Metformin plus rapamycin
Metformin plus rapamycin (Interventions Testing Program combination arm)
Written by Aaron CuhaReviewed Sep 2026
Also known as: Met + Rapa, Metformin and rapamycin combination, Met/Rapa
Fed together from 9 months, metformin 1,000 ppm and rapamycin 14 ppm extended median mouse lifespan 23 percent in both sexes. Metformin alone in the same cohort did nothing, there was no rapamycin-alone arm to compare against, and the ITP's own paper says the apparent extra benefit over historical rapamycin cohorts did not reach significance by its protocol test.
Overview
This is a page about one arm of one mouse experiment, because that arm is cited across the longevity world as evidence that metformin and rapamycin are synergistic, and the paper that reports it says something more careful. Both drugs have their own pages on this site; this entry is about what happens when they are combined.
In people, no trial has tested the two-drug combination. Rapamycin has small human healthspan trials and metformin has a very large diabetes literature and a stalled ageing trial, both described on their own pages. Two registered studies come close and neither is a test of the pair: a 2022 pilot of metformin, dasatinib, rapamycin and five supplements was withdrawn before enrolling anyone, and a 30-person pilot by a telehealth prescriber, active since 2025, gives rapamycin, metformin, low-dose naltrexone, intranasal NAD+ and a proprietary supplement together against fitness, cognition and an inflammation index, with no results yet. Neither could separate the contribution of either drug.
In mice, the NIA Interventions Testing Program's 2011 cohort fed metformin at 1,000 ppm (0.1 percent of diet) from 9 months, alone and combined with rapamycin at 14 ppm. Metformin alone did not significantly extend lifespan: male median 835 against 780 days (+7 percent, p = 0.35), 90th percentile -2 percent; female median 872 against 874 days (0 percent). The combination extended median lifespan 23 percent in males (959 days, p < 0.001) and 23 percent in females (1,078 days, p < 0.001), and 90th percentile survival by 10 percent in males and 17 percent in females. The ITP had no rapamycin-alone group in that cohort. Its comparison is against earlier cohorts given the same rapamycin dose alone, and the authors write that the male result is "suggestive of an added benefit" while stating that the apparent synergy "is not statistically significant by our standard site-stratified log-rank test (p = 0.12)" and reached significance only in an analysis that dropped site stratification. The programme's 2020 rapamycin paper restates the point: the combination's survival results "were not significantly higher than those noted in earlier experiments using the same dose (14.7 ppm) of rapamycin by itself". A 2024 Gehan reanalysis found metformin alone significant in males (p = 0.0495), and a 2022 meta-analysis found metformin not associated with mouse lifespan extension across the literature.
Both drugs are approved prescription medicines for other indications; the combination is off-label in every jurisdiction.
Mechanism of action
Rapamycin inhibits mTORC1, and at the doses used in mice lowers cancer incidence, alters immune function and shifts metabolism in ways that are distinct from dietary restriction. Metformin inhibits mitochondrial complex I, activates AMPK in some tissues and lowers hepatic glucose output. The rationale for combining them was that metformin might blunt the glucose intolerance and insulin resistance rapamycin causes in mice, and that the two act on partly separate nutrient-sensing pathways. The ITP paper reports the lifespan outcome and does not test that mechanism; it did not include a rapamycin-alone arm, so it cannot say whether metformin added anything, and the mechanistic case for synergy rests on inference from each drug's separate literature. In people there are no data on the combination. Each drug's human pharmacology is on its own page.
Human evidence
None for the combination. No trial has given metformin and rapamycin together to people as a two-drug test. One multi-drug pilot including both plus four other agents is running in 30 people without results; another was withdrawn before enrolling anyone. Each drug's separate human record is on its own page.
- NCT07475546: 30-person sponsor-run pilot combining rapamycin, metformin, naltrexone, NAD+ and supplements; active, no results; not designed to attribute effects to either drug.
- NCT04994561: planned pilot of metformin, dasatinib, rapamycin and supplements; withdrawn, zero enrolled.
- No pharmacokinetic study has examined whether the two drugs interact in people.
- Rapamycin alone: small trials in older adults (see the rapamycin page). Metformin alone: decades of diabetes trials and 21-year prevention follow-up null on mortality (see the metformin page).
What this does not tell you: There is no human evidence for or against this combination. Anyone taking both for ageing is acting on a single mouse cohort that lacked the control arm needed to show the combination beats rapamycin alone, plus the separate literatures of two drugs each of which has its own risks (immunosuppression, mouth ulcers and metabolic effects for rapamycin; gastrointestinal effects, B12 depletion and a randomised signal that it blunts exercise adaptation for metformin).
Reading the research record
The NIA Interventions Testing Program runs each compound in parallel at three sites (The Jackson Laboratory, the University of Michigan and UT Health San Antonio) in genetically heterogeneous UM-HET3 mice, tests both sexes, analyses them separately, pools the sites in a site-stratified log-rank test, and publishes every result whether or not the compound worked. It is publicly funded by the National Institute on Aging with no pharmaceutical sponsorship. The 2011 cohort tested metformin at 1,000 ppm alone and with rapamycin at 14 ppm, both from 9 months. Metformin alone did nothing significant in either sex. The combination produced a 23 percent median gain in both sexes with strong late-survival effects. The design flaw, which the ITP states plainly, is that the cohort had no rapamycin-alone group, so the claim that metformin added anything rests on comparison with rapamycin cohorts run in earlier years. By the protocol test that comparison gave p = 0.12 in males; it reached significance only when site stratification was dropped, which is not the pre-specified analysis. In females the authors call any added effect small. The programme's own later rapamycin paper says the combination's survival was not significantly higher than the same rapamycin dose alone in earlier experiments.
