Rapamycin vs Metformin for Longevity: What the Evidence Shows (2026)

By Ryan Bethencourt, biotech investor and co-founder of IndieBio · Published February 25, 2026 · Last updated October 21, 2026 · Trials and regulatory status checked October 21, 2026

As of October 21, 2026	Rapamycin (sirolimus)	Metformin
What it is	An mTOR inhibitor. FDA approved it (Rapamune) on September 15, 1999 to prevent kidney transplant rejection; it is also approved for the lung disease lymphangioleiomyomatosis (LAM)	A biguanide. FDA approved it (Glucophage) on March 3, 1995; its labeled use is type 2 diabetes
Main target	Binds FKBP12, and the pair blocks mTORC1; longer exposure also disrupts mTORC2	Lowers glucose output from the liver; acts on mitochondria and activates AMPK in laboratory studies; the exact mechanism is still debated
Mouse lifespan (ITP)	Extended in several ITP studies: median +10% (males) and +18% (females) from 9 months of age; +23% and +26% at a threefold higher dose; also extended when started at 600 days or 20 months of age	Alone: no significant effect (median +7% in males, not significant; 0% in females). With rapamycin: median +23% in both sexes
Other animal data	Significant lifespan extension in a 2025 meta-analysis of vertebrate studies, mostly in mice and rats; lifespan extension also reported in yeast, worms and flies	No significant lifespan extension in the same 2025 meta-analysis; mean lifespan +5.8% in one strain of male mice (2013), toxic at a tenfold higher dose; slower aging-clock readings in male monkeys (2024)
Key aging trial in people	PEARL: 114 adults analyzed, 48 weeks; primary endpoint missed; published April 4, 2025	TAME: designed for about 3,000 people aged 65 to 79; no results, and no ClinicalTrials.gov entry found for the aging trial
Long-term outcome data	None in healthy people	Diabetes Prevention Program: 3,234 adults at high risk of diabetes, median 21 years; no effect on death or major heart events
Effect on exercise gains	No improvement in a 13-week, 40-person trial (2026); sensitivity analyses favored placebo	Smaller muscle gains with strength training (MASTERS, 2019) and smaller fitness gains with aerobic training (2019)
Main labeled risks	Boxed warning: immunosuppression can raise the risk of infection, lymphoma and other cancers; high cholesterol and triglycerides, mouth sores, swelling, slow wound healing	Boxed warning for lactic acidosis; stomach upset; lower vitamin B12; not for people with eGFR below 30
Approved to treat aging	No	No

In this article: Which has better evidence? | How they work | Animal lifespan | Metformin in people | TAME status | Rapamycin in people | Exercise | Side effects | Together? | Trials table | What we do not know | FAQ

Rapamycin or metformin: which has better evidence for longevity?

Rapamycin has better evidence in animals, and neither has good evidence in people. Rapamycin’s mouse lifespan results have been replicated across several ITP studies, start ages and doses. A 2025 meta-analysis of lifespan studies in eight vertebrate species, mostly mice and rats, found that rapamycin, but not metformin, significantly extended lifespan, by an amount comparable to dietary restriction (Ivimey-Cook et al., Aging Cell, 2025). Metformin’s case for aging rests mostly on observational studies of people with diabetes, and the best known of those has not held up.

The comparison is uneven in another way. Metformin has been used to treat diabetes for decades, so its side effects are well mapped, but its randomized trials were run to prevent or treat diabetes, not to slow aging. Rapamycin is an immunosuppressant used after transplants, and its trials in healthy older people are small and short. The best-known metformin aging trial, TAME, has not reported, and PEARL, a year-long rapamycin trial in healthy older adults, missed its primary endpoint.

So “which is better” has no answer yet in people. What the evidence does show is where each drug is strong and weak, and that is laid out below. For the rapamycin evidence in more depth, see the Grey Area Labs guide to rapamycin for longevity.

How do rapamycin and metformin work?

Rapamycin blocks a growth-signaling hub called mTORC1. Metformin works mainly on the liver and on mitochondria, the cell’s energy producers, and activates an energy sensor called AMPK in laboratory studies. Both end up damping mTORC1, but by different routes (Strong et al., 2016).

