In plain terms

The claim being assessed: Intermittent low-dose oral rapamycin improves physical function in otherwise healthy adults aged 50 and older.

Where the evidence stands: Γ — Plausible mechanism. There is a believable biological story and partial support, but the causal step has not been demonstrated.

What this mechanism does: The evidence reviewed does not show this mechanism causing the outcome. That does not show it has no effect.

Strongest evidence for it: 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.

What decisive evidence would look like

In plain terms, researchers would change the proposed cause, confirm it changed as intended, and measure a meaningful health outcome while checking other explanations. The result should be able to support or count against the claim.

Relative explanatory fit: Alternative ranked ahead

What this review means

Rapamycin has strong animal longevity evidence, but intermittent dosing has not yet established improved physical function in otherwise healthy older adults.

Implications for health and treatment: Preregistered primary-subclaim aggregation returns SC2Γ. 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.

Limits for individual care: 55 primary reports with 3 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness. The grade applies to the exact registered claim; stronger findings for narrower subclaims remain separate. No complete-paper audit or blinded calibration is claimed. This educational review does not establish an individual treatment recommendation.

Medical information notice: This review provides general health information, not medical advice. It cannot diagnose a condition or replace an individual discussion with a qualified clinician.

Source checking used bounded original primary abstract passages/status records and selected original partial-body passages. No complete-abstract or complete-paper audit, or independent scientific peer review, is claimed. Detailed access counts and limitations appear in the review.

A low grade is not an accusation. It means the causal work has not been done yet, which is the ordinary state of most actively studied mechanisms in biology.

At a glance

Sub-claims assessed separately

Full assessment

From here the review is written for a technical reader: caps and thresholds, competing models, the independence basis, and the citation ledger.

Sources: 55 primary reports; claims: 60; verified: 60; unverified: 0. Verification is bounded attribution. Access: 3 partial-body and 52 bounded abstract/status examinations. Literature cutoff: 2026-10-13; source examination UTC date: 2026-10-13. No complete-paper audit or blinded calibration claimed. Adversarial review: Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-14. 3 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: Approved as revised.

AT A GLANCE

Rapamycin has strong animal longevity evidence, but intermittent dosing has not yet established improved physical function in otherwise healthy older adults.

Deciding 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.

Belief versus evidence: 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.

Best-supported rival: Animal regimen and context determine real benefit. 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.

COMPETING MECHANISTIC MODELS

Rank 1: Animal regimen and context determine real benefit (Ε). Rapamycin causes lifespan and selected health/function benefits in defined model contexts; translation to intermittent human function remains separate. 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 2: Target and immune effects differ from generalized healthspan (Δ). Defined mTOR interventions can change immune phenotypes or specific infection risk without establishing healthy-human physical benefit. 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 3: Intermittent mTOR modulation improves older-human function (Γ). Weekly low-dose oral rapamycin causes sustained physical-function improvement in otherwise healthy older adults. 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 4: Senolytics have separate clinical scope (Γ). Senescent-cell targeting may benefit defined conditions through another mechanism, without reproducing an established rapamycin benefit. 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.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

FULL REVIEW

Registered claim and scope

Intermittent low-dose oral rapamycin improves physical function in otherwise healthy adults aged 50 and older.

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.

Selection: position 22 in the registered editorial traffic-priority list; registration timestamp 2026-10-13T16:06:25.734540+00:00. Ranked editorial traffic priority rather than measured global popularity or a preset verdict. Registered claim assessed against original sources; no independent blinded calibration is claimed.

Evidence and causal interpretation

Rubric fit: 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.

The lead proposition is precise: intermittent low-dose oral rapamycin improves physical function in otherwise healthy adults aged 50 or older over 12–104 weeks. It is not an omnibus grade for allmTOR biology, animal longevity, immune effects or every senolytic drug. Baseline disease, activity, formulation and endpoints are specified before interpreting outcomes.

RAPA-EX is the closest direct functional test. Forty sedentary adults aged 65–85 adopted a matched home exercise program and received commercial Rapamune 6 mg weekly or placebo for 13 weeks. Original Methods include concealed allocation, ITT multiple imputation and prespecified complete-case/per-protocol analyses. The primary chair-stand estimate favored placebo with P = 0.089; sensitivity contrasts were significantly negative. Secondary walking, grip and functional scales did not show benefit. This does not support efficacy, while the small trial and setting prevent universal all-dose harm or absence claims.

RAPA-EX safety signals also need precision. At least one adverse event occurred in 85% of each arm. Total events were 99 versus 63, with IRR 1.57, 95% CI 0.86–2.87, P = 0.14. One pneumonia after a single dose was considered possibly related. A higher numerical event count is not a definitive infection-risk estimate or proof that every intermittent regimen is unsafe.

PEARL has a different endpoint hierarchy. Original Methods designate visceral fat as primary and composition/blood measures as secondary; surveys were not specific study endpoints. The analysis included 114 completers and excluded 11 discontinuers. Only eight women were in the 10 mg group. Visceral fat was null; female lean mass and pain signals remain small-stratum exploratory findings. WOMAC was null, and emotional wellbeing improved within both 5 mg and placebo groups. Within-arm significance cannot substitute for between-group efficacy.

PEARL formulation matters. The trial paused for a separate bioavailability assessment, which found compounded drug had about one-third the 24-hour blood concentration of the commercial formulation. Nominal milligrams cannot silently become equal exposure. This uncertainty narrows interpretation of both positive and null results; it does not justify defining responsive doses after outcomes.

The Kraig pilot actually enrolled 28 participants across two phases, with 25 completing at least eight weeks. Dosing was 1 mg daily, with an initial planned four-month phase and a second eight-week phase. Handgrip, walking and cognition did not improve; several erythrocyte measures declined. The TREG within-arm P = 0.008 did not survive the between-arm comparison P = 0.13. These screened small-cohort observations cannot establish long-term safety or weekly functional benefit.

Human immune studies contain genuine restricted positives. RAD001 improved vaccine response, and a low-dose combination phase 2a trial reported fewer infections. Later RTB101 phase 2b/3 work preserves the analysis hierarchy: the first combination comparison failed, a prespecified pooled analysis found a laboratory-confirmed infection reduction, and phase III clinical illness was null despite antiviral gene upregulation. Different agents and endpoint definitions cannot be relabeled weekly rapamycin physical function or general slowing of human aging.

Preclinical rapamycin evidence is strong within its actual scope. Late-life heterogeneous-mouse lifespan extension across sites and C57BL/6 stride/rotarod benefits are retained. Other models dissociate healthspan from lifespan or inflammation, and show sex, genetic, developmental and metabolic boundaries. Valid animal causality is not erased by uncertain human translation; it also does not prove the human claim.

Additional originals refine that translation. Intermittent late-life female-mouse treatment 27091134 extends survival. Transient treatment 27549339 has persistent benefits alongside a female dose without extension and with an altered tumor spectrum. Neff 23863708 increased lifespan while improving few aging traits, many of which also changed in young animals. Dose/sex-dependent heterogeneous-mouse survival 24341993 is genuine. Acute human contraction work 19188252 suppresses early protein synthesis, motivating timing studies without proving chronic harm from every weekly regimen.

Senolytics are a separate companion. Open-label IPF function improvement motivated a randomized pilot whose functional comparisons did not meaningfully differ. Postmenopausal D+Q had a primary CTx null with transient secondary/exploratory subset findings. Human kidney-disease markers and Alzheimer feasibility/penetrance findings do not demonstrate healthy physical function. Models contain causal benefits and negative acute-injury contexts. Reducedp16 alone cannot establish all-cell clearance or global rejuvenation.

Γ retains partial mechanistic and exploratory clinical support while reporting the direct functional negative. It does not mean that every rapamycin effect is disproven or that off-label treatment is recommended. A completed, independently corroborated physical-function experiment with verified exposure, prespecified endpoints and benefit-harm capture is needed to move the positive claim upward.

HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

Subclaim matrix and aggregation

Preregistered aggregation: primary-subclaim. 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. Sensitivities: weakest-link Α; primary-subclaim Γ; scope-matched Γ.

Decisive-perturbation inventory and causal tally

[1] 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.

[3] 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.

[4] 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.

[6] 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.

[7] 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.

[8] 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.

[11] 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.

[15] 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.

[23] nfκb1 deficientmice hadimprovedfrailty/memory/coordination/tissuehealth withrapamycin butnolifespan/inflammagingbenefit. Specificaccelerated-inflammationmodel; healthspan/survivaldissociationexcludesinflammationasassumednecessarybridge. Nothealthyhumanweeklyfunction.

[26] Human T cell genotoxic stress work shows lesional burden/senescencereduction; placebo-controlledolderadultlow-doserapamycin reducesimmune-cellp21. Mixedcell/humanmechanisticdesign; senescencemarkers and DNAresilience notobjectivephysicalfunctionoragingtrajectory. Actualdose/scheduleandtrialoverlapneed Methodscheck.

[28] Late-life C57BL/6 feedingrapamycin improvedsurvival, stride/rotarod andselectedlesions; targetinhibitionandtissue/sexresponsesvary, spontaneousactivitynull. Restrictedmousebackground, dailyfeeding andmultipleendpoints; notweeklyhumanfunction. No observedadverseconsequences heredoesn'teraseharmotherregimens.

[30] 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.

[32] Senescentcelltransfer inducedphysicaldysfunction inmice; intermittent D+Q intransferred andnaturallyagedmice improvedfunction andpost-treatment survival; humanadiposeexplantmarkersreduced. Forcedcelltransfer separatefromendogenousaging; oldmousepharmacologystrongrestrictedcontext butnotrapamycinorhumanfunction. Explantsnotclinicaloutcomes.

[44] D+Qpretreatment inacute FANmousekidneyinjury didnotpreservecreatinine/BUN andworsenedselecteddamage/SASPgenes withoutreducingp21 positivecells. Specificacuteinjurynot CKDorhealthyaging; markerharmdoesn'tshoweveryclinicalregimenharm. Importantnegativecontexts retainedratherthanall-senolyticsbeneficialassumption.

[47] 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.

[48] 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.

[50] Comprehensive male C57BL/6J evaluation found increasedlifespan withfewagingphenotypesimproved; manyrescuedtraits changed similarly inyoungmice. Aging-independentphenotypiceffectnotnecessarilyagingdelay; onebackground/sex doesn'teraseotherfunctionalpositives. Importantlifespan-healthspanseparation nothumanweeklyclinicaltest.

[51] 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.

[52] 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.

[53] Heterogeneousmousehigherdietarydose extendsmedianlifespan 23% male 26% female, maximallifespanalso; sex/dose effects andmetabolicdistinctionfromdietrestriction. Animaldietarylifespanvaliditynotregisteredclinicalphysicalfunction. ITPdose-study/histologyfamily mayoverlap 22587563;replicationdoesnotbyitselfcreateindependentcausalclasses.

[54] Acutehumanrapamycin beforecontractionblocks ~40% earlymuscleproteinsynthesisincrease andselectedmTORC1/ERKpathwayresponses. Acuteanabolicphysiology notweekly≥50 longtermfunctionalharm; age/dose mustnotbeassumedfromabstract. Itmotivatestiminginteractionchecks, notproofallintermittentregimensabolishadaptation.

Tally: 0 positive qualifying study units across scoped subclaims; 29 screened discriminating contrast units. These are not independent causal lines or proof of full-claim necessity/sufficiency. 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.

No positive field-valid crossing was verified for the registered causal scope in this bounded audit. Pivotal null or negative tests remain informative; their implications depend on comparator quality, target engagement, power and the registered scope.

Cap audit, precedence and Β/Γ/Δ boundary

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.

Universal six-cap audit: All six universal caps were considered: cell-only inference, unperturbed association, ectopic expression, biomarker-only intervention, forced transfer/seeding, and inherited-to-sporadic scope transfer. Each binds its offered inference; complementary same-scope causal classes are assessed together rather than re-capped in isolation.

Gamma hard-rule audit: 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.

SC1 cap: “Biomarker change without functional/phenotypic change caps at Γ.” 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.

SC1 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. 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.

SC2 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. 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.

SC3 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. 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.

SC4 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. 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.

SC1 applied rubric adaptation (distinct from the unchanged literal criterion): mTOR-related molecular response does not prove functional benefit; a measured drug concentration is exposure, not target-specific engagement or aging reversal.

SC2 applied rubric adaptation (distinct from the unchanged literal criterion): 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.

SC3 applied rubric adaptation (distinct from the unchanged literal criterion): Restricted immune clinical benefit and model survival must not be relabeled global slowing of human aging; acknowledge organismal positives while testing translation.

SC4 applied rubric adaptation (distinct from the unchanged literal criterion): Clinical senolytic trials retain their own diagnoses, agents and outcomes; equivalence to rapamycin requires direct matched evidence and an established comparator benefit.

SC1 literal Γ hard rule: “ROS change measurements alone” No ROS-onlyclinicalcrossingused.

SC1 literal Γ hard rule: “NAD level change measurements alone” No NAD-onlyclinicalcrossingused.

SC1 literal Γ hard rule: “Mitochondrial metrics alone” Mechanisticmarkers retain their scope, not clinicalfunctionproof.

SC1 literal Γ hard rule: “Senescence marker changes alone” Olderhumanimmune p21 andtopicalp16 changes aremarker-levelclinicalinference, notphysicalfunction.

SC1 literal Γ hard rule: “Single-species or single-strain evidence” Individualmodelscope retained; cross-species preclinical efficacy isnot falsely calledsingle-species evidence, nor humanproof.

SC1 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Triggered only when molecular/body-composition shifts areoffered asregisteredhumanphysicalfunction.

SC2 literal Γ hard rule: “ROS change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “NAD level change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Mitochondrial metrics alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Senescence marker changes alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Single-species or single-strain evidence” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “ROS change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “NAD level change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Mitochondrial metrics alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Senescence marker changes alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Single-species or single-strain evidence” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “ROS change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “NAD level change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Mitochondrial metrics alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Senescence marker changes alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Single-species or single-strain evidence” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

Upward threshold ladder

SC1 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: no. Prespecified intermittent older-human target-specific pharmacodynamics, with dose/time/assay controls and clinical phenotype linkage tested separately.

SC2 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: no. 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.

SC3 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: no. Independent controlled human clinical aging-trajectory or hard healthspan/survival effects; immune/animal-marker mediation must be tested rather than assumed.

SC4 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: no. Controlled agent- and disease-specific senolytic functional benefit plus direct comparative evidence; do not assume an established rapamycin reference benefit.

Upper ladder: 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.

Independence: 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.

Falsification and pitfalls

Pathway manipulation changes markers but not the registered phenotype. 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. Additional downgrade: False.

Relevant intervention does not improve function. 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. Additional downgrade: False.

Confirmation by biomarker. Lean mass, immune genes, p21,DNA clocks orautophagy becomeclinicalfunction/humansurvival proof.

Selective generalization. Mouse/dog/cell, topicalskin, dailytransplantdose orspecificinfectionresultsbecomehealthyweeklyolder-humanbenefit.

Missing-control interpretation. Within-arm SF36/TREG significance is mistaken for between-group benefit; open-label D+Qfunctionbecomescontrolledtherapy.

Negative field-valid perturbation read as a crossed threshold. Direct RAPA-EX andsenolyticfunctionalnulls arecounted aspositivecausal units.

Mechanism conflation. mTOR senomorphic, senolyticclearance andsenescentcellmarkers aretreatedasoneclinicalintervention.

