Sirtuins are a conserved family of NAD-dependent protein deacylases. Initially proposed as histone deacetylases, it is now known that they act on a variety of proteins including transcription factors and metabolic enzymes, having a key role in the regulation of cellular homeostasis. Seven isoforms are identified in mammals (SIRT1–7), all of them sharing a conserved catalytic core and showing differential subcellular localization and activities. Oxidative stress can affect the activity of sirtuins at different levels: expression, posttranslational modifications, protein-protein interactions, and NAD levels. Mild oxidative stress induces the expression of sirtuins as a compensatory mechanism, while harsh or prolonged oxidant conditions result in dysfunctional modified sirtuins more prone to degradation by the proteasome. Oxidative posttranslational modifications have been identified in vitro and in vivo, in particular cysteine oxidation and tyrosine nitration. In addition, oxidative stress can alter the interaction with other proteins, like SIRT1 with its protein inhibitor DBC1 resulting in a net increase of deacetylase activity. In the same way, manipulation of cellular NAD levels by pharmacological inhibition of other NAD-consuming enzymes results in activation of SIRT1 and protection against obesity-related pathologies. Nevertheless, further research is needed to establish the molecular mechanisms of redox regulation of sirtuins to further design adequate pharmacological interventions.
1. Introduction
Sirtuins are a conserved family of enzymes, originally defined as histone deacetylases (class III HDAC) [1]. They deacetylate not only histones but also other proteins. In addition, they catalyze the hydrolysis of lysines modified with longer acyl chains (deacylase activity) [2]. Unlike classes I, II, and IV HDAC that utilize zinc for catalysis, sirtuins use a complex mechanism depending on cofactor NAD that already discloses a fine-regulated activity.
Since the discovery of yeast Sir2 (Silent Information Regulator 2) 30 years ago [3], the founding member of the family, an intensive research went on to elucidate the biological functions of sirtuins, especially after the early found connection of sirtuins with lifespan [1, 4]. The number of publications grew exponentially in the search of potential activators or inhibitors of sirtuins that fight against metabolic disorders, cancer, and even aging [5].
In S. cerevisiae, besides Sir2, four more sirtuins were described, Hst1–4. In C. elegans, four homologs of yeast Sir2 were named Sir2.1–2.4, whereas seven paralogs were described in mammals, SIRT1–7. Phylogenetic analysis groups the mammalian SIRT1, SIRT2, and SIRT3 as subclass I which shows close homology to yeast Sir2, SIRT4, and SIRT5 as subclasses II and III, respectively, and SIRT6-SIRT7 in subclass IV [6].
The seven mammalian SIRT differ in sequence (although they all share a conserved catalytic core), in subcellular location, enzyme activity, and substrate specificity. The list depicted in Table 1 is by no means comprehensive since new in vivo substrates and specificities are discovered every day. The most studied human isoform is SIRT1, a nuclear protein reported to regulate critical physiological processes and associated with chronic inflammatory diseases and metabolic dysfunctions like diabetes, obesity, aging, and even cancer [7].
This review focuses on the effect of oxidative stress on structure and activity of sirtuins and the biological consequences of their redox regulation. Understanding the role and mechanism of action of sirtuins in the context of a pathophysiological inflammatory condition will help to identify novel interventions to manage important chronic diseases.
2. Sirtuins Structure
Crystal structures of sirtuins from archaea to eukaryotes show a central catalytic core comprised of 245 residues. The core is made up of a large domain containing a Rossmann fold typical of NAD-dependent proteins and a small domain containing a Zn2+ ribbon motif, separated by a cleft where the peptide substrate binds (Figure 1). The NAD molecule adopts an extended conformation binding to a grove between the two domains with the adenine base facing the large domain and the nicotinamide group close to the small domain (Figure 1). SIRT1 is the biggest isoform with extended N- and C-terminals very flexible, unstructured, which offers more sites of activity modulation (posttranslational modifications, interaction with proteins and ligands).
Structure of sirtuins. (a) Crystal structure of a partial sequence of hSIRT1 (PDB 4KXQ) with bound substrates, acetylated peptide, and NAD. The catalytic core is depicted in yellow with the Zn2+ binding domain. (b) Zoom of catalytic site with the catalytic histidine colored in yellow.
The Zn2+ binding site is composed of three antiparallel beta strands containing two Cys-X-X-Cys conserved motifs separated by 15–20 residues that coordinate a single zinc ion that has an important structural role. It has long been known that mutation of these cysteine residues by alanine causes loss of activity [8]. Although the zinc tetrathiolate is fairly exposed, only high concentrations of zinc chelator were able to disrupt it with the corresponding loss of activity [9]. Another report on P. falciparum Sir2 obtained the inactive apoenzyme by treatment with potent zinc chelator and restored activity upon reconstitution with exogenous zinc chloride [10].
The zinc ion is located in the small domain, far away from the NAD binding pocket, excluding the possibility of participation in the catalysis, in contrast with other HDAC types where zinc is part of the catalytic mechanism [11].
3. Enzymatic Activities of Sirtuins
Sirtuins are defined as protein deacylases. They catalyze the reaction depicted in Figure 2 using NAD as a cofactor, yielding the deacylated protein, nicotinamide (that displays inhibition by product), and acylated ADPR as final products.
Scheme of reactions catalyzed by sirtuins. Deacetylation is the most common reaction catalyzed by sirtuins, but some sirtuins catalyze deacylation of other posttranslational lysine modifications and mono ADP ribosylation. NAM = nicotinamide, OAADPR = O-acetyl-ADP-ribose.
Kinetic studies and isotope exchange indicate that sirtuins first bind the acetylated substrate, followed by NAD binding to form a ternary enzyme complex where the carbonyl oxygen of the acetyl group attacks ribose C1′ to form O-alkylamidate intermediate. Crystal structures of binary complexes were solved between Sir2-like enzyme and NAD [9], or ADP-ribose [12], or acetylated p53 [13]. Moreover, the crystal structure of a ternary complex was reported between yeast Hst2, an acetylated histone peptide, and a nonhydrolyzable NAD analog [14]. Crystal data confirm the peptide substrate binds in a narrow channel that positions the acylated lysine residue near the nicotinamide ring of NAD (Figure 1). Upon peptide binding, a conformational change on the NAD site must occur to facilitate the nucleophilic attack on ribose C1′ to cleave the nicotinamide-ribosyl bond, first step in the catalytic pathway. A conserved histidine residue (H363 in hSIRT1) has been identified as critical for the catalysis, first acting as a general base hydrogen bonded to 3′′ OH-ribose and, then, as a general acid protonating the lysine residue in the last step of the catalysis.
Besides protein deacetylation, it was early recognized that sirtuins can also catalyze ADP ribosylation of a protein acceptor (or the enzyme itself) via a similar mechanism (Figure 2) [14–17].
More recently, it has been found that some sirtuin isoforms previously considered poor deacetylases are actually good deacylases; that is, they catalyze the hydrolysis of lysine amides derivatized with a longer-chain carboxylic acid, for example, succinate or malonate. Indeed, SIRT5 functions as desuccinylase or demalonylase [18], whereas SIRT6 functions as demyristoylase [2, 19]. Moreover, SIRT6 deacetylase activity has been recently shown to be regulated by free-fatty acids in vitro, opening the possibility that fatty acids might be acting as endogenous regulators of sirtuin activity in vivo [2].
Acetylation is an important posttranslational modification even outside chromatin. The acetylome shows that many proteins are acetylated as a mechanism of regulation of cellular function, and it is even possible that is as common in cellular life as phosphorylation [20, 21]. Comparative studies on Drosophila and humans have demonstrated that acetylated lysines are highly conserved [22, 23]. An acetylome peptide microarray has been described that reveals new deacetylation substrate candidates for all sirtuin isoforms [24].
4. Sirtuins and Oxidative Stress
As mentioned above, increasing evidence supports the role of sirtuins in the regulation of cellular homeostasis, in particular metabolism and inflammation [25, 26]. During conditions of metabolic stress, like obesity and metabolic syndrome, an oxidative stress environment is created, mainly due to a state of chronic inflammation. Based on the key role of sirtuins in the regulation of metabolic responses [27, 28], it is pertinent to ask how changes in the redox status of the cells affect the activity of sirtuins and what are the biological consequences of these alterations.
