Dichotomous Sirtuins: Implications for Drug Discovery in Neurodegenerative and Cardiometabolic Diseases

Mammalian sirtuins (SIRT1–7) are NAD+-dependent deacylases with essential roles in the regulation of cellular homeostasis and stress responses. Research has shown that sirtuins, and SIRT1 in particular, are promising therapeutic targets for numerous diseases, particularly neurodegenerative and cardiometabolic diseases. Recent research has uncovered divergent findings resulting from the modulation of different sirtuin isoforms, which may stem from methodological differences and/or poorly characterized biological functions. Resolving these discrepancies is likely to expand our knowledge of the relevance of sirtuins in human disease, necessary to make an informed choice of the most appropriate pharmacological strategy for specific therapeutic applications. Sirtuins (SIRT1–7), a class of NAD+-dependent deacylases, are central regulators of metabolic homeostasis and stress responses. While numerous salutary effects associated with sirtuin activation, especially SIRT1, are well documented, other reports show health benefits resulting from sirtuin inhibition. Furthermore, conflicting findings have been obtained regarding the pathophysiological role of specific sirtuin isoforms, suggesting that sirtuins act as ‘double-edged swords’. Here, we provide an integrated overview of the different findings on the role of mammalian sirtuins in neurodegenerative and cardiometabolic disorders and attempt to dissect the reasons behind these different effects. Finally, we discuss how addressing these obstacles may provide a better understanding of the complex sirtuin biology and improve the likelihood of identifying effective and selective drug targets for a variety of human disorders. Sirtuins (SIRT1–7), a class of NAD+-dependent deacylases, are central regulators of metabolic homeostasis and stress responses. While numerous salutary effects associated with sirtuin activation, especially SIRT1, are well documented, other reports show health benefits resulting from sirtuin inhibition. Furthermore, conflicting findings have been obtained regarding the pathophysiological role of specific sirtuin isoforms, suggesting that sirtuins act as ‘double-edged swords’. Here, we provide an integrated overview of the different findings on the role of mammalian sirtuins in neurodegenerative and cardiometabolic disorders and attempt to dissect the reasons behind these different effects. Finally, we discuss how addressing these obstacles may provide a better understanding of the complex sirtuin biology and improve the likelihood of identifying effective and selective drug targets for a variety of human disorders. aggregation-prone presynaptic neuronal protein that is linked to the pathogenesis of PD. peptide derived from the amyloid precursor protein (APP) that forms the amyloid plaques found in the brains of patients with AD. removal of a malonyl group from a specific lysine residue of a target protein. removal of a myristoyl group attached covalently by an amide bond to the alpha-amino group of an N-terminal glycine residue. removal of a succinyl group from a specific lysine residue of a target protein. major metabolic pathway responsible for mitochondrial breakdown of long-chain acyl-CoA to acetyl-CoA, which can be used for ATP production via the TCA cycle and oxidative phosphorylation. excess triglyceride accumulation in hepatocytes due to defects in lipid metabolism, which may progress into more severe liver conditions. tissue damage caused by the interruption in the blood supply and subsequent damage induced by reperfusion. mechanism of excessive lipid accumulation in nonadipose tissues leading to cellular dysfunction and death. also known as spinocerebellar ataxia type 3 (SCA3); progressive and ultimately fatal neurodegenerative disorder caused by polyglutamine expansion in the gene encoding ataxin 3. transfer of an ADP-ribose group to a protein target. MPTP is a prodrug to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) that destroys dopaminergic neurons in the substantia nigra, thus recapitulating symptoms of PD in animal models. coenzyme involved in redox reactions in living cells and, thus, is crucial for many metabolism enzymes; also a co-substrate for NAD+-consuming enzymes, such as sirtuins. enzymes that cleave off acetyl, as well as other acyl groups, from the ε-amino group of lysines in histones and other substrate proteins, in a NAD+-dependent process. a spectrum of pathologies associated with excessive fat accumulation in the liver (steatosis) in the absence of significant alcohol consumption. transcriptional coactivator that regulates genes involved in energy metabolism, with a major role in mitochondrial biogenesis. microtubule-associated protein in neurons. Its abnormal aggregation in the form of filaments is associated with AD and related tauopathies.