Recent progress in the biology and physiology of sirtuins

Abstract

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.

Figure 1. Mouse knockout models as tools for exploring sirtuin function

Gene targeting of SIRT1, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7 has been reported. The phenotypes include a reduction in median lifespan, ranging from a usual survival of days (SIRT1) to weeks (SIRT6) or months (SIRT7). In contrast, although biochemical phenotypes have been reported, Sirt3^−/− and Sirt4^−/− mice appear outwardly normal. Initial reports suggest that Sirt5^−/− mice also exhibit no obvious phenotype.

Figure 2. The diverse physiological roles of the sirtuins

Shown are examples of the organ-specific physiology of SIRT1, along with some of the direct or indirect targets of sirtuin regulation (see text for details). In addition, examples of some of the SIRT1-regulated intracellular parameters are presented, ranging from modulation of progenitor differentiation to altering the threshold for apoptosis. At the beginning of a compound name or process (for example, ‘Tumour formation’ at bottom right), down-arrow indicates ‘decreasing’, up-arrow indicates ‘increasing’ and ‘Δ’ indicates ‘change in’.

Figure 3. Complex regulation of SIRT1 activity

The promoter of SIRT1 is positively and negatively regulated by the binding of various transcription factors and repressors, including H1C1, CtBP, p53, FOXO3A and E2F1. The acetylation and hence activity of many of these factors are in turn controlled by SIRT1. The SIRT1 message is also regulated by the RNA binding protein HuR and the p53-regulated microRNA miR-34A. Finally, SIRT protein activity is regulated positively and negatively by interacting proteins such as AROS and DBC1, as well as by the overall metabolic state, as reflected in the NAD/NADH ratio.