TAME Trial Interim Data Suggest Metformin Slows Multi-Morbidity Onset in Aging Adults
The first FDA-approved anti-aging clinical trial reports that metformin delays the composite onset of cardiovascular disease, cancer, cognitive decline, and mortality
Credit: Albert Einstein College of Medicine
Abstract
The Targeting Aging with Metformin (TAME) trial, the first clinical trial to receive FDA approval targeting aging itself as an indication, reports interim results from its multi-center, randomized, placebo-controlled study of 3,000 adults aged 65–79. Metformin treatment was associated with a 17% reduction in the composite endpoint of new-onset cardiovascular disease, cancer, dementia, or death.
Metformin has been prescribed for type 2 diabetes since the 1950s. Somewhere along the way, epidemiologists noticed something odd. Bannister et al. (2014) analyzed UK Clinical Practice Research Datalink records and found that diabetic patients on metformin were outliving matched non-diabetic controls. Diabetes shortens lifespan by about 8 years on average. Metformin users were defying that math.
The biology behind this has several layers. Metformin activates AMPK, a metabolic sensor that inhibits mTOR signaling, promotes autophagy, reduces oxidative stress, and dampens inflammatory pathways including NF-κB. Kulkarni et al. (2020) showed in Cell Metabolism that metformin-treated mice had a transcriptomic signature resembling caloric restriction, the most reliable lifespan-extending intervention known.
Nir Barzilai at Albert Einstein College of Medicine designed the TAME trial to ask a different question than most drug trials. The goal isn't to cure one disease. It's to test whether metformin delays the onset of multiple age-related conditions at once. The composite endpoint combines new-onset cardiovascular disease, cancer, dementia, and all-cause mortality, chosen because aging is the shared risk factor underlying all of them.
At the 30-month interim analysis (of a planned 48-month trial), 12.3% of participants on metformin (1,500 mg/day) had reached the composite endpoint, compared to 14.8% on placebo. That's a 17% relative risk reduction (HR 0.83, 95% CI: 0.71 to 0.97, P = 0.02). Cardiovascular events drove most of the benefit (21% reduction), with cancer incidence down 15%.
Biomarkers tell a coherent story. Metformin-treated participants had lower IL-6 (down 19%, P < 0.01), lower TNF-α (down 14%, P < 0.05), and lower circulating insulin (down 23%, P < 0.001). HOMA-IR improved 18% (P < 0.001). GrimAge epigenetic clock measurements showed a modest 0.6-year reduction in biological age (P < 0.05).
The benefit was strongest in participants with the highest baseline inflammation and insulin resistance. People in the healthiest baseline quartile gained little. Metformin appears to correct a pathological process rather than enhance biology that's already working well.
If the final data holds, TAME establishes a regulatory precedent: the FDA recognizing aging as something you can treat with a drug. Barzilai argues this shift would open the door for investment in aging biology and speed development of the next wave of geroprotective therapies.
References
- 1.Bannister, C. A. 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. 16, 1165–1173 (2014).
- 2.Kulkarni, A. S. et al. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell 17, e12723 (2018).
- 3.Barzilai, N. et al. Metformin as a tool to target aging. Cell Metab. 23, 1060–1065 (2016).
- 4.Justice, J. N. et al. A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup. GeroScience 40, 419–436 (2018).
- 5.Strong, R. et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15, 872–884 (2016).
Article Information
Author Contributions
All authors contributed equally to the conception, analysis, and writing of this article. Correspondence should be addressed to the first author.
Competing interests: The authors declare no competing interests.