Scope may not be defined by the outcome. Smallfemale 10 mg PEARLsignal orposthocp16 senolyticresponders redefineenrolledclinicalscopeafterresults.

Adversarial steelman: above, then below

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.

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.

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.

Final score, causal direction and M/S/D

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.

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.

Momentum: Mechanistic only. 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: Stable. 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: Contested. No manufactured field consensus or arithmetic gap. These dimensions do not change level or confidence.

PROPOSED DECISIVE EXPERIMENTS

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. Controls: 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: Clinically meaningful function improves versus placebo across a prespecified context with supported target specificity and an acceptable benefit-harm profile. Falsifying: 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

Independent positive healthy-older-human functional evidence with registered endpoints and longer follow-up.

Drug timing relative to training and dose-specific anabolic/metabolic tradeoffs in a prespecified factorial experiment.

Compounded/commercial bioequivalence and measured target responses before interpreting nominal PEARL doses.

Multiplicity, small sex strata and missing-data interpretation of PEARL exploratory signals.

Human aging trajectory and survival separate from vaccine, antiviral genes, infection, mouse tumor delay and clocks.

Long-term and uncommon infection/metabolic/wound risks; selected surveys or short screened trials cannot establish universal safety.

Controlled senolytic disease/agent-specific functional evidence, target-cell identity and independent replication.

REVIEWER NOTES

Fifty-five original reports were actually examined in complete abstract/status presentation, plus selected original Methods/Results from three clinical papers. Thirty-six reports address rapamycin/mTOR exposures, clinical endpoints or mechanistic/animal translation; nineteen address distinct senolytic clinical/mechanistic comparators. The research-summary/punctum 39212197 was excluded and replaced by verified primary 39117797. Most complete papers/supplements were not audited; secondary trial/survey reports are grouped. No exhaustive systematic synthesis, fresh blind calibration, independent scientific peer review or rendered video is claimed.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

Consensus and original-source reconciliation

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 PMID41985884.

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 PMID41985884.

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 PMID40188830.

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 PMID40188830.

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 PMID29408453.

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 PMID40704394.

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 PMID33977284.

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 PMID19587680.

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 PMID41985884.

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 PMID38956196.

Consensus was used to identify literature and cross-check specific claims about design, endpoints, scope and research gaps. Those aspects were checked against original primary abstracts/status records and selected original Methods/Results passages. Consensus output was not treated as original full text. Provider search omissions are not evidence that a study does not exist. Source access and examination receipts are retained. Scite use or monthly unavailability is recorded per case; provider citation counts do not change causal grades.

Research timeline and gaps: Rapamycin and Human Healthspan

Selected publication milestones, not an exhaustive history or discovery priority claim.

2009 — Late-life heterogeneous-mouse survival extension establishes genuine mammalian intervention efficacy. Original PMID19587680.

2009 — Acute human contraction study shows suppressed early muscle protein synthesis, motivating regimen/timing tradeoffs. Original PMID19188252.

2012 — Mouse tissue/activity benefits coexist with cataract and testicular effects, separating benefit-harm by phenotype. Original PMID22587563.

2013 — Comprehensive mouse assessment finds lifespan extension with limited aging-trait changes and aging-independent responses. Original PMID23863708.

2014 — Dose and sex modify heterogeneous-mouse longevity; dietary restriction is not the same metabolic intervention. Original PMID24341993.

2014 — Human RAD001 vaccine response positive provides an immune-specific translational signal. Original PMID25540326.

2014 — Late-life C57BL/6 function/survival positives retain tissue and sex distinctions. Original PMID23682161.

2016 — Alternative mouse schedules/rapalogs reduce selected daily-treatment metabolic/immune adverse effects. Original PMID26463117.

2016 — Late-life intermittent female-mouse treatment extends survival without establishing human functional equivalence. Original PMID27091134.

2016 — Transient mouse exposure produces persistent effects with a dose/sex tumor-spectrum boundary. Original PMID27549339.

2016 — Old selected low-capacity-runner rats show grip and running effects, adding a functional model context. Original PMID26997106.

2018 — Older-human daily pilot finds no grip/walking or cognition benefit with selected hematological changes. Original PMID29408453.

2018 — Short human TORC1 combination trial reports immune and infection positives in a defined context. Original PMID29997249.

2018 — Senescent-cell transfer and intermittent senolytics show mouse physical/survival effects and human-explant marker changes. Original PMID29988130.

2019 — Open-label IPFsenolytic functional signal motivates controlled testing rather than established clinical efficacy. Original PMID30616998.

2019 — Small open-label kidney-disease D+Qtrial reduces tissue markers without proving healthy human physical function. Original PMID31542391.

2019 — Topical human skin trial shows markers/appearance effects with high attrition and different exposure scope. Original PMID31761958.

2021 — Later mTOR-inhibitor phase III clinical illness is null despite target gene effects; endpoint definitions matter. Original PMID33977284.

2023 — Randomized IPFpilot supports feasibility but lacks meaningful functional superiority and is underpowered. Original PMID36857968.

2024 — Postmenopausal senolytic primary bone-resorption null coexists with early/exploratory signals. Original PMID38956196.

2025 — Female mouse exercise adaptations are preserved while glucose effects worsen, preventing wrong-direction blanket inference. Original PMID40704394.

2025 — PEARL 48-week primary visceral-fat null and small female composition/pain signals expose endpoint/exposure limits. Original PMID40188830.

2026 — Direct 13-week weekly rapamycin exercise trial is functional primary-null with negative sensitivity contrasts. Original PMID41985884.

2026 — Older-human immune marker/genoprotection experiments provide mechanism evidence separate from physical function. Original PMID41524558.

Research gaps

Independent positive healthy-older-human functional evidence with registered endpoints and longer follow-up.

Drug timing relative to training and dose-specific anabolic/metabolic tradeoffs in a prespecified factorial experiment.

Compounded/commercial bioequivalence and measured target responses before interpreting nominal PEARL doses.

Multiplicity, small sex strata and missing-data interpretation of PEARL exploratory signals.

Human aging trajectory and survival separate from vaccine, antiviral genes, infection, mouse tumor delay and clocks.

Long-term and uncommon infection/metabolic/wound risks; selected surveys or short screened trials cannot establish universal safety.

Controlled senolytic disease/agent-specific functional evidence, target-cell identity and independent replication.

Boundary 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.

ADVERSARIAL REVIEW AND APPROVAL

Authoring model: Sol 6.1. Adversarial reviewer: Claude Opus 5.5 (Anthropic). Date: 2026-10-14.

Scope of checks. All 55 REFERENCES PMIDs verified against PubMed metadata (55/55 resolve to the stated title, first author and journal; no retraction or expression-of-concern notice attached to any retained source; the excluded punctum 39212197 was also checked and is correctly identified as a research-summary record). Twelve load-bearing claims spot-checked against original abstracts (PMIDs 41985884, 40188830, 29408453, 33977284, 19587680, 24341993, 23682161, 25540326, 29997249, 30468013, 36857968, 19188252). Scoring logic checked against references/hsef-framework.md: hard caps before aggregation, declared primary-subclaim aggregation, scope-matched and weakest-link sensitivities, Ζ independence basis, Β/Γ/Δ boundary, confidence-band text, role-of-mechanism derivation order, and the four known upstream builder defects.

Rejected findings (checked, no change).

