Rapamycin (Sirolimus) for Longevity & Aging — Aging
mTOR inhibitor and FDA-approved immunosuppressant under investigation as the most robust pharmacological longevity intervention.
Overview
Rapamycin (sirolimus) is a macrolide compound produced by Streptomyces hygroscopicus, first discovered on Easter Island (Rapa Nui). It is an allosteric inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), a master kinase that integrates nutrient, energy, and growth factor signals to regulate cell growth, proliferation, and autophagy. FDA-approved as an immunosuppressant for organ transplant rejection prevention (Rapamune), rapamycin has emerged as the most consistently replicated pharmacological longevity intervention across species. The NIA Interventions Testing Program (ITP) demonstrated that rapamycin extends median lifespan in genetically heterogeneous mice by 10-15% even when started late in life. Additional preclinical studies show it delays age-related diseases including cancer, neurodegeneration, and cardiovascular disease. At immunosuppressive doses (daily), rapamycin increases infection risk and metabolic dysfunction. However, the longevity community employs intermittent low-dose protocols (e.g., 3-6 mg once weekly) hypothesizing that brief, pulsatile mTORC1 inhibition enhances autophagy and reduces senescent cell burden without chronic immunosuppression. Human trials are ongoing (PEARL trial, dog aging project), but clinical evidence for longevity in humans remains preliminary.
Indications
- FDA-approved: Prophylaxis of organ transplant rejection (kidney)
- FDA-approved: Lymphangioleiomyomatosis (LAM)
- Off-label: Longevity and healthspan extension (intermittent low-dose)
- Off-label: Anti-aging skin protocols (topical rapamycin)
- Investigational: Age-related disease prevention
Mechanism of Action
Rapamycin binds to the intracellular protein FKBP12, forming a complex that allosterically inhibits mTORC1
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Rapamycin (Sirolimus) | 3-6 mg | Once weekly | Most common longevity protocol; intermittent dosing |
| Rapamycin (Sirolimus) | 1-2 mg | Once weekly | Conservative starting dose for longevity |
| Rapamycin (Sirolimus) | 2 mg | Once daily (loading dose) | FDA-approved transplant dose — NOT for longevity use |
| Rapamycin cream | 0.1% | Once daily to face | Anti-aging skin application — investigational |
Evidence Grade
GRADE B
Safety & Contraindications
- Immunosuppression — increased infection risk (dose and frequency dependent)
- Aphthous ulcers (mouth sores) — most common side effect at any dose
- Dyslipidemia — elevates LDL cholesterol and triglycerides
- Impaired glucose tolerance and insulin resistance with chronic use
- Impaired wound healing
- Thrombocytopenia and leukopenia possible
- Drug interactions: strong CYP3A4 substrate — grapefruit dramatically increases levels
- Intermittent dosing may mitigate many side effects but long-term safety data in healthy humans is lacking