228-LB: Metformin Alleviates Aging-Associated Metabolic Disorders through Intestinal AMPK-Mediated Gut Microbiome Alteration

Abstract

The biguanide drug metformin combats age-related disorders and improves health span and is currently the first FDA approved drug to be tested for its age-targeting effects in the large clinical trial. However, the underlying molecular mechanisms remain unclear. AMPK is a key nutrient sensor for maintaining cellular energy status and a known therapeutic target of metformin to treat T2D. Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Our previous study uncovered a novel link between intestinal AMPK activation and energy metabolism through modulating the anti-microbial peptide (AMP)-controlled gut microbiota. We therefore ask whether intestinal AMPK also mediates metformin effects on aging-associated metabolic improvement. In this study, we showed that AMPKα1 deficiency in the intestine resulted in weight gain, impaired glucose tolerance and insulin resistance in aged mice. Interestingly, metformin administration ameliorated these aging-associated metabolic disorders in aged wild type but not intestinal AMPK α1 KO mice, which indicated that the beneficial effects of metformin were dependent on the intestinal AMPKα1 in aging animals. Moreover, we found that metformin treatment significantly altered the abundance of several gut bacterial genera in aged-AMPKα1fl/fl but not intestinal AMPK α1 KO mice. Mechanistically, we identified several key anti-microbial peptides were upregulated by metformin treatment in an intestinal AMPK-dependent manner in aged mice. In summary, our findings provide a new mechanistic underpinning by which intestinal AMPK regulates aging metabolism, which may shed light on not only the ongoing large clinical trials of metformin in aging patients, but also general drug discoveries utilizing enteral drug administration to treat aging-associated metabolic diseases. Disclosure E. Zhang: None. W. Huang: None.