1. Reference years differing by one from the PubMed publication-date year (PMIDs 30468013, 23682161, 26657143, 38062873, 26463117) — print/issue versus e-pub year; rejected by convention.
2. "Best-supported rival" field — checked against the score card: the named model M3 has is_nominal: false and rank_in_tournament: 1, so this review does not carry the renderer defect that prints the nominal model as the rival. No change.
3. The Kraig pilot's "28 participants enrolled, 25 completing at least eight weeks" — the abstract states 25 adults with three withdrawals and 11 + 14 completers; 28 enrolled and 25 completers is the arithmetically consistent body reading, and the review states it is taken from the original Methods. No change.
4. Momentum "Mechanistic only" — correct value, and the artifact text explains why the completed PEARL and RAPA-EX reports are not evidence of work underway rather than reciting boilerplate.
5. Role of mechanism epiphenomenon — derivation step 2 correctly applied to the endpoint-specific proposition and explicitly not taken from tournament rank.
6. Primary-subclaim aggregation returning Γ from SC2 — SC2 is the scope-matched subclaim; the scope-matched sensitivity also returns Γ, and the Ε- and Δ-level entries in the tournament are rival models, not subclaims, so they cannot set the headline.
7. Pitfall where fields phrased as the failure mode ("markers become proof") rather than as a guard — house-style variation in a free-text field, defensible once the spacing is repaired.
8. Collective-author rendering defect — no reference in this list has a consortium first author.
9. False-approval boilerplate ("the earlier adversarial approval refers to its original edition") — string absent from this package.
10. Empty DOI: . fields and "PMIDnot supplied" erratum strings — none found.

Residual limitations. Access remains bounded: 3 partial-body and 52 abstract/status examinations. The residual glued prose noted in finding 1 needs an authoring-side regeneration. PEARL's compounded-formulation exposure uncertainty is correctly flagged but unresolved, so its null and its exploratory positives both remain weakly interpretable. RAPA-EX is a 40-participant 13-week exploratory trial; the review is right that it neither establishes benefit nor excludes it for other doses or horizons.

Approval: Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-14.

REFERENCES

1. 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. PMID 41985884. DOI: 10.1002/jcsm.70274. Access: full_text_partial. Study: ACTRN12624000790549.

2. 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. PMID 26997106. DOI: 10.18632/aging.100929. Access: abstract_metadata. Study: PMID26997106.

3. 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. PMID 29408453. DOI: 10.1016/j.exger.2017.12.026. Access: full_text_partial. Study: NCT02874924.

4. Mannick JB, Morris M, Hockey HP et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Science translational medicine. 2018. PMID 29997249. DOI: 10.1126/scitranslmed.aaq1564. Access: abstract_metadata. Study: PMID29997249.

5. 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. PMID 27341957. DOI: 10.3402/pba.v6.31793. Access: abstract_metadata. Study: PMID27341957.

6. 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. PMID 38956196. DOI: 10.1038/s41591-024-03096-2. Access: abstract_metadata. Study: NCT04313634.

7. 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. PMID 30616998. DOI: 10.1016/j.ebiom.2018.12.052. Access: abstract_metadata. Study: NCT02874989-openlabel-cohort.

8. Nambiar A, Kellogg D, Justice J et al. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine. 2023. PMID 36857968. DOI: 10.1016/j.ebiom.2023.104481. Access: abstract_metadata. Study: NCT02874989-randomized-cohort.

9. Farr JN, Monroe DG, Atkinson EJ et al. Characterization of Human Senescent Cell Biomarkers for Clinical Trials. Aging cell. 2025. PMID 39823170. DOI: 10.1111/acel.14489. Access: abstract_metadata. Study: NCT04313634.

10. Yousefzadeh MJ, Flores RR, Zhu Y et al. An aged immune system drives senescence and ageing of solid organs. Nature. 2021. PMID 33981041. DOI: 10.1038/s41586-021-03547-7. Access: abstract_metadata. Study: PMID33981041.

11. Harrison DE, Strong R, Sharp ZD et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009. PMID 19587680. DOI: 10.1038/nature08221. Access: abstract_metadata. Study: PMID19587680.

12. Kaeberlein TL, Green AS, Haddad G et al. Evaluation of off-label rapamycin use to promote healthspan in 333 adults. GeroScience. 2023. PMID 37191826. DOI: 10.1007/s11357-023-00818-1. Access: abstract_metadata. Study: off-label 333-survey.

13. Chung CL, Lawrence I, Hoffman M et al. Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. GeroScience. 2019. PMID 31761958. DOI: 10.1007/s11357-019-00113-y. Access: abstract_metadata. Study: PMID31761958.

14. Gkioni L, Nespital T, Baghdadi M et al. The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan. Nature aging. 2025. PMID 40437307. DOI: 10.1038/s43587-025-00876-4. Access: abstract_metadata. Study: PMID40437307.

15. Moel M, Harinath G, Lee V et al. Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results. Aging. 2025. PMID 40188830. DOI: 10.18632/aging.206235. Access: full_text_partial. Study: NCT04488601.

16. Elliehausen CJ, Olszewski SS, Minton DM et al. Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice. Aging cell. 2025. PMID 40704394. DOI: 10.1111/acel.70183. Access: abstract_metadata. Study: PMID40704394.

17. Wassarman DR, Bankapalli K, Pallanck LJ et al. Tissue-restricted inhibition of mTOR using chemical genetics. Proceedings of the National Academy of Sciences of the United States of America. 2022. PMID 36095197. DOI: 10.1073/pnas.2204083119. Access: abstract_metadata. Study: PMID36095197.

18. Wahl D, Cavalier AN, Smith M et al. Healthy Aging Interventions Reduce Repetitive Element Transcripts. The journals of gerontology. Series A, Biological sciences and medical sciences. 2021. PMID 33257951. DOI: 10.1093/gerona/glaa302. Access: abstract_metadata. Study: PMID33257951.

19. Wilkinson JE, Burmeister L, Brooks SV et al. Rapamycin slows aging in mice. Aging cell. 2012. PMID 22587563. DOI: 10.1111/j.1474-9726.2012.00832.x. Access: abstract_metadata. Study: PMID22587563.

20. Zhang P, Catterson JH, Grönke S et al. Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system. Nature aging. 2024. PMID 38413780. DOI: 10.1038/s43587-024-00578-3. Access: abstract_metadata. Study: PMID38413780.

21. An JY, Kerns KA, Ouellette A et al. Rapamycin rejuvenates oral health in aging mice. eLife. 2020. PMID 32342860. DOI: 10.7554/eLife.54318. Access: abstract_metadata. Study: PMID32342860.

22. Ibrahim R, Bahilo Martinez M, Dobson AJ. Rapamycin's lifespan effect is modulated by mito-nuclear epistasis in Drosophila. Aging cell. 2024. PMID 39225061. DOI: 10.1111/acel.14328. Access: abstract_metadata. Study: PMID39225061.

23. Correia-Melo C, Birch J, Fielder E et al. Rapamycin improves healthspan but not inflammaging in nfκb1-/- mice. Aging cell. 2019. PMID 30468013. DOI: 10.1111/acel.12882. Access: abstract_metadata. Study: PMID30468013.

24. Landis GN, Baybutt B, Das S et al. Mifepristone and rapamycin have non-additive benefits for life span in mated female Drosophila. Fly. 2024. PMID 39440794. DOI: 10.1080/19336934.2024.2419151. Access: abstract_metadata. Study: PMID39440794.

25. Tang Y, Yang S, Qiu Z et al. Rapamycin Attenuates H2O2-Induced Oxidative Stress-Related Senescence in Human Skin Fibroblasts. Tissue engineering and regenerative medicine. 2024. PMID 39093548. DOI: 10.1007/s13770-024-00660-2. Access: abstract_metadata. Study: PMID39093548.

26. Kell L, Jones EJ, Gharahdaghi N et al. Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage. Aging cell. 2026. PMID 41524558. DOI: 10.1111/acel.70364. Access: abstract_metadata. Study: PMID41524558.

27. Hudson J, Kaeberlein T, Mahal A et al. Evaluation of off-label rapamycin use on oral health. GeroScience. 2024. PMID 38839644. DOI: 10.1007/s11357-024-01221-0. Access: abstract_metadata. Study: off-label 333-survey.