Oxidative stress, considered as an overwhelmed generation of reactive species (ROS/RNS) or a general disruption of redox cellular homeostasis [29, 30], can affect the activity of sirtuins at different levels:
Inducing or repressing the expression of SIRT gene.
Posttranslational oxidative modifications of SIRT.
Altering SIRT-protein interactions.
Changing NAD levels.
4.1. Changes in Sirtuin Expression during Oxidative Stress
It has been observed that mild oxidative stress conditions induce the expression of SIRT1, changing its activity and thus affecting SIRT1 targets that are involved in the response to changes in the redox state of the cell [31–33]. The first major SIRT1 substrate identified was p53, a transcription factor involved in activating antioxidant genes like SOD2 (superoxide dismutase 2, MnSOD) and GPx1 (glutathione peroxidase) [34]. Another redox transcription factor deacetylated by SIRT1 (as well as SIRT2 and SIRT3) is FOXO3a which induces an antioxidant response via SOD2 and catalase expression [35–40]. PGC1α, a known substrate of SIRT1, is reported to regulate expression of mitochondrial antioxidants like SOD2 [41–43]. SIRT1 can deacetylate p65 NFκB subunit diminishing its activity and, thus, the production of proinflammatory cytokines [44–46]. In addition, upon increased production of ROS at the mitochondria, induction of SIRT3 was observed [47]. It was reported that SIRT3 deacetylates and thus activates SOD2 reducing oxidative stress in the mitochondria [48]. In adult mouse hearts, SIRT1 was significantly upregulated (4-fold) in response to oxidative stress (paraquat injection) and, similarly, 3-fold increase in SIRT1 levels was observed in old versus young monkey hearts [49]. In the same way, modest overexpression of SIRT1 retarded age-dependent changes in the heart of transgenic mice [49]. Low levels of H2O2 promoted deacetylation of the tumor suppressor protein PLM in HeLa cells via SIRT1 and SIRT5 [50].
On the contrary, exposure to high levels of H2O2 or harsh oxidative stress resulted in increased proteasomal degradation of SIRT1, desumoylation, and enzyme inactivation that leads to apoptosis [51]. Human monocytes exposed to high dose of H2O2 (250 μM, 24 h) resulted in a significant decrease in SIRT1 activity (measured as levels of acetylated p53) and lower SIRT1 gene and protein expression [52]. Human lung epithelial cells exposed to oxidants (H2O2, aldehyde-acrolein, and cigarette smoke extract) presented decreased levels of SIRT1 concomitant with decreased SIRT1 activity [53]. A recent work on human endothelial cells showed no effect of low doses of H2O2 but a drastic drop to 50% SIRT1 activity after exposure to 100 μM H2O2 for 30 min, along with a decrease in free thiol content of SIRT1 [54].
An interesting view suggested by Tong et al. [55] is that active sirtuins provide an adequate level of O-acetyl-ADP-ribose (OAADPR) (product of the reaction catalyzed by sirtuins with deacetylase activity, Figure 2) that readily converts to ADP-ribose and both may function as cellular signals. Increased ADPR/OAADPR levels protect cells from oxidative stress via two mechanisms: (1) inhibition of Complex I of the mitochondrial electron transport chain with concomitant lower production of ROS and (2) inhibition of glyceraldehyde-3-phosphate dehydrogenase, central enzyme in glycolysis, diverting glucose to the pentose phosphate pathway with the concomitant increase in NADPH, main reductant for detoxifying ROS enzymes.
4.2. Posttranslational Modifications (PTM) of Sirtuins
Phosphorylation was the first PTM found in SIRT1. SIRT1 is the most studied mammalian isoform although a crystal structure of the whole protein is not available and we rely on a simulation model [56]. Apart from the central catalytic structured core, SIRT1 has long C- and N-terminal domains which are flexible and disordered, not present in the other SIRT structures, and considered potential sites of enzyme regulation. Early mass spectrometry (MS) analysis detected several serine/threonine phosphorylation sites at the N- and C-terminal domains of SIRT1 [57]. Several kinases are known to phosphorylate SIRT1, and many of them are regulated by oxidative stress. CdkI (also known as Cdc2), a kinase involved in cell cycle progression and regulated by oxidative stress [58], phosphorylates SIRT1 in its C-terminus domain (T530 and S540) [57]. Mutations of these two sites on SIRT1 affect cell cycle progression [58]. SIRT1 is also phosphorylated by Casein Kinase II (CKII) in serines S154, S649, S651, and S683 [59]. CKII activity is tightly regulated by oxidative stress [60], and, indeed, ionizing radiation activates CKII, leading to SIRT1 phosphorylation and activation [59]. Phosphorylation of SIRT1 in different residues by AMPK has also been shown to regulate its activity mainly by affecting binding to its protein inhibitor DBC1 [61, 62]. AMPK is a key sensor and regulator of redox state of the cell and its biological activity is regulated by oxidative stress [63], although no direct link between oxidative stress and SIRT1 involving AMPK has been shown until now. Finally, phosphorylation of SIRT1 at different C-term residues has been shown to change its enzymatic activity. SIRT1 phosphorylation (T530) triggers a conformational change that increases its deacetylase activity [64–66]. Also, PKA-dependent phosphorylation of SIRT1 (S434) stimulates its activity [67]. Sumoylation at the C-terminal domain of SIRT1 (K734) has been detected and shown to increase activity as well [51]. Phosphorylation sites at the C-terminal of SIRT2 (S368, S372) were also reported to regulate enzyme function [68, 69]. In the case of SIRT6, phosphorylation at T294 and S303 were identified in a proteomic analysis, with no report on functional consequences [70, 71]. Another report shows that phosphorylation of SIRT6 at S338 by AKT leads to its degradation in breast cancer cells [72]. Moreover, mutation of that phosphorylation site made breast cancer cells more sensitive to chemotherapeutic agents [72].
Oxidative modifications of sirtuins are less well studied. Treatment of recombinant hSIRT1 with nitrosoglutathione (GSNO) was first reported [73] to modify C67 (located in the noncatalytic C-terminal domain) by S-glutathionylation, with no effect on basal deacetylase activity but loss of stimulation by resveratrol in vitro (although it has to be mentioned that the activity was measured using the fluorimetric assay that it is known to yield an artefactual activation of SIRT by resveratrol [74]). In this work [73], differential alkylation revealed 5 out of the 19 cysteines on human SIRT1 as reactive towards GSNO. Three of those five modified cysteines are solvent exposed residues (C67, C268, and C623) as indicated in the computer generated model of human SIRT1 structure [56]. However, in that same year 2010, it was published that treatment of SIRT1 with GSNO resulted in nitrosylation (not glutathionylation) of the enzyme with loss of deacetylase activity [75]. The residues modified (C387 and C390 from the mouse ortholog that coordinates the zinc ion) were different from those proposed previously [75]. These authors reported that treatment of intact HEK293 cells with GSNO resulted in nitrosylation of SIRT1 (SIRT1-SNO) via transnitrosylation from GAPDH-SNO translocated to the nucleus [75]. Nitrosylation of nuclear SIRT1 inhibited deacetylation of PGC1α in HEK293 cells. Mutational analysis on transfected cells with mouse SIRT1 plasmids identified C387 and C390 from the zinc tetrathiolate motif as the sites of S-nitrosylation. Surprisingly, C363 and C366 that also participate in zinc coordination were not susceptible to transnitrosylation. More recently, C371 and C374 from hSIRT1 (corresponding to C363 and C366 in mSIRT1) have been identified as the cysteines reduced by APE/Ref-1 to stimulate endothelial SIRT1 activity (although the other two cysteines involved in zinc ion coordination were not tested) [54].
When HepG2 cells transiently transfected with mouse SIRT1 WT were treated with increasing concentrations of CysNO or H2O2, decrease in p53 deacetylase activity was observed [76]. However, when cells were transfected with mSIRT1 mutants C61S, C318S, and/or C613S, the deacetylase activity was initially higher than with WT overexpression and less susceptible to oxidants [76]. The authors suggested reversible oxidative modification of SIRT1 forming GSH-adducts with these cysteine residues that are reverted by glutaredoxin 1. In this case, the reported cysteine residues oxidatively modified are not part of the Zn-binding motif.
