9, 1:Methods:paragraph10, 1:Methods:paragraph11, 1:Methods:paragraph14, 1:Methods:paragraph15, 1:Methods:paragraph16, 1:Methods:paragraph17, 2:Results:paragraph3, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph7, 2:Results:paragraph9, 2:Results:paragraph10, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C2", "text": "Six-month dietaryrapamycin in 28 old low-capacity-runner rats improvedgrip andattenuatedrunningdecline withsex differences. Highdailyanimaldose andselectedriskbackground, notweeklyhealthyhuman. Baselineimprovement notnecessarilybetween-groupcontrast onallreportedmetrics; male MRDchange nonsignificant. Physicalpositive retainedwithoutclinicaltransfer.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C3", "text": "Actual older-person pilot enrolled 28 in two phases, 25 completed ≥8 weeks; daily 1 mg commercial drug for planned 16 or 8 weeks produced no handgrip/walk/cognition benefit and several erythrocyte declines. Daily schedule is a regimen boundary. TREG within-arm P = 0.008 but between-arm P = 0.13 does not establish immune superiority; short small screened sample cannot establish long-term safety. Unchangedfunction is not proven equivalence or weekly-regimen inefficacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2, 1:Methods:paragraph3, 1:Methods:paragraph4, 1:Methods:paragraph10, 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph3, 2:Results:paragraph5, 2:Results:paragraph6, 2:Results:paragraph8, 2:Results:paragraph9, 2:Results:paragraph10. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C4", "text": "264 elderly subjects randomized low-dose BEZ235/RAD001 combination for 6 weeks hadreportedone-yearinfection reduction(P = 0.001),antiviralexpression andvaccineresponse improvement. Different TORC1 agents, shortexposure andspecificinfectionendpoint; notweekly rapamycinphysicalfunction orhumansurvival. Self-reportinfection ascertainment andlater phase IIIboundary mustbechecked.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C5", "text": "Marmosetrapamycintissueanalysis reportsselectiveproteostasis/autophagychanges:muscle/adiposeautophagy+,livernot; proteasomeexpression+,activityunchanged. Modeltissuebiomarkers andpriorpilotoverlap; notlifespan orhumanfunction. Tissue-specificnulls preventuniformautophagyassertion; nonhumanprimate doesnotautomaticallytranslate.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C6", "text": "Sixty postmenopausal women randomizedintermittent D+Q had primary 20 week CTx null; P1NP early secondary positives not maintained 20 weeks; exploratoryhigh-p16 subsetradius BMDpositive. Biomarkers/BMDnotfractureorphysicalfunction; subgroupmustbeprospectivelydefined/replicated, notselectedresponders. Primarynullcannotbeoverriddenbyexploration; differentmechanism notrapamycinequivalence.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C7", "text": "Fourteen IPF patients open-label 3 week D+Q hadimprovedwalking/gait/chair-stands, unchangedpulmonary/frailty/reportedhealth; one serious AE; primaryfeasibility. Uncontrolledshortdiseasepilot, nothealthyagingorprimaryfunctional RCT. SASP-functioncorrelationinconclusiveandnotmediateddependency; regression/contact unresolved.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C8", "text": "Twelve IPF patients randomized 3 week D+Q versusplacebo completedassessments; physical/frailty/pulmonarychangesnotmeaningfullydifferentandactivearmmore AEs, anxiety/sleep 4/6 versus 0/6. Feasibility-powered, singleblind andveryshort; nullimprecisenotequivalence. Same NCT02874989 protocolfamilyasprioropenlabelbutdifferentallocationcohort, notassumedsameparticipants.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C9", "text": "Secondarypostmenopausal D+Qtrialbiomarkerstudy reports T cell p16 variant 5/SASPpredictingexploratoryskeletalresponse plusin-vitro DNA-damageexpressiontiming. Shares 38956196 allocation; markerpredictionnotindependentlyvalidatedclinicalselection orsenescentcellnecessity. Exploratoryresponderscannotredefinetheoverallprimarynull.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C10", "text": "Immune-specific Ercc 1 deletion mice developedprematureimmune/systemicsenescence; youngcelltransferattenuatedmarkers andrapamycinimprovedimmunefunction/markers. DNA-repairprogeroidmodelandforcedtransfersaremechanistic notnormalhumanagingorphysicalhealthspan. Rapamycin partial rescue is not necessity of mTORasglobalagingdriver.