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From Sirtuin Biology to Human Diseases: An Update*

  • Carlos Sebastián
    Footnotes
    Affiliations
    Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114
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  • F.Kyle Satterstrom
    Footnotes
    Affiliations
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

    Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts 02138
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  • Marcia C. Haigis
    Correspondence
    Supported by the Paul F. Glenn Foundation for Medical Research. To whom correspondence may be addressed.
    Affiliations
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
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  • Raul Mostoslavsky
    Correspondence
    Massachusetts General Hospital Research Scholar. To whom correspondence may be addressed.
    Affiliations
    Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114
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  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grant AG032375 (to M. C. H.), Grants DK088190 and GM093072 (to R. M.), and Training Grant T32 DK007260 (to F. K. S.). This is the fourth article in the Thematic Minireview Series on Sirtuins: From Biochemistry to Health and Disease.
    1 Both authors contributed equally to this work.
    2 Recipient of a Beatriu de Pinós postdoctoral fellowship.
Open AccessPublished:October 18, 2012DOI:https://doi.org/10.1074/jbc.R112.402768
      Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD+-dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas.

      Introduction

      Over three-quarters of a century ago, Clive McCay and colleagues first noted that rats kept on a calorie-restricted diet lived longer than freely fed controls (
      • McCay C.M.
      • Crowell M.F.
      • Maynard L.A.
      The effect of retarded growth upon the length of life and upon ultimate size.
      ). Despite the length of time that has elapsed since this discovery, the molecular mechanism that drives this life span extension has remained elusive. Originally described as a silencing factor in yeast (silencing information regulator), the protein Sir2 came out on top in a screen for modulators of yeast life span (
      • Kaeberlein M.
      • McVey M.
      • Guarente L.
      The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms.
      ). Moreover, Sir2 was required for the life span of yeast to be extended by calorie restriction (
      • Lin S.J.
      • Defossez P.A.
      • Guarente L.
      Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae.
      ). These discoveries launched a new field in biology: the study of Sir2 and its homologs in mammals, called sirtuins.
      Mammals have seven sirtuins (SIRT1–7) that possess NAD+-dependent deacetylase, deacylase, and ADP-ribosyltransferase activities (
      • Houtkooper R.H.
      • Pirinen E.
      • Auwerx J.
      Sirtuins as regulators of metabolism and healthspan.
      ). Sirtuins are found in different subcellular locations, including the nucleus (SIRT1, SIRT6, and SIRT7), cytosol (SIRT2), and mitochondria (SIRT3–5), although in some studies, SIRT1 has been found to possess cytosolic activities, and SIRT2 has been found to associate with nuclear proteins. Sirtuins have important functions in a diverse yet interrelated set of physiological processes. In this minireview, we discuss research done in the past four years featuring their roles in aging, metabolism, cancer biology, cardiovascular disease, inflammation, and brain pathology.