28. Zhang Y, Bokov A, Gelfond J et al. Rapamycin extends life and health in C57BL/6 mice. The journals of gerontology. Series A, Biological sciences and medical sciences. 2014. PMID 23682161. DOI: 10.1093/gerona/glt056. Access: abstract_metadata. Study: PMID23682161.

29. Fan X, Liang Q, Lian T et al. Rapamycin preserves gut homeostasis during Drosophila aging. Oncotarget. 2015. PMID 26431326. DOI: 10.18632/oncotarget.5895. Access: abstract_metadata. Study: PMID26431326.

30. Hickson LJ, Langhi Prata LGP, Bobart SA et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019. PMID 31542391. DOI: 10.1016/j.ebiom.2019.08.069. Access: abstract_metadata. Study: PMID31542391.

31. Yousefzadeh MJ, Zhu Y, McGowan SJ et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018. PMID 30279143. DOI: 10.1016/j.ebiom.2018.09.015. Access: abstract_metadata. Study: PMID30279143.

32. Xu M, Pirtskhalava T, Farr JN et al. Senolytics improve physical function and increase lifespan in old age. Nature medicine. 2018. PMID 29988130. DOI: 10.1038/s41591-018-0092-9. Access: abstract_metadata. Study: PMID29988130.

33. Palmer AK, Xu M, Zhu Y et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging cell. 2019. PMID 30907060. DOI: 10.1111/acel.12950. Access: abstract_metadata. Study: PMID30907060.

34. Victorelli S, Lagnado A, Halim J et al. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. The EMBO journal. 2019. PMID 31633821. DOI: 10.15252/embj.2019101982. Access: abstract_metadata. Study: PMID31633821.

35. Chang J, Wang Y, Shao L et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature medicine. 2016. PMID 26657143. DOI: 10.1038/nm.4010. Access: abstract_metadata. Study: PMID26657143.

36. Islam MT, Tuday E, Allen S et al. Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. Aging cell. 2023. PMID 36637079. DOI: 10.1111/acel.13767. Access: abstract_metadata. Study: PMID36637079.

37. Amor C, Fernández-Maestre I, Chowdhury S et al. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nature aging. 2024. PMID 38267706. DOI: 10.1038/s43587-023-00560-5. Access: abstract_metadata. Study: PMID38267706.

38. Gonzales MM, Garbarino VR, Kautz TF et al. Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. Nature medicine. 2023. PMID 37679434. DOI: 10.1038/s41591-023-02543-w. Access: abstract_metadata. Study: PMID37679434.

39. Ogrodnik M, Evans SA, Fielder E et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging cell. 2021. PMID 33470505. DOI: 10.1111/acel.13296. Access: abstract_metadata. Study: PMID33470505.

40. Mahoney SA, Venkatasubramanian R, Darrah MA et al. Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence. Aging cell. 2024. PMID 38062873. DOI: 10.1111/acel.14060. Access: abstract_metadata. Study: PMID38062873.

41. Liu Y, Liu X, Chen X et al. Senolytic and senomorphic agent procyanidin C1 alleviates structural and functional decline in the aged retina. Proceedings of the National Academy of Sciences of the United States of America. 2024. PMID 38657052. DOI: 10.1073/pnas.2311028121. Access: abstract_metadata. Study: PMID38657052.

42. Fuentes-Flores A, Geronimo-Olvera C, Girardi K et al. Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury. EMBO molecular medicine. 2023. PMID 37860842. DOI: 10.15252/emmm.202317907. Access: abstract_metadata. Study: PMID37860842.

43. Liu J, Zhang J, Lin X et al. Age-associated callus senescent cells produce TGF-β1 that inhibits fracture healing in aged mice. The Journal of clinical investigation. 2022. PMID 35426372. DOI: 10.1172/JCI148073. Access: abstract_metadata. Study: PMID35426372.

44. Battaglia-Vieni A, Marchant V, Tejedor-Santamaria L et al. Dasatinib and Quercetin Combination Increased Kidney Damage in Acute Folic Acid-Induced Experimental Nephropathy. Pharmaceuticals (Basel, Switzerland). 2025. PMID 40573218. DOI: 10.3390/ph18060822. Access: abstract_metadata. Study: PMID40573218.

45. Xu C, Yu C, Zhang J et al. YTHDF1 differentiates the contributing roles of mTORC1 in aging. Molecular cell. 2025. PMID 40441158. DOI: 10.1016/j.molcel.2025.05.003. Access: abstract_metadata. Study: PMID40441158.

46. Portier I, Manne BK, Kosaka Y et al. Aging-related alterations in mechanistic target of rapamycin signaling promote platelet hyperreactivity and thrombosis. Journal of thrombosis and haemostasis : JTH. 2024. PMID 38849085. DOI: 10.1016/j.jtha.2024.05.025. Access: abstract_metadata. Study: PMID38849085.

47. Mannick JB, Del Giudice G, Lattanzi M et al. mTOR inhibition improves immune function in the elderly. Science translational medicine. 2014. PMID 25540326. DOI: 10.1126/scitranslmed.3009892. Access: abstract_metadata. Study: PMID25540326.

48. Mannick JB, Teo G, Bernardo P et al. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. The lancet. Healthy longevity. 2021. PMID 33977284. DOI: 10.1016/S2666-7568(21)00062-3. Access: abstract_metadata. Study: PMID33977284.

49. Hofer SJ, Daskalaki I, Bergmann M et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nature cell biology. 2024. PMID 39117797. DOI: 10.1038/s41556-024-01468-x. Access: abstract_metadata. Study: PMID39117797.

50. Neff F, Flores-Dominguez D, Ryan DP et al. Rapamycin extends murine lifespan but has limited effects on aging. The Journal of clinical investigation. 2013. PMID 23863708. DOI: 10.1172/JCI67674. Access: abstract_metadata. Study: PMID23863708.

51. Arriola Apelo SI, Pumper CP, Baar EL et al. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. The journals of gerontology. Series A, Biological sciences and medical sciences. 2016. PMID 27091134. DOI: 10.1093/gerona/glw064. Access: abstract_metadata. Study: PMID27091134.

52. Bitto A, Ito TK, Pineda VV et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. 2016. PMID 27549339. DOI: 10.7554/eLife.16351. Access: abstract_metadata. Study: PMID27549339.

53. 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. Aging cell. 2014. PMID 24341993. DOI: 10.1111/acel.12194. Access: abstract_metadata. Study: PMID24341993.

54. Drummond MJ, Fry CS, Glynn EL et al. Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. The Journal of physiology. 2009. PMID 19188252. DOI: 10.1113/jphysiol.2008.163816. Access: abstract_metadata. Study: PMID19188252.

55. Arriola Apelo SI, Neuman JC, Baar EL et al. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging cell. 2016. PMID 26463117. DOI: 10.1111/acel.12405. Access: abstract_metadata. Study: PMID26463117.

Source-specific evidence cards

[1] Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA-EX-01 Randomised, Double-Blind, Placebo-Controlled Trial.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[2] Rapamycin increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats.

Shows: Six-month dietaryrapamycin in 28 old low-capacity-runner rats improvedgrip andattenuatedrunningdecline withsex differences.

Does not show: Highdailyanimaldose andselectedriskbackground, notweeklyhealthyhuman. Baselineimprovement notnecessarilybetween-groupcontrast onallreportedmetrics; male MRDchange nonsignificant. Physicalpositive retainedwithoutclinicaltransfer.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[3] A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[4] TORC1 inhibition enhances immune function and reduces infections in the elderly.

Shows: 264 elderly subjects randomized low-dose BEZ235/RAD001 combination for 6 weeks hadreportedone-yearinfection reduction(P = 0.001),antiviralexpression andvaccineresponse improvement.

Does not show: Different TORC1 agents, shortexposure andspecificinfectionendpoint; notweekly rapamycinphysicalfunction orhumansurvival. Self-reportinfection ascertainment andlater phase IIIboundary mustbechecked.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[5] Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate.

