Rapamycin (sirolimus) — evidence review

Regulatory status: prescription medication (immunosuppressant / mTOR inhibitor), used off-label for longevity

• **Prevention of kidney-transplant rejection** (approved use).
• **Stabilization of lung function in LAM** (approved use).
• **Human lifespan extension** (longevity claim).
• **Human healthspan / delayed age-related disease** (longevity claim).
• **Improvement of human aging biomarkers** (body composition, blood markers, epigenetic clocks, quality-of-life scores).
• **Improved immune function / fewer respiratory infections in older adults** (often cited from everolimus / RTB101 trials, not sirolimus).
• **Preservation or gain of lean mass; less visceral fat.**
• **Better physical function or larger exercise adaptations.**
• **Better cardiac aging** (mostly dog and mouse data).
• **Cancer prevention** (longevity / transplant-conversion claim).

Sirolimus is a real drug with two established human indications — kidney-transplant immunosuppression and LAM — and a boxed warning for infection and malignancy. In genetically heterogeneous mice, NIA ITP and independent labs have repeatedly extended median and late-life survival, sometimes by more than 20% at higher dietary doses; that is strong **animal** evidence and it is **not** a human aging result. In humans who are not transplant or LAM patients, the longest dedicated RCT (PEARL, 48 weeks, compounded weekly product, sponsor sells the drug) missed its primary endpoint; the only other modern weekly-sirolimus RCT in older adults (RAPA-EX-01, 13 weeks) did not improve function and, on sensitivity analyses, blunted the exercise response, with a heavier AE load and a pneumonia SAE. Immune “rejuvenation” citations are mostly **everolimus / RTB101**, and the phase 3 infection trial failed. Metabolic harm (lipids, insulin resistance via mTORC2), stomatitis, impaired wound healing, and fertility effects are documented, not hypothetical.