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C11", "text": "Late-life dietary rapamycin extended median/maximal survival in both sexes of heterogeneous mice at three sites, with 90%-mortality-age gains 14% female 9% male. Strong restricted mammalian lifespan evidence retained; possiblecancer-delay anddailyfeedexposure notweeklyhumanfunction. Sitesreplicate one experimentalclass, notindependenthuman causalclasses.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C12", "text": "Survey 333 off-labelrapamycinusers compared 172 never-users characterizes use andreported safety in normalhealth. Self-selection, healthyuser/confoundedcomparison, recall andunverifieddose/outcomes; notrandomizedfunctiontrajectory orincidencerare AE. Conclusionofsafeuse isexploratory notuniversal.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C13", "text": "Topicalskintrial 36 enrolled/19 discontinuedlost reports reducedp16,increasedcollagen VII andsomeclinical/histologicalappearanceimprovement. Topicalroute, photoaging≥40,highattrition andbiopsy subset; notoralweekly≥50 physicalfunction. Reducedp16 is notproofsenescentcellclearance orslowglobalaging.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C14", "text": "Mouse trametinib/rapamycincombination extendedsurvivaladditivelyinbothsexes andreducedselectedtumors/inflammatorytissuephenotypes. Combination MEK/mTOReffects inmodelnotintermittenthealthyhuman benefit; tumors, healthspan andfunctionnotidenticaloutcomes. Synergy/additivitydoesn'tprovesinglemediator necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C15", "text": "PEARL 48-week weekly compounded 5/10 mg trial had primary visceral-fat null; female 10 mg lean mass secondary positive. Original body: 114 completers analyzed, 11 excluded discontinuers, only 8 women in 10 mg; WOMAC null and emotional wellbeing improved within placebo too. Surveys were explicitly not specific endpoints; lean mass is not strength/function and selected within-armSF36changes are not between-arm efficacy. Compounded 24-hour blood concentration was about one-third commercial in a separate assessment. Multiple outcomes/small sex strata/missing data and exposure variation constrain inference.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph1, 1:RESULTS:paragraph3, 1:RESULTS:paragraph5, 1:RESULTS:paragraph7, 1:RESULTS:paragraph9, 1:RESULTS:paragraph10, 1:RESULTS:paragraph13, 3:METHODS:paragraph0, 3:METHODS:paragraph1, 3:METHODS:paragraph2, 3:METHODS:paragraph3, 3:METHODS:paragraph9, 3:METHODS:paragraph11, 3:METHODS:paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C16", "text": "Femaleadultmiceweekly versus 3 xweekly rapamycin with 8 weekweightedrunning had preservedgrip/exercisecapacity/hypertrophy butglucose/insulinsensitivity impairment; weeklylesssevere. Five-monthadultfemale modelnotoldhealthyhumans; exercisecompatible isnotaddedfunctionalbenefit. Preservedmuscle plusmetabolicharm needseparate outcomes.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C17", "text": "Chemicalgeneticselec TORrapalog/mutant FKBP12 system enablescell/tissuerestrictedmTORinhibition andmaps Drosophila developmentdelaytissues. Specificitytool inyeast/humancells/flydevelopment, notoralweeklyolderadulttargetengagement oragingfunctionaltherapy. Developmentaldelay distinct fromretardedaging.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C18", "text": "Original RNA-seqreanalysis acrossmousegeroprotectors/transgenics plusexercisedhuman data findsrepetitive-elementtranscriptsreducedbyselectedinterventions. Transcriptcorrelation/sharedpublicdatasets notcausalmediation, newindependentclinicalrapaexperiment orhumansloweraging. Originalanalysiscountretainedbutnotcausalunit.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C19", "text": "Rapamycintreatedmice showedsomeage-relatedtissue/activitychangesslower, alongsidehighercataract/testiculardegenerationincidence. Organ/tissuehealthspanheterogeneityandharmpreventuniformagingreversal; dailyexposuremousecontext nothumanweeklyfunction. Lifespan/functionalphenotypes andcancersuppressiondistinct.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C20", "text": "Flyfat-body S6Kactivationblockedrapamycinsurvivalextension; lysosomal Syntaxin/IMDmechanisticperturbations andmidlife IMDrepressionlinkedlifespan, inflammationeffectssex-specific. Specificflies/mouselivermarkersnothealthyhumanweeklyfunction; endpointsnotuniformacrosssex. Mechanisticnarrowingretainedwithoutclaiminghumannecessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C21", "text": "Shortrapamycinolder-mousetreatment regeneratesperiodontalbone, reducesinflammation andshiftsmicrobiome. Restrictedoralphenotype, notgeneralphysicalfunctionorhumansurvival. Bone/inflammation/microbiomecochanges notisolatewhichmediatesbenefit.