Figure 1. Role of Sirt1 in mammalian aging. Mammalian aging is the time-dependent loss of health with increased occurrence of chronic degenerative, neoplastic and inflammatory diseases. These fundamental pathologic processes are profoundly affected by nutrients and their metabolism. Current evidence points to a major role for the protein deacetylase Sirt1 as a metabolic sensor that translates nutrient availability into largely protective cell responses, thus prolonging healthspan. Molecular interactions whereby Sirt1 exerts this role are in the focus of the present article. Protein lysine deacetylation by Sirt1 involves hydrolysis of NAD+ into nicotinamide (NAM), itself an inhibitor of the enzyme activity, and yields O-acetyl-ADP-ribose (not shown) and the deacetylated substrate. The dependence on NAD links Sirt1 activity to the energy status of the cell via the cellular NAD:NADH ratio and the absolute levels of NAD.