Rapamycin Longevity Protocol: Dosing, Risks & What the Research Shows
The only drug proven to extend mammalian lifespan even when started late in life. But the dose, schedule, and drug interactions matter enormously.
TL;DR -- Rapamycin for longevity is taken WEEKLY (1--6mg), not daily. Intermittent dosing captures mTOR inhibition benefits while minimizing immunosuppression. Prescription only. Grapefruit warning. Not for everyone.
Background
What Is Rapamycin?
Rapamycin (sirolimus) is an mTOR inhibitor originally developed as an immunosuppressant for organ transplant rejection. At the high daily doses used in transplant medicine, it meaningfully blunts immune function. At the low intermittent doses used off-label for longevity, the mechanism is entirely different.
mTOR (mechanistic target of rapamycin) is a central cellular nutrient sensor. When mTOR is active, cells are in growth and anabolic mode. When inhibited -- as happens during fasting or caloric restriction -- cells shift toward autophagy (cellular cleanup), repair, and maintenance. Rapamycin mimics this signal pharmacologically.
The Interventions Testing Program (ITP), a rigorous NIA-funded multi-site study, found rapamycin extended median lifespan in mice by 14% in males and 9% in females -- even when treatment began at the equivalent of 60 human years. It is the first drug to demonstrate mammalian lifespan extension starting in old age.
Why it matters: Virtually every longevity intervention tested in mice has failed to translate. Rapamycin is the rare exception with replicated data across multiple independent labs and species.
The Key Insight
Why Weekly Dosing -- Not Daily
This is the most important and misunderstood aspect of longevity rapamycin use. Context matters entirely:
Daily high-dose (transplant dosing): Approved for organ transplant rejection. Causes clinically significant immunosuppression. Not what longevity researchers use.
Weekly low-dose (longevity dosing): mTOR is inhibited for 1--3 days, then recovers before the next dose. Net mTOR inhibition benefit is captured during the inhibition window. Immune function recovers during off days.
The theoretical basis comes from Blagosklonny's intermittent dosing hypothesis: the immune system is allowed to rebound during the days between doses, meaning chronic immunosuppression does not develop the way it does with daily dosing. The net result is mTOR inhibition benefit with substantially reduced immune risk.
What researchers actually take:
Peter Attia protocol: 5--6mg weekly
Bryan Johnson protocol: 13mg biweekly (higher, more controversial, not widely recommended)
Protocol Reference
Rapamycin Longevity Dosing
These ranges reflect off-label longevity use as discussed in published literature and by longevity physicians. This is not a prescription. Always work with a physician.
Starting dose
1mg/week (assess tolerance)
Common longevity dose
2--6mg/week
Attia protocol
5mg/week
Johnson protocol
13mg biweekly
Form
Oral tablet or compounded liquid
Timing
Same day each week, with or without food
Grapefruit
Strictly avoid -- see below
Prescription
Required in the US
Blood level monitoring: Some physicians check sirolimus trough levels periodically to confirm appropriate exposure. This is especially important when adjusting dose or if side effects appear.
Critical Interaction
Grapefruit and CYP3A4 Warning
Rapamycin is metabolized by the CYP3A4 enzyme in the liver and intestinal wall. Grapefruit and grapefruit juice contain furanocoumarins that irreversibly inhibit CYP3A4 -- meaning the enzyme cannot clear rapamycin at a normal rate.
Grapefruit can increase rapamycin blood levels by 3--7x. At 5mg/week, that is the equivalent of taking 15--35mg -- entering transplant-level dosing territory. This dramatically raises the risk of immunosuppression and toxicity.
Also dangerous: Seville oranges (used in marmalades), starfruit, and pomelo. Avoid for at least 48 hours around each dose -- ideally eliminate entirely.
The same CYP3A4 pathway is shared by many common drugs: statins (especially simvastatin/lovastatin), calcium channel blockers (amlodipine, diltiazem), antifungals (fluconazole, itraconazole), and more. Always review drug interactions with your prescribing physician.
Safety
Side Effects at Longevity Doses
At low weekly doses, most users tolerate rapamycin well. Side effects that appear at transplant doses are substantially less common at longevity doses, though individual response varies.
| Side Effect | Frequency | Management |
|---|
Mouth sores
Aphthous ulcers |
Common at start |
Usually resolves; dose-reduce if severe |
| Elevated triglycerides / cholesterol |
Moderate |
Monitor lipids quarterly |
| Delayed wound healing |
Higher doses |
Pause 2 weeks before any surgery |
| GI upset |
Mild |
Take with food |
| Increased infection risk |
Low at weekly doses |
Monitor; avoid if immunocompromised |
Testicular atrophy
Animal studies; low human evidence |
Unconfirmed at longevity doses |
Discuss with physician if fertility is a concern |
Contraindications
Who Should Not Take Rapamycin
Rapamycin is not appropriate for everyone. Even at low longevity doses, certain situations make use inadvisable or outright dangerous.
Do not use rapamycin if you have any of the following:
- Active infection of any kind
- Pregnancy or breastfeeding
- Immunocompromised baseline (HIV, active cancer treatment, primary immunodeficiency)
- Surgery planned within 4 weeks -- rapamycin impairs wound healing and should be paused
- Taking strong CYP3A4 inhibitors (azole antifungals, certain macrolide antibiotics, HIV protease inhibitors) or inducers (rifampin, carbamazepine, St. John's Wort) without physician supervision and dose adjustment
- Known hypersensitivity to sirolimus or its derivatives
FAQ
Common Questions
Is rapamycin safe for longevity use?
At the low weekly doses used for longevity (1--6mg/week), rapamycin appears well-tolerated in most healthy adults based on off-label use data. Common side effects include mouth sores and mild GI upset, which often resolve with time or dose reduction. However, rapamycin is a prescription drug with real risks including delayed wound healing and lipid changes. It should only be used under physician supervision with periodic monitoring.
How does rapamycin extend lifespan?
Rapamycin inhibits mTOR (mechanistic target of rapamycin), a central nutrient-sensing pathway. When mTOR is periodically inhibited, cells upregulate autophagy (cellular cleanup), reduce senescent cell accumulation, and shift toward maintenance and repair mode -- similar to the effects of caloric restriction. In multiple model organisms including mice, this has translated to measurable lifespan extension replicated across independent labs.
What dose does Peter Attia take?
Peter Attia has publicly discussed taking approximately 5mg of rapamycin once per week as part of his longevity protocol. He has noted adjusting this over time and emphasizes that dose must be individualized with physician oversight. He monitors lipids and other markers regularly while on it.
Can I get rapamycin without a prescription?
No. Rapamycin (sirolimus) is a prescription-only medication in the United States and most countries. It is not available legally over the counter. Obtaining it through longevity-focused physicians who prescribe it off-label is the standard approach. Compounding pharmacies can also provide liquid formulations when prescribed.
Does rapamycin affect fertility?
Animal studies have shown testicular atrophy and fertility impairment at high doses. Human evidence at low weekly longevity doses is limited and inconclusive. Until more data exists, individuals concerned about fertility -- especially males -- should discuss this risk with their physician before starting rapamycin. Some physicians advise a washout period before attempting conception.
Can I eat grapefruit while taking rapamycin?
No. Grapefruit and grapefruit juice strongly inhibit CYP3A4, the enzyme that metabolizes rapamycin. Eating grapefruit can increase rapamycin blood levels by 3--7x, dramatically raising the risk of side effects and toxicity. Avoid grapefruit, Seville oranges, and starfruit for at least 48 hours around each dose -- many physicians recommend avoiding them entirely while on rapamycin.
