Strikingly, although sirtuins have been studied for over a decade, the scientific field is still arguing about the role of sirtuins in regulating longevity. This long-time debate is summarized herein, together

with an explanation regarding the current knowledge of this issue. The discovery of sirtuins as regulators of aging began in yeast. Several studies originally reported that a yeast protein, namely silence information regulator 4 (Sir4), is involved in the regulation of yeast lifespan. Yeast carrying Inhibitors,research,lifescience,medical a mutation in Sir4 has extended lifespan along with short telomeres.5 These observations led to the conclusion that in the absence of normal telomere length, Sir4 localizes to an unknown aging regulator locus. Later on, this site was recognized in the yeast learn more genome as the rDNA locus, a tandem repeat of the coding Inhibitors,research,lifescience,medical sequences for the ribosomal RNA (rRNA).6 This knowledge led to the discovery that the basis for yeast aging is the recombination events within rDNA that release a single repeat in its circular form, since the extrachromosomal rDNA circle (ERC) can exponentially accumulate and kill the cell.7 Soon after, it was shown that Sir2, a member of the Sir4 complex, regulates the rate of ERC creation and therefore the rate of yeast aging.8 In the late 1990s a study from the

Guarente lab, led mainly by Matt Kaeberlein, Inhibitors,research,lifescience,medical demonstrated that deletion of Sir2 shortens yeast lifespan and Inhibitors,research,lifescience,medical that Sir2 overexpression extends yeast lifespan.8 However, a possible explanation of the mechanism by which Sir2 regulates yeast aging came after an elegant study by Shin Imai and Lenny

Guarente that revealed for the first time the true enzymatic activity of Sir2—a NAD+ dependent histone deacetylase.9 Moreover, another study showed that deletion of Sir2 blocked the beneficial effects of dietary restriction (DR) on lifespan.10 The latter observation suggests that sirtuins were required for the DR-mediated increase in lifespan. Dietary restrictions or reducing caloric Inhibitors,research,lifescience,medical intake by 30% were shown to extend the lifespan of many organisms from yeast to rodents. Moreover, the lifespan extension was accompanied with increased health-span, expressed by decreased incidence Adenylyl cyclase of tumorigenesis, diabetes type II, and other age-related diseases.11 However, whether DR also affects primates is currently under debate, as two recent studies on rhesus monkeys fed a DR diet published contradicting results regarding DR-mediated increase in lifespan.12,13 While one study showed that DR significantly increased lifespan, the other failed to find an effect. These results may be due to dietary differences between the studies, or the origin of the monkeys. Thus, even before sirtuins entered the picture, possible treatments to extend lifespan were fraught with debate and conflict.