SGLT2 Inhibition is Senolytic in Overweight Mice

SGLT2 inhibitors are a class of diabetes medication that falls within the broad present enthusiasm for pharmacological treatments that can reduce weight in obese individuals. In today's open access paper, researchers demonstrate that the SGLT2 inhibitor canagliflozin reduces the burden of senescent cells in obese mice fed a high fat diet. The researchers identify the mechanism as an increase in the efficiency with which immune cells clear senescent cells from tissues.

It is known that being overweight, specifically meaning a greater burden of metabolically active, inflammatory visceral fat tissue, increases the pace at which senescent cells accumulate. The consequent greater burden of senescent cells may contribute meaningfully to many of the negative consequences of visceral fat and excess weight. Given that cellular senescence is a hallmark of aging, it may be reasonable to say that being overweight accelerates aging.

However, it may well be the case that the senolytic effects of SGLT2 inhibitors will not occur to any great degree outside the context of obesity, a high fat diet, and their disruptions to normal metabolism. One would certainly want to see studies in aged mice of a normal weight before becoming too enthusiastic. While there is considerable interest in mining the panoply of diabetes drugs for compounds that might modestly slow aging, it remains to be seen as to whether benefits observed in overweight individuals with metabolic syndrome will also occur in individuals of normal weight and metabolism to any meaningful degree. One might suspect not, given the animal data.

SGLT2 inhibition eliminates senescent cells and alleviates pathological aging

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes.

In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age.

Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), a metabolite well known to activate AMP-activated protein kinase (AMPK), enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1 (PD-L1). These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.