Molecular mechanisms of metformin action: From metabolic effects to lifespan extension and healthspan promotion

Background: Metformin, a biguanide primarily used for the treatment of type 2 diabetes mellitus, has attracted significant attention for its potential anti-ageing effects. As ageing becomes the primary risk factor for chronic diseases, interventions targeting fundamental ageing processes are gaining traction in biomedical research. Methods: Accumulating evidence suggests that metformin exerts geroprotective effects through multiple interconnected pathways. These include activation of AMP-activated protein kinase (AMPK), inhibition of the mechanistic target of mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) (mTOR), attenuation of oxidative stress, modulation of mitochondrial biogenesis, and reduction of low-grade systemic inflammation. Together, these actions address key hallmarks of ageing such as cellular senescence(definition), dysregulated nutrient sensing, and altered proteostasis(definition). Results: Animal studies have consistently shown that metformin extends both lifespan and healthspan(definition). In humans, retrospective epidemiological data indicate reduced incidence of cancer, cardiovascular disease, and cognitive decline among metformin users. The TAME (Targeting Ageing with Metformin) trial represents the first large-scale attempt to assess ageing-related outcomes in a non-diabetic population formally. Despite promising data, uncertainties remain regarding optimal dosing, long-term safety, and applicability in healthy ageing populations. Furthermore, individual variability in response to metformin suggests the need for precision medicine approaches. Conclusions: Metformin stands at the intersection of metabolic regulation and ageing biology. While not a panacea, its favourable safety profile and multi-targeted actions make it a leading candidate for repurposing as an anti-ageing therapy. Continued clinical validation is essential to translate these insights into practice.