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C22", "text": "Flymitochondrial/nucleargeneticcombinations modulatedrapamycinsurvivalandage-specificmortalityeffects, decoupledfromearlyfitnesscost. Mappedgeneticvariation notvalidatedhumanresponseprediction. Showscontextdependence, notabsenceofgenuineanimalbenefit orall-genotypeuniversalextension.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C23", "text": "nfκb1 deficientmice hadimprovedfrailty/memory/coordination/tissuehealth withrapamycin butnolifespan/inflammagingbenefit. Specificaccelerated-inflammationmodel; healthspan/survivaldissociationexcludesinflammationasassumednecessarybridge. Nothealthyhumanweeklyfunction.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C24", "text": "Originalmated-female-flyrapamycintitrationandcombinationexperiments showlifespanbenefitbutmifepristonecombinationnonadditive/lowerthanmonotherapy; mitophagy/midgutphenotypesmeasured. Includesbackgroundmeta-analysis butneworiginalexperimentsearncredit. Nonadditivityandsharedmarkersdon'tprovesinglepathway; sex/matingcontextnothumanhealthyfunction.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C25", "text": "Primaryhumanfibroblast H2 O2 model 48-hourrapamycin improvesmigration/proliferation andsenescence/ROS/autophagymarkers. Inducedstresscellculture/proxymarkers notendogenousolderhumanphysicalfunction. Autophagyincreasenotnecessarilycausalwithoutblockade/rescue; noorganismalhealthspan.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C26", "text": "Human T cell genotoxic stress work shows lesional burden/senescencereduction; placebo-controlledolderadultlow-doserapamycin reducesimmune-cellp21. Mixedcell/humanmechanisticdesign; senescencemarkers and DNAresilience notobjectivephysicalfunctionoragingtrajectory. Actualdose/scheduleandtrialoverlapneed Methodscheck.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C27", "text": "Secondary 333 off-labeluserssurveyreportsoralchanges in 26% andno dose/intervalcorrelationwithulcers, withselected AI-periodontalcasestudies. Shares 37191826 survey; absenceofassociationisnotzerooralharm; selectedcaseimages/confounding cannot establishoralregeneration orincidence. No non-userfocusedoralcontrol.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C28", "text": "Late-life C57BL/6 feedingrapamycin improvedsurvival, stride/rotarod andselectedlesions; targetinhibitionandtissue/sexresponsesvary, spontaneousactivitynull. Restrictedmousebackground, dailyfeeding andmultipleendpoints; notweeklyhumanfunction. No observedadverseconsequences heredoesn'teraseharmotherregimens.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C29", "text": "Flyrapamycin slowsage-relatedgutstem-cellproliferation, inducesepithelialautophagy andalteredimmune/FOXOgeneswithdelayedmicrobialexpansion. Specificflyintestinalphenotype, notdirecthumansystemichealthspan; cochangesnotallnecessarymediators. Broadhealthy-agingtransferremainsunverified.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C30", "text": "Nine diabetic-kidney-disease patients 3-day D+Q openlabel showedreducedadipose/skinp16/p21/SAβgal and SASP 11 days later. Cellburdenmarkers, beforeafter, diseasecontext nothealthyphysicalfunctionorrapamycinequivalence. Linkederratum 31982828 metadataonly; markerdecline notsenescentcellspecificity/rescueproof.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C31", "text": "Fisetinscreening/oldwild-type/progeroidmice andhumanadiposeexplants showcell-specificsenotherapeuticactivity, late-lifemousetissuebenefit andlifespanextension. Genuineoriginalpreclinicalsupport, notcontrolledhumantreatment. Flavonoidpolypharmacology, cellheterogeneity andmouseregimenconstraincausality/translation.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C32", "text": "Senescentcelltransfer inducedphysicaldysfunction inmice; intermittent D+Q intransferred andnaturallyagedmice improvedfunction andpost-treatment survival; humanadiposeexplantmarkersreduced. Forcedcelltransfer separatefromendogenousaging; oldmousepharmacologystrongrestrictedcontext butnotrapamycinorhumanfunction. Explantsnotclinicaloutcomes.