Senotherapeutic repurposing of metformin for age-related diseases and their signaling pathways

Drug repurposing is the process of using currently approved drugs for a novel treatment or medical condition for which it was not previously indicated. Despite promising preclinical and clinical results, most of the newly designed senotherapeutic agents synthesized have limited clinical utility due to individual and organ-specific variations in aging phenotype and adverse side effects. All these limitations indicate that further clinical research is required to determine the effectiveness of repurposed senotherapeutic drug interventions, such as metformin, for age-related diseases. Metformin exerts diverse senotherapeutic effects on various aging tissues at different metabolic conditions. Although not exhibiting senolytic properties, metformin has effectively suppressed cellular senescence and senescence-associated secretory phenotype (SASP) in age-related diseases (ARDs). Targeting specific SASP-related signaling pathways with metformin may offer new therapeutic benefits to alleviate the detrimental effects of senescent cells accumulated in most common ARDs in the elderly. Metformin was also the first drug evaluated for its senescence-targeting effects in a large clinical trial named "Targeting Aging with Metformin (TAME)". In this review, we critically evaluate the literature to highlight senotherapeutic mechanisms in which metformin can be therapeutically repurposed for the prevention and treatment of ARDs.