Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)?

Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent deacetylase that is at the pinnacle of metabolic control, all the way from yeast to humans. SIRT1 senses changes in intracellular NAD(+) levels, which reflect energy level, and uses this information to adapt the cellular energy output such that it matches cellular energy requirements. The changes induced by SIRT1 activation are generally (but not exclusively) transcriptional in nature and are related to an increase in mitochondrial metabolism and antioxidant protection. These attractive features have validated SIRT1 as a therapeutic target in the management of metabolic disease and prompted an intensive search to identify pharmacological SIRT1 activators. In this review, we first give an overview of the SIRT1 biology with a particular focus on its role in metabolic control. We then analyze the pros and cons of the current strategies used to activate SIRT1 and explore the emerging evidence indicating that modulation of NAD(+) levels could provide an effective way to achieve such goals.