Rapamycin: The Most Promising Longevity Drug?

Rapamycin (also called sirolimus) was discovered in 1972 in soil samples from Easter Island (Rapa Nui—hence the name). Originally developed as an antifungal, it was later found to have powerful immunosuppressive properties and is now FDA-approved for:

• Organ transplant rejection prevention: Used since 1999 to prevent the body from rejecting transplanted kidneys, livers, and hearts
• Coating for heart stents: Drug-eluting stents use rapamycin to prevent tissue regrowth
• Certain cancers: mTOR inhibitors are used in some cancer treatments

It works by inhibiting a protein complex called mTOR (mechanistic target of rapamycin)—named after the drug that led to its discovery. mTOR is a master regulator of cell growth, metabolism, and aging.

To understand why rapamycin is so interesting for longevity, you need to understand mTOR.

What mTOR Does

mTOR integrates signals from nutrients, growth factors, and energy status to control:

• Protein synthesis: Building new proteins (growth)
• Autophagy: Cellular cleanup and recycling (suppressed when mTOR is active)
• Cell division: Proliferation and growth
• Metabolism: Energy use and storage

The Aging Connection

Here's the key insight: mTOR activity tends to remain high throughout life, even when it might be better to dial it back.

In youth, high mTOR makes sense—you need to grow, develop, and reproduce. But in later life, persistently high mTOR may contribute to:

• Reduced autophagy (garbage accumulates in cells)
• Cellular senescence (zombie cells that won't die)
• Stem cell exhaustion
• Increased cancer risk (uncontrolled growth)
• Metabolic dysfunction

This is sometimes called the "hyperfunction theory of aging"—the idea that aging isn't just about things breaking down, but about developmental programs that continue running when they shouldn't.

Caloric restriction, which consistently extends lifespan across species, works partly by reducing mTOR activity. Rapamycin essentially mimics this effect pharmacologically.

Rapamycin has been tested extensively in the NIA Interventions Testing Program (ITP), the gold standard for rodent longevity studies. The results are striking:

ITP Findings

• First ITP test (2009): Even when started at 20 months (elderly for mice), rapamycin extended median lifespan by 9% in males and 14% in females
• Started earlier: When begun at 9 months, lifespan extension was even greater—up to 23% in some studies
• Consistent across sites: Results replicated across all three independent ITP testing facilities
• Robust across strains: Works in genetically diverse mice, not just one inbred strain

For context: No other drug has shown this level of consistent, robust lifespan extension in the ITP. Metformin showed modest effects only in males. Resveratrol failed. NR (nicotinamide riboside) failed. Rapamycin works—repeatedly.

Effects Beyond Lifespan

Mouse studies also show rapamycin improves:

• Cardiac function in aged mice
• Cognitive function and memory
• Immune function (paradoxically, despite immunosuppression—more on this later)
• Muscle maintenance
• Tendon strength

The Dog Aging Project

The Dog Aging Project, led by Matt Kaeberlein (before he left academia), has been testing low-dose rapamycin in companion dogs. Early results showed improvements in cardiac function after just 10 weeks of treatment. Larger, longer studies are ongoing.

Dogs are important because they're more similar to humans than mice, share our environment, and develop many of the same age-related diseases.

Here's where it gets interesting and counterintuitive. Rapamycin is used clinically as an immunosuppressant—it's given to transplant patients specifically to prevent immune rejection. So why would an immunosuppressant extend lifespan?

High Dose vs. Low Dose: Different Effects

The answer lies in dosing and timing:

• High-dose, continuous rapamycin (transplant doses): Suppresses T-cell function, increases infection risk
• Low-dose, intermittent rapamycin (longevity protocols): May actually improve immune function

A 2014 study in Science Translational Medicine by Novartis scientists found that in elderly humans, a rapamycin analog (everolimus) given at low doses for 6 weeks improved response to flu vaccination by about 20%—the opposite of what you'd expect from an immunosuppressant.