Rapamycin and mTOR

Rapamycin, called sirolimus as a medicine, forms a complex with a protein called FKBP12. That complex binds mTOR, a kinase that tells cells when to grow, build proteins and stop recycling their own parts (autophagy). The rapamycin complex directly inhibits mTORC1, one of the two complexes mTOR forms. The other, mTORC2, resists rapamycin at first, but prolonged treatment disrupts it too (Saxton and Sabatini, Cell, 2017). The same review notes that rapamycin has extended lifespan in yeast, worms, flies and mice.

That second effect matters for side effects. In mice, rapamycin’s insulin resistance was traced to its disruption of mTORC2, which the liver needs to respond normally to insulin, while genetically modified female mice with lower mTORC1 activity lived longer with normal glucose tolerance (Lamming et al., Science, 2012). Intermittent dosing has been studied in mice partly to reduce side effects such as glucose intolerance (Strong et al., 2020), and trials in people, such as PEARL below, have used low, once-weekly doses; whether such schedules avoid the metabolic costs over years has not been shown. For another drug that targets the same pathway, see rapamycin vs omipalisib.

Metformin, AMPK and mitochondria

Metformin’s main glucose-lowering effect comes from reducing glucose production in the liver (LaMoia and Shulman, Endocrine Reviews, 2021). In 2000, researchers reported that it inhibits complex I of the mitochondrial respiratory chain (Owen et al., Biochemical Journal, 2000). In 2001, another group showed that it activates AMPK, a sensor of low cellular energy, in liver cells, and that AMPK was needed for its effect on glucose production in those cells (Zhou et al., Journal of Clinical Investigation, 2001).

That story is now contested. A 2021 review notes that complex I inhibition and AMPK activation have been observed only at metformin concentrations above 1 mM, higher than those reached in patients, and that a redox-based mechanism has been proposed instead (LaMoia and Shulman, 2021). Metformin also changes the gut microbiome, which a 2026 review lists among the routes that may matter for aging (Manneh et al., Aging, 2026). In worms, metformin extended lifespan by changing how the bacteria they feed on metabolize folate and methionine, and it lengthened or shortened worm lifespan depending on the bacterial strain and glucose levels (Cabreiro et al., Cell, 2013). The mechanism that would slow aging in people, if any does, is not known.

Do rapamycin and metformin extend lifespan in mice and other animals?

Rapamycin does, repeatedly; metformin alone did not in the most rigorous test. The National Institute on Aging’s Interventions Testing Program (ITP) tests each compound in genetically diverse mice at three sites at once and publishes negative results as well as positive ones, which makes it some of the most rigorous mouse evidence available.

ITP study	Treatment	Started	Lifespan result
Harrison et al., Nature, 2009	Rapamycin in food	600 days of age	Median and maximum lifespan extended in both sexes; age at 90% mortality +14% (females) and +9% (males)
Miller et al., J Gerontol A, 2011	Rapamycin in food	9 months	Median +10% (males), +18% (females)
Miller et al., Aging Cell, 2014	Rapamycin at a threefold higher dose	9 months	Median +23% (males), +26% (females)
Strong et al., Aging Cell, 2020	Rapamycin at the higher dose, continuous or intermittent	20 months	Survival increased in both sexes with continuous treatment and with alternating months; a 3-month course helped males only
Strong et al., Aging Cell, 2016	Metformin alone (0.1% of diet)	9 months	Median +7% (males, not significant, P = 0.35), 0% (females)
Strong et al., Aging Cell, 2016	Metformin plus rapamycin	9 months	Median +23% (males), +23% (females)

Rapamycin. The first ITP rapamycin study was notable because treatment began late, at 600 days of age, and still extended life in both sexes (Harrison et al., 2009). Started at 9 months, it extended median lifespan by 10% in males and 18% in females (Miller et al., 2011), and a threefold higher dose raised that to 23% and 26%, with larger effects in females at every dose (Miller et al., 2014). Started at 20 months, the higher dose still increased survival in both sexes, including when given every other month (Strong et al., Aging Cell, 2020).

