Metformin for Longevity: The TAME Trial and What We Are Actually Testing
Metformin is a widely used diabetes drug with decades of experience behind it. A 2014 UK study suggested that people with diabetes who started on metformin survived longer than matched people without diabetes,1 but a 2022 Danish analysis that included twins found the opposite.4 The TAME trial was designed to test directly whether metformin delays age-related disease in older people without diabetes.3
- Metformin activates AMPK, the cell's energy sensor, although AMPK activation may not explain all of its actions.2
- A 2014 UK study of 78,241 people starting metformin found they survived longer than matched people without diabetes,1 but a 2022 study of Danish national registers, including twins, found higher mortality with metformin-treated diabetes than without diabetes, even after adjustment.4
- The TAME trial (Targeting Aging with Metformin) was designed to test whether metformin delays age-related diseases in people without diabetes.3 It has not reported results, and AFAR is still raising the money to launch it.
- Randomized trials in older adults found that metformin blunted some gains from exercise: it attenuated improvements in VO2 max and insulin sensitivity after aerobic training5 and reduced lean-mass gains from resistance training.7
- Long-term metformin use is associated with low vitamin B12: in the Diabetes Prevention Program, low B12 was more common with metformin at 5 years (4.3% vs 2.3%), and the authors suggest considering routine B12 testing.6
Interest in metformin and longevity grew from a 2014 Cardiff University study of 78,241 people with type 2 diabetes who started on metformin, 12,222 who started on a sulphonylurea and 90,463 matched people without diabetes. The matched people without diabetes had 15% shorter adjusted median survival than the metformin group, while those starting a sulphonylurea fared worse than both.1 A 2022 analysis of Danish national registers, including twins discordant for diabetes, did not reproduce the finding: metformin-treated diabetes was associated with higher mortality than no diabetes (adjusted rate ratios 1.32, and 1.64 in twins), across a range of study designs.4
Metformin's Mechanisms: Why It Might Slow Aging
Metformin's activation of AMPK, the cell's energy sensor, is well documented, but it may not account for all of the drug's actions; researchers describe both AMPK-dependent and AMPK-independent mechanisms.2 Metformin has shown protective effects against several age-related diseases in humans, which is why it was proposed for the TAME trial.3
The TAME Trial: Testing Aging Itself
TAME was designed to test whether a single drug can delay multiple age-related diseases in people without diabetes.3 According to AFAR, which manages the trial, it is planned as six-year trials at 14 US research institutions in more than 3,000 people aged 65 to 79, and AFAR is leading the fundraising needed to launch it; no results exist yet.
What the Newest Human Trials Show
While TAME waits, two 2026 studies tested metformin against broad, aging-related outcomes, and neither favored it. The Diabetes Prevention Program randomized 3,234 adults with prediabetes to intensive lifestyle change, metformin or placebo in the late 1990s, and its follow-up continued for more than two decades. Among 1,173 participants with Medicare data through 2021, those in the lifestyle group were less likely to develop multimorbidity, two or more of 15 common chronic conditions (hazard ratio 0.79), but those taking metformin were not (hazard ratio 0.91, no significant difference from placebo).8
In the DEMFOS trial, 114 adults aged 65 to 85 with obesity were assigned to an intensive diet-and-exercise program with metformin or placebo, or to diet education with metformin. After 6 months, intensive lifestyle change improved physical performance, but adding metformin to it made no difference.9 Neither study is the definitive test of metformin as an aging drug, but both suggest that for healthy aging, lifestyle change has stronger human evidence than metformin.
The Exercise Interaction: A Critical Concern
In a randomized trial in older adults, metformin attenuated the increases in insulin sensitivity and VO2 max produced by aerobic training and abolished the exercise-induced rise in muscle mitochondrial respiration, although the effect varied widely between people.5 In another trial, people taking a placebo gained more lean body mass and thigh muscle from resistance training than those taking metformin.7 For anyone who relies on exercise for their health, this is a reason to weigh metformin carefully with a clinician.
B12 Depletion: The Overlooked Side Effect
In the Diabetes Prevention Program Outcomes Study, low vitamin B12 (203 pg/mL or less) was more common with metformin than placebo at 5 years (4.3% vs 2.3%), though not significantly at 13 years (7.4% vs 5.4%).6 Each year of metformin use raised the odds of B12 deficiency by about 13%, anemia was more common with metformin, and neuropathy was more common in metformin users with low B12.6 The authors suggest considering routine B12 testing for people taking metformin.6
Taking metformin for longevity is a decision to make with a physician. The case for it rests on its long record in diabetes and its effects on aging-related pathways; the case against includes the lack of a completed longevity trial, Danish data contradicting the earlier survival finding, its interference with some exercise adaptations and its effect on vitamin B12. TAME, if it is funded and completed, should clarify the question.
Put this research into practice: Supplement Evidence Database
References
- 1Bannister CA, et al. "Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls." Diabetes Obes Metab. 2014;16(11):1165-73. PubMed · DOI
- 2Foretz M, et al. "Metformin: from mechanisms of action to therapies." Cell Metab. 2014;20(6):953-66. PubMed · DOI
- 3Barzilai N, et al. "Metformin as a Tool to Target Aging." Cell Metab. 2016;23(6):1060-1065. PubMed · DOI
- 4Keys MT, et al. "Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study." Int J Epidemiol. 2022;51(6):1886-1898. PubMed · DOI
- 5Konopka AR, et al. "Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults." Aging Cell. 2019;18(1):e12880. PubMed · DOI
- 6Aroda VR, et al. "Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study." J Clin Endocrinol Metab. 2016;101(4):1754-61. PubMed · DOI
- 7Walton RG, et al. "Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial." Aging Cell. 2019;18(6):e13039. PubMed · DOI
- 8Salive ME, et al. "Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes." JAMA. 2026;336(7):577-586. PubMed · DOI
- 9Nava MLD, et al. "Metformin added to lifestyle intervention for physical function in older adults with obesity (DEMFOS trial): a randomised controlled trial." Lancet Healthy Longev. 2026;7(7):100883. PubMed · DOI
