Rapamycin: does the evidence add up?

AgeingRapamycin

11 Dec

By Dr Ran Crooke

Rapamycin has moved from transplant medicine into one of the most talked about longevity molecules. Headlines now report it can extend life “as well as” calorie restriction.

The question is not whether rapamycin is interesting. It is.

The real question is whether a healthy, high functioning individuals should be adding it to their routine stack, outside a well-conducted trial.

We run through what the newest human and animal data actually show, where the gaps are, and how we should think about rapamycin in the context of a rational longevity strategy.

In terms of our foundational approach, this sits at the very top of the pyramid, not the base.

Why rapamycin is back in the spotlight

Rapamycin inhibits mTOR, a central nutrient sensing pathway that affects growth, metabolism, and cellular stress responses.

In multiple species, mTOR inhibition extends lifespan and delays some age related changes.

A September 2025 meta analysis took 167 vertebrate studies across eight species, mostly rodents but including dogs and primates1. It compared lifespan extension from rapamycin and metformin against classic dietary restriction. Rapamycin and dietary restriction both produced robust lifespan gains. Metformin, on average, did not.

When adjusted for bias, the estimated log response ratios translated to roughly 19% longer life with dietary restriction and 24% with rapamycin versus controls. The difference between those two was not statistically significant. Metformin’s average effect overlapped zero and was significantly smaller than both.

So the animal story is clear:

Rapamycin is a real lifespan extending intervention in vertebrates.
Its average effect is similar in magnitude to classical dietary restriction.
Metformin is not in the same category, at least for lifespan, in these models.

The obvious temptation is to say: “Great, it must do the same in humans.”

The problem is that the human data are far thinner and much narrower than the headline suggests and let’s not forget the JAMA analysis of 76 highly cited animal experiments, where only about a third were later confirmed in human randomised trials, and around a fifth were contradicted (PMID: 17032985).

New pharmacokinetic data: your “5 mg” may not be 5 mg

One of the most useful recent papers, again from 2025, for critical thinking is not an outcome trial but a pharmacokinetic study of real world rapamycin use in adults attending an online longevity clinic2.

People were taking once weekly doses of either:

Commercial generic sirolimus tablets (2 to 8 mg)
Compounded capsules (5 to 15 mg)

The researchers looked at dose, formulation, and timing of blood draws against measured sirolimus levels.

They found that formulation changes blood levels by a factor of about three.

When they normalised for milligrams, compounded rapamycin produced roughly one third of the blood levels of commercial generics, despite independent testing showing that the compounded capsules contained the expected amount of the drug.

In other words:

5 mg compounded drug did not equate to 5 mg generic drug in the bloodstream.
Nominal dose in milligrams is not interchangeable across formulations.

For anyone using rapamycin, this means that:

Source pharmacy is a critical variable.
Two patients both “on 5 mg weekly” may have completely different blood exposure.

Furthermore, at any given weekly dose, sirolimus levels varied widely between individuals too.

Sex and BMI did not explain this difference. However, when the same person was tested again at the same dose and formulation, levels were relatively stable and rose appropriately when doses were increased.

The practical implication:

Between people, milligram dosing is also variable.
Within a person, once you fix formulation and dose, exposure is reasonably repeatable and titrates as one would expect.

If rapamycin is ever used alongside a longevity programme, a tailored test and personalise approach would be required. A target exposure range for an individual would be set, not copy a one size weekly dose from an online protocol.

The PEARL trial: what weekly rapamycin did and did not do

The PEARL trial is the first decentralised, double blind randomised study of low dose intermittent rapamycin in healthy, normative ageing adults3. Another 2025 paper. Participants received:

Placebo
5 mg compounded rapamycin once weekly
10 mg compounded rapamycin once weekly

for 48 weeks. The cohort were community dwelling older adults without major disease. The primary endpoint was change in visceral adipose tissue (VAT) by DEXA.

Across the three arms:

Adverse events and serious adverse events were similar.
Routine blood tests stayed within reference ranges.
There was a small excess of gastrointestinal symptoms in the rapamycin arms.
There was no clear signal of immune suppression, cytopenias, renal dysfunction, or dysglycaemia within the limits of the sample and duration.

You cannot infer long term safety from a 48 week trial, but for this design and exposure, the safety suggestion is reassuring.

One crucial nuance, often missed in popular commentary: PEARL used the compounded formulation that the pharmacokinetic study showed had only about one third of the blood exposure per milligram compared with generics.

So:

“5 mg” compounded is closer to 1.5 mg generic in exposure.
“10 mg” compounded is closer to 3.3 mg generic.