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C33", "text": "Obesemicegeneticsuicide/p16 andsenolyticinterventions improvedglucose/insulin/adiposeresponses andrenal/cardiacphenotypes. Specificobesitydiseasecontext, genetic/pharmacologicconcordancenarrowssomeconfoundingbutnotgeneralhealthyaging. Off-target/cellidentity andclinicaltranslationunresolved.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C34", "text": "Agedhumanmelanocytemarkers and 3 Depidermalequivalentslink SASP-inducedparacrine dysfunction; ABT737 or Mito Qsuppressesatrophy/proliferationeffect. Human-derivedsimplifiedsystemnotwholehumanfunction; senolytic/antioxidantalternativesdo notprovesenescentcellspecificsystemicnecessity. Oralrapa equivalenceuntested.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C35", "text": "ABT263 inducesselectivesenescentcellapoptosis inculture andoralaged/irradiatedmice improveshematopoietic/musclestem-cellphenotypes. BCL2/BCLx Ldrugandspecificstemcell/radiationcontexts, notgeneralphysicalfunctionorhumantrial. Celltype/transplantassays andtherapeuticspecificity requirecontrols.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C36", "text": "Oldmice D+Q decreasesadiposesenescence/inflammation andimprovesglucose/lipidphenotypes, withliver/musclesenescencemarkers notrobustlychanged. Tissuerestriction andmetabolicendpoints notweekly rapamycinphysicalfunction; concomitantmarkerseffectsnotmediatornecessity orhumansurvival.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C37", "text": "Anti-u PARCART aged/high-fat-dietmice improveexercisecapacity/glucosewithlonglasting single-treatmentpreventiveeffects. Actualgenetic-cellularpharmacologydistinctfrom D+Q/rapamycin; u PARisnotuniquesenescenceidentity, mousefitnessnothumanfunction. Publishedupdatesupersedespreprint 37841853 notextracredit.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C38", "text": "Five ADpatients 12 week D+Q openlabelhadmeasurable CSFdasatinibnotquercetin, unchangedcognitive/imagingendpoints andmixedinflammatorymarkers. Feasibility/smalluncontrolledtrial notefficacyorsafetyqualification; nullcognitionisnotfavorablesafetyevidencebyitself. Publishedreportsupersedespreprint, nothealthyaging orrapa equivalence.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C39", "text": "Aged INK-ATTACgeneticclearance and D+Qbothreducedmicroglialp16/SASP andimprovedcognition. Mousecognitivereadout/tissuerestriction ratherthanwholehumanphysicalhealthspan; concordance narrowsmechanismbutnotallcelltypesorrapamycinsamepathway.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C40", "text": "Oldmice intermittentfisetin improvedarterialdilation/stiffness withsenescencemarkerdecline; ex-vivogeneticclearance showednoadditionalimprovementafterfisetin. Helpfulmechanisticocclusion butnotcompletehumansenolysis-specificity orhealthyphysicalfunction. Vessel/functioncontext distinctfromrapa, notclinicalequivalence.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C41", "text": "PCC1 senolytic/senomorphic oldmousework improvesretinalstructure/function anduses sc RNAseqtocellmapchanges. Agentpolypharmacologyandretinalscoped endpointsnotgeneralfunction/survival orhumantrial; SASPcochangesnotestablishsinglemediatornecessity.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C42", "text": "Aged/chronic-denervated Schwann-cellsenescence andsystemicdrug/genetictargeting linkclearance toimprovednerveregeneration/functionalrecovery. Injury/regenerationcontextsnotgeneralhealthyaging; genetic/drugconcordancenarrowssomecausalquestions butdrug-specificoff-targets/humanscope remain.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C43", "text": "Oldfracture-callusmice D+Qimprovehealing; TGFβneutralization rescuesprogenitorinhibition andhealingphenotypes. Definedfractureinjury andmousebackground, targeted TGFβmechanismnotrapamycinorhumanphysicalhealthspan. Senescencebenefitmaydependontiming/repaircontext.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C44", "text": "D+Qpretreatment inacute FANmousekidneyinjury didnotpreservecreatinine/BUN andworsenedselecteddamage/SASPgenes withoutreducingp21 positivecells. Specificacuteinjurynot CKDorhealthyaging; markerharmdoesn'tshoweveryclinicalregimenharm. Importantnegativecontexts retainedratherthanall-senolyticsbeneficialassumption.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C45", "text": "Ythdf 1 loss acceleratedmouseaging throughmTORC1/cholesterolaxis; rapamycin restoredhealthspan inthisbackground. Geneticbackground-specificrescuenotweeklyhealthyhumanfunction; lifespan/healthspan distinct andglobalmTORnecessitynotproved. m 6 A-independentmechanism narrowerthan generictranslationnarrative.