Rapamycin

No confirmed human lifespan extension data exists yet. The strongest evidence remains the NIA Interventions Testing Program showing 9 to 26 percent median lifespan extension in mice across three independent sites, dose-dependent and female-biased. Human data is limited to immune biomarker and surrogate endpoints: Mannick 2018 n=264 showed 30.6 percent reduction in respiratory infections persisting 12 months after just 6 weeks of treatment. Mannick 2014 showed ~20 percent improvement in flu vaccine response in elderly subjects on everolimus. The Dog Aging Project TRIAD Phase 1 showed cardiac function improvements in 24 dogs. AgelessRx PEARL (48 weeks, ~150 subjects) showed preliminary visceral fat reduction signal. None of these are lifespan endpoints, though they align with healthspan extension mechanisms.

Community and clinical consensus is 3 to 8 mg once weekly, with 6 mg being a common starting dose for adults 50+. This is dramatically lower than the transplant dose (typically 2 to 5 mg daily) that causes immunosuppression. The key mechanism reason: weekly intermittent dosing selectively targets mTORC1 while sparing mTORC2 per Lamming 2012; continuous daily dosing disrupts both complexes, producing the metabolic side effects (insulin resistance, immune suppression) seen at transplant doses. Trough blood levels on weekly dosing typically run 5 to 15 ng/mL (vs 5 to 15 ng/mL target for transplant but with continuous daily exposure). CYP3A5 polymorphisms significantly affect metabolism; some individuals need level monitoring to land in the target range. Starting low (3 mg) and titrating to effect or target blood level is conservative and appropriate.

Low-dose intermittent rapamycin has a substantially different safety profile than transplant dosing. Zero cases of pneumonitis have been reported at longevity doses (3 to 8 mg weekly), though pneumonitis is idiosyncratic and can be fatal at oncology doses (2 to 15 percent incidence). No catastrophic floor triggered because zero cases exist at longevity doses and the mechanism appears dose-dependent. Lipid elevation (15 to 30 percent) and potential insulin resistance from chronic mTORC2 disruption are real metabolic concerns. Wound healing impairment requires holding the drug 1 to 2 weeks before and after surgery. Mouth ulcers (aphthous stomatitis) occur in 5 to 15 percent of trial participants and 20 to 40 percent of forum users. No long-term controlled safety data beyond ~12 months in healthy adults (PEARL 48 weeks was the longest). Safety Risk scored 2.8 reflects real pharmacological risks, but well below the catastrophic floor.

Most common: mouth ulcers (5 to 15 percent in clinical trials, 20 to 40 percent in community surveys) presenting as aphthous stomatitis within days of dosing, typically resolving within a week. Lipid elevation: LDL and triglycerides rise 15 to 30 percent in a subset of users and require monitoring. Mild GI effects in early weeks. Fatigue on dose day is a common forum complaint. Acne or skin changes occasionally reported. Insulin resistance emerges in roughly 10 percent with chronic use and may be more common with daily than weekly dosing (mTORC2 mechanism). Most side effects are manageable with dose adjustment, supportive care (L-lysine or colloidal silver for mouth ulcers), and lipid-management supplements like berberine or bergamot if needed. Dropout from longevity protocols is typically 10 to 20 percent due to side effects.

Several legitimate paths. Telehealth longevity services including AgelessRx and Healthspan offer rapamycin prescribing with integrated blood work monitoring; convenient and affordable but requires navigating their protocols. Longevity and functional medicine clinics including Healthspan Clinic, Modern Aging, and individual longevity-oriented physicians prescribe increasingly frequently; find via word-of-mouth in longevity community forums, podcast listener communities, and directories like the American Academy of Anti-Aging Medicine. Primary care physicians rarely prescribe off-label rapamycin without specialty referral. Geroscience-trained physicians are the target: those who have attended conferences like TAME, RAADfest, or the American Academy of Anti-Aging Medicine. Dr. Alan Green was a pioneer but is not accepting new patients. Expect $200 to $400 initial visit + quarterly follow-ups plus blood work costs. Compounding pharmacies (Strive, Belmar, Empower) are preferred fill sources for the weekly-dose size.

Seven contraindications. History of interstitial lung disease or pneumonitis (even at low doses the mechanism exists). Active immunosuppression from other drugs (tacrolimus, cyclosporine, corticosteroids, chemotherapy). HIV infection with low CD4 count. Pregnancy, planning pregnancy within 3 months, or breastfeeding (teratogenic class C). Upcoming surgery without 1 to 2 week drug-free window. Active infection including recurrent herpes, hepatitis, or tuberculosis. Concurrent CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir, grapefruit) without prescriber guidance on dose adjustment. Relative cautions include unwillingness to do regular blood work, lipid disorders already requiring management, type 2 diabetes with HbA1c above 8, age under 40 (risk-benefit likely unfavorable), elite WADA-tested athletes (not on banned list but complicates immune health during training blocks).

Rapamycin stacks cleanly with most longevity protocols. Metformin is frequently combined, though 2025 data suggested metformin may blunt some rapamycin benefits in animals; Nir Barzilai's TAME trial is the standard reference. NAD+ precursors (NMN, NR) target an orthogonal mechanism (sirtuin activation, NAD pool restoration) and are commonly stacked. Senolytics (quercetin, fisetin, dasatinib) complement mTORC1 inhibition with direct senescent-cell elimination; Peter Attia's protocol pairs rapamycin weekly with monthly senolytic cycles. Exercise, sauna, and caloric restriction all activate autophagy pathways that rapamycin also engages; stacking reinforces the mechanism but the marginal return declines. Creatine, omega-3, vitamin D, and magnesium are all neutral-positive with rapamycin. Avoid high-dose BCAAs around dose days (mTORC1 activation counter to the mTORC1 inhibition goal). Avoid grapefruit during the dosing day (CYP3A4 inhibition increases peak blood level).