Rapamycin
/ Macrolide mTOR inhibitor (small molecule); endogenously produced by Streptomyces hygroscopicusALIAS · Sirolimus (generic) · Rapamune (trade) · Sirolimus · AY-22989
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Tier 1. FDA-approved 1999 (Rapamune) for prophylaxis of organ rejection in renal transplantation; subsequent approvals for lymphangioleiomyomatosis (Fyarro nab-sirolimus is a related albumin-bound formulation in the malignant PEComa indication). Geroscience interest in rapamycin and rapalogs is extensive: NIA Interventions Testing Program murine longevity (Harrison and colleagues 2009), the everolimus immune-aging Phase 2 work (Mannick and colleagues), and the PEARL trial of low-dose rapamycin in older adults (Kraig, Walker, and colleagues).
Rapamycin is a 31-membered macrocyclic lactone produced by Streptomyces hygroscopicus, originally isolated from soil samples collected on Easter Island (Rapa Nui — the source of the name). The molecule binds the cytosolic immunophilin FKBP12 and the resulting drug-receptor complex engages the FRB domain of mTOR, allosterically inhibiting mTOR complex 1 (mTORC1) — the principal nutrient-sensing and growth-regulating kinase complex. mTORC1 inhibition suppresses cap-dependent translation (via 4E-BP1 dephosphorylation), reduces ribosome biogenesis, and induces autophagy.
Prolonged exposure secondarily inhibits mTORC2 in some cell types, contributing to the metabolic side effect profile (hyperglycaemia, dyslipidaemia, insulin resistance) characteristic of chronic high-dose use in transplant medicine. The geroscience hypothesis rests on extensive evidence that mTORC1 inhibition extends lifespan in yeast, worms, flies, and mice across multiple genetic backgrounds — making rapamycin the most consistently positive lifespan-extension intervention in the NIA Interventions Testing Program murine pipeline.
Tier 1 for the approved transplant rejection indication. Geroscience evidence: Harrison and colleagues (2009) reported the NIA Interventions Testing Program finding that rapamycin extended median lifespan in genetically heterogeneous mice when started at 600 days of age — the first pharmacological intervention to extend mammalian lifespan when started in middle age. Mannick and colleagues evaluated everolimus (a rapalog) in older adults for influenza vaccine response (Sci Transl Med 2014) and a related rapalog combination for respiratory tract infection (Lancet Healthy Longev 2018), reporting improvements in immune aging biomarkers. The PEARL trial (Participatory Evaluation of Aging with Rapamycin for Longevity, Kraig and colleagues) is a Phase 2 trial of intermittent low-dose rapamycin in older adults investigating safety and surrogate aging endpoints.
The transplant-medicine safety database includes hyperlipidaemia, hyperglycaemia, peripheral oedema, stomatitis, impaired wound healing, anaemia, and proteinuria — a profile dose- and duration-dependent and generally less burdensome at the lower intermittent doses studied in geroscience contexts. Class concerns about immunosuppression and infection risk apply but are dose-related; intermittent low-dose protocols (such as PEARL) attempt to dissociate geroscience-relevant mTORC1 inhibition from the immunosuppression that drives transplant-medicine adverse events. Drug interactions through CYP3A4 are extensive.
Regulatory status
- FDA status:
- FDA-approved
- Compounding:
- Not eligible for compounding (approved, not in shortage)
The transplant-rejection prophylaxis indication is well-established. The geroscience translation depends on whether intermittent low-dose rapamycin reproduces the murine lifespan-extension finding in humans — a question the existing trials are not powered to answer with hard-endpoint data. PEARL and similar trials report on surrogate biomarkers (epigenetic age, frailty measures, immune aging panels); long-term outcome data on morbidity or mortality in healthy older adults do not yet exist. Compounded rapamycin sourced through age-management physician channels operates outside the FDA-approved use case and the quality-assurance environment of transplant pharmacy distribution.