Metformin. In a 2013 study from the National Institute on Aging’s own laboratories, metformin at 0.1% of the diet, started in middle age, extended mean lifespan of male C57BL/6 mice by 5.8%, while a tenfold higher dose was toxic (Martin-Montalvo et al., Nature Communications, 2013). The ITP tested the same 0.1% dose, starting at 9 months of age, in genetically diverse male and female mice. Median lifespan rose 7% in males, which was not statistically significant, and did not change in females; the age at 90% mortality fell 2% in males (Strong et al., 2016). The ITP authors noted that the 2013 study used only males, a different statistical test and fewer mice, and that other doses might give a different result.

Another diabetes drug did better in the ITP: acarbose raised median lifespan by 22% in males and 5% in females (Harrison et al., Aging Cell, 2014). Grey Area Labs compares the two in metformin or acarbose: which diabetes drug extends lifespan?

Across vertebrates. A 2025 meta-analysis pooled 911 lifespan effect sizes from 167 papers on eight vertebrate species, mostly mice and rats. Most of the papers tested dietary restriction; 38 tested rapamycin and 17 tested metformin. Rapamycin, but not metformin, produced a significant lifespan extension, comparable to that from dietary restriction. The authors also reported high heterogeneity and significant publication bias, and rapamycin’s effect was no longer significant when only mean lifespans were analyzed without adjusting for that bias (Ivimey-Cook et al., Aging Cell, 2025).

Monkeys. A 40-month study of adult male cynomolgus monkeys reported that metformin slowed several molecular “aging clocks”, including about 6 years less brain aging by the authors’ clock (Yang et al., Cell, 2024). It measured markers of aging, not lifespan, and included no females. For how such clocks work and their limits, see epigenetic clocks and biological age.

What does the human evidence show for metformin?

It is mixed and mostly observational. The famous 2014 finding that people with diabetes on metformin outlived people without diabetes did not replicate in a 2022 Danish analysis, and randomized follow-up of more than 3,000 people at high risk of diabetes found no effect on death rates.

Observational studies

The study behind much of the interest used UK primary care records from 2000 onward. It compared 78,241 people with type 2 diabetes who started metformin alone, 12,222 who started a sulfonylurea, and 90,463 matched people without diabetes. After adjustment, median survival was 15% lower in the matched people without diabetes than in the metformin group, and 38% lower in the sulfonylurea group (Bannister et al., Diabetes, Obesity and Metabolism, 2014).

A 2017 meta-analysis of 53 studies reported lower all-cause mortality in people with diabetes taking metformin than in people without diabetes (hazard ratio 0.93), while noting baseline differences between groups that could bias the results (Campbell et al., Ageing Research Reviews, 2017).

A 2022 study using Danish national registers from 1996 to 2012 found the opposite. People who started metformin alone for type 2 diabetes had higher mortality than matched people without diabetes, both among unrelated individuals (adjusted rate ratio 1.32) and in twin pairs where only one twin had diabetes (1.64). The authors concluded that their contrasting results were unlikely to be explained by differences in study design (Keys et al., International Journal of Epidemiology, 2022).

A 2025 analysis of the Women’s Health Initiative matched 438 women aged 60 or older with new type 2 diabetes. Women who started metformin had a 30% lower risk of dying before age 90 than women who started a sulfonylurea (hazard ratio 0.70). The authors note that this compares two diabetes drugs, not metformin with placebo, and that causality cannot be inferred (Shadyab et al., Journals of Gerontology, 2025).

Randomized trials

In people who already had type 2 diabetes, the UK Prospective Diabetes Study randomized 753 overweight patients to metformin (342) or conventional, mainly diet-based treatment (411). Over a median of 10.7 years, all-cause mortality was 36% lower in the metformin group (UKPDS 34, Lancet, 1998). In a smaller randomized comparison reported in the same paper, adding metformin early for 268 people already on maximum sulfonylurea treatment was linked to a 96% higher risk of diabetes-related death than continuing the sulfonylurea alone (269 people), although the authors’ wider analysis of 4,416 patients did not show a higher risk with the combination. Both comparisons tested diabetes treatments, not aging treatments.

