Metformin, a commonly used agent for treating diabetes acts by reducing hepatic gluconeogenesis and improving insulin sensitivity. Besides, information available from several studies indicate its role in modulating cellular processes related to aging including oxidative stress, inflammation, cellular senescence, autophagy, and apoptosis.

It has been reported that aministration of metformin increases lifespan in model systems. Moreover, findings of some clinical trials and observational studies suggests that it contributes in delaying various age‐related morbidities. A randomized, double‐blind, placebo‐controlled, crossover trialdetermined the pleiotropic effects of metformin on the biology of human aging in around 70‐year‐old individuals. The study involved 14 participants who were treated with 6 weeks each of metformin and placebo. After each treatment period, subcutaneous adipose tissue and skeletal muscle biopsies were obtained, and a mixed‐meal challenge test was done. The results showed that reductions in 2‐hour glucose, insulin area under the curve, and insulin secretion were better with metformin compared to placebo. On using FDR<l0.05, it was seen that 647 and 146 genes were differentially expressed in muscle and adipose tissue, respectively. Metabolic as well as non-metabolic pathways were influencedsignificantly, including peroxisome proliferator-activated receptors and sterol regulatory element binding proteins signalling, mitochondrial fatty acid oxidation, and collagen trimerization in adipose tissue, and pyruvate metabolism and deoxyribonucleic acid (DNA) repair in muscle. Although every tissue had a signature reflecting its own function, a cascade of predictive upstream transcriptional regulators were identified. These included MYC (oncogene), mammalian target of rapamycin complex 1, tumor necrosis factor, transforming growth factor beta-1, and miRNA‐29b, that may describetissue‐specific transcriptomic changes in response to administration of metformin.

This study that served as the first evidence for the metabolic and non-metabolic actions of metformin associated with aging, in the elderly showed that 6 weeks treatment with metformin can improve age‐associated metabolic derangements in glucose intolerant older people. Moreover, due to the tissue-specific effects of metformin on gene expression in both muscle and adipose tissue, it is likely to target common upstream transcriptional regulators linked to pathways implicated in aging. It is noteworthy that metformin not only influenced metabolic genes and pathways, but also DNA repair genes in muscle, and collagen and mitochondrial genes in adipose, which highlight its potential to target several hallmarks of aging.

Reference

1. Kulkarni AS, Brutsaert EF, Anghel V, et al. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell. 2018;17(2):e12723.