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C46", "text": "Humanagedplateletphosphoproteomics/ex-vivo Torin 1 andmouseplateletmTORdeletion linkmTORtohyperreactivity; agedknockout rescuesinducedthrombosistime-to-death. Humanex-vivo Torin 1 andmousecell-specificgenetics—notolderadultrapamycinsurvivaltrial. Inducedpulmonarythrombosisendpointnothabitualphysicalfunction oragingnecessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C47", "text": "Older-volunteer RAD001 controlledtrial reports~20% enhanced influenza-vaccineresponse andreduced PD1 positive T cell proportions. Immunephenotypes, nothumanphysicalfunction, lifespan orgeneralagingtrajectory; differentdrug/doseandclinicalinfectionendpointdistinct. Vaccineimmunity not necessity proof that mTOR drives aging.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C48", "text": "RTB101 phase 2b 652/phase 3 ~1024 participants trials:combination-firstphase 2b primary contrast null; pooled 10 mgsecondaryprespecifiedanalysislab RTIpositive; phase III clinical-illness null 26% versus 25%, with antiviral genes up in both. Twoactualtrialunits inonereport; endpointdefinition changedbetweenphases, notidenticalreplication. Immune-targetengagementcanpersistwithoutclinicalbenefit; differentagent andinfectionoutcome notweeklyrapafunction.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C49", "text": "Originalcross-speciesfasting/polyamineperturbations showsspermidine-pathwayblockade attenuatesautophagy andmodelhealth/lifespan effects, humanfastingpolyaminechanges. Humancomponentnotrapamycinclinicalfunction; matchedrapamycinexperimentsreportedinsummaryneedoriginalbodyassessment beforeassigningmechanisticdetail. Parentoriginalreplacespunctum 39212197;noextrareviewcredit.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C50", "text": "Comprehensive male C57BL/6J evaluation found increasedlifespan withfewagingphenotypesimproved; manyrescuedtraits changed similarly inyoungmice. Aging-independentphenotypiceffectnotnecessarilyagingdelay; onebackground/sex doesn'teraseotherfunctionalpositives. Importantlifespan-healthspanseparation nothumanweeklyclinicaltest.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C51", "text": "Intermittent 2 mg/kg every 5 days from 20 months extendsfemale C57BL/6Jsurvival, withlessmetabolic/immuneimpactthanchronictreatment inrelatedwork. True intermittentlate-lifeanimalpositive; female-onlystrain anddifferentexposuresnotolderhumanfunction/safety. Reducedharmvsdaily isnotnoharm orsame 5–10 mghumanexposure.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C52", "text": "Three-monthmiddle-agedmousetreatment producespersistenthealth/survivalbenefits andmicrobiomeremodeling; onefemaledose failslifespanextension withshifttoaggressivehematopoieticcancers. Dose/sex/cancercontextmatters; headlineup-to 60% life expectancy cannotbecome 60% longer total human lifespan. Microbiomecochange notcausalmediation; modeltranslationrequiresownfunctionoutcome.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C53", "text": "Heterogeneousmousehigherdietarydose extendsmedianlifespan 23% male 26% female, maximallifespanalso; sex/dose effects andmetabolicdistinctionfromdietrestriction. Animaldietarylifespanvaliditynotregisteredclinicalphysicalfunction. 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Healthy longevity. 2021.", "tier": "A", "kind": "rct", "pmid": "33977284", "doi": "10.1016/S2666-7568(21)00062-3", "url": "https://pubmed.ncbi.nlm.nih.gov/33977284/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID33977284", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C48", "CSC1", "CSC3", "CH" ] }, { "n": 49, "citation": "Hofer SJ, Daskalaki I, Bergmann M et al. Spermidine is essential for fasting-mediated autophagy and longevity. 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Series A, Biological sciences and medical sciences. 2016.", "tier": "A", "kind": "primary", "pmid": "27091134", "doi": "10.1093/gerona/glw064", "url": "https://pubmed.ncbi.nlm.nih.gov/27091134/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID27091134", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C51", "CSC1", "CSC3" ] }, { "n": 52, "citation": "Bitto A, Ito TK, Pineda VV et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. 