The Diabetes Prevention Program randomized 3,234 adults at high risk of type 2 diabetes to metformin, an intensive lifestyle program or placebo from 1996 to 1999, and followed them for a median of 21 years. Metformin prevented diabetes, but compared with placebo it did not change deaths from all causes (hazard ratio 0.99), cancer or cardiovascular disease (Lee et al., Diabetes Care, 2021). It also did not reduce heart attacks, strokes or cardiovascular deaths (hazard ratio 1.03). The authors note that metformin use outside the study and wide statin use may have diluted any effect (Goldberg et al., Circulation, 2022).

MILES (Metformin in Longevity Study) was a small biology study, not an outcome trial. Fourteen people about 70 years old with impaired glucose tolerance received metformin and placebo for 6 weeks each in random order. Metformin lowered glucose and insulin after a meal and changed the expression of 647 genes in muscle and 146 in fat, including pathways linked to aging (Kulkarni et al., Aging Cell, 2018; NCT02432287).

What is the status of the TAME trial?

As of October 21, 2026, TAME (Targeting Aging with Metformin) has published no results. Grey Area Labs found no ClinicalTrials.gov registration for the TAME aging trial and no announcement from the American Federation for Aging Research, which funded its planning, that enrollment has begun.

Its published design calls for about 3,000 people aged 65 to 79 at about 14 U.S. centers, measuring time to a composite of cardiovascular events, cancer, dementia and death. Its designers described it as a way to create a model for testing drugs that delay aging itself rather than one disease at a time (Barzilai et al., Cell Metabolism, 2016). A 2025 study of metformin and survival to age 90 stated that TAME had not been launched because it still needed funding (Shadyab et al., 2025), and an August 2026 review in Aging still describes TAME as a trial that “seeks to evaluate” metformin (Manneh et al., 2026). For other aging trials and their status, see longevity clinical trials.

What does the human evidence show for rapamycin, including PEARL?

It comes from small, short trials, and none has measured lifespan. PEARL missed its primary endpoint. In the 48-week trial, published April 4, 2025, rapamycin did not change visceral fat, while lean tissue mass and self-reported pain improved in women in the 10 mg group, and adverse events were similar to placebo (Moel et al., Aging, 2025).

The details matter for reading it:

• Design. A decentralized, double-blind, placebo-controlled trial of generally healthy adults aged 50 to 85; people with well-managed, stable chronic diseases could take part (NCT04488601, 129 enrolled). Participants received placebo or 5 mg or 10 mg of compounded rapamycin once a week. Of the 114 analyzed, 40 were in the 5 mg group, 35 in the 10 mg group and 39 on placebo.
• Results. No significant change in visceral fat, the primary outcome. Lean tissue mass and self-reported pain improved significantly for women in the 10 mg group; that group had 8 women. The 5 mg group reported better emotional well-being and general health. No other significant effects were found.
• Safety. Adverse and serious adverse events were similar across groups. Rapamycin users appeared to have more gastrointestinal symptoms, and one participant in the 5 mg group had anemia treated with a transfusion.
• Caveats. The authors report that the compounded rapamycin produced about one third of the blood level of the commercial drug. All authors are employees and shareholders of AgelessRx, the company that ran the trial.

Other human evidence. In older volunteers, everolimus, a rapamycin derivative, improved the response to a flu vaccine by about 20% (Mannick et al., Science Translational Medicine, 2014). A 2024 systematic review of 19 studies found improvements in some immune, cardiovascular and skin measures, no significant effects on endocrine, muscle or neurological measures, no serious adverse events attributed to the drugs in healthy people, and more infections and higher cholesterol and triglycerides in people with age-related diseases (Lee et al., Lancet Healthy Longevity, 2024). No trial has measured whether rapamycin extends human life.

Planned. VITAL-H, a placebo-controlled trial funded by ARPA-H with up to $38 million and led by UT Health San Antonio, plans to compare rapamycin, dapagliflozin and semaglutide with placebo in 726 adults in their 60s (ARPA-H award page). On March 4, 2026, the university said enrollment would start the following year (UT Health San Antonio, 2026), and Grey Area Labs found no ClinicalTrials.gov record for it on October 21, 2026.

Do metformin or rapamycin interfere with exercise?

