ReviewBiological and Potential Therapeutic Roles of SirtuinDeacetylasesD. M. Taylora, M. M. Maxwellb, R. Luthi-Cartera, A. G. Kazantsevb,*aBrain Mind Institute, Ecole Polytechnique Fdrale de Lausanne (EPFL), 1015 Lausanne (Switzerland)bMass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard MedicalSchool, 114 16thStreet, Charlestown, MA 02129 (USA), Fax: 617-724-1480, e-mail: [email protected] 25 June 2008; received after revision 20 August 2008; accepted 29 August 2008Online First 27 September 2008Abstract. Sirtuins comprise a unique class of nicoti-namide adenine dinucleotide (NAD+)-dependent de-acetylases that target multiple protein substrates toexecute diverse biological functions. These enzymesare key regulators of clinically important cellular andorganismal processes, including metabolism, cell di-vision and aging. The desire to understand theimportant determinants of human health and lifespanhas resulted in a firestorm of work on the sevenmammalian sirtuins in less than a decade. Theimplication of sirtuins in medically important areassuch as diabetes, cancer, cardiovascular dysfunctionand neurodegenerative disease has further catapultedthem to a prominent status as potential targets fornutritional and therapeutic development. Here, wepresent a review of published results on sirtuin biologyand its relevance to human disease.Keywords. Sirtuin, deacetylase, longevity, human disease, therapeutics.IntroductionThe biological function of most proteins relies onreversible post-translational modification. Recentyears have linked regulation of nearly every cellularsignaling pathway to phosphorylation, acetylation,methylation, O-GlcNacylation, and/or ubiquitinationof one or many of its contributors. Although crosstalkbetween post-translational modifications can regulatemultiple aspects of a particular biological pathway, asingular modification, when applied to a crucialmediator, can lead to dramatic effects that modifyhealth at the organism level [1]. For this reason, as wellas the fact that enzymes are among the most tractabletargets for pharmaceutical intervention, disea se-re-lated research has placed a great emphasis on thestudy of post-translational modification cascades.The post-translational addition of an acetyl moiety tothe e-amino group of a lysine residue, known asprotein acetylation, can have varying effects onprotein function [2]. The most prominently studiedsubstrates are histones, whose deacetylation typicallyresults in decreased gene expression [2]. Nonetheless,numerous other proteins such as transcription factors,cytoskeletal proteins, metabolic enzymes and othersignaling mediators can also be modified by acetyla-tion. Historically, enzymes that perform acetylationhave been known as histone acetyltransferases(HATs), whereas enzymes providing the counterbal-ancing activity are known as histone deacetylases(HDACs). This nomenclature remains in commonuse, despite the fact that histones are not exclusivesubstrates for HDAC enzymes [3].* Corresponding author.Cell. Mol.Life Sci. 65 (2008) 4000 –40181420-682X/08/244000-19DOI 10.1007/s00018-008-8357-y Birkhuser Verlag, Basel, 2008Cellular and Molecular Life SciencesEnzymes belonging to the HDAC superfamily playcritical roles in the regulation of cellular metabolism,and constitute promising drug targets for treatmentof a broad range of human diseases. The classicalHDACs are grouped into three subfamilies (termedclass I, II, and IV), comprised of eleven enzymes thatshare sequence homology and require Zn2+fordeacetylase activity [2]. Although the sirtuins(SIRTs) nominally comprise the class III HDAC s,they possess unique NAD+-dependent enzymaticactivities and share no sequence similarity with theclassical enzymes [4]. The present review will focuson the c lass III HDACs, summarizing current knowl-edge of the biology of the mammalian sirtuins andhighlighting their potential utility as therapeutictargets.Sirtuin family homologs and orthologsThe first known members of the sirtuin family werediscovered in yeast. Among these was the nucleolar S.cerevisiae protein Sir2p, which was shown to interactwith histones and effect transcriptional silencing attelomeres [5–8]. Although early studies showed thatoverexpression of Sir2p resulte d in histone deacety-lation [9], this enzymatic activity was not immediatelyattributed to Sir2p itself. In 1995, a mutation in thegene encoding the Sir2p inter actor Sir4p was shown toextend replicative lifespan in S. cerevisiae [10],reinforcing an earlier hypotheses that transcriptionalcontrol and telomere maintenance are crucial regu-lators of aging [11]. Further investigation revealedthat Sir2p regulates the rate of ribosomal DNA(rDNA) recombination and formation of toxic ex-trachromosomal rDNA circles (ERCs), which accu-mulate with replicative age in yeast [12]. Deletion ofSIR2 results in increased ERC levels, thereby reduc-ing replicative lifespan, while overexpression of Sir2phas the expected opposite effect [13].The discovery that the longevity-enhancing deacety-lase activity of Sir2p was dependent on the nutrientNAD+sparked interest in a possible relationship withcellular metabolism, especially in light of the previ-ously ascribed benefit of calorie restriction on lifespan[14–16]. Indeed, a 75% reduction in glucose signifi-cantly increases the yeast replicative lifespan, anddeletion of SIR2 abrogates this beneficial effect [17].The intense interest in discovering longevity genes inhigher species prompted a search for additional Sir2phomologs and orthologs (Fig. 1). S. cerevisiae wasfound to express five sirtuins: SIR2 and four homologstermed HST1–4. A ll are implicated in transcriptionalsilencing at mating type loci and at telomeres [18]. C.elegans has four sirtuins [19]; one of these (SIR-2.1)extends lifespan, while limited information exists as tothe biological function of the other three [20, 21].Similarly, increased expression of the well-studied D.melanogaster Sir2 has shown a positive effect on flylifespan, while four other Drosophila sirtuins remainlargely uncharacterized [20, 22]. Mammals have sevensirtuins, SIRTs1–7 [19, 23], which are described indetail below.Sirtuin enzymatic activitiesThe sirtuin-mediated deacetylation reaction involveshydrolysis of one NAD+and formation of bothnicotinamide and a unique byproduct called O-acetyl-ADP-ribose (OAADPr) [24]; OAADPr isformed by transfer of the removed acetyl group