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Review
. 2014 Jun;12:e9-e17.
doi: 10.1016/j.ddtec.2012.08.003.

The Controversial World of Sirtuins

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Free PMC article
Review

The Controversial World of Sirtuins

Weiwei Dang. Drug Discov Today Technol. .
Free PMC article

Abstract

The controversy around sirtuins and their functions in aging has drawn in the past few years as much attention, if not more, from the scientific community and the public as they did when first proposed as the key conserved aging regulators in eukaryotes. With some of the basic observations on sirtuin longevity promoting functions being questioned in popular model systems, researchers are wondering if this family of conserved enzymes still holds strong potential as therapeutic targets. This review examines the several controversial issues around sirtuins and their functions in aging, calorie restriction, as well as age-related diseases in light of recent studies in mammalian systems and discusses whether modulators of sirtuins still hold the secret of life.:

Figures

Figure 1
Figure 1
Typical chemical reactions catalyzed by sirtuin enzymes. (A) Protein lysine deacetylation by sirtuins requires NAD+ as a cofactor, releasing deaceylated protein, nicotinamide, and 2’-O-acetyl-ADP-ribose. (B) Certain sirtuins are ADP-ribosyltransferases, attaching the ADP-ribose moiety to the ε-amine of lysine, releasing nicotinamide.
Figure 2
Figure 2
NAD+ salvage pathway recycles nicotinamide from the sirtuin catalyzed deacetylation reaction and regenerates NAD+. Activation of this pathway may play an important role in modulating sirtuin activities by removing the sirtuin inhibitor nicotinamide and generating the cofactor NAD+. Key yeast enzymes and metabolites in this pathway are shown.
Figure 3
Figure 3
A proposed mechanism of both sirtuins and TOR regulated pathways are modulated by the availability of nutrition states. The red “up” and green “down” arrows indicate increased and decreased activity or abundance, respectively. The thickness of the blue arrows indicates the relative impact to the downstream targets.

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