Trends in Biochemical Sciences
ReviewA therapeutic role for sirtuins in diseases of aging?
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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