Dissecting out the unexpected effects of SGLT2 inhibitors on human aging

Sodium-glucose cotransporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubules, thereby promoting urinary glucose excretion. Although originally developed as antidiabetic agents, large-scale clinical trials have demonstrated that SGLT2 inhibitors not only lower blood glucose levels but also significantly reduce cardiovascular and renal events in patients with diabetes. Subsequent studies further established that these agents confer cardiorenal protection in individuals with heart failure or chronic kidney disease, irrespective of diabetes status. Beyond these established clinical benefits, accumulating evidence suggests that SGLT2 inhibitors may exert antiaging effects. Mechanistically, they induce metabolic adaptations that resemble caloric restriction and ketogenic states, attenuate systemic inflammation, improve mitochondrial function, and enhance cellular resilience against the burden of senescence. Supporting this concept, multiple preclinical studies have shown that SGLT2 inhibitors extend lifespan and ameliorate age-related functional decline in animal models. Notably, recent findings indicate that SGLT2 inhibitors can reduce senescent cell burden and modulate the senescence-associated secretory phenotype, raising the possibility that they possess senotherapeutic-or even senolytic-properties targeting a fundamental driver of aging. Collectively, these data suggest that SGLT2 inhibitors may influence core aging pathways beyond their glucose-lowering and cardiorenal protective effects. In this review, we summarize current insights into the molecular and physiological mechanisms by which SGLT2 inhibitors may modulate aging biology and discuss their emerging potential as therapeutic agents capable of extending health span and preventing age-related diseases.