Treatment of human epithelial cells with alkylating agent NEM diminished SIRT1 protein levels and free cysteine residues on immunoprecipitated SIRT1, although the specific residues modified were not identified [53].
Increased protein carbonylation of SIRT3 was found in liver mitochondrial extracts of ethanol-consuming mice [77]. The authors identified in vitro covalent modification of rSIRT3 by the electrophilic compound 4-hydroxynonenal at C280 (critical zinc-binding cysteine residue), resulting in inhibition of rSIRT3 activity [77].
More recently, mapping protein S-sulfenylation in cells treated with exogenous H2O2 as well as endogenous H2O2 (EGF treatment in A431 cells), SIRT6 was found among the most highly and consistently S-sulfenylated proteins [78]. Cysteine C18, a highly conserved residue close to the amino terminus, was identified as Cys-SOH that could form a covalent complex with HIF1α via disulfide bond, suggesting SIRT6-mediated redox control of HIF1α transcriptional activity [78].
Even though sirtuins do not have critical cysteine residues that participate in the mechanism of catalysis, modification of cysteine residues affects their activity, because it alters either the enzyme structure or the interaction with other proteins. The four cysteines in the zinc tetrathiolate motif, highly conserved, are essential for having a properly folded enzyme; thus, mutation of these cysteines to serine, not surprisingly, diminished deacetylase activity [54].
Another PTM (tyrosine nitration) on SIRT6 was recently reported [79]. Treatment of recombinant SIRT6 with the peroxynitrite donor SIN-1 revealed nitration of the enzyme and diminished activity. The authors identified tyrosine Y257 as one of the amino acid residues modified and mutation Y257F causes loss of deacetylase activity and susceptibility to nitration by SIN-1. Nitrated SIRT6 was also found in retina in a model of endotoxin-induced retinal inflammation [79].
4.3. Regulation of Sirtuins by Protein-Protein Interaction during Oxidative Stress
Oxidative stress regulates the activity of different sirtuins by altering their binding to regulatory proteins. From all sirtuins, the most extensively studied in terms of regulation by protein-protein interaction is SIRT1. The main protein regulators of SIRT1 described so far are DBC1 (deleted in breast cancer 1) [80] and AROS (active regulator of SIRT1) [81], and both have been involved in SIRT1-mediated response to oxidative stress [81, 82]. In the case of AROS, it was shown that its knock-down decreases SIRT1-mediated response to oxidative stress in cells, although it is not clear whether the protein plays an active role in such response or it is binding to SIRT1 the critical event. Oxidative stress also alters the interaction of SIRT1 with its protein inhibitor DBC1. Oxidative stress promotes phosphorylation of DBC1 (Thr454) by an ATM/ATR-dependent mechanism, increasing its affinity for SIRT1 and leading to sirtuin inhibition [82]. Interestingly, in mice, both obesity and aging [83, 84] promote SIRT1 binding to DBC1 [80], leading to a decrease in SIRT1 activity. Finally, it was shown recently that during oxidative stress SIRT1 can be inactivated by cytoplasmic sequestration and localization into caveolae by direct binding to caveolin-1 [85].
Thus, many different mechanisms might be operating to regulate SIRT1 activity during oxidative stress.
4.4. Alterations of Intracellular NAD Levels and Sirtuin Regulation during Oxidative Stress
NAD availability is key in the regulation of all sirtuins [86]. In fact, it has been shown that NAD levels decline during aging, obesity, and other metabolic diseases [87], affecting the activities of sirtuins in different tissues. Importantly, interventions that prevent NAD decline in tissues protect against metabolic and age-related diseases [87–91]. Genetic deletion [90] and also pharmacological inhibition of the protein CD38 [92], the main NAD glycohydrolase in mammalian tissues [92], activate SIRT1 [93] and protect against obesity and metabolic syndrome [90]. Similar results were found by inhibition of other major NAD-consuming enzymes in tissues like PARP-1 [91]. In fact, SIRT1 and PARP-1 activities can influence each other, since it has also been reported that SIRT1 can deacetylate PARP-1, decreasing its activity [94]. Furthermore, pharmacological treatment with NAD precursors, like nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), prevents NAD decline and protects against many aspects of metabolic syndrome, including glucose intolerance [87, 88]. Altogether, these results open the possibility of using NAD therapy for the treatment of metabolic and age-related diseases.
It is well established that aging and also metabolic disorders like obesity lead to an increased oxidative stress in tissues. In addition, it has been shown that NAD decline inversely correlates with oxidative stress during aging [95] and that oxidative stress negatively impacts on mitochondria, leading to NAD depletion in the matrix [96]. Interestingly, caloric restriction, an intervention shown to increase healthspan and to prevent metabolic syndrome, decreases oxidative stress leading to increased NAD levels and improving mitochondrial function by SIRT3-mediated increase in SOD2 activity [48].
5. Sirtuins as Pharmacological Targets for Metabolic and Age-Related Diseases
There has been considerable debate about pharmacological sirtuin activation and its effect on metabolism, cancer, and aging. The original observation that the polyphenol resveratrol and other small molecules (STACs, for sirtuin activating compounds) extend lifespan in S. cerevisiae through activation of Sir2 and that resveratrol could also activate human SIRT1 [97] puts sirtuins on the spot as ideal pharmacological targets for the treatment of aging and age-related diseases. Early on, an intense debate started about the role of resveratrol and other STACs as direct SIRT1 activators, since such activation appeared to rely on a specific activity assay and could not be reproduced by other means in vitro [98]. Since then, many molecular mechanisms have been proposed for SIRT1 activation by resveratrol in vivo, including direct SIRT1 activation [97, 99], activation of the AMPK-SIRT1 axis with NAD levels linking AMPK activation to SIRT1 activation [100], activation of the AMPK-SIRT1 axis through SIRT1 phosphorylation and dissociation from DBC1 [61], and SIRT1 activation through increase in cAMP levels by phosphodiesterase inhibition [101].
The development of novel, structurally different STACs by Sirtris Pharmaceuticals showed that SIRT1 activation by these new molecules (SRT1720, SRT1460, and SRT2183) prevents metabolic diseases in mice [99], and in the case of SRT1720, it was later shown that it also increases healthspan and lifespan in mice [102, 103]. Interestingly, the debate rose again about the specificity of these STACs for SIRT1 [104]. Recent research, however, has provided new evidence showing that these STACs, and even more potent new generations (STAC-5, STAC-9, and STAC-10), are indeed SIRT1 activators [105, 106].
Although the mechanism of action of resveratrol and other STACs may still need to be further investigated, it is clear that they provide beneficial effects against age-related disease in vivo. Resveratrol protects against high-fat diet induced obesity, type II diabetes, cardiovascular diseases, and cancer [99, 101, 107–114]. Similar results have been found with newly developed STACS [107, 107, 115, 116]. Interestingly, both resveratrol and the newly developed STACs decrease oxidative stress in vitro and in vivo, either by promoting antioxidant defenses or by improving mitochondrial function [103, 117–122].
The effect of STACS on human subjects has also been debated. Most of the evidence relies on studies conducted on volunteers who received resveratrol at different doses and for different periods of time. The evidence, reviewed in [153], shows that resveratrol might have some beneficial effects in humans, although its bioavailability is poor. Recently, phase I and II clinical trials were published with a new STAC (SRT2104), showing that it is well tolerated by the elderly, who showed decrease in cholesterol, LDL, and triglycerides levels, opening the possibility that STACs might become an available treatment for age-related diseases in humans [154, 155].
Finally, it is worth mentioning that SIRT6 might also be a pharmacological target for the treatment of age-related diseases, including inflammation, genomic stability, and cancer. The fact that SIRT6 is activated by fatty acids [2] might provide new avenues into the treatment of age-related diseases [156, 157].
