Rapamycin

Rapamycin (an mTORC1 inhibitor) has the most robust lifespan-extension evidence of any pharmacological agent in animal models, and the first randomized human healthspan data have now emerged. In the NIA Interventions Testing Program, dietary rapamycin extended median lifespan in genetically heterogeneous mice in a dose- and sex-dependent way — roughly +9–23% in males and +14–26% in females, with larger effects at higher doses (Harrison et al., Nature 2009; later ITP dose-response and late-life-dosing studies). The 48-week randomized, double-blind, placebo-controlled PEARL trial (114 adults aged 50–85 on 5 mg or 10 mg compounded rapamycin weekly) did not meet its primary visceral-fat endpoint, but women on 10 mg/week showed statistically significant gains in lean tissue mass and reductions in self-reported pain, while the 5 mg group reported improved emotional well-being and general health. Serious adverse events occurred at rates similar to placebo, with mild gastrointestinal symptoms most common. Human longevity outcomes remain unproven; low-dose intermittent rapamycin for healthy aging is investigational and used off-label under physician supervision. UPDATE (August 23, 2026): PREPRINT — NOT PEER-REVIEWED. A bioRxiv preprint (posted 24 June 2026) profiled male UM-HET3 mice treated from 4 to 12 months with rapamycin, acarbose, 17-alpha-estradiol, canagliflozin or caloric restriction, using untargeted metabolomics across seven tissues. A feature-stabilized XGBoost pipeline identified treated animals as recipients of a lifespan-extending intervention well before survival curves separate, and a leave-one-intervention-out procedure showed that models trained on any four interventions correctly classified mice receiving a fifth, unseen intervention — implying a partly shared metabolic signature across mechanistically distinct treatments. The dietary antioxidant ergothioneine rose consistently in brain, plasma and muscle, alongside common lipid remodelling. If this survives peer review it is a candidate short-horizon readout for geroprotector screening, and it is a notable hint that this drug does not act in complete metabolic isolation. It is explicitly NOT evidence that ergothioneine mediates the effect or that supplementing it reproduces any benefit — the association is correlative and untested causally, the cohort is male-only, and no human data exist.

Evidence Scale