{
  "cutoff": "2026-10-13",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "19587680",
      "year": "2009",
      "title": "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.",
      "doi": "10.1038/nature08221",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19587680/",
      "interpretation": "Late-life heterogeneous-mouse survival extension establishes genuine mammalian intervention efficacy."
    },
    {
      "pmid": "19188252",
      "year": "2009",
      "title": "Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis.",
      "doi": "10.1113/jphysiol.2008.163816",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19188252/",
      "interpretation": "Acute human contraction study shows suppressed early muscle protein synthesis, motivating regimen/timing tradeoffs."
    },
    {
      "pmid": "22587563",
      "year": "2012",
      "title": "Rapamycin slows aging in mice.",
      "doi": "10.1111/j.1474-9726.2012.00832.x",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22587563/",
      "interpretation": "Mouse tissue/activity benefits coexist with cataract and testicular effects, separating benefit-harm by phenotype."
    },
    {
      "pmid": "23863708",
      "year": "2013",
      "title": "Rapamycin extends murine lifespan but has limited effects on aging.",
      "doi": "10.1172/JCI67674",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23863708/",
      "interpretation": "Comprehensive mouse assessment finds lifespan extension with limited aging-trait changes and aging-independent responses."
    },
    {
      "pmid": "24341993",
      "year": "2014",
      "title": "Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction.",
      "doi": "10.1111/acel.12194",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24341993/",
      "interpretation": "Dose and sex modify heterogeneous-mouse longevity; dietary restriction is not the same metabolic intervention."
    },
    {
      "pmid": "25540326",
      "year": "2014",
      "title": "mTOR inhibition improves immune function in the elderly.",
      "doi": "10.1126/scitranslmed.3009892",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25540326/",
      "interpretation": "Human RAD001 vaccine response positive provides an immune-specific translational signal."
    },
    {
      "pmid": "23682161",
      "year": "2014",
      "title": "Rapamycin extends life and health in C57BL/6 mice.",
      "doi": "10.1093/gerona/glt056",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23682161/",
      "interpretation": "Late-life C57 BL/6 function/survival positives retain tissue and sex distinctions."
    },
    {
      "pmid": "26463117",
      "year": "2016",
      "title": "Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system.",
      "doi": "10.1111/acel.12405",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26463117/",
      "interpretation": "Alternative mouse schedules/rapalogs reduce selected daily-treatment metabolic/immune adverse effects."
    },
    {
      "pmid": "27091134",
      "year": "2016",
      "title": "Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice.",
      "doi": "10.1093/gerona/glw064",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27091134/",
      "interpretation": "Late-life intermittent female-mouse treatment extends survival without establishing human functional equivalence."
    },
    {
      "pmid": "27549339",
      "year": "2016",
      "title": "Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice.",
      "doi": "10.7554/eLife.16351",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27549339/",
      "interpretation": "Transient mouse exposure produces persistent effects with a dose/sex tumor-spectrum boundary."
    },
    {
      "pmid": "26997106",
      "year": "2016",
      "title": "Rapamycin increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats.",
      "doi": "10.18632/aging.100929",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26997106/",
      "interpretation": "Old selected low-capacity-runner rats show grip and running effects, adding a functional model context."
    },
    {
      "pmid": "29408453",
      "year": "2018",
      "title": "A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects.",
      "doi": "10.1016/j.exger.2017.12.026",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29408453/",
      "interpretation": "Older-human daily pilot finds no grip/walking or cognition benefit with selected hematological changes."
    },
    {
      "pmid": "29997249",
      "year": "2018",
      "title": "TORC1 inhibition enhances immune function and reduces infections in the elderly.",
      "doi": "10.1126/scitranslmed.aaq1564",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29997249/",
      "interpretation": "Short human TORC1 combination trial reports immune and infection positives in a defined context."
    },
    {
      "pmid": "29988130",
      "year": "2018",
      "title": "Senolytics improve physical function and increase lifespan in old age.",
      "doi": "10.1038/s41591-018-0092-9",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29988130/",
      "interpretation": "Senescent-cell transfer and intermittent senolytics show mouse physical/survival effects and human-explant marker changes."
    },
    {
      "pmid": "30616998",
      "year": "2019",
      "title": "Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.",
      "doi": "10.1016/j.ebiom.2018.12.052",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30616998/",
      "interpretation": "Open-label IPFsenolytic functional signal motivates controlled testing rather than established clinical efficacy."
    },
    {
      "pmid": "31542391",
      "year": "2019",
      "title": "Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease.",
      "doi": "10.1016/j.ebiom.2019.08.069",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31542391/",
      "interpretation": "Small open-label kidney-disease D+Qtrial reduces tissue markers without proving healthy human physical function."
    },
    {
      "pmid": "31761958",
      "year": "2019",
      "title": "Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial.",
      "doi": "10.1007/s11357-019-00113-y",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31761958/",
      "interpretation": "Topical human skin trial shows markers/appearance effects with high attrition and different exposure scope."
    },
    {
      "pmid": "33977284",
      "year": "2021",
      "title": "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials.",
      "doi": "10.1016/S2666-7568(21)00062-3",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33977284/",
      "interpretation": "Later m TOR-inhibitor phase III clinical illness is null despite target gene effects; endpoint definitions matter."
    },
    {
      "pmid": "36857968",
      "year": "2023",
      "title": "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.",
      "doi": "10.1016/j.ebiom.2023.104481",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36857968/",
      "interpretation": "Randomized IPFpilot supports feasibility but lacks meaningful functional superiority and is underpowered."
    },
    {
      "pmid": "38956196",
      "year": "2024",
      "title": "Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial.",
      "doi": "10.1038/s41591-024-03096-2",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38956196/",
      "interpretation": "Postmenopausal senolytic primary bone-resorption null coexists with early/exploratory signals."
    },
    {
      "pmid": "40704394",
      "year": "2025",
      "title": "Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice.",
      "doi": "10.1111/acel.70183",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40704394/",
      "interpretation": "Female mouse exercise adaptations are preserved while glucose effects worsen, preventing wrong-direction blanket inference."
    },
    {
      "pmid": "40188830",
      "year": "2025",
      "title": "Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results.",
      "doi": "10.18632/aging.206235",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40188830/",
      "interpretation": "PEARL48-week primary visceral-fat null and small female composition/pain signals expose endpoint/exposure limits."
    },
    {
      "pmid": "41985884",
      "year": "2026",
      "title": "Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA-EX-01 Randomised, Double-Blind, Placebo-Controlled Trial.",
      "doi": "10.1002/jcsm.70274",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41985884/",
      "interpretation": "Direct 13-week weeklyrapamycin exercise trial is functional primary-null with negative sensitivity contrasts."
    },
    {
      "pmid": "41524558",
      "year": "2026",
      "title": "Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage.",
      "doi": "10.1111/acel.70364",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41524558/",
      "interpretation": "Older-human immune marker/genoprotection experiments provide mechanism evidence separate from physical function."
    }
  ],
  "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."
  ],
  "decisive_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."
}