6. Conclusions and Perspectives
Sirtuins are NAD-dependent deacylases that catalyze not only deacetylation of histones but also deacylation of other proteins including transcription factors and metabolic enzymes thereby regulating cell cycle, differentiation, metabolism, stress resistance, senescence, and aging. Fine regulation of expression and activity of sirtuins is critical to maintain cellular homeostasis. Although it is clear that sirtuins are modulated by oxidative stress, the molecular mechanisms are not well understood. Active sirtuins protect cells from ROS-induced damage via their product OAADPR/ADPR that inhibits mitochondrial ROS production and increases NADPH levels from pentose phosphate pathway. Mild oxidative stress induces sirtuin expression as a compensatory mechanism, while harsh or prolonged oxidant conditions result in dysfunctional modified sirtuins more prone to degradation by the proteasome. The increase in the NAD/NADH ratio under oxidative stress conditions can result in higher availability of the NAD cofactor, thus an apparent increase in sirtuin activity. Oxidative PTM of sirtuins have been identified, both in vitro and in vivo, to inhibit deacylase activity, although they can also affect the interaction with modulators, like SIRT1 with its endogenous inhibitor DBC1, resulting in a net increase of SIRT1 activity. Further research is needed to establish the mechanisms of redox regulation of sirtuins. Particularly interesting is to investigate redox modulation of SIRT3 in the mitochondrial matrix where most of cellular oxidants are formed. The fact that sirtuins can be activated, either by modulating NAD bioavailability in tissues or by pharmacological activation by small molecules, gives a therapeutic opportunity for the treatment of metabolic and age-related diseases.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Acknowledgments
Comisión Sectorial de Investigación Científica CSIC, UdelaR; Agencia Nacional de Investigación e Innovación ANII, Uruguay; Programa de Desarrollo de las Ciencias Básicas PEDECIBA; and INNOVA II are acknowledged.
ImaiS.-I.ArmstrongC. M.KaeberleinM.GuarenteL.Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase2000403677179580010.1038/350016222-s2.0-0034677535FeldmanJ. L.BaezaJ.DenuJ. M.Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by Mammalian Sirtuins201328843313503135610.1074/jbc.c113.5112612-s2.0-84886686038ShoreD.SquireM.NasmythK. A.Characterization of two genes required for the position-effect control of yeast mating-type genes1984312281728232-s2.0-0021734287GottaM.Strahl-BolsingerS.RenauldH.LarocheT.KennedyB. K.GrunsteinM.GasserS. M.Localization of Sir2p: the nucleolus as a compartment for silent information regulators199716113243325510.1093/emboj/16.11.32432-s2.0-0030978951HubbardB. P.SinclairD. A.Small molecule SIRT1 activators for the treatment of aging and age-related diseases201435314615410.1016/j.tips.2013.12.0042-s2.0-84896739647FryeR. A.Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins2000273279379810.1006/bbrc.2000.30002-s2.0-0033887456FinkelT.DengC.-X.MostoslavskyR.Recent progress in the biology and physiology of sirtuins2009460725558759110.1038/nature081972-s2.0-67949102053ShermanJ. M.StoneE. M.Freeman-CookL. L.BrachmannC. B.BoekeJ. D.PillusL.The conserved core of a human SIR2 homologue functions in yeast silencing19991093045305910.1091/mbc.10.9.30452-s2.0-0032823749MinJ.LandryJ.SternglanzR.XuR.-M.Crystal structure of a SIR2 homolog-NAD complex2001105226927910.1016/s0092-8674(01)00317-82-s2.0-0035917536ChakrabartyS. P.BalaramH.Reversible binding of zinc in Plasmodium falciparum Sir2: structure and activity of the apoenzyme2010180491743175010.1016/j.bbapap.2010.06.0102-s2.0-77955096525FinninM. S.DonigianJ. R.PavletichN. P.Structure of the histone deacetylase SIRT220018762162510.1038/896682-s2.0-0034956304ChangJ.-H.KimH.-C.HwangK.-Y.LeeJ.-W.JacksonS. P.BellS. D.ChoY.Structural basis for the NAD-dependent deacetylase mechanism of Sir2200227737344893449810.1074/jbc.m2054602002-s2.0-0037072885AvalosJ. L.CelicI.MuhammadS.CosgroveM. S.BoekeJ. D.WolbergerC.Structure of a Sir2 enzyme bound to an acetylated p53 peptide200210352353510.1016/s1097-2765(02)00628-72-s2.0-0036753953ZhaoK.HarshawR.ChaiX.MarmorsteinR.Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD+-dependent Sir2 histone/protein deacetylases2004101238563856810.1073/pnas.04010571012-s2.0-2942534101FryeR. A.Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (Sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity1999260127327910.1006/bbrc.1999.08972-s2.0-0033600176LisztG.FordE.KurtevM.GuarenteL.Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase200528022213132132010.1074/jbc.m4132962002-s2.0-20444409132HaigisM. C.MostoslavskyR.HaigisK. M.FahieK.ChristodoulouD. C.MurphyA.ValenzuelaD. M.YancopoulosG. D.KarowM.BlanderG.WolbergerC.ProllaT. A.WeindruchR.AltF. W.GuarenteL.SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β cells2006126594195410.1016/j.cell.2006.06.0572-s2.0-33748316536DuJ.ZhouY.SuX.YuJ. J.KhanS.JiangH.KimJ.WooJ.KimJ. H.ChoiB. H.HeB.ChenW.ZhangS.CerioneR. A.AuwerxJ.HaoQ.LinH.Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase2011334605780680910.1126/science.12078612-s2.0-81055122671JiangH.KhanS.WangY.CharronG.HeB.SebastianC.DuJ.KimR.GeE.MostoslavskyR.HangH. C.HaoQ.LinH.SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine2013496744311011310.1038/nature120382-s2.0-84875881601ChoudharyC.KumarC.GnadF.NielsenM. L.RehmanM.WaltherT. C.OlsenJ. V.MannM.Lysine acetylation targets protein complexes and co-regulates major cellular functions2009325594283484010.1126/science.11753712-s2.0-68949212379SmithK. T.WorkmanJ. L.Introducing the acetylome2009271091791910.1038/nbt1009-9172-s2.0-70349971418WeinertB. T.WagnerS. A.HornH.HenriksenP.LiuW. R.OlsenJ. V.JensenL. J.ChoudharyC.Proteome-wide mapping of the Drosophila acetylome demonstrates a high degree of conservation of lysine acetylation20114183, article ra4810.1126/scisignal.20019022-s2.0-79960797509ZhaoS.XuW.JiangW.YuW.LinY.ZhangT.YaoJ.ZhouL.ZengY.LiH.LiY.ShiJ.AnW.HancockS. M.HeF.QinL.ChinJ.YangP.ChenX.LeiQ.XiongY.GuanK.