SAT046 Canagliflozin Leads To Less Weight Gain, Confers Changes In The Gut Microbiota And Extends Life Span In Male C57BL6 Mice

Abstract

Abstract Disclosure: E.E. Habeos: None. F. Filippopoulou: None. M. Kanakis: None. G.I. Habeos: None. N. Belmokhtar: None. P. Stathopoulou: None. G. Tsiamis: None. S. Taraviras: None. G. Lagoumintzis: None. D.V. Chartoumpekis: None. Introduction: SGLT2 inhibitors (SGLT2i) are widely prescribed drugs for the treatment of diabetes. Their beneficial health effects appear to be pleiotropic and are not limited to the amelioration of glycemic profile. The SGLT2i-induced glycosuria is suggested to provoke a metabolic shift that mimics the fasting response. Since calorie restriction has been shown to enhance longevity in mice, we hypothesized that treating mice with SGLT2i would also increase their life span. Methods: To this end, 4-months old male C57BL6 mice were fed with a standard chow diet (Control, n=83) or a diet supplemented with 200 mg/kg canagliflozin (Cana, n=92) and were observed up to the natural end of their life. Results: The canagliflozin-treated mice gained less weight over time. For instance, at the age of 10 months, the body weight of control mice was higher (means ± SEM: 33.1 ± 0.26 g) than the body weight of their canagliflozin-treated counterparts (means ± SEM: 31.4± 0.21 g; p<0.01). The development and severity of age-related cataracts were also examined at the age of 14 months, but no statistically significant difference was found in the severity score between the 2 groups. The survival curves of the control and the Cana mice diverged significantly, with the median survival of the control being 107.5 weeks versus 112.5 weeks of the Cana group (p=0.011). As the gut microbiome is known to change with age and be associated with the development of age-related diseases, feces were collected from 17-month-old mice (n=10 per group) and analysis of fecal bacterial 16S rRNA sequences was performed. Differences in beta diversity (diversity of bacterial species across samples) and relative abundance of bacterial species were noted between the Control and the Cana groups. Conclusions-Discussion: Our study highlights the effect of SGLT2i on longevity in a widely used mouse model (C57BL6). The underlying mechanisms leading to the enhancement of longevity are not clear yet. Some microbiota changes associated with the SGLT2i treatment, as described in other mouse models with enhanced longevity, warrant further investigation and analysis. It would be useful to extend these studies employing various SGLT2i with different potencies and selectivity against SGLT so as to determine if the observed effect on longevity is independent of the type of the drug. Presentation: Saturday, June 17, 2023