# 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](https://pubmed.ncbi.nlm.nih.gov/19587680/).

**2009 — Acute human contraction study shows suppressed early muscle protein synthesis, motivating regimen/timing tradeoffs.** [Original PMID19188252](https://pubmed.ncbi.nlm.nih.gov/19188252/).

**2012 — Mouse tissue/activity benefits coexist with cataract and testicular effects, separating benefit-harm by phenotype.** [Original PMID22587563](https://pubmed.ncbi.nlm.nih.gov/22587563/).

**2013 — Comprehensive mouse assessment finds lifespan extension with limited aging-trait changes and aging-independent responses.** [Original PMID23863708](https://pubmed.ncbi.nlm.nih.gov/23863708/).

**2014 — Dose and sex modify heterogeneous-mouse longevity; dietary restriction is not the same metabolic intervention.** [Original PMID24341993](https://pubmed.ncbi.nlm.nih.gov/24341993/).

**2014 — Human RAD001 vaccine response positive provides an immune-specific translational signal.** [Original PMID25540326](https://pubmed.ncbi.nlm.nih.gov/25540326/).

**2014 — Late-life C57 BL/6 function/survival positives retain tissue and sex distinctions.** [Original PMID23682161](https://pubmed.ncbi.nlm.nih.gov/23682161/).

**2016 — Alternative mouse schedules/rapalogs reduce selected daily-treatment metabolic/immune adverse effects.** [Original PMID26463117](https://pubmed.ncbi.nlm.nih.gov/26463117/).

**2016 — Late-life intermittent female-mouse treatment extends survival without establishing human functional equivalence.** [Original PMID27091134](https://pubmed.ncbi.nlm.nih.gov/27091134/).

**2016 — Transient mouse exposure produces persistent effects with a dose/sex tumor-spectrum boundary.** [Original PMID27549339](https://pubmed.ncbi.nlm.nih.gov/27549339/).

**2016 — Old selected low-capacity-runner rats show grip and running effects, adding a functional model context.** [Original PMID26997106](https://pubmed.ncbi.nlm.nih.gov/26997106/).

**2018 — Older-human daily pilot finds no grip/walking or cognition benefit with selected hematological changes.** [Original PMID29408453](https://pubmed.ncbi.nlm.nih.gov/29408453/).

**2018 — Short human TORC1 combination trial reports immune and infection positives in a defined context.** [Original PMID29997249](https://pubmed.ncbi.nlm.nih.gov/29997249/).

**2018 — Senescent-cell transfer and intermittent senolytics show mouse physical/survival effects and human-explant marker changes.** [Original PMID29988130](https://pubmed.ncbi.nlm.nih.gov/29988130/).

**2019 — Open-label IPFsenolytic functional signal motivates controlled testing rather than established clinical efficacy.** [Original PMID30616998](https://pubmed.ncbi.nlm.nih.gov/30616998/).

**2019 — Small open-label kidney-disease D+Qtrial reduces tissue markers without proving healthy human physical function.** [Original PMID31542391](https://pubmed.ncbi.nlm.nih.gov/31542391/).

**2019 — Topical human skin trial shows markers/appearance effects with high attrition and different exposure scope.** [Original PMID31761958](https://pubmed.ncbi.nlm.nih.gov/31761958/).

**2021 — Later m TOR-inhibitor phase III clinical illness is null despite target gene effects; endpoint definitions matter.** [Original PMID33977284](https://pubmed.ncbi.nlm.nih.gov/33977284/).

**2023 — Randomized IPFpilot supports feasibility but lacks meaningful functional superiority and is underpowered.** [Original PMID36857968](https://pubmed.ncbi.nlm.nih.gov/36857968/).

**2024 — Postmenopausal senolytic primary bone-resorption null coexists with early/exploratory signals.** [Original PMID38956196](https://pubmed.ncbi.nlm.nih.gov/38956196/).

**2025 — Female mouse exercise adaptations are preserved while glucose effects worsen, preventing wrong-direction blanket inference.** [Original PMID40704394](https://pubmed.ncbi.nlm.nih.gov/40704394/).

**2025 — PEARL48-week primary visceral-fat null and small female composition/pain signals expose endpoint/exposure limits.** [Original PMID40188830](https://pubmed.ncbi.nlm.nih.gov/40188830/).

**2026 — Direct 13-week weeklyrapamycin exercise trial is functional primary-null with negative sensitivity contrasts.** [Original PMID41985884](https://pubmed.ncbi.nlm.nih.gov/41985884/).

**2026 — Older-human immune marker/genoprotection experiments provide mechanism evidence separate from physical function.** [Original PMID41524558](https://pubmed.ncbi.nlm.nih.gov/41524558/).

## 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.