-L.Regulation of cellular metabolism by protein lysine acetylation201032759681000100410.1126/science.11796892-s2.0-77149148756RauhD.FischerF.GertzM.LakshminarasimhanM.BergbredeT.AladiniF.KambachC.BeckerC. F. W.ZerweckJ.SchutkowskiM.SteegbornC.An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms20134, article 232710.1038/ncomms33272-s2.0-84884163378HaigisM. C.SinclairD. A.Mammalian sirtuins: biological insights and disease relevance2010525329510.1146/annurev.pathol.4.110807.0922502-s2.0-77949887506SebastiańC.SatterstromF. K.HaigisM. C.MostoslavskyR.From sirtuin biology to human diseases: an update201228751424444245210.1074/jbc.r112.4027682-s2.0-84871119123HoutkooperR. H.PirinenE.AuwerxJ.Sirtuins as regulators of metabolism and healthspan201213422523810.1038/nrm32932-s2.0-84858797950VerdinE.The Many Faces of Sirtuins: coupling of NAD metabolism, sirtuins and lifespan2014201252710.1038/nm.34472-s2.0-84891860991JonesD. P.Redefining oxidative stress200689-101865187910.1089/ars.2006.8.18652-s2.0-33744962865SiesH.Oxidative stress: oxidants and antioxidants199782229129510.1113/expphysiol.1997.sp0040242-s2.0-0030894162NemotoS.FergussonM. M.FinkelT.Nutrient availability regulates SIRT1 through a forkhead-dependent pathway200430657042105210810.1126/science.11017312-s2.0-10844236451ProzorovskiT.Schulze-TopphoffU.GlummR.BaumgartJ.SchröterF.NinnemannO.SiegertE.BendixI.BrüstleO.NitschR.ZippF.AktasO.Sirt1 contributes critically to the redox-dependent fate of neural progenitors200810438539410.1038/ncb17002-s2.0-42349085704PengC.-H.ChangY.-L.KaoC.-L.TsengL.-M.WuC.-C.ChenY.-C.TsaiC.-Y.WoungL.-C.LiuJ.-H.ChiouS.-H.ChenS.-J.SirT1—a sensor for monitoring self-renewal and aging process in retinal stem cells20101066172619410.3390/s1006061722-s2.0-77954776603SablinaA. A.BudanovA. V.IlyinskayaG. V.AgapovaL. S.KravchenkoJ. E.ChumakovP. M.The antioxidant function of the p53 tumor suppressor200511121306131310.1038/nm13202-s2.0-28644447272BrunetA.SweeneyL. B.SturgillJ. F.ChuaK. F.GreerP. L.LinY.TranH.RossS. E.MostoslavsyR.CohenH. Y.HuL. S.ChengH.-L.JedrychowskiM. P.GygiS. P.SinclairD. A.AltF. W.GreenbergM. E.Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase200430356662011201510.1126/science.10946372-s2.0-12144290563HasegawaK.WakinoS.YoshiokaK.TatematsuS.HaraY.MinakuchiH.WashidaN.TokuyamaH.HayashiK.ItohH.Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression20083721515610.1016/j.bbrc.2008.04.1762-s2.0-46349096040WangF.NguyenM.QinF. X.-F.TongQ.SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction20076450551410.1111/j.1474-9726.2007.00304.x2-s2.0-34447626095MottaM. C.DivechaN.LemieuxM.KamelC.ChenD.GuW.BultsmaY.McBurneyM.GuarenteL.Mammalian SIRT1 represses forkhead transcription factors2004116455156310.1016/s0092-8674(04)00126-62-s2.0-1342264308PardoP. S.MohamedJ. S.LopezM. A.BoriekA. M.Induction of Sirt1 by mechanical stretch of skeletal muscle through the early response factor EGR1 triggers an antioxidative response201128642559256610.1074/jbc.m110.1491532-s2.0-78951491794TsengA. H. H.ShiehS.-S.WangD. L.SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage20136322223410.1016/j.freeradbiomed.2013.05.0022-s2.0-84879059766LuZ.XuX.HuX.FassettJ.ZhuG.TaoY.LiJ.HuangY.ZhangP.ZhaoB.ChenY.PGC-1alpha regulates expression of myocardial mitochondrial antioxidants and myocardial oxidative stress after chronic systolic overload20101371011102210.1089/ars.2009.29402-s2.0-77955871829RodgersJ. T.LerinC.HaasW.GygiS. P.SpiegelmanB. M.PuigserverP.Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT12005434702911311810.1038/nature033542-s2.0-14544282413St-PierreJ.DroriS.UldryM.SilvaggiJ. M.RheeJ.JägerS.HandschinC.ZhengK.LinJ.YangW.SimonD. K.BachooR.SpiegelmanB. M.Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators2006127239740810.1016/j.cell.2006.09.0242-s2.0-33749999530RajendrasozhanS.YangS.-R.KinnulaV. L.RahmanI.SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease2008177886187010.1164/rccm.200708-1269oc2-s2.0-42649146208VaziriH.DessainS. K.EatonE. N.ImaiS.-I.FryeR. A.PanditaT. K.GuarenteL.WeinbergR. A.hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase2001107214915910.1016/s0092-8674(01)00527-x2-s2.0-0035913903LeeJ.-H.SongM.-Y.SongE.-K.KimE.-K.MoonW. S.HanM.-K.ParkJ.-W.KwonK.-B.ParkB.-H.Overexpression of SIRT1 protects pancreatic β-cells against cytokine toxicity by suppressing the nuclear factor-κB signaling pathway200958234435110.2337/db07-17952-s2.0-63249112836ChenY.ZhangJ.LinY.LeiQ.GuanK.-L.ZhaoS.XiongY.Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS201112653454110.1038/embor.2011.652-s2.0-79957979314QiuX.BrownK.HirscheyM. D.VerdinE.ChenD.Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation201012666266710.1016/j.cmet.2010.11.0152-s2.0-78649521247AlcendorR. R.GaoS.ZhaiP.ZablockiD.HolleE.YuX.TianB.WagnerT.VatnerS. F.SadoshimaJ.Sirt1 regulates aging and resistance to oxidative stress in the heart2007100101512152110.1161/01.RES.0000267723.65696.4a2-s2.0-34249669270GuanD.LimJ. H.PengL.LiuY.LamM.SetoE.KaoH.-Y.Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death201457e134010.1038/cddis.2014.1852-s2.0-84905442969YangY.FuW.ChenJ.OlashawN.ZhangX.NicosiaS. V.BhallaK.BaiW.SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress20079111253126210.1038/ncb16452-s2.0-35748962613de KreutzenbergS. V.CeolottoG.PapparellaI.BortoluzziA.SempliciniA.Dalla ManC.CobelliC.FadiniG. P.AvogaroA.Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms20105941006101510.2337/db09-11872-s2.0-77951174682CaitoS.RajendrasozhanS.CookS.ChungS.YaoH.FriedmanA. E.BrookesP. S.RahmanI.SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress20102493145315910.1096/fj.09-1513082-s2.0-77956180402JungS.-B.KimC.-S.KimY.-R.NaqviA.YamamoriT.KumarS.KumarA.IraniK.Redox factor-1 activates endothelial SIRTUIN1 through reduction of conserved cysteine sulfhydryls in its deacetylase domain201386e6541510.1371/journal.pone.00654152-s2.0-84878661672TongL.LeeS.DenuJ. M.Hydrolase regulates NAD+ metabolites and modulates cellular redox200928417112561126610.1074/jbc.m8097902002-s2.0-66449123334AutieroI.CostantiniS.ColonnaG.Human sirt-1: molecular modeling and structure-function relationships of an unordered protein2009410e735010.1371/journal.pone.00073502-s2.0-77957655795SasakiT.MaierB.KoclegaK. D.ChruszczM.GlubaW.StukenbergP. T.MinorW.ScrableH.Phosphorylation regulates SIRT1 function2008312e402010.1371/journal.pone.00040202-s2.0-58149202185AlexandrouA. T.LiJ. J.Cell cycle regulators guide mitochondrial activity in radiation-induced adaptive response20142091463148010.1089/ars.2013.56842-s2.0-84896811731KangH.JungJ.-W.KimM. K.ChungJ. H.CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA-damage200948e661110.1371/journal.pone.00066112-s2.0-69949138641KimK. M.SongJ. D.ChungH. T.ParkY. C.Protein kinase CK2 mediates peroxynitrite-induced heme oxygenase-1 expression in articular chondrocytes20122961039104410.3892/ijmm.2012.9492-s2.0-84860524792NinV.EscandeC.ChiniC. C.GiriS.Camacho-PereiraJ.MatalongaJ.LouZ.ChiniE. N.Role of deleted in breast cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase201228728234892350110.1074/jbc.m112.3658742-s2.0-84863622561LauA. W.LiuP.InuzukaH.GaoD.SIRT1 phosphorylation by AMP-activated protein kinase regulates p53 acetylation201443245255WuS.