Trends in Pharmacological Sciences
ReviewSmall molecule SIRT1 activators for the treatment of aging and age-related diseases
Section snippets
The quest to delay aging
History and myth abound with discoveries of potions that impart longer life. Only recently, however, has our level of knowledge reached a point where a ‘panacea’ – a medicine that prevents and treats multiple age-related diseases – is scientifically possible. This optimism is afforded by the relatively recent discovery of genes and small molecules that can extend lifespan in yeast, worms, flies, and mice 1, 2, 3, 4, 5. There are at least three main pathways that control lifespan in mammals:
The sirtuin longevity pathway
The silent information regulator (SIR) genes promote longevity in diverse species and mediate many of the beneficial effects of calorie restriction (CR), such as a reduced incidence of cancer, cardiovascular disease, and diabetes 9, 10. The link between sirtuins and aging was first made in budding yeast: overexpression of the SIR2 gene increased longevity by suppressing rDNA circle formation, a cause of aging in yeast [11]. Overexpression of Sir2 homologs in worms and flies also extended their
Natural and synthetic SIRT1 activating compounds (STACs)
Given their apparent role in mediating the health benefits of CR, and the subsequent demonstration of therapeutic value in preclinical animal models, sirtuins have attracted considerable interest as drug targets [34]. Most studies indicate that the broadest utility would come from molecules that activate one or more of the sirtuins, and inhibition of SIRT1 also shows promise in some cancer models [6]. Both inhibitors (Box 1) and activators have been discovered for sirtuins; some act
Mechanism of sirtuin activation
Although it is generally accepted that STACs increase SIRT1 activity in vivo, the mechanism by which they activate SIRT1 was the subject of intense debate 40, 41. Two opposing models were proposed to account for STAC activity: (i) direct allosteric activation of Sir2/SIRT1 through a lowering of peptide substrate Km 5, 38 and (ii) coincidental, indirect activation resulting from off-target effects 42, 43. Skepticism about the direct mechanism arose from questions about the assay used. The
Aging
Resveratrol and other related STACs extend the lifespan of numerous organisms including S. cerevisiae [5], Caenorhabditis elegans, Drosophila melanogaster [1], Nothobranchius furzeri, a short-lived fish, [48], and Apis mellifera, the common honeybee [49]. In the first three instances, the longevity effects were shown to require Sir2 1, 5. Consistent with the original sirtuin–CR hypothesis of Guarente [50], resveratrol and STACs induce physiological and gene expression changes consistent with
Concluding remarks
Only 10 years ago, the idea that a drug could treat one disease and prevent a dozen others was considered fanciful by many scientists. Today, however, with abundant data showing that multiple diseases of aging can be prevented (and in some cases reversed) by small molecules in rodents [2] and primates [85], this possibility seems within reach. Despite progress, many key questions remain. For example, which phenotypes are due to the action of resveratrol and STACs directly on SIRT1, and which
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Current address: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.