Review
A therapeutic role for sirtuins in diseases of aging?

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The sirtuins are a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Among the many genes that have been shown to affect aging in model organisms, sirtuin genes are unique in that their activity level is positively correlated with lifespan (i.e. they are anti-aging genes). Sirtuins are a druggable class of enzymes (i.e. amenable to intervention by small molecules) that could have beneficial effects on a variety of human diseases. In view of the many functions of Sirtuin 1 (SIRT1) in cells, this review focuses on its role in regulating important aspects of mitochondrial biology. Mitochondria have been linked to aging, and also to diseases of aging. Thus, sirtuins might provide a key link between mitochondrial dysfunction, aging and metabolic disease.

Section snippets

Therapeutic applications of sirtuins for metabolic diseases

Sirtuins are a family of related proteins that were first linked to longevity and stress tolerance in budding yeast and other lower eukaryotic organisms 1, 2. Genes encoding sirtuins are distinguished from many other genes that affect aging because they are anti-aging genes (i.e. increasing their activity extends life span). As such, in Saccharomyces cerevisiae (yeast), Caenorhabditis elegans (worms) and Drosophila melanogaster (flies), Sirtuin 2 (SIRT2) orthologs retard aging as a function of

Sirtuin drug discovery

At present, several inhibitors and activators of SIRT1 have been described 50, 51, 52. Inhibitors such as nicotinamide (NAM), sirtinol and splitomycin have been useful in helping to dissect the function of SIRT1 in the laboratory. Sirtinol and splitomycin function as competitive inhibitors by blocking the active site, whereas high concentrations of NAM drive reversal of the first step in deacetylation – the cleavage of NAD to an ADP-ribosyl intermediate and NAM. However, the therapeutic use of

Conclusion

Sirtuins are anti-aging proteins that have therapeutic potential for a range of diseases of aging, including metabolic disorders, neurodegenerative disorders, cancer and cardiovascular disease. The link between sirtuin activation and mitochondrial biogenesis by the SIRT1-mediated activation of PGC-1α provides a novel mechanism of action for the treatment of diseases for which therapy is currently limited. We expect that the many other physiological pathways regulated by SIRT1, as well as the

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