Rapamycin (Sirolimus)

Mechanism of Action

Rapamycin binds the intracellular protein FKBP12, and the rapamycin-FKBP12 complex inhibits mechanistic target of rapamycin complex 1 (mTORC1), a serine/threonine kinase that integrates nutrient sensing, growth factor signaling, and cellular energy status. mTORC1 inhibition suppresses S6K1-mediated ribosomal protein synthesis, activates ULK1-mediated autophagy and mitophagy, enhances lysosomal biogenesis via TFEB nuclear translocation, reduces senescent cell accumulation, and suppresses the SASP (senescence-associated secretory phenotype). At higher chronic doses, rapamycin also inhibits mTORC2, which regulates Akt-mediated insulin signaling — this is believed to drive the metabolic side effects.

Dosing Protocol

Notes

Rapamycin is the most robust pharmacological lifespan extender identified in the NIA Interventions Testing Program, extending median lifespan in mice by 9-14% even when started late in life. The PEARL trial demonstrated safety of 5 mg or 10 mg weekly in healthy older adults for 12 months, with the 10 mg dose preventing muscle loss in women and bone loss in men. CRITICAL: Weekly pulsed dosing is essential for longevity use — daily dosing causes mTORC2 inhibition and metabolic side effects (insulin resistance, immunosuppression). Required bloodwork: CBC with differential, CMP, lipid panel, fasting glucose, fasting insulin, rapamycin trough levels (optional), inflammatory markers (hs-CRP, IL-6). Monitor every 3 months for first year, then every 6 months. Lipid management (statin or lifestyle) may be needed. Dental hygiene is important (mouth ulcer prevention). Medical supervision required.

Stacking

• Metformin (complementary AMPK activation)
• Acarbose (ITP-validated combination)
• Vitamin D3 (immune support during mild immunomodulation)
• NAD+ precursors

Interactions

• CYP3A4 inhibitors (ketoconazole, grapefruit, erythromycin) [HIGH] — Dramatically increase rapamycin blood levels. Grapefruit is sometimes used intentionally but requires careful dose adjustment.
• CYP3A4 inducers (rifampin, carbamazepine, St. John's Wort) [HIGH] — Significantly reduce rapamycin levels, potentially below therapeutic threshold.
• Live vaccines [HIGH] — Rapamycin is immunosuppressive; live vaccines are contraindicated.
• Cyclosporine [HIGH] — Synergistic nephrotoxicity. Do not combine.
• Metformin [LOW] — Complementary longevity mechanisms. The ITP tested acarbose + rapamycin with additive lifespan extension in mice.
• CYP3A4 substrate — grapefruit increases levels
• Avoid with strong CYP3A4 inhibitors (ketoconazole, clarithromycin)
• Monitor with statins

Contraindications

• Active infections (immunosuppression risk)
• Poorly healing wounds or planned surgery (delays wound healing)
• Severe hepatic impairment
• Uncontrolled hyperlipidemia
• Pregnancy and breastfeeding
• Organ transplant patients on calcineurin inhibitors (specialized dosing required)
• Active infection
• Immunocompromised states
• Poorly controlled diabetes
• Wound healing (pause 2 weeks pre-surgery)

Side Effects

• Mouth ulcers/canker sores (most common, dose-dependent)
• Elevated lipids (triglycerides and LDL — typically manageable with weekly dosing)
• Impaired wound healing
• Mild immunosuppression (increased susceptibility to infections)
• Insulin resistance (primarily from mTORC2 inhibition at higher/daily doses)
• Acne-like skin eruptions
• Thrombocytopenia and leukopenia (rare at longevity doses)

Key Papers

• 10.1126/scitranslmed.aaa5509
• 10.1016/S2666-7568(23)00258-1
• 10.18632/aging.206300
• Mannick et al. 2018 - mTOR inhibition improves immune function in elderly (Science Translational Medicine)

Source Quality

FDA-approved pharmaceutical (Rapamune). Generic sirolimus available. Tablets (1 mg, 2 mg) or oral solution. Store at room temperature. Some longevity practitioners use compounding pharmacies for custom dosing.

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