2181-P: Metformin Use and Epigenetic Aging in the Million Veteran Program

Introduction and Objective: Metformin is a widely used glucose-lowering agent with purported pleiotropic effects on health including potential extension of lifespan and healthspan. Epigenetic clocks are versatile aging biomarkers reflective of morbidity and mortality. However, the potential impact of metformin on biological aging in human populations is poorly understood. Methods: We assessed diabetes medication history using VA electronic health records and epigenome-wide DNA methylation in whole blood among 13,910 participants of the Million Veteran Program (mean age: 66.3 years, 95.4% male) with diabetes. We examined associations between metformin usage and diabetes treatment courses and 10 epigenetic aging biomarkers in multivariate regression models adjusted for age, sex, BMI, smoking, technical factors, genetics, cell proportions, time since diabetes diagnosis, and HbA1c levels. Results: Participants with any history of metformin prescriptions exhibited consistently reduced epigenetic biomarkers of aging compared to participants who used only other medication across several clocks including 0.46 years lower GrimAge2 (95% CI: -0.67, -0.25) and 0.01 lower DunedinPACE (95% CI: -0.02, -0.004). Similarly, participants with diabetes treatment courses characterized by consistent metformin, metformin-to-other medication, or other-to-metformin medication exhibited consistently lower epigenetic aging compared to participants with consistent-other medication. Evidence for a dose-response relationship between metformin and epigenetic aging was mixed, with some clocks showing higher epigenetic age with higher metformin usage, while associations with AdaptAge indicated protective changes in sites causally linked to aging. Conclusion: Metformin use was modestly linked to slower epigenetic aging across several biomarkers in a large cohort of Veterans with diabetes, although the effects were generally small and could still be affected by the progression and severity of diabetes.