1547-P: SGLT Inhibitor Canagliflozin Modulates Hypothalamic Function with Aging

The hypothalamus, a critical brain region intricately involved in metabolic regulation and homeostasis, undergoes substantial changes with aging, influencing age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), such as Canagliflozin, are anti-diabetic agents that enhance glucose elimination, resulting in a net calorie loss. Previously, we demonstrated Canagliflozin's ability to extend the median lifespan of genetically heterogeneous UM-HET3 male mice and improve hypothalamic insulin responsiveness in aging males. Here, we sought to evaluate Canagliflozin's impact on hypothalamic metabolic function during aging. Energy homeostasis was measured in 12- and 26-month-old UM-HET3 mice treated with Canagliflozin from 7 months of age. Canagliflozin-fed mice exhibited increased food consumption and water intake. Notably, 12-month-old Canagliflozin-fed males, but not females, displayed a significant increase in energy expenditure compared to controls. By 26 months, both male and female Canagliflozin-treated mice exhibited elevated metabolic rates, indicating sustained effects. This shift in energy expenditure correlated with alterations in hypothalamic orexigenic and anorexigenic projections in aged mice. Subsequently, bulk RNA-seq analysis of the hypothalamus from Canagliflozin-treated mice at 12 and 26 months revealed sex-specific transcriptional signatures, impacting glycolysis, oxidative phosphorylation, and insulin receptor signaling in aged mice leading to alterations in metabolic pathways. Our findings suggest that Canagliflozin's metabolic and health span effects in genetically diverse mice may be linked to its central effects, presenting it as a promising geroprotective intervention with implications for age-related metabolic changes.