2016.", "tier": "A", "kind": "primary", "pmid": "27549339", "doi": "10.7554/eLife.16351", "url": "https://pubmed.ncbi.nlm.nih.gov/27549339/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID27549339", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C52", "CSC2", "CSC3" ] }, { "n": 53, "citation": "Miller RA, Harrison DE, Astle CM et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. 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Aging cell. 2016.", "tier": "A", "kind": "primary", "pmid": "26463117", "doi": "10.1111/acel.12405", "url": "https://pubmed.ncbi.nlm.nih.gov/26463117/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID26463117", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C55", "CSC1", "CSC3" ] } ], "independence_basis": { "required": false, "lines": [], "shared_failure_mode_checked": true, "note": "No clinical subclaim reaches Ζ. Mouse backgrounds/sites strengthen model confidence but do not create independent causal classes merely by separate reports or laboratories. Survey reanalyses, trial secondary reports and transcript assays share underlying allocations or measurements." }, "gamma_hard_rules_considered": [ { "subclaim_id": "SC1", "rule_quoted": "ROS change measurements alone", "trigger_status": "No ROS-onlyclinicalcrossingused." }, { "subclaim_id": "SC1", "rule_quoted": "NAD level change measurements alone", "trigger_status": "No NAD-onlyclinicalcrossingused." }, { "subclaim_id": "SC1", "rule_quoted": "Mitochondrial metrics alone", "trigger_status": "Mechanisticmarkers retain their scope, not clinicalfunctionproof." }, { "subclaim_id": "SC1", "rule_quoted": "Senescence marker changes alone", "trigger_status": "Olderhumanimmune p21 andtopicalp16 changes aremarker-levelclinicalinference, notphysicalfunction." }, { "subclaim_id": "SC1", "rule_quoted": "Single-species or single-strain evidence", "trigger_status": "Individualmodelscope retained; cross-species preclinical efficacy isnot falsely calledsingle-species evidence, nor humanproof." }, { "subclaim_id": "SC1", "rule_quoted": "Biomarker-only improvement without organismal benefit", "trigger_status": "Triggered only when molecular/body-composition shifts areoffered asregisteredhumanphysicalfunction." }, { "subclaim_id": "SC2", "rule_quoted": "ROS change measurements alone", "trigger_status": "Not triggered literally for this assembled scoped case. 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Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale." }, { "subclaim_id": "SC3", "rule_quoted": "Single-species or single-strain evidence", "trigger_status": "Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale." }, { "subclaim_id": "SC3", "rule_quoted": "Biomarker-only improvement without organismal benefit", "trigger_status": "Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale." }, { "subclaim_id": "SC4", "rule_quoted": "ROS change measurements alone", "trigger_status": "Not triggered literally for this assembled scoped case. 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Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale." } ], "supplementary_source_checks": [], "consensus_validation": { "completed": true, "status": "completed_original_source_reconciliation", "provider_mode": "Consensus Pro signed-in browser; observed output and citation link mappings", "queries": [ "https://consensus.app/search/intermittent-rapamycin-effects-aging/npYAPuOsTsiiYWqvevUzQw/" ], "query_record_note": "Exact provider question/response retained privately in its retrieval receipt.", "primary_comparison_count": 10, "primary_comparisons": [ { "pmid": "41985884", "doi": "10.1002/jcsm.70274", "source_type": "primary study report", "study_group": "ACTRN12624000790549", "access_depth": "full_text_partial", "consensus_aspect": "Functional primary result versus universal no-effect language", "result_comparison": "Consensus correctly gives the chair-stand estimate −2.13, P = 0.089 and per-protocol negative contrast. Its categorical headline that intermittent rapamycin does not improve function exceeds this 40-person 13-week exercise regimen. The original ITT result is negative-direction nonsignificance, with prespecified sensitivity attenuation; neither definitive equivalence nor every-dose ineffectiveness follows.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/41985884/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-0-10-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\41985884-s1-p0-8-9-10-11-14-15-16-17.