-B.WuY.-T.WuT.-P.WeiY.-H.Role of AMPK-mediated adaptive responses in human cells with mitochondrial dysfunction to oxidative stress2014184041331134410.1016/j.bbagen.2013.10.0342-s2.0-84895555985GuoX.WilliamsJ. G.SchugT. T.LiX.DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1201028517132231323210.1074/jbc.m110.1025742-s2.0-77951225449KangH.SuhJ.-Y.JungY.-S.JungJ.-W.KimM. K.ChungJ. H.Peptide switch is essential for Sirt1 deacetylase activity201144220321310.1016/j.molcel.2011.07.0382-s2.0-82455219091NasrinN.KaushikV. K.FortierE.WallD.PearsonK. J.de CaboR.BordoneL.JNK1 phosphorylates SIRT1 and promotes its enzymatic activity2009412e841410.1371/journal.pone.00084142-s2.0-77949539030Gerhart-HinesZ.DominyJ. E.BlättlerS. M.JedrychowskiM. P.BanksA. S.LimJ.-H.ChimH.GygiS. P.PuigserverP.The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD+201144685186310.1016/j.molcel.2011.12.0052-s2.0-84255198350NahhasF.DrydenS. C.AbramsJ.TainskyM. A.Mutations in SIRT2 deacetylase which regulate enzymatic activity but not its interaction with HDAC6 and tubulin20073031-222123010.1007/s11010-007-9478-62-s2.0-34547920351NorthB. J.VerdinE.Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation200728227195461955510.1074/jbc.m7029902002-s2.0-34547098165BianY.SongC.ChengK.DongM.WangF.HuangJ.SunD.WangL.YeM.ZouH.An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome20149625326210.1016/j.jprot.2013.11.0142-s2.0-84890300195DephoureN.ZhouC.VillénJ.BeausoleilS. A.BakalarskiC. E.ElledgeS. J.GygiS. P.A quantitative atlas of mitotic phosphorylation200810531107621076710.1073/pnas.08051391052-s2.0-49449085504ThirumurthiU.ShenJ.XiaW.LaBaffA. M.WeiY.LiC.ChangW.ChenC.LinH.YuD.HungM.MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer20147336ra7110.1126/scisignal.2005076ZeeR. S.YooC. B.PimentelD. R.PerlmanD. H.BurgoyneJ. R.HouX.McCombM. E.CostelloC. E.CohenR. A.BachschmidM. M.Redox regulation of sirtuin-1 by S-glutathiolation20101371023103210.1089/ars.2010.32512-s2.0-77955862787BorraM. T.SmithB. C.DenuJ. M.Mechanism of human SIRT1 activation by resveratrol200528017171871719510.1074/jbc.m5012502002-s2.0-20444444649KornbergM. D.SenN.HaraM. R.JuluriK. R.NguyenJ. V. K.SnowmanA. M.LawL.HesterL. D.SnyderS. H.GAPDH mediates nitrosylation of nuclear proteins201012111094110010.1038/ncb21142-s2.0-78149284226ShaoD.FryJ. L.HanJ.HouX.PimentelD. R.MatsuiR.CohenR. A.BachschmidM. M.A redox-resistant Sirtuin-1 mutant protects against hepatic metabolic and oxidant stress2014289117293730610.1074/jbc.m113.5204032-s2.0-84896292959FritzK. S.GalliganJ. J.SmathersR. L.RoedeJ. R.ShearnC. T.ReiganP.PetersenD. R.4-hydroxynonenal inhibits SIRT3 via thiol-specific modification201124565166210.1021/tx100355a2-s2.0-79956150193YangJ.GuptaV.CarrollK. S.LieblerD. C.Site-specific mapping and quantification of protein S-sulphenylation in cells20145, article 477610.1038/ncomms57762-s2.0-84907339922HuS.LiuH.HaY.LuoX.MotamediM.GuptaM. P.MaJ.-X.TiltonR. G.ZhangW.Posttranslational modification of Sirt6 activity by peroxynitrite20157917618510.1016/j.freeradbiomed.2014.11.0112-s2.0-84920713849KimJ.-E.ChenJ.LouZ.DBC1 is a negative regulator of SIRT12008451717858358610.1038/nature065002-s2.0-38749088678KimE.-J.KhoJ.-H.KangM.-R.UmS.-J.Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity200728227729010.1016/j.molcel.2007.08.0302-s2.0-35349011726YuanJ.LuoK.LiuT.LouZ.Regulation of SIRT1 activity by genotoxic stress201226879179610.1101/gad.188482.1122-s2.0-84859871053EscandeC.ChiniC. C. S.NinV.DykhouseK. M.NovakC. M.LevineJ.Van DeursenJ.GoresG. J.ChenJ.LouZ.ChiniE. N.Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice2010120254555810.1172/jci393192-s2.0-76649085804EscandeC.NinV.PirtskhalavaT.ChiniC. C. S.TchkoniaT.KirklandJ. L.ChiniE. N.Deleted in breast cancer 1 limits adipose tissue fat accumulation and plays a key role in the development of metabolic syndrome phenotype2015641122210.2337/db14-01922-s2.0-84919967626VolonteD.ZouH.BartholomewJ. N.LiuZ.MorelP. A.GalbiatiF.Oxidative stress-induced inhibition of Sirt1 by caveolin-1 promotes p53-dependent premature senescence and stimulates the secretion of interleukin 6 (IL-6)201529074202421410.1074/jbc.m114.5982682-s2.0-84922769591ChiniE. N.CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions2009151576310.2174/1381612097871857882-s2.0-62149151357YoshinoJ.MillsK. F.YoonM. J.ImaiS.-I.Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice201114452853610.1016/j.cmet.2011.08.0142-s2.0-80053920774CantóC.HoutkooperR. H.PirinenE.YounD. Y.OosterveerM. H.CenY.Fernandez-MarcosP. J.YamamotoH.AndreuxP. A.Cettour-RoseP.GademannK.RinschC.SchoonjansK.SauveA. A.AuwerxJ.The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity201215683884710.1016/j.cmet.2012.04.0222-s2.0-84862022077EscandeC.NinV.PriceN. L.CapelliniV.GomesA. P.BarbosaM. T.O'NeilL.WhiteT. A.SinclairD. A.ChiniE. N.Flavonoid apigenin is an inhibitor of the NAD+ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome20136241084109310.2337/db12-1139BarbosaM. T. P.SoaresS. M.NovakC. M.SinclairD.LevineJ. A.AksoyP.ChiniE. N.The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity200721133629363910.1096/fj.07-8290com2-s2.0-36049038217BaiP.CantóC.OudartH.BrunyánszkiA.CenY.ThomasC.YamamotoH.HuberA.KissB.HoutkooperR. H.SchoonjansK.SchreiberV.SauveA. A.Menissier-De MurciaJ.AuwerxJ.PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation201113446146810.1016/j.cmet.2011.03.0042-s2.0-79953752384AksoyP.WhiteT. A.ThompsonM.ChiniE. N.Regulation of intracellular levels of NAD: a novel role for CD38200634541386139210.1016/j.bbrc.2006.05.0422-s2.0-33744509311AksoyP.EscandeC.WhiteT. A.ThompsonM.SoaresS.BenechJ. C.ChiniE. N.Regulation of SIRT 1 mediated NAD dependent deacetylation: a novel role for the multifunctional enzyme CD382006349135335910.1016/j.bbrc.2006.08.066RajamohanS. B.PillaiV. B.GuptaM.SundaresanN. R.BirukovK. G.SamantS.HottigerM. O.GuptaM. P.SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1200929154116412910.1128/mcb.00121-092-s2.0-67651210858BraidyN.GuilleminG. J.MansourH.Chan-LingT.PoljakA.GrantR.Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats201164e1919410.1371/journal.pone.00191942-s2.0-79955591489DuL.ZhangX.HanY. Y.BurkeN. A.KochanekP. M.WatkinsS. C.GrahamS. H.CarcilloJ. A.SzabóC.ClarkR. S. B.Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress200327820184261843310.1074/jbc.m3012952002-s2.0-0038043242HowitzK. T.BittermanK. J.CohenH. Y.LammingD. W.LavuS.WoodJ. G.ZipkinR. E.ChungP.KisielewskiA.ZhangL.-L.SchererB.SinclairD. A.Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan2003425695419119610.1038/nature019602-s2.0-0141719702KaeberleinM.McDonaghT.HeltwegB.HixonJ.WestmanE. A.CaldwellS. D.NapperA.CurtisR.DiStefanoP. S.FieldsS.BedalovA.KennedyB. K.Substrate-specific activation of sirtuins by resveratrol200528017170381704510.1074/jbc.m5006552002-s2.0-20444431507MilneJ. C.LambertP. D.SchenkS.CarneyD. P.SmithJ. J.GagneD. J.JinL.BossO.PerniR. B.VuC. B.BemisJ. E.XieR.DischJ. S.NgP. Y.NunesJ. J.LynchA. V.YangH.GalonekH.IsraelianK.ChoyW.IfflandA.LavuS.MedvedikO.SinclairD. A.OlefskyJ. M.JirousekM. R.ElliottP. J.WestphalC. H.Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes2007450717071271610.1038/nature062612-s2.0-36749087548CantóC.Gerhart-HinesZ.FeigeJ. N.LagougeM.NoriegaL.MilneJ. C.ElliottP. J.PuigserverP.AuwerxJ.AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity200945872411056106010.1038/nature078132-s2.0-67349276169ParkS.-J.AhmadF.PhilpA.BaarK.WilliamsT.LuoH.KeH.RehmannH.TaussigR.BrownA. L.KimM. K.BeavenM. A.BurginA. B.ManganielloV.ChungJ. H.Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases2012148342143310.1016/j.cell.2012.01.0172-s2.0-84863011114MitchellS. J.Martin-MontalvoA.MerckenE. M.PalaciosH. H.WardT. M.AbulwerdiG.MinorR. K.VlasukG. P.EllisJ. L.SinclairD. A.DawsonJ.AllisonD. B.ZhangY.BeckerK. G.BernierM.de CaboR.The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet20146583684310.1016/j.celrep.2014.01.0312-s2.0-84895925833MinorR. K.BaurJ. A.GomesA. P.WardT. M.CsiszarA.MerckenE. M.AbdelmohsenK.ShinY.-K.CantoC.Scheibye-KnudsenM.KrawczykM.IrustaP. M.Martín-MontalvoA.HubbardB. P.ZhangY.LehrmannE.WhiteA. A.PriceN. L.SwindellW. R.PearsonK. J.BeckerK. G.BohrV. A.GorospeM.EganJ. M.TalanM. I.AuwerxJ.WestphalC. H.EllisJ. L.UngvariZ.VlasukG. P.ElliottP. J.SinclairD. A.De CaboR.SRT1720 improves survival and healthspan of obese mice20111, article 7010.1038/srep000702-s2.0-84859909860PacholecM.BleasdaleJ. E.ChrunykB.CunninghamD.FlynnD.GarofaloR. S.GriffithD.GrifforM.LoulakisP.PabstB.QiuX.StockmanB.ThanabalV.VargheseA.WardJ.WithkaJ.AhnK.SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT12010285118340835110.1074/jbc.m109.0886822-s2.0-77950246109HubbardB. P.GomesA. P.DaiH.LiJ.CaseA. W.ConsidineT.RieraT. V.LeeJ. E.Yen ES.LammingD. W.PenteluteB. L.SchumanE. R.StevensL. A.LingA. J. Y.ArmourS. M.MichanS.ZhaoH.JiangY.SweitzerS. M.BlumC. A.DischJ. S.NgP. Y.HowitzK. T.RoloA. P.HamuroY.MossJ.PerniR. B.EllisJ. L.VlasukG. P.SinclairD. A.Evidence for a common mechanism of SIRT1 regulation by allosteric activators201333961241216121910.1126/science.12310972-s2.0-84874721105DaiH.KustigianL.CarneyD.CaseA.ConsidineT.HubbardB. P.PerniR. B.RieraT. V.SzczepankiewiczB.VlasukG. P.SteinR. L.SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator201028543326953270310.1074/jbc.m110.1338922-s2.0-77958488312SmithJ. J.KenneyR. D.GagneD. J.FrushourB. P.LaddW.GalonekH. L.IsraelianK.SongJ.RazvadauskaiteG.LynchA. V.CarneyD. P.JohnsonR. J.LavuS.IfflandA.ElliottP. J.LambertP. D.EllistonK. O.JirousekM. R.MilneJ. C.BossO.Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo200931, article 3110.1186/1752-0509-3-312-s2.0-63549094179BoilyG.HeX. H.PearceB.JardineK.McBurneyM. W.SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol200928322882289310.1038/onc.2009.1472-s2.0-68949113934PearsonK. J.BaurJ. A.LewisK. N.PeshkinL.PriceN. L.LabinskyyN.SwindellW. R.KamaraD.MinorR. K.PerezE.JamiesonH. A.ZhangY.DunnS. R.SharmaK.PleshkoN.WoollettL. A.CsiszarA.IkenoY.Le CouteurD.ElliottP. J.BeckerK. G.NavasP.IngramD. K.WolfN. S.UngvariZ.SinclairD. A.de CaboR.Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span20088215716810.1016/j.cmet.2008.06.0112-s2.0-48349144852AjmoJ. M.LiangX.RogersC. Q.PennockB.YouM.Resveratrol alleviates alcoholic fatty liver in mice20082954G833G84210.1152/ajpgi.90358.20082-s2.0-57349114641HwangJ.-T.KwakD. W.LinS. K.KimH. M.KimY. M.ParkO. J.Resveratrol induces apoptosis in chemoresistant cancer cells via modulation of AMPK signaling pathway2007109544144810.1196/annals.1397.0472-s2.0-34247844379LagougeM.ArgmannC.Gerhart-HinesZ.MezianeH.LerinC.DaussinF.MessadeqN.MilneJ.LambertP.ElliottP.GenyB.LaaksoM.PuigserverP.AuwerxJ.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α200612761109112210.1016/j.cell.2006.11.0132-s2.0-33845399894BaurJ. A.PearsonK. J.PriceN. L.JamiesonH. A.LerinC.KalraA.PrabhuV. V.AllardJ. S.Lopez-LluchG.LewisK.PistellP. J.PoosalaS.BeckerK. G.BossO.GwinnD.WangM.RamaswamyS.FishbeinK. W.SpencerR. G.LakattaE. G.Le CouteurD.ShawR. J.NavasP.PuigserverP.IngramD. K.De CaboR.SinclairD. A.Resveratrol improves health and survival of mice on a high-calorie diet2006444711733734210.1038/nature053542-s2.0-33751072349WoodJ. G.RoginaB.LavuS.HewitzK.HelfandS. L.TatarM.SinclairD.Sirtuin activators mimic caloric restriction and delay ageing in metazoans2004430700068668910.1038/nature027892-s2.0-3943071801YamazakiY.UsuiI.KanataniY.MatsuyaY.TsuneyamaK.FujisakaS.BukhariA.SuzukiH.SendaS.ImanishiS.HirataK.IshikiM.HayashiR.UrakazeM.NemotoH.KobayashiM.TobeK.Treatment with SRT1720, a SIRT1 activator, ameliorates fatty liver with reduced expression of lipogenic enzymes in MSG mice20092975E1179E118610.1152/ajpendo.90997.20082-s2.0-70350452395FeigeJ. M.LagougeM.CantoC.Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation20088534735810.1016/j.cmet.2008.08.017TannoM.KunoA.YanoT.MiuraT.HisaharaS.IshikawaS.ShimamotoK.HorioY.Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure2010285118375838210.1074/jbc.m109.0902662-s2.0-77950901103ShinS. M.ChoI. J.KimS. G.Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3β inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway200976488489510.1124/mol.109.058479Brookins DanzE. D.SkramstedJ.HenryN.BennettJ. A.KellerR. S.Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway200946121589159710.1016/j.freeradbiomed.2009.03.0112-s2.0-67349234999HwangJ.-T.KwonD. Y.ParkO. J.KimM. S.Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells20082432332610.1007/s12263-007-0069-72-s2.0-41349084391CsiszarA.LabinskyyN.PodlutskyA.KaminskiP. M.WolinM. S.ZhangC.MukhopadhyayP.PacherP.HuF.De CaboR.BallabhP.UngvariZ.Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations20082946H2721H273510.1152/ajpheart.00235.20082-s2.0-49249100288YaoH.SundarI. K.AhmadT.LernerC.GerloffJ.FriedmanA. E.PhippsR. P.SimeP. J.McBurneyM. W.GuarenteL.RahmanI.SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism20143069L816L82810.1152/ajplung.00323.20132-s2.0-84900538900VaqueroA.ScherM.LeeD.Erdjument-BromageH.TempstP.ReinbergD.Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin20041619310510.1016/j.molcel.2004.08.0312-s2.0-4944245398KongS.KimS.-J.SandalB.LeeS.-M.GaoB.ZhangD. D.FangD.The type III histone deacetylase Sirt1 protein suppresses p300-mediated histone H3 lysine 56 acetylation at Bclaf1 promoter to inhibit T cell activation201128619169671697510.1074/jbc.m111.2182062-s2.0-79955773522PonugotiB.KimD.