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Recently, the Interventions Testing Program demonstrated that the anti\u2010diabetes drug, Canagliflozin (Cana), a sodium\u2010glucose 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\u2010month\u2010old male mice. Aged males produce more robust neuroimmune responses than aged females. Remarkably, Cana\u2010treated male and female mice showed significant reductions in age\u2010associated 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\u2010treated 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\u2010month\u2010old male but not female mice. Taken together, we demonstrate the sex\u2010specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.<\/jats:p>","DOI":"10.1111\/acel.13653","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T02:48:10Z","timestamp":1655347690000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM\u2010HET3 mice"],"prefix":"10.1111","volume":"21","author":[{"given":"Hashan S. 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