Shows: Marmosetrapamycintissueanalysis reportsselectiveproteostasis/autophagychanges:muscle/adiposeautophagy+,livernot; proteasomeexpression+,activityunchanged.

Does not show: Modeltissuebiomarkers andpriorpilotoverlap; notlifespan orhumanfunction. Tissue-specificnulls preventuniformautophagyassertion; nonhumanprimate doesnotautomaticallytranslate.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[6] Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.

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.

Does not show: Biomarkers/BMDnotfractureorphysicalfunction; subgroupmustbeprospectivelydefined/replicated, notselectedresponders. Primarynullcannotbeoverriddenbyexploration; differentmechanism notrapamycinequivalence.

Access/status: 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. none_found. Subclaims: SC4.

[7] Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.

Shows: Fourteen IPF patients open-label 3 week D+Q hadimprovedwalking/gait/chair-stands, unchangedpulmonary/frailty/reportedhealth; one serious AE; primaryfeasibility.

Does not show: Uncontrolledshortdiseasepilot, nothealthyagingorprimaryfunctional RCT. SASP-functioncorrelationinconclusiveandnotmediateddependency; regression/contact unresolved.

Access/status: 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. none_found. Subclaims: SC4.

[8] Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability.

Shows: Twelve IPF patients randomized 3 week D+Q versusplacebo completedassessments; physical/frailty/pulmonarychangesnotmeaningfullydifferentandactivearmmore AEs, anxiety/sleep 4/6 versus 0/6.

Does not show: Feasibility-powered, singleblind andveryshort; nullimprecisenotequivalence. Same NCT02874989 protocolfamilyasprioropenlabelbutdifferentallocationcohort, notassumedsameparticipants.

Access/status: 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. none_found. Subclaims: SC4.

[9] Characterization of Human Senescent Cell Biomarkers for Clinical Trials.

Shows: Secondarypostmenopausal D+Qtrialbiomarkerstudy reports T cell p16 variant 5/SASPpredictingexploratoryskeletalresponse plusin-vitro DNA-damageexpressiontiming.

Does not show: Shares 38956196 allocation; markerpredictionnotindependentlyvalidatedclinicalselection orsenescentcellnecessity. Exploratoryresponderscannotredefinetheoverallprimarynull.

Access/status: 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. none_found. Subclaims: SC1, SC4.

[10] An aged immune system drives senescence and ageing of solid organs.

Shows: Immune-specific Ercc 1 deletion mice developedprematureimmune/systemicsenescence; youngcelltransferattenuatedmarkers andrapamycinimprovedimmunefunction/markers.

Does not show: DNA-repairprogeroidmodelandforcedtransfersaremechanistic notnormalhumanagingorphysicalhealthspan. Rapamycin partial rescue is not necessity of mTORasglobalagingdriver.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[11] Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.

Shows: 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.

Does not show: Strong restricted mammalian lifespan evidence retained; possiblecancer-delay anddailyfeedexposure notweeklyhumanfunction. Sitesreplicate one experimentalclass, notindependenthuman causalclasses.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[12] Evaluation of off-label rapamycin use to promote healthspan in 333 adults.

Shows: Survey 333 off-labelrapamycinusers compared 172 never-users characterizes use andreported safety in normalhealth.

Does not show: Self-selection, healthyuser/confoundedcomparison, recall andunverifieddose/outcomes; notrandomizedfunctiontrajectory orincidencerare AE. Conclusionofsafeuse isexploratory notuniversal.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[13] Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial.

Shows: Topicalskintrial 36 enrolled/19 discontinuedlost reports reducedp16,increasedcollagen VII andsomeclinical/histologicalappearanceimprovement.

Does not show: Topicalroute, photoaging≥40,highattrition andbiopsy subset; notoralweekly≥50 physicalfunction. Reducedp16 is notproofsenescentcellclearance orslowglobalaging.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[14] The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.

Shows: Mouse trametinib/rapamycincombination extendedsurvivaladditivelyinbothsexes andreducedselectedtumors/inflammatorytissuephenotypes.

Does not show: Combination MEK/mTOReffects inmodelnotintermittenthealthyhuman benefit; tumors, healthspan andfunctionnotidenticaloutcomes. Synergy/additivitydoesn'tprovesinglemediator necessity.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[15] Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results.

Shows: 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.

Does not show: 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.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC3.

[16] Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice.

Shows: Femaleadultmiceweekly versus 3 xweekly rapamycin with 8 weekweightedrunning had preservedgrip/exercisecapacity/hypertrophy butglucose/insulinsensitivity impairment; weeklylesssevere.

Does not show: Five-monthadultfemale modelnotoldhealthyhumans; exercisecompatible isnotaddedfunctionalbenefit. Preservedmuscle plusmetabolicharm needseparate outcomes.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC3.

[17] Tissue-restricted inhibition of mTOR using chemical genetics.

Shows: Chemicalgeneticselec TORrapalog/mutant FKBP12 system enablescell/tissuerestrictedmTORinhibition andmaps Drosophila developmentdelaytissues.

Does not show: Specificitytool inyeast/humancells/flydevelopment, notoralweeklyolderadulttargetengagement oragingfunctionaltherapy. Developmentaldelay distinct fromretardedaging.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[18] Healthy Aging Interventions Reduce Repetitive Element Transcripts.

Shows: Original RNA-seqreanalysis acrossmousegeroprotectors/transgenics plusexercisedhuman data findsrepetitive-elementtranscriptsreducedbyselectedinterventions.

Does not show: Transcriptcorrelation/sharedpublicdatasets notcausalmediation, newindependentclinicalrapaexperiment orhumansloweraging. Originalanalysiscountretainedbutnotcausalunit.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[19] Rapamycin slows aging in mice.

Shows: Rapamycintreatedmice showedsomeage-relatedtissue/activitychangesslower, alongsidehighercataract/testiculardegenerationincidence.

Does not show: Organ/tissuehealthspanheterogeneityandharmpreventuniformagingreversal; dailyexposuremousecontext nothumanweeklyfunction. Lifespan/functionalphenotypes andcancersuppressiondistinct.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[20] Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system.

Shows: Flyfat-body S6Kactivationblockedrapamycinsurvivalextension; lysosomal Syntaxin/IMDmechanisticperturbations andmidlife IMDrepressionlinkedlifespan, inflammationeffectssex-specific.

Does not show: Specificflies/mouselivermarkersnothealthyhumanweeklyfunction; endpointsnotuniformacrosssex. Mechanisticnarrowingretainedwithoutclaiminghumannecessity.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[21] Rapamycin rejuvenates oral health in aging mice.

Shows: Shortrapamycinolder-mousetreatment regeneratesperiodontalbone, reducesinflammation andshiftsmicrobiome.

Does not show: Restrictedoralphenotype, notgeneralphysicalfunctionorhumansurvival. Bone/inflammation/microbiomecochanges notisolatewhichmediatesbenefit.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[22] Rapamycin's lifespan effect is modulated by mito-nuclear epistasis in Drosophila.

Shows: Flymitochondrial/nucleargeneticcombinations modulatedrapamycinsurvivalandage-specificmortalityeffects, decoupledfromearlyfitnesscost.

Does not show: Mappedgeneticvariation notvalidatedhumanresponseprediction. Showscontextdependence, notabsenceofgenuineanimalbenefit orall-genotypeuniversalextension.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[23] Rapamycin improves healthspan but not inflammaging in nfκb1-/- mice.

Shows: nfκb1 deficientmice hadimprovedfrailty/memory/coordination/tissuehealth withrapamycin butnolifespan/inflammagingbenefit.

Does not show: Specificaccelerated-inflammationmodel; healthspan/survivaldissociationexcludesinflammationasassumednecessarybridge. Nothealthyhumanweeklyfunction.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[24] Mifepristone and rapamycin have non-additive benefits for life span in mated female Drosophila.

