Rapamycin for Longevity: Dosing Recommendations
There is no FDA-approved or guideline-supported dosing regimen for rapamycin specifically for longevity purposes, as this remains an off-label use without established clinical standards for healthy aging. However, emerging research and real-world data suggest intermittent low-dose regimens may offer a therapeutic window that balances potential benefits against known risks 1, 2.
Critical Context: Off-Label Use Without Regulatory Approval
Rapamycin (sirolimus) and its analogs are FDA-approved only for transplant rejection prevention and seizure treatment in Tuberous Sclerosis Complex—not for anti-aging or longevity 1. The use for longevity represents experimental off-label prescribing by physicians and "biohackers" despite lacking broad clinical recognition 1.
Dosing Strategies from Research Evidence
Intermittent Dosing Approach
The most promising strategy for longevity appears to be intermittent rather than daily dosing, which may reduce metabolic and immunosuppressive side effects while preserving anti-aging benefits:
2 mg/kg every 5 days extended lifespan in female mice when started at 20 months of age (equivalent to late middle age), with reduced impact on glucose homeostasis and immune function compared to chronic treatment 3
Transient treatment for just 3 months in middle-aged mice increased life expectancy by up to 60% with persistent effects, suggesting short-term treatment may have durable benefits 4
Real-World Human Dosing Patterns
In actual longevity medicine practice, two formulations show different bioavailability profiles:
Commercial rapamycin: Doses of 2-8 mg weekly are commonly used, with linear dose-to-blood level relationships 5
Compounded rapamycin: Doses of 5-15 mg weekly show approximately 31% bioavailability compared to commercial formulations per milligram 5
Peak blood levels occur 2 days post-dose with gradual decline thereafter, suggesting once-weekly dosing may be appropriate 5
Monitoring Requirements (Extrapolated from Approved Uses)
If rapamycin is used off-label for longevity, rigorous monitoring based on transplant medicine guidelines is essential:
Baseline assessment: Obtain cholesterol, triglycerides, CBC, creatinine, and blood pressure before initiating therapy 6
Ongoing monitoring: Check CBC, creatinine, blood pressure, and lipid panels regularly during treatment 6
Drug concentration monitoring: Measure trough levels when safety concerns arise, adherence is questioned, or efficacy appears inadequate 6
Target trough levels: For approved indications, everolimus targets 5-15 ng/mL, though levels should not exceed 15 ng/mL 6. For sirolimus in transplant, targets are 3-10 ng/mL 7
Individual blood level monitoring is critical due to substantial inter-individual variability in rapamycin bioavailability, though individuals show relative consistency over time 5
Critical Safety Considerations
The side effect profile from approved uses must inform longevity applications:
Hyperlipidemia is a major concern requiring monitoring and potential treatment 6
Pulmonary toxicity: Evaluate for new or worsening respiratory symptoms, as sirolimus can cause pneumonitis 6
Wound healing impairment: Dose adjustments or alternative approaches needed in patients at risk for poor wound healing 6
Immunosuppression and infection risk: While intermittent dosing may reduce this risk, it remains a concern from continuous use data 1, 2
Metabolic disruptions: Including effects on glucose homeostasis, though intermittent dosing appears to mitigate this 2, 3
Stomatitis and menstrual irregularities: Common with everolimus, dose-dependent 7
The Therapeutic Window Hypothesis
Current scientific thinking suggests that mTORC1 inhibition promotes healthy aging, while "off-target" mTORC2 inhibition causes many adverse effects 2. Intermittent dosing may exploit differences in inhibition kinetics between these two complexes, allowing selective mTORC1 inhibition 2. However, optimal dosing schedules and long-term efficacy in humans remain unknown and are subjects of ongoing clinical trials 2.
Major Caveats and Clinical Pitfalls
No established efficacy data in humans for longevity outcomes (mortality, morbidity, quality of life) exist 1, 2
Formulation matters significantly: Compounded rapamycin has markedly lower bioavailability than commercial products, requiring dose adjustment 5
Drug interactions are extensive: Rapamycin is metabolized via cytochrome P-450 3A4 and P-glycoprotein pathways, with numerous medications affecting levels 6
The dose that fails to extend lifespan may shift cancer patterns: Research shows certain doses can increase aggressive hematopoietic cancers while reducing other malignancies 4
Rebound growth of treated lesions: In TSC patients, discontinuing mTOR inhibitors after 12 months can lead to angiomyolipoma regrowth, suggesting continuous or repeated treatment may be necessary 7