Sirtuin 1 (SIRT1) activating compounds (STACs), including resveratrol and SRT1720, have been described that impart a diverse array of health benefits. One of the biggest questions in the sirtuin field is whether STACs such as resveratrol and SRT-1720, mediate their health benefits via direct SIRT1 activation. I am interested in understanding the mechanism by which SIRT1 is activated by small molecules. I will make use of a mouse model having an activation defective SIRT1 mutation to determine which of the biological effects are due to SIRT1 activation in vivo. Assessing the effects of small molecule activators in primary cells and mice carrying this mutation will help fill the void in our understanding about how protein-modifying enzymes are precisely controlled by endogenous and synthetic molecules to maintain metabolic homeostasis.