Research Synthesis: Rapamycin — full paper

Researka accepted publication: f02d4a53-03e5-47ed-9876-75a416e3bd24 Source submission: 48a5b934-32db-4192-ad9c-49738c5183ab Rapamycin, an mTOR pathway inhibitor, has emerged as a leading candidate geroprotective agent, yet translating its robust preclinical lifespan benefits to humans requires reconciling mechanistic promise with functional and safety trade-offs. We conducted a structured evidence synthesis across curated preclinical, clinical, and observational sources, applying transparent inclusion criteria and an audit trail to adjudicate tensions between mechanistic plausibility and clinical signal. Pharmacokinetic analyses of real-world low-dose cohorts reveal considerable inter-individual variability in trough blood rapamycin levels, with compounded formulations showing different bioavailability profiles than commercial generics (P < 0.001 for formulation comparisons; Harinath 2025), a finding that complicates dose standardization across aging-relevant trials. On the mechanistic side, additive geroprotection has been demonstrated when rapamycin is combined with trametinib (Gkioni 2025, multiple endpoints at P < 0.05), and even two weeks of treatment increased ovarian lifespan in young and middle-aged female mice (Dou 2017, P < 0.05), while rapamycin reversed age-related vascular dysfunction in old B6D2F1 mice (P < 0.05 across endpoints; Lesniewski 2016). The weight of evidence supports rapamycin's mechanistic plausibility as a geroprotector—autophagy induction, senescence suppression, and imm