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\41985884-s2-p3-4-5-7-9-10-13-14-16.json" ] }, { "pmid": "41985884", "doi": "10.1002/jcsm.70274", "source_type": "primary study report", "study_group": "ACTRN12624000790549", "access_depth": "full_text_partial", "consensus_aspect": "Adverse-event uncertainty and pneumonia attribution", "result_comparison": "Consensus says event burden was elevated and calls pneumonia drug-related. Original Results give 99 versus 63 events, IRR 1.57, 95% CI 0.86–2.87, P = 0.14. The single hospitalized pneumonia after one dose was possibly related, with causal contribution not excluded. We preserve the concern without turning an imprecise count or possible attribution into proven increased infection risk.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/41985884/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-0-10-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\41985884-s1-p0-8-9-10-11-14-15-16-17.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\41985884-s2-p3-4-5-7-9-10-13-14-16.json" ] }, { "pmid": "40188830", "doi": "10.18632/aging.206235", "source_type": "primary study report", "study_group": "NCT04488601", "access_depth": "full_text_partial", "consensus_aspect": "Primary hierarchy, functional outcomes and female subset", "result_comparison": "Consensus accurately identifies visceral-fat primary null and female lean mass/pain signals. Original Methods state SF36/WOMAC were not specific study endpoints. Actual Results analyzed 114 completers excluding 11 discontinuers; only eight women received 10 mg. WOMAC was null and emotional wellbeing improved within placebo too. Selected composition/survey findings are retained with small-subgroup, multiplicity and between-versus-within-arm limits.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/40188830/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-10-20-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\40188830-s1-p0-1-3-5-7-9-10-13.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\40188830-s3-p0-1-2-3-9-11-12.json" ] }, { "pmid": "40188830", "doi": "10.18632/aging.206235", "source_type": "primary study report", "study_group": "NCT04488601", "access_depth": "full_text_partial", "consensus_aspect": "Bioavailability measurement versus exact dose equivalence", "result_comparison": "Consensus translates compounded 5/10 mg into true circulating 1.65/3.3 mg weekly equivalents. Original PEARL says a separate assessment found approximately one-third the 24-hour blood concentration of commercial drug. A single concentration comparison is not verified AUC or clinical-effect bioequivalence. Nominal dose and actual exposure remain distinct; exact interchangeable milligram claims are not carried.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/40188830/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-10-20-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\40188830-s1-p0-1-3-5-7-9-10-13.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\40188830-s3-p0-1-2-3-9-11-12.json" ] }, { "pmid": "29408453", "doi": "10.1016/j.exger.2017.12.026", "source_type": "primary study report", "study_group": "NCT02874924", "access_depth": "full_text_partial", "consensus_aspect": "Daily pilot duration, denominators and concentration", "result_comparison": "Consensus treats Kraig as eight-week daily dosing and cites 6.1–8.2 ng/mL. Actual Methods include an initial eight-person planned four-month phase and 20-person eight-week phase;28 enrolled and 25 ≥8-week completers. The cited concentrations are phase 1 maxima, while the Results report wider individual levels. Daily/short pilot function null does not become the registered 12–104 week intermittent trial or universal safety result.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/29408453/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-0-10-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\29408453-s1-p0-1-2-3-4-10.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\29408453-s2-p0-1-3-5-6-8-9-10.json" ] }, { "pmid": "40704394", "doi": "10.1111/acel.70183", "source_type": "primary study report", "study_group": "PMID40704394", "access_depth": "abstract_metadata", "consensus_aspect": "Mouse exercise-adaptation direction and clinical transfer", "result_comparison": "Consensus cites Elliehausen 2025 for the assertion that intermittent mTOR inhibition impedes muscular adaptations. The selected original explicitly found preserved exercise capacity, grip and hypertrophy in adult female mice under weekly/frequent schedules, while glucose tolerance worsened. We retain both findings and reject the wrong-direction transfer to human training impairment. Acute human 19188252 protein-synthesis suppression is a different original and endpoint.