PEARL is therefore a trial of very low exposure rapamycin, not of the higher weekly generic doses some online protocols now copy from transplant or oncology practice.

The primary VAT endpoint was neutral. There was no significant change in visceral fat between placebo, 5 mg, and 10 mg.

Secondary and subgroup findings were more interesting, though it’s relevant to note that because PEARL was designed and powered to test a single primary outcome (change in visceral fat), the null result for this outcome carries more weight than a handful of “positive” secondary and subgroup signals. Once you slice the secondary outcome data into many endpoints and tiny subgroups, some will look statistically significant by chance alone, especially with eight women in the 10 mg arm and huge confidence intervals, so these findings below are exploratory rather than proof that rapamycin improves lean mass or pain:

Women randomised to 10 mg weekly had increases in lean tissue mass and reductions in self reported pain compared with placebo and 5 mg.
Participants on 5 mg reported better emotional wellbeing and general health scores than placebo.
These effects were not consistently seen in men.
Most other body composition and biomarker outcomes did not change.

The honest conclusion is that PEARL is hypothesis generating, not proof that weekly rapamycin broadly improves healthspan in healthy adults.

It also does not validate common “higher dose” weekly strategies used off label with generic sirolimus. Those regimens likely deliver substantially higher exposure than any arm in PEARL.

System level human evidence: targeted effects, not whole body rejuvenation

A 2024 systematic review in The Lancet Healthy Longevity mapped all human rapamycin and rapalog trials in adults, both healthy volunteers and people with ageing related diseases4. The authors screened over 18,000 records and included 19 studies.

Across this diverse set of trials, mTOR inhibition has shown:

Immune effects

Enhanced response to influenza vaccination in older adults treated with everolimus and related agents
Partial reversal of immunosenescence markers

Cardiovascular signals

Improvements in selected haemodynamic parameters in specific disease contexts

Integumentary effects

Improved markers of skin ageing in small, targeted trials

These are condition specific physiological improvements, not sweeping rejuvenation.

For endocrine, muscular, and neurological systems, effects were mostly neutral in the available trials. Several major organ systems, including respiratory, digestive, renal, and reproductive systems, have little or no human data in the ageing context.

So the current narrative for the human data we have is:

mTOR inhibition may modulate some ageing related physiological changes in specific systems.
The safety profile looks acceptable in the short term at carefully controlled doses.
We do not yet have evidence that rapamycin reduces all cause mortality or major chronic disease incidence in healthy midlife or older adults.

The bottom line

It is easy to hear “rapamycin extends life as well as calorie restriction” and conclude “Why bother with diet or training. I can just take the pill.”

That leap rests on several shaky assumptions:

That animal lifespan gains translate cleanly to human outcomes.
That very low exposure weekly dosing delivers the same benefits seen in more aggressive animal protocols.
That the long term safety profile in healthy, primary prevention populations will mirror short term trial data.
That you personally have more to gain from a drug at the top of the pyramid than from tightening the foundations of your health programme.

A more grounded view looks like this:

Biological plausibility is strong: Rapamycin is the closest pharmacological mirror of dietary restriction in vertebrate lifespan experiments so far1.
Human systems level data are encouraging but narrow: We see specific benefits in immune function and some cardiovascular and skin parameters, not global rejuvenation4.
The safety signal at very low exposure over 48 weeks is acceptable. That does not guarantee safety at higher exposures, longer durations, or in all individuals3.
Formulation, dose, and individual pharmacokinetics matter a lot. Milligram numbers alone are misleading2.

FAQs

Is rapamycin “as powerful as” calorie restriction for humans?
No. Rapamycin and dietary restriction show similar average lifespan gains in vertebrate models. Human data on lifespan and major disease outcomes are not available yet.

Is there a “safe weekly dose” I can copy from PEARL?
PEARL supports the relative safety of very low exposure weekly rapamycin using compounded capsules over 48 weeks in older adults. It does not validate higher exposure regimens or long term use in younger, high performing individuals.

Should I take metformin instead for longevity?
The vertebrate meta analysis suggests metformin does not deliver consistent lifespan extension compared with rapamycin or dietary restriction. That does not erase its value in diabetes or specific metabolic indications. It simply means it is unlikely to be a dedicated longevity drug in its own right.

If I am already on rapamycin, what should I do now?
At a minimum: review your rationale, ensure you understand your formulation, discuss monitoring with a clinician who is transparent about the experimental nature of this use, and check that you are not neglecting better validated levers.