Metformin did in two randomized trials in older adults, and rapamycin did not help in a 2026 trial. This matters because, as the MASTERS authors note, progressive resistance training is the most effective known intervention against muscle loss with age.

MASTERS (strength training). Healthy adults aged 65 and older received 1,700 mg a day of metformin (46 people) or placebo (48) during 14 weeks of supervised progressive resistance training. The placebo group gained more lean body mass and thigh muscle than the metformin group, and strength gains trended lower with metformin without reaching significance (Walton et al., Aging Cell, 2019; NCT02308228).

Aerobic training. In 53 older adults given metformin or placebo during 12 weeks of aerobic training, metformin reduced the gains in whole-body insulin sensitivity and VO2 max and abolished the training-induced rise in muscle mitochondrial respiration. Responses varied widely between people (Konopka et al., Aging Cell, 2019).

RAPA-EX-01 (rapamycin). Forty sedentary adults aged 65 to 85 received 6 mg of sirolimus once a week or placebo for 13 weeks alongside a home exercise program. Both groups improved. The primary comparison, chair-stand repetitions, did not differ significantly (2.13 fewer with sirolimus, P = 0.089), but two prespecified sensitivity analyses favored placebo significantly. The sirolimus group had more adverse events in total (99 vs 63), which the authors described as a higher burden of minor events, and one serious case of pneumonia was possibly drug-related (Stanfield et al., Journal of Cachexia, Sarcopenia and Muscle, 2026).

What are the side effects and risks of rapamycin and metformin?

Rapamycin’s labeled risks come from its use as an immunosuppressant: infections, some cancers, raised blood lipids and mouth sores. Metformin’s most common effects are digestive, it can lower vitamin B12 over time, and its label carries a boxed warning for lactic acidosis.

Rapamycin (sirolimus)

• Boxed warning. Immunosuppression can increase susceptibility to infection and the possible development of lymphoma and other cancers. The label covers kidney transplant patients, who take sirolimus daily alongside other immunosuppressants, and people with LAM. PEARL and RAPA-EX-01 used lower, once-weekly doses; whether such doses avoid these risks over years has not been shown, and in RAPA-EX-01 one case of pneumonia was judged possibly drug-related.
• Common effects in trials. In kidney transplant trials, the most common effects (30% or more) included swelling in the limbs (peripheral edema), high triglycerides and cholesterol, high blood pressure, digestive symptoms, headache and anemia. In the LAM trial, mouth sores (stomatitis) were among the most common (20% or more).
• Other warnings. Slow wound healing and fluid buildup, lung inflammation, harm to a fetus, reduced sperm counts, and a warning against live vaccines. New-onset diabetes and high blood sugar are listed among adverse reactions.
• Interactions. Sirolimus is processed by CYP3A4 and P-glycoprotein. Strong inhibitors (such as ketoconazole and clarithromycin) and inducers (such as rifampin) change its blood levels, and the label says it must not be taken with grapefruit juice (sirolimus label, DailyMed).

Metformin

• Boxed warning. Lactic acidosis, which has caused deaths in postmarketing reports. Risk factors listed include kidney impairment, age 65 or older, contrast imaging, surgery, low-oxygen states, heavy alcohol use and liver impairment.
• Contraindications. The label lists severe kidney impairment (eGFR below 30), metabolic acidosis and allergy to metformin as contraindications.
• Common effects. Diarrhea, nausea or vomiting, gas, weakness, indigestion, abdominal discomfort and headache.
• Vitamin B12. The label notes that metformin may lower B12 levels. In the Diabetes Prevention Program, low or borderline-low B12 was more common with metformin than placebo at 5 years (19.1% vs 9.5%) and 13 years (20.3% vs 15.6%) (Aroda et al., Journal of Clinical Endocrinology and Metabolism, 2016).
• Interactions. The label lists carbonic anhydrase inhibitors (such as topiramate), drugs that slow metformin’s kidney clearance (such as cimetidine and ranolazine), alcohol, and insulin or insulin-releasing drugs, which raise the risk of low blood sugar (metformin label, DailyMed).

Both are prescription drugs, and neither is approved to treat aging. Questions about either drug belong with a clinician who knows the person’s medications and health conditions.

Can rapamycin and metformin be combined?