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/40704394/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-10-20-10000.json" ], "body_receipts": [] }, { "pmid": "33977284", "doi": "10.1016/S2666-7568(21)00062-3", "source_type": "primary study report", "study_group": "PMID33977284", "access_depth": "abstract_metadata", "consensus_aspect": "Contradictory immune clinical evidence", "result_comparison": "Consensus summarizes vaccine/infection benefits using review-mediated citations. Our selected originals preserve those positives and also the later RTB101 phase III clinical-illness null despite antiviral gene upregulation. Phase 2b first-comparison failure and pooled laboratory-infection positive remain distinct. Immune effects cannot be treated as uniformly positive or as weekly rapamycin physical-function/survival proof.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/33977284/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-46-49-10000.json" ], "body_receipts": [] }, { "pmid": "19587680", "doi": "10.1038/nature08221", "source_type": "primary study report", "study_group": "PMID19587680", "access_depth": "abstract_metadata", "consensus_aspect": "Animal longevity validity and translation", "result_comparison": "Consensus correctly acknowledges preclinical longevity/function. Actual late-life heterogeneous-mouse original extends survival across sites and both sexes; further originals map dose, sex and healthspan-survival dissociations. These are real restricted causal results. Neither a human functional null erases them nor do they establish human intermittent physical benefit.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/19587680/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-10-20-10000.json" ], "body_receipts": [] }, { "pmid": "41985884", "doi": "10.1002/jcsm.70274", "source_type": "primary study report", "study_group": "ACTRN12624000790549", "access_depth": "full_text_partial", "consensus_aspect": "Provider washout requirement is unsupported", "result_comparison": "Consensus claims 3–6 week washouts are required to clear a 62-hour half-life and prevent anabolic interference. This is not an established treatment schedule from the original. RAPA-EX tested weekly dosing around exercise; its results motivate prospective timing/dose experiments without proving a required washout duration. No dosing advice or unsupported requirement is copied into the review.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/41985884/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-0-10-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\41985884-s1-p0-8-9-10-11-14-15-16-17.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\body-presentation-receipts\\41985884-s2-p3-4-5-7-9-10-13-14-16.json" ] }, { "pmid": "38956196", "doi": "10.1038/s41591-024-03096-2", "source_type": "primary study report", "study_group": "NCT04313634", "access_depth": "abstract_metadata", "consensus_aspect": "Provider coverage is not a primary evidence count", "result_comparison": "Consensus matrices include review/protocol-mediated counts across regimens. Our independently selected senolytic originals show different pathways and endpoint limits: postmenopausal primary CTx null, exploratory subset/early markers, and controlled IPF functional null. Provider paper counts are discovery indicators, not examined originals, independent studies or evidence that senolytics reproduce a proven rapamycin benefit.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/38956196/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\examinations\\original-0-10-10000.json" ], "body_receipts": [] } ], "grade_changed": false, "grade_change_note": "Source-based adjudication; no independent blinded regrade claimed.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\rapamycin-human-healthspan\\consensus-browser-2026-10-13.json", "sha256": "8b6cbc52045e016189f06c7c59d9bd92f7249254047497d77ed025d079cdad48" } ], "independent_blinded_audit": false, "cutoff": "2026-10-13", "completed_utc": "2026-10-13T17:35:01.519453+00:00", "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them." } }