Rapamycin (Sirolimus)
Executive Summary
Rapamycin is an FDA-approved immunosuppressant (primarily used in organ transplant) that inhibits the mechanistic Target of Rapamycin (mTOR) pathway. It is currently considered the most robust pharmacological intervention for lifespan extension in mammalian models (ITP data). Human trials for geroprotection are ongoing, utilizing a once-weekly pulsed dosing schedule to mitigate side effects.
Mechanism of Action
Rapamycin forms a complex with FKBP12, which then binds to and inhibits the mTOR Complex 1 (mTORC1). mTOR is a central nutrient-sensing kinase. When nutrients (especially amino acids) are abundant, mTORC1 promotes cellular growth, protein synthesis, and proliferation while inhibiting autophagy (cellular cleanup).
By inhibiting mTORC1, Rapamycin essentially tricks the cell into a state of perceived nutrient scarcity, inducing autophagy and downregulating processes associated with cellular senescence and aging.
Chronic, daily dosing of Rapamycin (as used in transplant patients) eventually inhibits mTORC2, leading to negative metabolic consequences including insulin resistance and hyperlipidemia. Geroprotective protocols use pulsed (weekly) dosing to selectively inhibit mTORC1 while sparing mTORC2.
Standard Geroprotective Protocol (Off-label)
Note: This protocol reflects current practices by longevity physicians indexed in our directory. It is not medical advice.
| Dosage | 5mg to 8mg |
| Frequency | Once weekly |
| Administration | Oral, typically taken with a fatty meal to increase bioavailability. |
| Monitoring | Lipid panel, HbA1c, Complete Blood Count (CBC) every 8-12 weeks. |
Clinical Trial Status (Human)
- PEARL Trial (Participatory Evaluation of Aging with Rapamycin for Longevity): A double-blind, randomized, placebo-controlled trial evaluating safety and efficacy of multiple dosing regimens in healthy adults. Status: Active, data expected 2025.
- Mannick et al. (2014 & 2018): Demonstrated that RAD001 (a rapalog) improved immune function and decreased infection rates in the elderly. View Paper
Known Adverse Effects (Weekly Dosing)
While weekly dosing drastically reduces the side effects seen in transplant patients, clinicians commonly report:
- Aphthous ulcers (mouth sores) - affects ~15% of patients, usually transient.
- Mild, reversible dyslipidemia (increase in LDL-C and triglycerides).
- Slight elevations in fasting glucose.