      Aging

      Following the first publication describing a role for yeast Sir2 in promoting longevity (
      • Kaeberlein M.
      • McVey M.
      • Guarente L.
      The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms.
      ), many laboratories focused on elucidating whether sirtuins might play similar roles in other organisms. Sirtuins have been shown to regulate life span in lower organisms, including yeast, nematodes, and fruit flies (
      • Haigis M.C.
      • Guarente L.P.
      Mammalian sirtuins–emerging roles in physiology, aging, and calorie restriction.
      ), although their role in worm and fly life span has recently been debated (
      • Burnett C.
      • Valentini S.
      • Cabreiro F.
      • Goss M.
      • Somogyvári M.
      • Piper M.D.
      • Hoddinott M.
      • Sutphin G.L.
      • Leko V.
      • McElwee J.J.
      • Vazquez-Manrique R.P.
      • Orfila A.M.
      • Ackerman D.
      • Au C.
      • Vinti G.
      • Riesen M.
      • Howard K.
      • Neri C.
      • Bedalov A.
      • Kaeberlein M.
      • Soti C.
      • Partridge L.
      • Gems D.
      Absence of effects of Sir2 overexpression on lifespan in C. elegansDrosophila.
      ,
      • Viswanathan M.
      • Guarente L.
      Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes.
      ). Most of these studies have described a key role for SIRT1 in regulating the metabolic response to calorie restriction (CR)
      The abbreviations used are: CR
      calorie restriction
      ROS
      reactive oxygen species
      IGF-1
      insulin-like growth factor 1
      HIF-1α
      hypoxia-inducible factor 1α
      PPAR
      peroxisome proliferator-activated receptor.
      (
      • Cantó C.
      • Auwerx J.
      Caloric restriction, SIRT1 and longevity.
      ), a dietary intervention that robustly extends life span across numerous species. However, whole-body overexpression of SIRT1 in mice does not affect life span (
      • Herranz D.
      • Muñoz-Martin M.
      • Cañamero M.
      • Mulero F.
      • Martinez-Pastor B.
      • Fernandez-Capetillo O.
      • Serrano M.
      Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer.
      ). Nevertheless, SIRT1 does appear to promote healthy aging by protecting against several age-related pathologies (
      • Guarente L.
      Franklin H. Epstein lecture: sirtuins, aging, and medicine.
      ).
      The strongest link between mammalian sirtuins and the anti-aging effects of CR comes from SIRT3, which mediates the prevention of age-related hearing loss by CR (
      • Someya S.
      • Yu W.
      • Hallows W.C.
      • Xu J.
      • Vann J.M.
      • Leeuwenburgh C.
      • Tanokura M.
      • Denu J.M.
      • Prolla T.A.
      Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction.
      ). Hearing loss is a hallmark of mammalian aging and is characterized by a gradual loss of spiral ganglion neurons and sensory hair cells in the cochlea of the inner ear, which is triggered by oxidative damage in these cells (
      • Liu X.Z.
      • Yan D.
      Ageing and hearing loss.
      ). Remarkably, CR prevents hearing loss and oxidative damage in wild-type mice, whereas Sirt3-deficient mice are resistant to the effects of CR. In addition, SIRT3 is required for the CR-mediated reduction of oxidative damage in multiple tissues via regulation of the glutathione antioxidant system (
      • Someya S.
      • Yu W.
      • Hallows W.C.
      • Xu J.
      • Vann J.M.
      • Leeuwenburgh C.
      • Tanokura M.
      • Denu J.M.
      • Prolla T.A.
      Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction.
      ). Indeed, SIRT3 has been shown to directly modulate reactive oxygen species (ROS) by deacetylating manganese superoxide dismutase (
      • Qiu X.
      • Brown K.
      • Hirschey M.D.
      • Verdin E.
      • Chen D.
      Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation.
      ,
      • Tao R.
      • Coleman M.C.
      • Pennington J.D.
      • Ozden O.
      • Park S.H.
      • Jiang H.
      • Kim H.S.
      • Flynn C.R.
      • Hill S.
      • Hayes McDonald W.
      • Olivier A.K.
      • Spitz D.R.
      • Gius D.
      Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress.
      ). This evidence suggests a broader role for SIRT3 in regulating age-related pathologies that depend on cellular levels of ROS.
      Evidence for a positive effect of sirtuins on longevity also comes from the recent discovery that SIRT6 overexpression extends life span in mice (
      • Kanfi Y.
      • Naiman S.
      • Amir G.
      • Peshti V.
      • Zinman G.
      • Nahum L.
      • Bar-Joseph Z.
      • Cohen H.Y.
      The sirtuin SIRT6 regulates lifespan in male mice.
      ). Although early experiments using Sirt6 knock-out mice suggested a role in aging (
      • Mostoslavsky R.
      • Chua K.F.
      • Lombard D.B.
      • Pang W.W.
      • Fischer M.R.
      • Gellon L.
      • Liu P.
      • Mostoslavsky G.
      • Franco S.
      • Murphy M.M.
      • Mills K.D.
      • Patel P.
      • Hsu J.T.
      • Hong A.L.
      • Ford E.
      • Cheng H.L.
      • Kennedy C.
      • Nunez N.
      • Bronson R.
      • Frendewey D.
      • Auerbach W.
      • Valenzuela D.
      • Karow M.
      • Hottiger M.O.
      • Hursting S.
      • Barrett J.C.
      • Guarente L.
      • Mulligan R.
      • Demple B.
      • Yancopoulos G.D.
      • Alt F.W.
      Genomic instability and aging-like phenotype in the absence of mammalian SIRT6.
      ), this is the first demonstration that a mammalian sirtuin positively regulates life span. Notably, the observed life span extension seems to be modest (the median life span increases between 10 and 15%) and gender-specific (affecting males only) for reasons that remain unclear. Despite reduced levels of insulin-like growth factor 1 (IGF-1) in serum, a phenotype previously associated with life span regulation, the “anti-aging” effect of SIRT6 could be explained by SIRT6 acting as a tumor suppressor (as described below) (
      • Lombard D.B.
      • Miller R.A.
      Ageing: sorting out the sirtuins.
      ). These results provide encouraging evidence that mammalian sirtuins may in fact represent critical modulators of life span and age-related diseases.

