Rapamycin

Rapamycin (Sirolimus) is a macrolide compound originally discovered in soil bacteria on Easter Island (Rapa Nui). Initially used as an immunosuppressant for organ transplant, it has become the most studied pharmacological longevity intervention due to its consistent lifespan extension across species — from yeast to mice. Low-dose, intermittent protocols are being studied for human longevity.

Binds FKBP12 protein, and this complex inhibits mTOR complex 1 (mTORC1), a master regulator of cell growth and metabolism. mTORC1 inhibition activates autophagy (cellular recycling), reduces protein synthesis overhead, shifts metabolism toward oxidative phosphorylation, reduces cellular senescence, and mimics caloric restriction signaling. Intermittent dosing avoids chronic mTORC2 suppression that causes immunosuppression.

Oral half-life approximately 60 hours in healthy adults. Peak plasma levels reached in 1–2 hours. Highly lipophilic with extensive tissue distribution. Longevity protocols typically use 3–8 mg once weekly (rather than daily immunosuppressive dosing).

Longevity and healthspan extension, mTOR pathway modulation, immunomodulation (paradoxical immune enhancement at low doses), senolytic synergy, cancer prevention, cognitive preservation.

FDA-approved as immunosuppressant (Rapamune, 1999) and for lymphangioleiomyomatosis. Lifespan extension proven in mice (ITP, NIA). Human longevity trials ongoing (PEARL, AgelessRx trials). Low-dose safety profile favorable in early human data.

• Rapamycin and aging — Nature · doi.org
• mTOR pathway in longevity — Cell · doi.org
• Low-dose rapamycin in elderly — Science Translational Medicine · doi.org
• Sirolimus clinical pharmacokinetics · doi.org