No human trial has shown whether the combination is safe or useful as an aging treatment. In mice, the pair extended median lifespan by 23% in both sexes, and metformin reduced rapamycin’s glucose intolerance in female mice but not in males.

What is known in mice. The ITP added metformin to rapamycin on the idea that metformin might counter the glucose problems rapamycin causes. The combination raised median lifespan 23% in both sexes, more than earlier ITP cohorts given the same rapamycin dose alone (10% and 13% in males; 18% and 21% in females). The authors called the evidence of an added benefit inconclusive: the comparison was with historical cohorts, and the male difference was not significant in their standard analysis (P = 0.12) (Strong et al., 2016). In a separate study, adding metformin removed rapamycin’s glucose intolerance in female mice but not in males (Weiss et al., Aging, 2018).

What is known in people. Very little. As of October 21, 2026, no randomized trial testing the two drugs together as an aging treatment had reported results. A 90-day pilot sponsored by AgelessRx, planned for up to 30 people, gives one group rapamycin and metformin along with several other drugs and supplements, so it cannot isolate the pair; it was listed as active, not recruiting, with an estimated completion date of April 2026 that has passed and no results posted (NCT07475546, last updated March 16, 2026). In a pharmacodynamic study of 24 people with advanced solid tumors, 18 of whom could be evaluated, adding metformin to sirolimus did not deepen inhibition of an mTOR marker in blood cells (P = 0.64) (Sehdev et al., Cancer Chemotherapy and Pharmacology, 2018; NCT02145559). Results in people with advanced cancer say little about healthy people. PEARL excluded people taking metformin unless they stopped it for 6 months first.

What is not known. Whether the mouse result applies to people, whether the combination changes infection risk or blood sugar in older adults, and whether two drugs that each showed signs of blunting exercise gains would compound that effect. Neither drug’s label lists the other as an interacting drug, but that is not evidence that the pair is safe. Anyone asking whether they can use both should ask a clinician who knows their medications.

Key human trials of rapamycin and metformin, with dates

Trial (published)	Drug	People	Length	Main result
UKPDS 34 (1998)	Metformin	753 overweight adults with newly diagnosed type 2 diabetes	Median 10.7 years	36% lower all-cause mortality than conventional treatment; a diabetes trial, not an aging trial. A smaller comparison in the same paper linked adding metformin to a sulfonylurea with more diabetes-related deaths
Diabetes Prevention Program and follow-up (2021, 2022)	Metformin	3,234 adults at high risk of type 2 diabetes	Median 21 years	Prevented diabetes; no effect on all-cause, cancer or cardiovascular death, or on major cardiovascular events
MILES (2018)	Metformin	14 adults about 70 years old with impaired glucose tolerance	6 weeks per treatment (crossover)	Lower glucose and insulin; gene expression changes in muscle and fat
MASTERS (2019)	Metformin	94 healthy adults aged 65 and older	14 weeks with strength training	Smaller gains in lean mass and thigh muscle than placebo
Konopka et al. (2019)	Metformin	53 older adults	12 weeks with aerobic training	Smaller gains in insulin sensitivity and VO2 max
TAME (planned; nothing published)	Metformin	About 3,000 planned, aged 65 to 79	Not reported	No results as of October 21, 2026
PEARL (April 4, 2025)	Rapamycin (compounded)	114 analyzed, aged 50 to 85	48 weeks	Primary endpoint (visceral fat) missed; lean mass and pain improved in women at 10 mg
VITAL-H (planned; nothing published)	Rapamycin, dapagliflozin or semaglutide vs placebo	726 planned, in their 60s	Not reported	Enrollment due to start in 2027, per a March 4, 2026 university release; no ClinicalTrials.gov record found on October 21, 2026
RAPA-EX-01 (April 2026)	Sirolimus	40 sedentary adults aged 65 to 85	13 weeks with home exercise	No improvement in exercise gains; more minor adverse events

What we still do not know

• Whether either drug slows aging, delays age-related disease or extends life in healthy people. No completed trial in healthy people has tested this as its main outcome.
• Whether and when TAME will start and report.
• Whether PEARL’s lean mass finding in 8 women holds up in a larger trial with commercial rapamycin.
• What VITAL-H, the ARPA-H-funded trial that includes rapamycin, will show once it enrolls and reports.
• Whether intermittent, low-dose rapamycin avoids the infection and metabolic effects seen at transplant doses over years of use.
• Why the UK and Danish metformin survival studies disagree, and whether either reflects a drug effect.
• Whether metformin’s blunting of exercise gains outweighs any benefit for active older adults, and whether rapamycin has a similar effect.
• Whether the ITP’s rapamycin and metformin combination result applies to people.

