METFORMIN BEYOND DIABETES: A COMPREHENSIVE PHARMACOLOGICAL REVIEW OF THE ANTI-AGING AND ANTI-CANCER PLEIOTROPY, THE AMPK/MTOR AND MITOCHONDRIAL MECHANISMS, THE TAME TRIAL, AND THE CRITICAL APPRAISAL OF GERO PROTECTION AND ONCOLOGICAL REPURPOSING

Metformin, a biguanide derived from Galega officinalis (French lilac), has been the first-line oral therapy for type 2 diabetes mellitus for decades. Beyond its glucose-lowering effects, metformin has attracted considerable scientific attention because of its potential anti-cancer and anti-aging (geroprotective) properties. Its pharmacological actions include inhibition of mitochondrial complex I, activation of AMP-activated protein kinase (AMPK), suppression of mechanistic target of rapamycin (mTOR) signaling, reduction of circulating insulin and insulin-like growth factor-1 (IGF-1) levels, modulation of the gut microbiome, and effects on growth/differentiation factor 15 (GDF15). These mechanisms influence pathways implicated in carcinogenesis and aging, providing biological plausibility for its broader therapeutic potential. Early observational studies reported associations between metformin use and reduced cancer incidence, lower cancer-related mortality, and improved overall survival, generating enthusiasm for its use beyond diabetes management. However, many of these findings are affected by important methodological limitations, particularly immortal time bias and time-window bias, which may have overstated the apparent benefits. Consistent with these concerns, randomized controlled trials evaluating metformin for cancer prevention and treatment have largely produced neutral or inconclusive results, warranting a more cautious interpretation of its anti-cancer effects. Metformin has also emerged as a leading candidate geroprotective agent. The Targeting Aging with Metformin (TAME) trial represents a landmark effort to determine whether metformin can delay the onset of multiple age-related diseases and modify the aging process in humans. This review critically examines the molecular mechanisms underlying metformin’s pleiotropic actions, evaluates the evidence for its anti-cancer and anti-aging effects, discusses key methodological challenges, and summarizes safety considerations, the Indian perspective, and future research priorities. While metformin remains a promising candidate for broader clinical applications, definitive evidence will require well-designed randomized clinical trials.

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