Project Summary During aging, pancreatic beta cells undergo a decline in insulin secretion capacity, and this contributes to nearly 3-fold high diabetes prevalence in people aged over 65 years compared to the general population. Sirtuin 6 (SIRT6), a histone deacetylase, has been suggested to be a longevity factor. In the preliminary study, we have demonstrated that SIRT6 is required to maintain normal beta cell function and SIRT6 is downregulated in the beta cells during aging. Therefore, we hypothesize that SIRT6 plays an important role in the protection of pancreatic beta cells against aging-associated cellular damage. In this application, we will investigate the SIRT6 function and mechanism in the regulation of pancreatic beta cell aging. It is our expectation that the findings from this project will advance our understanding of the fundamental process of the aging of pancreatic beta cells and provide potential novel targets for the development of prevention and treatment of the age-related diabetes.