Metformin: A Promising Candidate for Slowing the Progression of Cardiovascular Aging.

Abstract

Cardiovascular aging, characterized by endothelial dysfunction, arterial stiffening, and myocardial remodeling, is a major contributor to the development of age-related cardiovascular disease. Metformin, a first-line therapy for type 2 diabetes, has attracted interest as a promising geroprotective agent due to its ability to target several fundamental aging pathways. Mechanism: Beyond glucose-lowering effects, metformin may confer cardiovascular benefits through activation of AMP-activated protein kinase and inhibition of mitochondrial complex I. Preclinical work suggests these pathways enhance mitochondrial biogenesis, reduce oxidative stress, promote autophagy, and suppress chronic inflammation. Furthermore, metformin has been reported to modulate epigenetic clocks and support genomic stability, potentially mitigating several hallmarks of aging. Clinical Evidence: Although preclinical evidence is substantial, clinical findings remain heterogeneous. Observational studies and trials like UKPDS suggest cardiovascular benefits, whereas randomized controlled trials (RCTs) such as TAYSIDE, GIPS-III, REMOVAL and GOMET yielded inconsistent results for both clinical and surrogate cardiovascular endpoints. Result interpretations are often limited by relatively small sample sizes and short follow-up durations. Sex Differences and Limitations: Emerging evidence suggests sexual dimorphism in metformin responses, potentially influenced by hormonal status and pharmacokinetics. Additional challenges include the hormetic dose-response, the heterogeneity and frailty of older populations, and the absence of validated aging-specific cardiovascular endpoints. Metformin remains a promising candidate to mitigate cardiovascular aging. However, definitive conclusions regarding its efficacy in non-diabetic older adults will require large-scale, long-term RCTs incorporating aging-related biomarkers and stratification according to sex and metabolic status.