Pharmaceutical strategies for activating sirtuins.

The sirtuins are protein modifying enzymes widely distributed in all forms of life. The sirtuins are principally NAD(+)-dependent protein acetyl-lysine deacetylases that reverse acetyl-modifications of proteins. The sirtuins are implicated in a variety of adaptations to reduced nutritional intake, and increase lifespan in several model organisms, such as yeast, flies and worms. The human sirtuins (SIRT1-7) have been identified to regulate a variety of biological processes, such as glucose homeostasis, gluconeogenesis, mitochondrial biogenesis, insulin secretion, adipogenesis and adipolysis, apoptosis, senescence and metabolism. The potency of sirtuins in regulating mammalian biological processes invites consideration of them as potential drug targets. This review considers small molecule approaches to activate sirtuins in a biochemical and biological context. These approaches include allosteric activation, which has been demonstrated for the SIRT1 enzyme. Another approach discussed is enhancement of NAD+ levels in cells, since sirtuins appear to be responsive to increased cellular NAD+. Finally, a sirtuin-specific approach is considered that is called nicotinamide derepression. This approach is designed to antagonize physiologic nicotinamide inhibition of sirtuins as a means to upregulate sirtuin function. Biological data that provides evidence of effectiveness of these approaches in in vitro and in vivo contexts is presented along with a discussion of the theoretical considerations that underpin these strategies. Efficacies and shortcomings of the various approaches are also discussed.