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Review
. 2010 Aug;1804(8):1626-34.
doi: 10.1016/j.bbapap.2009.10.025. Epub 2009 Nov 6.

Biochemical Effects of SIRT1 Activators

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Free PMC article
Review

Biochemical Effects of SIRT1 Activators

Joseph A Baur. Biochim Biophys Acta. .
Free PMC article

Abstract

SIRT1 is the closest mammalian homologue of enzymes that extend life in lower organisms. Its role in mammals is incompletely understood, but includes modulation of at least 34 distinct targets through its nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase activity. Recent experiments using small molecule activators and genetically engineered mice have provided new insight into the role of this enzyme in mammalian biology and helped to highlight some of the potentially relevant targets. The most widely employed activator is resveratrol, a small polyphenol that improves insulin sensitivity and vascular function, boosts endurance, inhibits tumor formation, and ameliorates the early mortality associated with obesity in mice. Many of these effects are consistent with modulation of SIRT1 targets, such as PGC1alpha and NFkappaB, however, resveratrol can also activate AMPK, inhibit cyclooxygenases, and influence a variety of other enzymes. A novel activator, SRT1720, as well as various methods to manipulate NAD(+) metabolism, are emerging as alternative methods to increase SIRT1 activity, and in many cases recapitulate effects of resveratrol. At present, further studies are needed to more directly test the role of SIRT1 in mediating beneficial effects of resveratrol, to evaluate other strategies for SIRT1 activation, and to confirm the specific targets of SIRT1 that are relevant in vivo. These efforts are especially important in light of the fact that SIRT1 activators are entering clinical trials in humans, and "nutraceutical" formulations containing resveratrol are already widely available.

Figures

Figure 1
Figure 1
Substrates and products of the reaction catalyzed by SIRT1. Note that only the side chain is shown for lysine, since SIRT1 does not have a conventional consensus sequence [139], although preference for specific peptides can be demonstrated [140].
Figure 2
Figure 2
Substrates, transcriptional targets, and binding partners of SIRT1. At least 34 direct deacetylation targets are known, with activities that impact almost every aspect of cellular physiology. For simplicity, only a few of the major themes are indicated. Several transcriptional targets of SIRT1 have been indicated because they are likely to be physiologically important and are not obvious results of the deacetylation targets and binding partners listed (although silencing of IGFBP1 is probably related to deacetylation of FOXOs). Note that the interaction of SIRT1 with binding partners can have varying results. SIRT1 overexpression silences PPARγ targets [21], but enhances expression of PPARα targets [64]. DBC1 directly inhibits SIRT1 activity [141, 142], while HIC1 directs it to its own promoter, silencing SIRT1 expression [143]. TLE1 mediates deacetylation of NFκB [144], and Clock directs SIRT1 to the promoters of genes involved in circadian rhythms [22, 145].
Figure 3
Figure 3
Structures of SIRT1 activators. Resveratrol is a naturally occurring polyphenol, and SRT1720 was synthesized by Sirtris Pharmaceuticals.

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