The honest one-line reading is: rapamycin works, and metformin added to rapamycin did not demonstrably improve on rapamycin. That is a weaker statement than the one in circulation, and it is what the primary source says. It is also not a demonstration that metformin adds nothing; a properly controlled test would need contemporaneous single-drug arms, and the ITP has since run exactly that design for rapamycin plus acarbose, where the historical comparison problem recurs because that cohort too lacked single-drug arms. No sponsor exists for a human test of two generic drugs, so the question will not be settled in people by a commercial trial.
The evidence, charted
Fig. 1 · evidence composition
2of 8 citations (25%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 6 distinct years, 2014 to 2025, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Approved
UK
Approved
AU
Approved
CA
Approved
Approved in all four jurisdictions shown. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Animal2016
Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an alpha-glucosidase inhibitor or a Nrf2-inducer
ITP 2011 cohort. Metformin 1,000 ppm from 9 months alone: male median +7 percent (p = 0.35), 90th percentile -2 percent; female 0 percent; not significant. Metformin plus rapamycin 14 ppm: male median 959 versus 780 days (+23 percent), 90th percentile +10 percent; female median 1,078 versus 874 days (+23 percent), 90th percentile +17 percent; all p < 0.001. No rapamycin-alone arm; comparison with historical rapamycin cohorts described as suggestive of added benefit, with the male synergy test p = 0.12 by the protocol analysis. NIA funded.
Aging Cell - Animal2020
Rapamycin-mediated mouse lifespan extension: late-life dosage regimes with sex-specific effects
The ITP's own later summary: the metformin plus rapamycin survival results "were not significantly higher than those noted in earlier experiments using the same dose (14.7 ppm) of rapamycin by itself". Also reports rapamycin at 42 ppm from 20 months extending lifespan in both sexes. NIA funded.
Aging Cell - Animal2014
Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction
Rapamycin alone at 42 ppm extended median lifespan 23 percent in males and 26 percent in females, with maximal lifespan increased in both sexes, and females gained more at every dose. The benchmark showing rapamycin alone can match the combination's 23 percent when its dose is tripled. NIA funded.
Aging Cell - Animal2024
The Gehan test identifies life-extending compounds overlooked by the log-rank test in the NIA Interventions Testing Program: metformin, enalapril, caffeic acid phenethyl ester, green tea extract, and 17-DMAG
Metformin alone, 1,000 ppm from 9 months, 148 males against 294 controls: median +8 percent, log-rank p = 0.35, Gehan p = 0.0495, proportional hazards violated. No female effect. Borderline, in a 132-comparison reanalysis with no multiplicity correction reported. NIA funded.
GeroScience - Review2022
Metformin has heterogeneous effects on model organism lifespans and is beneficial when started at an early age in Caenorhabditis elegans: a systematic review and meta-analysis
Pooled model-organism lifespan data: metformin was not associated with mouse lifespan extension, and the null persisted when ITP data were excluded. Independent academic review.
Aging Cell - Review2025
Emerging uncertainty on the anti-aging potential of metformin
Review co-authored by an ITP site director and a pharmacoepidemiologist setting out why the animal and observational human case for metformin as an anti-ageing drug has weakened, including the combination arm's lack of a contemporaneous rapamycin control.
Ageing Research Reviews - Human2025
A pilot randomized controlled study of combinatorial gerotherapeutics for healthspan improvement
30 participants, sponsor AgelessRx (a telehealth prescriber), active not recruiting. Arms combine rapamycin 2 to 6 mg weekly, metformin 500 mg daily, low-dose naltrexone, intranasal NAD+, topical glutathione and a proprietary supplement; primary endpoints VO2 max, a cognitive composite and an inflammation index. Cannot isolate either drug. No results posted.
ClinicalTrials.gov - Human2022
Pilot study of metformin, dasatinib, rapamycin and nutritional supplements in aging
Phase 1, Vitality in Aging Research Group. WITHDRAWN with zero participants enrolled.
ClinicalTrials.gov
Frequently asked questions
Is metformin plus rapamycin synergistic?
The ITP's own paper does not claim that. The combination extended median mouse lifespan 23 percent in both sexes, but the cohort had no rapamycin-alone arm, and against historical rapamycin cohorts the extra male benefit did not reach significance by the protocol test (p = 0.12). The programme's 2020 paper says the combination was not significantly better than the same rapamycin dose alone.
Did metformin alone extend lifespan in that experiment?
No. Male median lifespan was 7 percent higher with p = 0.35 and 90th percentile survival was 2 percent lower; females showed no change. A 2024 Gehan reanalysis put the male effect at p = 0.0495, a borderline result in a large multiple-comparison setting.
Has anyone tested the combination in people?
No. One 30-person pilot gives both drugs together with four other agents and cannot separate them; another planned pilot was withdrawn without enrolling anyone. There is no pharmacokinetic study of the pair.
What dose did the mice get?
Metformin at 1,000 ppm in food, which is 0.1 percent of the diet, and rapamycin at 14 ppm, from 9 months of age for life. Rapamycin alone at three times that dose (42 ppm) produced 23 to 26 percent median gains without metformin in a separate ITP experiment.