Frequently asked questions

Is rapamycin or metformin better for longevity?

Neither has been shown to slow aging or extend life in healthy people, so neither is proven better. Rapamycin has much stronger animal evidence: it extended mouse lifespan in several National Institute on Aging Interventions Testing Program studies, while metformin alone did not, and a 2025 meta-analysis of lifespan studies in eight vertebrate species, mostly mice and rats, found a significant extension with rapamycin but not with metformin. Metformin has far more human safety data, but in the randomized Diabetes Prevention Program it did not change death rates over a median of 21 years.

Does metformin extend lifespan?

No randomized trial has shown that it extends life in people without diabetes. A 2014 UK study found that people with diabetes on metformin outlived matched people without diabetes, but a 2022 Danish study found the opposite, and in the Diabetes Prevention Program metformin did not change all-cause mortality over a median of 21 years. In mice, one 2013 study reported a 5.8% longer mean lifespan in males, but the larger Interventions Testing Program found no significant extension.

Did metformin extend lifespan in the Interventions Testing Program?

No. In the ITP study published in Aging Cell in 2016, metformin at 0.1% of the diet from 9 months of age raised median lifespan in genetically diverse mice by 7% in males, which was not statistically significant, and did not change it in females. In the same mouse study, metformin combined with rapamycin raised median lifespan by 23% in both sexes; no human trial of the pair as an aging treatment has reported results.

What did the PEARL rapamycin trial find?

PEARL, published on April 4, 2025, gave 5 mg or 10 mg of compounded rapamycin or placebo once a week for 48 weeks to healthy adults aged 50 to 85, with 114 analyzed. It found no change in visceral fat, its primary endpoint. Lean tissue mass and self-reported pain improved in women in the 10 mg group, which had 8 women, and adverse events were similar across groups.

What is the status of the TAME trial?

As of October 21, 2026, TAME has published no results, and Grey Area Labs found no ClinicalTrials.gov registration for the TAME aging trial. Its published design calls for about 3,000 people aged 65 to 79 at about 14 U.S. centers, measuring time to cardiovascular events, cancer, dementia and death.

Can you take rapamycin and metformin together?

No human trial has shown whether the combination is safe or useful as an aging treatment. In mice, the pair extended median lifespan by 23% in both sexes, though the study’s authors called the evidence of a benefit over rapamycin alone inconclusive, and in a separate study metformin reduced rapamycin’s glucose intolerance in female mice but not in males. Whether the pair changes infection risk, blood sugar or exercise gains in older adults is not known. Ask a clinician who knows your medications and health conditions.

Does metformin reduce the benefits of exercise?

In two randomized trials in older adults, it reduced some of them. In the MASTERS trial, people on metformin gained less lean mass and thigh muscle from 14 weeks of strength training than people on placebo, and in a 12-week aerobic training trial metformin reduced gains in insulin sensitivity and VO2 max. Responses varied between people.

Which has more side effects, rapamycin or metformin?

Their risks differ. Rapamycin’s label carries a boxed warning that immunosuppression can increase the risk of infection, lymphoma and other cancers, and lists high cholesterol and triglycerides, mouth sores, swelling and slow wound healing. In PEARL, which used low weekly doses, adverse events were similar to placebo, while in RAPA-EX-01 the sirolimus group had more adverse events in total. Metformin’s most common effects are digestive, it can lower vitamin B12 over time, and its label carries a boxed warning for lactic acidosis.

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More on Grey Area Labs

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• The complete guide to rapamycin for longevity
• Metformin or acarbose: which diabetes drug extends lifespan?
• Longevity clinical trials and their status

This article explains published research. It is not medical advice. How we write about health.