      Metabolism

      Because sirtuin enzymatic activity is dependent upon the presence of NAD+, sirtuin activity is directly linked to the metabolic state of the cell. Indeed, nearly every sirtuin has been shown to play a role in regulating metabolism and energy homeostasis, often in roles that help the cell adapt to periods of low-energy input (Fig. 1). Indeed, sirtuins are involved in multiple metabolic pathways, as described below.
      Figure thumbnail gr1
      FIGURE 1Metabolic functions of mammalian sirtuins in different tissues. For specific molecular targets, see text. PGC1α, PPARγ coactivator 1α; PEPCK, phosphoenolpyruvate carboxykinase; LCAD, long-chain acyl-CoA dehydrogenase; OTC, ornithine transcarbamoylase.

      Lipid Metabolism

      Lipid catabolism is especially important during fasting. SIRT1 is induced in several tissues during CR (
      • Cohen H.Y.
      • Miller C.
      • Bitterman K.J.
      • Wall N.R.
      • Hekking B.
      • Kessler B.
      • Howitz K.T.
      • Gorospe M.
      • de Cabo R.
      • Sinclair D.A.
      Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.
      ) and responds to the organism's need for energy by stimulating lipid breakdown through the transcription factor FoxO1, which directly induces expression of the rate-limiting lipolytic enzyme adipose triglyceride lipase (
      • Chakrabarti P.
      • English T.
      • Karki S.
      • Qiang L.
      • Tao R.
      • Kim J.
      • Luo Z.
      • Farmer S.R.
      • Kandror K.V.
      SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL.
      ). SIRT1 also inhibits cells' ability to synthesize fat by deacetylating the lipogenic activator SREBP-1c, preventing this factor from binding the promoters of lipogenic genes (
      • Ponugoti B.
      • Kim D.H.
      • Xiao Z.
      • Smith Z.
      • Miao J.
      • Zang M.
      • Wu S.Y.
      • Chiang C.M.
      • Veenstra T.D.
      • Kemper J.K.
      SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism.
      ,
      • Walker A.K.
      • Yang F.
      • Jiang K.
      • Ji J.Y.
      • Watts J.L.
      • Purushotham A.
      • Boss O.
      • Hirsch M.L.
      • Ribich S.
      • Smith J.J.
      • Israelian K.
      • Westphal C.H.
      • Rodgers J.T.
      • Shioda T.
      • Elson S.L.
      • Mulligan P.
      • Najafi-Shoushtari H.
      • Black J.C.
      • Thakur J.K.
      • Kadyk L.C.
      • Whetstine J.R.
      • Mostoslavsky R.
      • Puigserver P.
      • Li X.
      • Dyson N.J.
      • Hart A.C.
      • Näär A.M.
      Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.
      ). Notably, when SIRT1 is absent from specific tissues, mice have significant defects in their ability to metabolize lipids normally, leading to fat accumulation (
      • Houtkooper R.H.
      • Pirinen E.
      • Auwerx J.
      Sirtuins as regulators of metabolism and healthspan.
      ), and even haploinsufficiency was shown to lead to increased weight gain on a high-fat diet (
      • Purushotham A.
      • Xu Q.
      • Li X.
      Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding.
      ).
      Despite these seemingly clear results, further study has shown that the effects of SIRT1 may in fact be dose- or context-dependent. Although SIRT1-overexpressing mice were protected from hepatic steatosis when placed on a high-fat diet in one study (
      • Pfluger P.T.
      • Herranz D.
      • Velasco-Miguel S.
      • Serrano M.
      • Tschöp M.H.
      Sirt1 protects against high-fat diet-induced metabolic damage.
      ), another study found the opposite result (
      • Qiang L.
      • Lin H.V.
      • Kim-Muller J.Y.
      • Welch C.L.
      • Gu W.
      • Accili D.
      Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation.