How This Might Work

The immune system ages too (immunosenescence). Low-dose mTOR inhibition may:

• Reduce production of dysfunctional, senescent immune cells
• Improve stem cell function in the immune system
• Shift immune cells toward a more "youthful" phenotype
• Reduce chronic inflammation (inflammaging)

In other words, a tired, aging immune system might benefit from mTOR inhibition more than it's harmed by it—at least at low doses.

Here's the honest assessment: we don't have randomized trials showing rapamycin extends human lifespan. But we have some interesting signals:

The Mannick/Novartis Studies

Joan Mannick at Novartis (now at resTORbio/Tornado Therapeutics) has run the most relevant human studies:

• 2014 study: Low-dose everolimus improved flu vaccine response in elderly by ~20%
• 2018 study: Low-dose combination of mTOR inhibitors reduced respiratory infections in elderly by ~40%

These aren't lifespan studies, but they suggest low-dose mTOR inhibition can provide health benefits in older humans.

Transplant Patient Observations

Interestingly, transplant patients on rapamycin (sirolimus) have been observed to have:

• Lower cancer rates compared to other immunosuppressants (like cyclosporine)
• Potentially better cardiovascular outcomes
• Some suggestion of reduced age-related disease

These are observational findings with many confounders, but they're consistent with the mechanism.

What We Don't Have

No randomized controlled trial has tested:

• Whether low-dose rapamycin extends human lifespan
• Long-term safety of low-dose, intermittent protocols in healthy adults
• Optimal dosing for longevity (dose, frequency, duration)

Rapamycin has a well-characterized side effect profile from clinical use, but remember—that's at high, continuous doses. Low-dose, intermittent protocols may have different risk profiles.

Known Side Effects (Clinical Doses)

• Mouth sores (aphthous ulcers): Common, often dose-limiting. Usually reversible.
• Metabolic effects: Can raise blood glucose, cholesterol, and triglycerides
• Infection risk: Increased at immunosuppressive doses
• Wound healing: Slowed wound healing (problematic for surgery)
• Blood counts: Can lower platelets and white blood cells
• Edema: Leg swelling in some patients
• Interstitial lung disease: Rare but serious (more common with higher doses)

Low-Dose Observations

At low, intermittent doses used in longevity protocols (typically 5-6mg once weekly):

• Mouth sores are less common but still occur in some people
• Metabolic effects are generally minimal but should be monitored
• Infection risk appears low, though long-term data is limited
• Some people report feeling "off" or having GI symptoms

Specific Concerns for Self-Experimenters

• Wound healing: Stop rapamycin before any planned surgery (weeks in advance)
• Vaccines: May affect response to live vaccines (avoid or time carefully)
• Infections: Be cautious during cold/flu season; monitor for infections
• Drug interactions: Rapamycin interacts with many medications; check carefully
• Testicular effects: Animal data suggests possible testicular atrophy; relevance to humans unclear

Unlike metformin, where longevity experts are split, rapamycin generates more consistent interest—though approaches vary.

Matt Kaeberlein (Former UW Researcher)

Kaeberlein is perhaps the most prominent rapamycin researcher/advocate. He:

• Led the Dog Aging Project testing rapamycin
• Has taken rapamycin himself (intermittent, low-dose protocol)
• Believes the mouse data is strong enough to warrant careful human experimentation
• Emphasizes the importance of intermittent dosing and monitoring

Peter Attia, MD

Attia has discussed rapamycin extensively on his podcast and in his practice:

• Uses rapamycin with some patients (carefully selected, monitored)
• Typically prescribes 5-6mg weekly (intermittent protocol)
• Monitors metabolic markers, immune function
• More enthusiastic about rapamycin than metformin based on the data

Alan Green, MD

A physician who has been prescribing rapamycin for longevity since 2016:

• Has treated hundreds of patients with weekly rapamycin
• Reports minimal side effects at low doses
• Claims improvements in various aging markers
• More aggressive advocate than most researchers

Typical Longevity Protocol

When rapamycin is used off-label for longevity, common approaches include:

• Dose: 3-6mg once weekly (varies by body weight)
• Cycling: Some take it every week continuously; others do 8 weeks on, 4 weeks off
• Monitoring: Lipids, blood glucose, CBC, immune markers every 3-6 months
• Adjustments: Dose reductions if side effects occur

Rapamycin is a prescription medication, so you can't just buy it over the counter. Here's the landscape:

Prescription Access

• Off-label prescribing: Some physicians will prescribe rapamycin off-label for longevity purposes. This requires a willing, knowledgeable doctor.
• Longevity clinics: Some specialized longevity/anti-aging clinics offer rapamycin as part of their protocols
• Telehealth: A few telehealth providers now prescribe rapamycin for longevity (with appropriate screening)

Cost

• Generic sirolimus: Relatively affordable at longevity doses—often $50-150/month
• Brand name Rapamune: More expensive, rarely necessary
• Compounded versions: Some compounding pharmacies offer custom formulations

Insurance

Insurance typically won't cover rapamycin for longevity purposes. Some patients have gotten coverage by having it prescribed for an FDA-approved indication if applicable, but this isn't usually an option for healthy adults.

International Sources

Some people obtain rapamycin from international pharmacies, which is legally gray and carries additional risks around authenticity and quality. This approach isn't recommended.

This is the central question, and reasonable people disagree. Here's a framework for thinking about it:

Arguments For Trying It

• Mouse data is the strongest of any longevity intervention
• Mechanism (mTOR inhibition) is well-understood and conserved across species
• Human safety data exists (decades of clinical use, though at higher doses)
• Early human studies show immune benefits at low doses
• Some leading researchers take it themselves
• We have limited time—waiting for perfect data means missing potential benefits

Arguments For Waiting

• No human lifespan data exists
• Long-term safety of low-dose, intermittent use is unknown
• Side effects are real, even at low doses
• Mice aren't humans—translation isn't guaranteed
• Unknown interactions with other health behaviors (exercise, fasting)
• It's a serious medication, not a supplement

Who Might Reasonably Consider It

• Older adults (60+) who are optimizing aggressively
• People who understand and accept the uncertainty
• Those with access to proper medical supervision
• Individuals willing to monitor and adjust

Who Should Probably Wait

• Young, healthy people with decades ahead (more to lose from unknown risks)
• Anyone without physician oversight
• People with immune system issues or active infections
• Those planning surgery in the near future
• Anyone uncomfortable with experimental approaches

Rapamycin is arguably the most interesting longevity drug we have. The evidence is better than anything else we've covered:

What makes rapamycin compelling:

• Most robust and reproducible lifespan extension in mice of any drug
• Works even when started late in life
• Clear mechanism tied to fundamental aging biology (mTOR)
• Some human evidence of benefits at low doses (immune function)
• Decades of clinical experience (at higher doses)
• Leading longevity researchers take it themselves

What gives us pause:

• It's still an immunosuppressant—even if low-dose effects differ
• No human lifespan data
• Long-term low-dose safety isn't established
• Side effects are real (mouth sores, metabolic changes)
• Requires physician oversight and monitoring
• We don't know optimal protocols for longevity

Our take:

Of all the longevity drugs, rapamycin has the strongest scientific case. The mouse data is genuinely impressive—more robust than metformin, NAD+ precursors, or any supplement. The mechanism is sound and conserved.

But "strongest case" doesn't mean "proven safe and effective for humans." We're still in uncertain territory. If you're considering rapamycin:

• Work with a physician who understands both the drug and the longevity rationale
• Use low-dose, intermittent protocols (not transplant dosing)
• Monitor regularly (bloodwork every 3-6 months)
• Be prepared to stop if issues arise
• Don't let rapamycin substitute for proven interventions (exercise, diet, sleep)

The next decade will likely bring much better human data. The question is whether you want to wait for that data or begin careful experimentation now. There's no universally right answer—it depends on your age, health, risk tolerance, and values.