SIRT1 is a member of the silent information regulator 2 (Sir2a) protein family of enzymes that is ubiquitous in terrestrial life. Following the discovery of the yeast Sir2 protein, mammalian homologues were subsequently identified and were designated sirtuins. 1, 2 In humans, these enzymes possess either NAD þ dependent deacetylase activity or protein ADP-ribosyltransferase activity.

As shown in Figure 1, all seven human sirtuins share a conserved catalytic core domain (designated in yellow), although overall the proteins vary significantly in length. The sirtuins also differ in their subcellular localization and substrate specificity and have distinct downstream effects. 3 SIRT1, which is the focus of this review, is by far the most studied of all the seven human sirtuins. Interest in SIRT1 has grown since the initial reports that the S. cerevisae and C. elegansorthologues mediate the effects of calorie restriction (CR) to extend the lifespan of these organisms. 4 In mammals, SIRT1 transgenic mice show phenotypes and gene expression profiles that resemble those observed in mice on CR, 5 and further studies have provided evidence that SIRT1 plays a central role in regulating metabolic responses to nutrient conditions. 6-11 SIRT1 knockout mice, however, have been harder to assess, as they have poor viability and developmental deficits on most genetic backgrounds. 12 Nonetheless, SIRT1 overexpression and knockdown in a variety of cell systems and in mice have supported the notion that SIRT1 regulates not only metabolic responses but also circadian rhythm, 13-16