Shows: Originalmated-female-flyrapamycintitrationandcombinationexperiments showlifespanbenefitbutmifepristonecombinationnonadditive/lowerthanmonotherapy; mitophagy/midgutphenotypesmeasured.

Does not show: Includesbackgroundmeta-analysis butneworiginalexperimentsearncredit. Nonadditivityandsharedmarkersdon'tprovesinglepathway; sex/matingcontextnothumanhealthyfunction.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[25] Rapamycin Attenuates H2O2-Induced Oxidative Stress-Related Senescence in Human Skin Fibroblasts.

Shows: Primaryhumanfibroblast H2 O2 model 48-hourrapamycin improvesmigration/proliferation andsenescence/ROS/autophagymarkers.

Does not show: Inducedstresscellculture/proxymarkers notendogenousolderhumanphysicalfunction. Autophagyincreasenotnecessarilycausalwithoutblockade/rescue; noorganismalhealthspan.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[26] Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage.

Shows: Human T cell genotoxic stress work shows lesional burden/senescencereduction; placebo-controlledolderadultlow-doserapamycin reducesimmune-cellp21.

Does not show: Mixedcell/humanmechanisticdesign; senescencemarkers and DNAresilience notobjectivephysicalfunctionoragingtrajectory. Actualdose/scheduleandtrialoverlapneed Methodscheck.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[27] Evaluation of off-label rapamycin use on oral health.

Shows: Secondary 333 off-labeluserssurveyreportsoralchanges in 26% andno dose/intervalcorrelationwithulcers, withselected AI-periodontalcasestudies.

Does not show: Shares 37191826 survey; absenceofassociationisnotzerooralharm; selectedcaseimages/confounding cannot establishoralregeneration orincidence. No non-userfocusedoralcontrol.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[28] Rapamycin extends life and health in C57BL/6 mice.

Shows: Late-life C57BL/6 feedingrapamycin improvedsurvival, stride/rotarod andselectedlesions; targetinhibitionandtissue/sexresponsesvary, spontaneousactivitynull.

Does not show: Restrictedmousebackground, dailyfeeding andmultipleendpoints; notweeklyhumanfunction. No observedadverseconsequences heredoesn'teraseharmotherregimens.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[29] Rapamycin preserves gut homeostasis during Drosophila aging.

Shows: Flyrapamycin slowsage-relatedgutstem-cellproliferation, inducesepithelialautophagy andalteredimmune/FOXOgeneswithdelayedmicrobialexpansion.

Does not show: Specificflyintestinalphenotype, notdirecthumansystemichealthspan; cochangesnotallnecessarymediators. Broadhealthy-agingtransferremainsunverified.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[30] Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease.

Shows: Nine diabetic-kidney-disease patients 3-day D+Q openlabel showedreducedadipose/skinp16/p21/SAβgal and SASP 11 days later.

Does not show: Cellburdenmarkers, beforeafter, diseasecontext nothealthyphysicalfunctionorrapamycinequivalence. Linkederratum 31982828 metadataonly; markerdecline notsenescentcellspecificity/rescueproof.

Access/status: 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. ErratumIn: PMID31982828. Subclaims: SC1, SC4.

[31] Fisetin is a senotherapeutic that extends health and lifespan.

Shows: Fisetinscreening/oldwild-type/progeroidmice andhumanadiposeexplants showcell-specificsenotherapeuticactivity, late-lifemousetissuebenefit andlifespanextension.

Does not show: Genuineoriginalpreclinicalsupport, notcontrolledhumantreatment. Flavonoidpolypharmacology, cellheterogeneity andmouseregimenconstraincausality/translation.

Access/status: 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. none_found. Subclaims: SC4.

[32] Senolytics improve physical function and increase lifespan in old age.

Shows: Senescentcelltransfer inducedphysicaldysfunction inmice; intermittent D+Q intransferred andnaturallyagedmice improvedfunction andpost-treatment survival; humanadiposeexplantmarkersreduced.

Does not show: Forcedcelltransfer separatefromendogenousaging; oldmousepharmacologystrongrestrictedcontext butnotrapamycinorhumanfunction. Explantsnotclinicaloutcomes.

Access/status: 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. none_found. Subclaims: SC3, SC4.

[33] Targeting senescent cells alleviates obesity-induced metabolic dysfunction.

Shows: Obesemicegeneticsuicide/p16 andsenolyticinterventions improvedglucose/insulin/adiposeresponses andrenal/cardiacphenotypes.

Does not show: Specificobesitydiseasecontext, genetic/pharmacologicconcordancenarrowssomeconfoundingbutnotgeneralhealthyaging. Off-target/cellidentity andclinicaltranslationunresolved.

Access/status: 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. none_found. Subclaims: SC4.

[34] Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.

Shows: Agedhumanmelanocytemarkers and 3 Depidermalequivalentslink SASP-inducedparacrine dysfunction; ABT737 or Mito Qsuppressesatrophy/proliferationeffect.

Does not show: Human-derivedsimplifiedsystemnotwholehumanfunction; senolytic/antioxidantalternativesdo notprovesenescentcellspecificsystemicnecessity. Oralrapa equivalenceuntested.

Access/status: 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. none_found. Subclaims: SC1, SC4.

[35] Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.

Shows: ABT263 inducesselectivesenescentcellapoptosis inculture andoralaged/irradiatedmice improveshematopoietic/musclestem-cellphenotypes.

Does not show: BCL2/BCLx Ldrugandspecificstemcell/radiationcontexts, notgeneralphysicalfunctionorhumantrial. Celltype/transplantassays andtherapeuticspecificity requirecontrols.

Access/status: 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. none_found. Subclaims: SC4.

[36] Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age.

Shows: Oldmice D+Q decreasesadiposesenescence/inflammation andimprovesglucose/lipidphenotypes, withliver/musclesenescencemarkers notrobustlychanged.

Does not show: Tissuerestriction andmetabolicendpoints notweekly rapamycinphysicalfunction; concomitantmarkerseffectsnotmediatornecessity orhumansurvival.

Access/status: 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. none_found. Subclaims: SC4.

[37] Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Shows: Anti-u PARCART aged/high-fat-dietmice improveexercisecapacity/glucosewithlonglasting single-treatmentpreventiveeffects.

Does not show: Actualgenetic-cellularpharmacologydistinctfrom D+Q/rapamycin; u PARisnotuniquesenescenceidentity, mousefitnessnothumanfunction. Publishedupdatesupersedespreprint 37841853 notextracredit.

Access/status: 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. UpdateOf: PMID37841853. Subclaims: SC4.

[38] Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial.

Shows: Five ADpatients 12 week D+Q openlabelhadmeasurable CSFdasatinibnotquercetin, unchangedcognitive/imagingendpoints andmixedinflammatorymarkers.

Does not show: Feasibility/smalluncontrolledtrial notefficacyorsafetyqualification; nullcognitionisnotfavorablesafetyevidencebyitself. Publishedreportsupersedespreprint, nothealthyaging orrapa equivalence.

Access/status: 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. UpdateOf: PMID37162971. Subclaims: SC4.

[39] Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

Shows: Aged INK-ATTACgeneticclearance and D+Qbothreducedmicroglialp16/SASP andimprovedcognition.

Does not show: Mousecognitivereadout/tissuerestriction ratherthanwholehumanphysicalhealthspan; concordance narrowsmechanismbutnotallcelltypesorrapamycinsamepathway.

Access/status: 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. none_found. Subclaims: SC4.

[40] Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence.

Shows: Oldmice intermittentfisetin improvedarterialdilation/stiffness withsenescencemarkerdecline; ex-vivogeneticclearance showednoadditionalimprovementafterfisetin.

Does not show: Helpfulmechanisticocclusion butnotcompletehumansenolysis-specificity orhealthyphysicalfunction. Vessel/functioncontext distinctfromrapa, notclinicalequivalence.

