Therapeutic potential of activators and inhibitors of sirtuins

Sirtuins are evolutionary conserved NAD(+)-dependent acetyl-lysine deacetylases and ADP ribosyltransferases dual-function enzymes involved in the regulation of metabolism and lifespan. Sirtuins are also implicated in determining the balance between apoptosis, cell survival, and cell proliferation. In humans, seven sirtuins isoforms (SIRT₁₋₇) have been identified that localize either in the nucleus, cytoplasm, or mitochondria. The genetic demonstration that increasing gene dosage of sirtuin orthologs in eukaryotes, including yeast and multicellular Caenorhabditis elegans and Drosophila melanogaster, leads to prolonged lifespan induced considerable interest toward the discovery of sirtuin-activating molecules, on the ground that the phenomenon of sirtuin-induced lifespan prolongation-which is consequential to improved metabolic control-can be exploited therapeutically to counteract insulin resistance and diabetes. Conversely, ample evidence that either pharmacological inhibition or activation of sirtuin isoforms is potentially beneficial in study models of cancer and neurodegenerative diseases have been obtained. Here, we (i) survey the key roles of sirtuin isoforms and discuss the evidence in favor of activatory versus inhibitory targeting of sirtuins, (ii) discuss some of the inhibitors and activators of the sirtuin family members that have been described in the literature, (iii) review model systems in which these molecules have proved to exert therapeutic effects, and (iv) discuss the outcome of pharmacokinetic studies and phase I and II clinical trials employing sirtuin modulators.