The study investigates the effect of sodium-glucose co-transporter 2 (SGLT2) inhibition on senescent cell clearance and its potential therapeutic implications for pathological aging. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the burden of senescent cells in visceral adipose tissue, improved metabolic dysfunction, and alleviated inflammation. Insulin treatment, which normalizes glucose metabolism, did not affect senescent cell clearance. Metabolomic analysis revealed that canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1β-d-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating programmed cell death-ligand 1 (PD-L1). These findings suggest that SGLT2 inhibition has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells. The study also demonstrates that SGLT2 inhibition extends the lifespan of mice with premature aging and improves physical activity and metabolic parameters. These results highlight the potential of SGLT2 inhibitors as a therapeutic strategy for age-related diseases by targeting senescent cell accumulation.The study investigates the effect of sodium-glucose co-transporter 2 (SGLT2) inhibition on senescent cell clearance and its potential therapeutic implications for pathological aging. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the burden of senescent cells in visceral adipose tissue, improved metabolic dysfunction, and alleviated inflammation. Insulin treatment, which normalizes glucose metabolism, did not affect senescent cell clearance. Metabolomic analysis revealed that canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1β-d-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating programmed cell death-ligand 1 (PD-L1). These findings suggest that SGLT2 inhibition has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells. The study also demonstrates that SGLT2 inhibition extends the lifespan of mice with premature aging and improves physical activity and metabolic parameters. These results highlight the potential of SGLT2 inhibitors as a therapeutic strategy for age-related diseases by targeting senescent cell accumulation.