Recent progress in the biology and physiology of sirtuins

Abstract

Since the discovery that the life extending benefits of caloric restriction in yeast require Sir2, a protein originally isolated in a screen for gene silencing factors (and called silent information regulator 2), there has been considerable interest in the family of proteins collectively known as the sirtuins. This week Toren Finkel, Chu-Xia Deng and Raul Mostoslavsky review recent advances in sirtuin biology. These NAD-dependent enzymes have been implicated in a wide array of cell-fate decisions, in maintaining genomic stability and regulating overall energy metabolism. Increasing evidence also implicates the sirtuins in the progression of a number of disease states ranging from diabetes to cancer. These observations, coupled with the recent progress in the rationale design of small molecule sirtuin activators, raise the possibility of new therapies targeted to a host of age-related diseases, as well as potential pharmacological strategies to slow mammalian ageing. The sirtuins are a highly conserved family of NAD+-dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long we live.