Access/status: 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. none_found. Subclaims: SC4.

[41] Senolytic and senomorphic agent procyanidin C1 alleviates structural and functional decline in the aged retina.

Shows: PCC1 senolytic/senomorphic oldmousework improvesretinalstructure/function anduses sc RNAseqtocellmapchanges.

Does not show: Agentpolypharmacologyandretinalscoped endpointsnotgeneralfunction/survival orhumantrial; SASPcochangesnotestablishsinglemediatornecessity.

Access/status: 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. none_found. Subclaims: SC4.

[42] Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury.

Shows: Aged/chronic-denervated Schwann-cellsenescence andsystemicdrug/genetictargeting linkclearance toimprovednerveregeneration/functionalrecovery.

Does not show: Injury/regenerationcontextsnotgeneralhealthyaging; genetic/drugconcordancenarrowssomecausalquestions butdrug-specificoff-targets/humanscope remain.

Access/status: 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. none_found. Subclaims: SC4.

[43] Age-associated callus senescent cells produce TGF-β1 that inhibits fracture healing in aged mice.

Shows: Oldfracture-callusmice D+Qimprovehealing; TGFβneutralization rescuesprogenitorinhibition andhealingphenotypes.

Does not show: Definedfractureinjury andmousebackground, targeted TGFβmechanismnotrapamycinorhumanphysicalhealthspan. Senescencebenefitmaydependontiming/repaircontext.

Access/status: 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. none_found. Subclaims: SC4.

[44] Dasatinib and Quercetin Combination Increased Kidney Damage in Acute Folic Acid-Induced Experimental Nephropathy.

Shows: D+Qpretreatment inacute FANmousekidneyinjury didnotpreservecreatinine/BUN andworsenedselecteddamage/SASPgenes withoutreducingp21 positivecells.

Does not show: Specificacuteinjurynot CKDorhealthyaging; markerharmdoesn'tshoweveryclinicalregimenharm. Importantnegativecontexts retainedratherthanall-senolyticsbeneficialassumption.

Access/status: 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. none_found. Subclaims: SC4.

[45] YTHDF1 differentiates the contributing roles of mTORC1 in aging.

Shows: Ythdf 1 loss acceleratedmouseaging throughmTORC1/cholesterolaxis; rapamycin restoredhealthspan inthisbackground.

Does not show: Geneticbackground-specificrescuenotweeklyhealthyhumanfunction; lifespan/healthspan distinct andglobalmTORnecessitynotproved. m 6 A-independentmechanism narrowerthan generictranslationnarrative.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[46] Aging-related alterations in mechanistic target of rapamycin signaling promote platelet hyperreactivity and thrombosis.

Shows: Humanagedplateletphosphoproteomics/ex-vivo Torin 1 andmouseplateletmTORdeletion linkmTORtohyperreactivity; agedknockout rescuesinducedthrombosistime-to-death.

Does not show: Humanex-vivo Torin 1 andmousecell-specificgenetics—notolderadultrapamycinsurvivaltrial. Inducedpulmonarythrombosisendpointnothabitualphysicalfunction oragingnecessity.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[47] mTOR inhibition improves immune function in the elderly.

Shows: Older-volunteer RAD001 controlledtrial reports~20% enhanced influenza-vaccineresponse andreduced PD1 positive T cell proportions.

Does not show: Immunephenotypes, nothumanphysicalfunction, lifespan orgeneralagingtrajectory; differentdrug/doseandclinicalinfectionendpointdistinct. Vaccineimmunity not necessity proof that mTOR drives aging.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[48] Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials.

Shows: 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.

Does not show: Twoactualtrialunits inonereport; endpointdefinition changedbetweenphases, notidenticalreplication. Immune-targetengagementcanpersistwithoutclinicalbenefit; differentagent andinfectionoutcome notweeklyrapafunction.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[49] Spermidine is essential for fasting-mediated autophagy and longevity.

Shows: Originalcross-speciesfasting/polyamineperturbations showsspermidine-pathwayblockade attenuatesautophagy andmodelhealth/lifespan effects, humanfastingpolyaminechanges.

Does not show: Humancomponentnotrapamycinclinicalfunction; matchedrapamycinexperimentsreportedinsummaryneedoriginalbodyassessment beforeassigningmechanisticdetail. Parentoriginalreplacespunctum 39212197;noextrareviewcredit.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[50] Rapamycin extends murine lifespan but has limited effects on aging.

Shows: Comprehensive male C57BL/6J evaluation found increasedlifespan withfewagingphenotypesimproved; manyrescuedtraits changed similarly inyoungmice.

Does not show: Aging-independentphenotypiceffectnotnecessarilyagingdelay; onebackground/sex doesn'teraseotherfunctionalpositives. Importantlifespan-healthspanseparation nothumanweeklyclinicaltest.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[51] Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice.

Shows: Intermittent 2 mg/kg every 5 days from 20 months extendsfemale C57BL/6Jsurvival, withlessmetabolic/immuneimpactthanchronictreatment inrelatedwork.

Does not show: True intermittentlate-lifeanimalpositive; female-onlystrain anddifferentexposuresnotolderhumanfunction/safety. Reducedharmvsdaily isnotnoharm orsame 5–10 mghumanexposure.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[52] Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice.

Shows: Three-monthmiddle-agedmousetreatment producespersistenthealth/survivalbenefits andmicrobiomeremodeling; onefemaledose failslifespanextension withshifttoaggressivehematopoieticcancers.

Does not show: Dose/sex/cancercontextmatters; headlineup-to 60% life expectancy cannotbecome 60% longer total human lifespan. Microbiomecochange notcausalmediation; modeltranslationrequiresownfunctionoutcome.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[53] Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction.

Shows: Heterogeneousmousehigherdietarydose extendsmedianlifespan 23% male 26% female, maximallifespanalso; sex/dose effects andmetabolicdistinctionfromdietrestriction.

Does not show: Animaldietarylifespanvaliditynotregisteredclinicalphysicalfunction. ITPdose-study/histologyfamily mayoverlap 22587563;replicationdoesnotbyitselfcreateindependentcausalclasses.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[54] Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis.

Shows: Acutehumanrapamycin beforecontractionblocks ~40% earlymuscleproteinsynthesisincrease andselectedmTORC1/ERKpathwayresponses.

Does not show: Acuteanabolicphysiology notweekly≥50 longtermfunctionalharm; age/dose mustnotbeassumedfromabstract. Itmotivatestiminginteractionchecks, notproofallintermittentregimensabolishadaptation.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[55] Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system.

Shows: Mousealternative schedulesandrapalogs reduceglucose/pyruvate/immune sideeffectsthanchronicrapamycin whileinhibitingmTORC1.

Does not show: Comparativesafety-windowmechanism nothumanfunctionalbenefit, absenceofallrisk orlifespanqualifier; youngshortexperimentandmTORC1/2 specificitycontext retained.

Access/status: 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. none_found. Subclaims: SC1, SC3.

Documentary record

Every grade on this site is reproducible from its record. The files below are the posted edition exactly as assessed.

• ADVERSARIAL_REVIEW.md
• CONSENSUS_CROSSCHECK.html
• CONSENSUS_CROSSCHECK.md
• RESEARCH_TIMELINE.html
• RESEARCH_TIMELINE.md
• SHA256.txt
• adversarial-findings.json
• codex-correction-provenance.json
• consensus-validation.json
• edition-approval-audit.json
• rapamycin-human-healthspan.review.md
• rapamycin-human-healthspan.scorecard.json
• reader-summary.json
• research-timeline.json
• validation-report.json
• validation-round2-2026-10-14.json
• validation.txt
• video-insert.md
• web-page.md

Sources: 55 · load-bearing claims: 60 · verified: 60 · unverified: 0 · contradicted: 0 · schema 5.3