Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM‐HET3 mice

The aging brain is characterized by progressive increases in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program demonstrated that the anti‐diabetes drug, Canagliflozin (Cana), a sodium‐glucose transporter 2 inhibitor, led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% in male mice only. Here, we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30‐month‐old male mice. Aged males produce more robust neuroimmune responses than aged females. Remarkably, Cana‐treated male and female mice showed significant reductions in age‐associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia. However, in the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially correlated with reduced phosphorylation of S6 kinase in microglia of Cana‐treated aged male, but not female mice. Thus, Cana treatment improved insulin responsiveness in aged male mice. Furthermore, Cana treatment improved exploratory and locomotor activity of 30‐month‐old male but not female mice. Taken together, we demonstrate the sex‐specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.