-H.XiaoZ.SmithZ.MiaoJ.ZangM.WuS.-Y.ChiangC.-M.VeenstraT. D.KemperJ. K.SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism201028544339593397010.1074/jbc.m110.1229782-s2.0-77958595135PicardF.KurtevM.ChungN.Topark-NgarmA.SenawongT.De OliveiraR. M.LeidM.McBurneyM. W.GuarenteL.Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ2004429699377177610.1038/nature025832-s2.0-3042681042YeungF.HobergJ. E.RamseyC. S.KellerM. D.JonesD. R.FryeR. A.MayoM. W.Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase200423122369238010.1038/sj.emboj.76002442-s2.0-3242719545MattagajasinghI.KimC.-S.NaqviA.YamamoriT.HoffmanT. A.JungS.-B.DeRiccoJ.KasunoK.IraniK.SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase200710437148551486010.1073/pnas.07043291042-s2.0-35549008884NakaeJ.CaoY.DaitokuH.FukamizuA.OgawaW.YanoY.HayashiY.The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity200611692473248310.1172/jci255182-s2.0-33748335578LimJ.-H.LeeY.-M.ChunY.-S.ChenJ.KimJ.-E.ParkJ.-W.Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha201038686487810.1016/j.molcel.2010.05.0232-s2.0-77955499804TannoM.SakamotoJ.MiuraT.ShimamotoK.HorioY.Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1200728296823683210.1074/jbc.m6095542002-s2.0-34250365395HallowsW. C.LeeS.DenuJ. M.Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases200610327102301023510.1073/pnas.06043921032-s2.0-33745931074SundaresanN. R.PillaiV. B.WolfgeherD.SamantS.VasudevanP.ParekhV.RaghuramanH.CunninghamJ. M.GuptaM.GuptaM. P.The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy20114182, article ra4610.1126/scisignal.20014652-s2.0-79960620082LiuY.DentinR.ChenD.HedrickS.RavnskjaerK.SchenkS.MilneJ.MeyersD. J.ColeP.YatesJ.IIIOlefskyJ.GuarenteL.MontminyM.A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange2008456721926927310.1038/nature073492-s2.0-56249100986YamamoriT.DeRiccoJ.NaqviA.HoffmanT. A.MattagajasinghI.KasunoK.JungS.-B.KimC.-S.IraniK.SIRT1 deacetylates APE1 and regulates cellular base excision repair2009383832845gkp103910.1093/nar/gkp10392-s2.0-77950351604JiangW.WangS.XiaoM.LinY.ZhouL.LeiQ.XiongY.GuanK.-L.ZhaoS.Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase2011431334410.1016/j.molcel.2011.04.0282-s2.0-79959906869TengY.-B.JingH.AramsangtienchaiP.HeB.KhanS.HuJ.LinH.HaoQ.Efficient demyristoylase activity of SIRT2 revealed by kinetic and structural studies20155, article 852910.1038/srep08529DrydenS. C.NahhasF. A.NowakJ. E.GoustinA.-S.TainskyM. A.Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle20032393173318510.1128/mcb.23.9.3173-3185.20032-s2.0-0037405043VaqueroA.ScherM. B.DongH. L.SuttonA.ChengH.-L.AltF. W.SerranoL.SternglanzR.ReinbergD.SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis200620101256126110.1101/gad.14127062-s2.0-33646550204ChenT.LiuJ.LiN.WangS.LiuH.LiJ.ZhangY.BuP.GuptaS.Mouse SIRT3 attenuates hypertrophy-related lipid accumulation in the heart through the deacetylation of LCAD2015103e011890910.1371/journal.pone.0118909HirscheyM. D.ShimazuT.CapraJ. A.PollardK. S.VerdinE.SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,22011366356422-s2.0-81055127044YuW.Dittenhafer-ReedK. E.DenuJ. M.SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status201228717140781408610.1074/jbc.m112.3552062-s2.0-84859951790OzdenO.ParkS.-H.WagnerB. A.Yong SongH.ZhuY.VassilopoulosA.JungB.BuettnerG. R.GiusD.SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells20147616317210.1016/j.freeradbiomed.2014.08.0012-s2.0-84907186695MathiasR. A.GrecoT. M.ObersteinA.BudayevaH. G.ChakrabartiR.RowlandE. A.KangY.ShenkT.CristeaI. M.Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity201415971615162510.1016/j.cell.2014.11.0462-s2.0-84919933749ParkJ.ChenY.TishkoffD. X.PengC.TanM.DaiL.XieZ.ZhangY.ZwaansB. M. M.SkinnerM. E.LombardD. B.ZhaoY.SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways201350691993010.1016/j.molcel.2013.06.0012-s2.0-84880791239TanM.PengC.AndersonK. A.ChhoyP.XieZ.DaiL.ParkJ.ChenY.HuangH.ZhangY.RoJ.WagnerG. R.GreenM. F.MadsenA. S.SchmiesingJ.PetersonB. S.XuG.IlkayevaO. R.MuehlbauerM. J.BraulkeT.MühlhausenC.BackosD. S.OlsenC. A.McGuireP. J.PletcherS. D.LombardD. B.HirscheyM. D.ZhaoY.Lysine glutarylation is a protein posttranslational modification regulated by SIRT5201419460561710.1016/j.cmet.2014.03.0142-s2.0-84897565291SundaresanN. R.VasudevanP.ZhongL.KimG.SamantS.ParekhV.PillaiV. B.RavindraP. V.GuptaM.JeevanandamV.CunninghamJ. M.DengC.-X.LombardD. B.MostoslavskyR.GuptaM. P.The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun201218111643165010.1038/nm.29612-s2.0-84869201195MichishitaE.McCordR. A.BerberE.KioiM.Padilla-NashH.DamianM.CheungP.KusumotoR.KawaharaT. L. A.BarrettJ. C.ChangH. Y.BohrV. A.RiedT.GozaniO.ChuaK. F.SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin2008452718649249610.1038/nature067362-s2.0-41349090663MichishitaE.McCordR. A.BoxerL. D.BarberM. F.HongT.GozaniO.ChuaK. F.Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT620098162664266610.4161/cc.8.16.93672-s2.0-69249221533MaoZ.HineC.TianX.MeterM. V.AuM.VaidyaA.SeluanovA.GorbunovaV.SIRT6 promotes DNA repair under stress by activating PARP1201133260361443144610.1126/science.12027232-s2.0-79959363092ChenS.SeilerJ.Santiago-ReicheltM.FelbelK.GrummtI.VoitR.Repression of RNA polymerase I upon stress is caused by inhibition of RNA-dependent deacetylation of PAF53 by SIRT7201352330331310.1016/j.molcel.2013.10.0102-s2.0-84887172167BarberM. F.Michishita-KioiE.XiY.TasselliL.KioiM.MoqtaderiZ.TennenR. I.ParedesS.YoungN. L.ChenK.StruhlK.GarciaB. A.GozaniO.LiW.ChuaK. F.SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation2012486740511411810.1038/nature110432-s2.0-84863453769Tomé-CarneiroJ.LarrosaM.González-SarríasA.Tomás-BarberánF. A.García-ConesaM. T.EspínJ. C.Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence201319346064609310.2174/138161281131999904072-s2.0-84886461893BaksiA.KraydashenkoO.ZalevkayaA.StetsR.ElliottP.HaddadJ.HoffmannE.VlasukG. P.JacobsonE. W.A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes2014781697710.1111/bcp.123272-s2.0-84902983036LibriV.BrownA. P.GambarotaG.HaddadJ.ShieldsG. S.DawesH.PinatoD. J.HoffmanE.ElliotP. J.VlasukG. P.JacobsonE.WilkinsM. R.MatthewsP. M.A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers2012712e5139510.1371/journal.pone.00513952-s2.0-84871431259LeeH.KimK. R.NohS. J.ParkH. S.KwonK. S.ParkB.-H.JungS. H.YounH. J.LeeB. K.ChungM. J.KohD. H.MoonW. S.JangK. Y.Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma201142220421310.1016/j.humpath.2010.05.0232-s2.0-78751567751YuX.-M.LiuY.JinT.LiuJ.WangJ.MaC.PanX.-L.The expression of SIRT1 and DBC1 in laryngeal and hypopharyngeal carcinomas201386e6697510.1371/journal.pone.00669752-s2.0-84879268616