Rapamycin (Sirolimus) for Longevity & mTOR Inhibition — Aging
FDA-approved mTOR inhibitor repurposed for longevity through intermittent low-dose protocols targeting cellular aging pathways.
Overview
Rapamycin (Sirolimus) is an FDA-approved mTOR (mechanistic target of rapamycin) inhibitor originally approved for organ transplant rejection prevention (Rapamune). It is the most robustly validated pharmacological intervention for lifespan extension in preclinical models. The NIA Interventions Testing Program (ITP) demonstrated 9-14% lifespan extension in genetically heterogeneous mice across three independent sites (Harrison et al., Nature 2009, PMID: 19587680). Rapamycin works by inhibiting mTORC1, which reduces cellular senescence, enhances autophagy, improves stem cell function, and modulates immune aging. The PEARL trial (Participatory Evaluation of Aging with Rapamycin for Longevity) and multiple other human aging studies are ongoing. Mannick et al. (Science Translational Medicine 2014, PMID: 25540326) showed that the rapamycin analog everolimus improved immune function in elderly subjects by ~20%. Low-dose intermittent protocols (1-6mg weekly) are used in longevity medicine to minimize immunosuppressive side effects while maintaining autophagy-enhancing benefits.
Indications
- Longevity optimization and healthspan extension
- Age-related immune decline (immunosenescence)
- Autophagy enhancement and cellular quality control
- mTOR-driven aging pathway modulation
Mechanism of Action
Chronic mTORC1 overactivation drives cellular senescence, suppresses autophagy, and accelerates aging across tissues
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Rapamycin (Sirolimus) | 1-2 mg | Once weekly | Starting dose for longevity protocol; minimal immunosuppression at this level |
| Rapamycin (Sirolimus) | 3-5 mg | Once weekly | Most commonly used longevity dose; target trough <3 ng/mL |
| Rapamycin (Sirolimus) | 5-6 mg | Once weekly, 8 weeks on / 2 weeks off | Higher dose with cycling to prevent chronic immunosuppression |
Safety & Contraindications
- FDA-approved for transplant rejection at HIGH doses; longevity use is OFF-LABEL at LOW doses
- Immunosuppression risk at chronic high doses; intermittent low-dose protocols aim to minimize this
- Monitor lipid panels: may increase LDL cholesterol and triglycerides
- Impaired wound healing possible; hold for 2 weeks before/after surgical procedures
- Mouth ulcers (stomatitis) are the most common side effect; typically mild and dose-dependent
- Contraindicated in active infections, pregnancy, and severe hepatic impairment