New insights into the roles of sirtuins in metabolic decline and disease of aging
David A. Sinclair
Sirtuins are NAD+-dependent deacetylases that are implicated in mediating health benefits of calorie restriction and possibly exercise. We will report on novel roles of SIRT1-3 in diseases of aging and recent progress in using small molecules to activate SIRT1. Small molecule activators of SIRT1 (STACs), such as resveratrol and SRT1720, improve multiple health parameters in mice including protection from type II diabetes and hepatic steatosis. We developed an system that permits whole-body deletion of SIRT1 in adult mice and have tested whether the effects of resveratrol and SRT1720 on mitochondrial function are SIRT1-dependent. We have also developed novel substrate-agnostic sirtuin assay to discover that SIRT1 activation is facilitated by specific hydrophobic amino acids in native SIRT1 substrates such as PGC-1α and FOXO3α, thus explaining substrate specificity. A structured N-terminal domain is critical for the direct activation of SIRT1 by all known STACs and we find that cells with alterations in this domain are insensitive to the effects of STACs. Together, these data point to a common mechanism for allosteric activation of SIRT1 by small molecules.