Abstract This review is based on a systematic search and qualitative synthesis of studies from PubMed, Scopus, Web of Science, and Google Scholar, examining pharmacogenomic, genetic, and epigenetic factors influencing metformin's effects on aging and longevity. Additional references were identified from bibliographies and clinical trial registries. Metformin, a widely used antidiabetic drug, has gained attention in longevity research for its biological effects beyond glycemic control. However, responses to metformin vary considerably, especially in aging populations. This review examines the pharmacogenomic, genetic, and epigenetic factors that shape its efficacy and tolerability, emphasizing their relevance to personalized longevity medicine. We discuss key pharmacogenomic variants in drug transporter genes such as SLC22A1 (OCT1), SLC22A2 (OCT2), and SLC47A1/SLC47A2 (MATE1/2-K), which affect metformin absorption, distribution, and clearance. Additionally, polymorphisms in metabolic regulators like ataxia telangiectasia mutated (ATM), LKB1, PRKAB2, and TCF7L2 modulate downstream signaling pathways, most notably adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) that are central to metformin's anti-aging effects. Beyond genetic influences, metformin may exert epigenetic modifications, such as alterations in DNA methylation, histone acetylation, and non-coding RNA expression. These changes have been reported to impact aging-related pathways such as oxidative stress response, mitochondrial function, inflammation, and autophagy. Notably, metformin has been shown in preclinical and translational studies to downregulate aging-associated microRNAs (such as miR-34a) and modulate epigenetic enzymes and antioxidant responses, thereby supporting cellular homeostasis. Preclinical evidence and select human studies suggest that metformin may influence risk trajectories of age-related conditions (e.g., cardiometabolic disease, cancer, neurodegeneration), although direct effects on human longevity remain unproven. Ongoing trials like Targeting Aging with Metformin (TAME) aim to reposition metformin as a first-in-class therapy targeting the biology of aging itself. However, recent findings from trials like MET-PREVENT underscore the need for precision in patient selection, dose optimization, and biomarker integration. By integrating pharmacogenomic and epigenetic profiling, personalized metformin therapy could become a cornerstone in geroscience. This review supports a personalized approach to optimize metformin's benefits in diverse aging populations and outlines future steps for clinical translation.
Alam et al. (Tue,) studied this question.