Moderate Evidence

Rapamycin

The Easter Island drug

mTOR Inhibitor

Last updated: December 2024

Evidence Level: Moderate Evidence

Some human data, strong animal studies, plausible mechanism

Regulatory Status: FDA-approved as an immunosuppressant (organ transplants) and for certain cancers. Off-label longevity use is experimental.

Rapamycin has the strongest lifespan extension data of any drug tested in mammals. Discovered in the soil of Easter Island in the 1970s, it extended lifespan by 9-26% in mice—even when started late in life. This made longevity researchers take notice. But here's the uncomfortable truth: we don't yet have proof it works in humans for longevity. The 2025 PEARL trial (48 weeks, 114 participants) showed it was safe and well-tolerated at low intermittent doses, with some promising signals for muscle mass in women. But we're far from definitive evidence. Rapamycin works by inhibiting mTOR, a master growth regulator that's overactive with aging. The theory is compelling. The mouse data is remarkable. But translating this to humans requires caution—rapamycin is a potent immunosuppressant at high doses, and long-term effects of low-dose use are unknown.

How It Works

Rapamycin directly inhibits mTOR (mechanistic Target of Rapamycin)—a protein kinase named after the drug itself. Here's why that matters:

The mTOR Pathway
mTOR is your cells' master growth switch. When nutrients are abundant, mTOR signals cells to grow, divide, and build. When resources are scarce (like during fasting), mTOR quiets down, and cells shift to maintenance mode—repairing damage and recycling components. According to Nature Aging, mTOR pathway activity accelerates aging and age-related diseases including cancer, atherosclerosis, diabetes, and declining immune function.

Why Inhibiting mTOR Extends Lifespan
Reduced mTOR signaling is one of the most consistent findings across long-lived species and interventions. Caloric restriction, which extends lifespan across species, works partly through mTOR inhibition. Research in Nature showed rapamycin extended median lifespan by 14% in female mice and 9% in males, even when started at 600 days of age (equivalent to ~60 human years).

Autophagy Enhancement
When mTOR is inhibited, cells activate autophagy—the cellular recycling program that clears damaged proteins, dysfunctional mitochondria, and other debris. This "cellular spring cleaning" may be a key mechanism behind rapamycin's benefits.

mTORC1 vs mTORC2
Rapamycin primarily inhibits mTORC1 (associated with longevity benefits) but with chronic use also affects mTORC2 (which may cause some side effects like insulin resistance). Intermittent dosing may preferentially target mTORC1 while sparing mTORC2—one rationale for weekly rather than daily dosing.

The Caloric Restriction Mimetic Theory
Many researchers consider rapamycin the closest thing to a "caloric restriction in a pill." Both interventions work through overlapping pathways, though rapamycin's effects are metabolically distinct from diet restriction according to research in PLOS Genetics.

Potential Benefits

Most robust lifespan extension in mammalian studies—9-26% in mice across multiple labs
Works even when started late in life (equivalent to 60+ human years in mice)
Delays or ameliorates multiple age-related conditions in animal models: cancer, neurodegeneration, cardiovascular disease
PEARL trial (2025) showed low-dose weekly rapamycin was safe and well-tolerated over 48 weeks
Women in the trial showed significant gains in lean muscle mass at 10mg weekly dose
May enhance vaccine response and immune function at low intermittent doses (paradoxically, despite being an immunosuppressant)
Well-characterized mechanism—we understand why it might work

Risks & Considerations

Human longevity data is limited—we don't have proof it extends human lifespan
Immunosuppression risk, especially at high or continuous doses—increases infection susceptibility
Can impair wound healing and tissue repair
May elevate blood glucose and lipids (cholesterol, triglycerides)
Bryan Johnson discontinued use citing blood glucose elevation, infection susceptibility, and impaired healing
Potential cancer concerns—while rapamycin suppresses tumor initiation, it may support growth of existing tumors
Long-term safety of low-dose intermittent use is unknown
Individual response varies significantly—blood levels can differ 3-4x between people at the same dose
Drug interactions are extensive (metabolized by CYP3A4)—avoid grapefruit, many medications interact

Dosing Information

For longevity (off-label), most protocols use intermittent dosing: typically 3-10mg once weekly, rather than the daily dosing used for transplant immunosuppression. The PEARL trial tested 5mg and 10mg weekly. The goal is to achieve peak blood levels above 10 ng/mL shortly after dosing, with levels dropping below 1 ng/mL within 24-48 hours. This pulsatile exposure may preferentially inhibit mTORC1 (good for longevity) while minimizing mTORC2 inhibition (associated with side effects).

•Commercial (brand-name) and compounded rapamycin have different bioavailability—compounded may be ~31% as bioavailable per mg
•Blood level testing is recommended to personalize dosing, given high individual variability
•Most longevity clinicians start at 3-6mg weekly and adjust based on blood levels and tolerance
•Avoid grapefruit and grapefruit juice—significantly affects drug metabolism
•Some practitioners recommend periodic breaks ("drug holidays") though optimal protocols are unknown
•Take consistently with or without food (absorption may vary with meals)

Practical Tips

1This requires a physician—you cannot (and should not) attempt this without medical supervision
2Consider blood rapamycin level testing (24h post-dose) to verify you're in target range
3Monitor fasting glucose and lipid panels periodically—these can elevate
4Watch for signs of immunosuppression: slow wound healing, frequent infections, mouth sores
5If you get sick or need surgery, discuss pausing rapamycin with your doctor
6Be aware of drug interactions—this interacts with dozens of common medications
7Don't combine with other mTOR-affecting supplements without guidance
8Consider this experimental—the risk/benefit for healthy adults is not established

Key Research

PEARL Trial: 48-Week Safety and Efficacy

GeroScience / medRxiv, 2025

The longest rapamycin longevity trial to date. 114 participants (ages 50-85) received 5mg or 10mg weekly for 48 weeks. Low-dose rapamycin was safe and well-tolerated. Women taking 10mg showed significant gains in lean muscle. Participants on 5mg reported improved emotional well-being and general health.

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Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

Nature, 2009

The landmark study that launched rapamycin longevity research. Rapamycin extended median lifespan by 14% in females and 9% in males when started at 600 days of age. Effects were consistent across three independent test sites.

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Rapamycin-mediated lifespan increase in mice is dose and sex dependent

PLOS Genetics, 2014

Higher doses (threefold increase) extended median lifespan by 23% (males) to 26% (females). Effects were stronger in females at all doses tested. Rapamycin's metabolic effects differ from caloric restriction.

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Targeting the biology of aging with mTOR inhibitors

Nature Aging, 2023

Comprehensive review of mTOR inhibition and aging. Notes that mTOR pathway activity accelerates aging and age-related diseases. Discusses both potential benefits and risks of pharmacological mTOR inhibition in humans.

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Clinical evidence for rapamycin in healthy adults

Aging (Albany NY), 2024

Review concluding that while animal studies show promising effects, human trials have not yet proven rapamycin can safely or effectively slow aging. Calls for larger, better-designed trials before recommending off-label use.

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