      ), attributing the outcome to SIRT1 inhibition of cAMP-responsive element-binding protein, a transcription factor that normally activates fatty acid metabolism and gluconeogenesis. Additionally, overexpression of SIRT1 in the forebrain of female mice led to increased fat mass and increased expression of adipogenic genes in white adipose tissue (
      • Wu D.
      • Qiu Y.
      • Gao X.
      • Yuan X.B.
      • Zhai Q.
      Overexpression of SIRT1 in mouse forebrain impairs lipid/glucose metabolism and motor function.
      ). Taken together, these studies suggest that whether SIRT1 promotes lipid catabolism or instead promotes adipogenesis may be tissue- and expression level-dependent.
      The metabolic effects of SIRT3 appear thus far to be more straightforward (Fig. 1). SIRT3 is up-regulated by fasting in liver and brown adipose tissue and promotes mitochondrial oxidative metabolism via deacetylation of numerous metabolic enzymes (
      • Verdin E.
      • Hirschey M.D.
      • Finley L.W.
      • Haigis M.C.
      Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling.
      ), including long-chain acyl-CoA dehydrogenase, an enzyme involved in fatty acid catabolism (
      • Hirschey M.D.
      • Shimazu T.
      • Goetzman E.
      • Jing E.
      • Schwer B.
      • Lombard D.B.
      • Grueter C.A.
      • Harris C.
      • Biddinger S.
      • Ilkayeva O.R.
      • Stevens R.D.
      • Li Y.
      • Saha A.K.
      • Ruderman N.B.
      • Bain J.R.
      • Newgard C.B.
      • Farese Jr., R.V.
      • Alt F.W.
      • Kahn C.R.
      • Verdin E.
      SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.
      ,
      • Hallows W.C.
      • Yu W.
      • Smith B.C.
      • Devries M.K.
      • Ellinger J.J.
      • Someya S.
      • Shortreed M.R.
      • Prolla T.
      • Markley J.L.
      • Smith L.M.
      • Zhao S.
      • Guan K.L.
      • Denu J.M.
      Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction.
      ). The importance of this activity is demonstrated by an abnormal accumulation of fatty acid oxidation intermediates in Sirt3 knock-out mice. When fasted, these mice also show reduced ATP production and are intolerant to cold. Conversely, Sirt3 knock-out mice are unable to cope with a high-fat diet and gain more weight than their wild-type counterparts, developing hepatic steatosis and exhibiting signs of inflammation (
      • Hirschey M.D.
      • Shimazu T.
      • Jing E.
      • Grueter C.A.
      • Collins A.M.
      • Aouizerat B.
      • Stančáková A.
      • Goetzman E.
      • Lam M.M.
      • Schwer B.
      • Stevens R.D.
      • Muehlbauer M.J.
      • Kakar S.
      • Bass N.M.
      • Kuusisto J.
      • Laakso M.
      • Alt F.W.
      • Newgard C.B.
      • Farese Jr., R.V.
      • Kahn C.R.
      • Verdin E.
      SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome.
      ). Furthermore, wild-type animals on a high-fat diet have reduced hepatic SIRT3 activity and increased protein acetylation relative to those on a control diet (
      • Kendrick A.A.
      • Choudhury M.
      • Rahman S.M.
      • McCurdy C.E.
      • Friederich M.
      • Van Hove J.L.
      • Watson P.A.
      • Birdsey N.
      • Bao J.
      • Gius D.
      • Sack M.N.
      • Jing E.
      • Kahn C.R.
      • Friedman J.E.
      • Jonscher K.R.
      Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation.
      ), suggesting that a feedback mechanism may be involved in the interplay between SIRT3 activity and diet.
      SIRT6 promotes fatty acid oxidation as well, interestingly through a mechanism involving another sirtuin. SIRT1 and the transcription factors FoxO3a and NRF1 form a complex on the Sirt6 promoter, leading to SIRT6 expression and promotion of fat oxidation in wild-type mice (
      • Kim H.S.
      • Xiao C.
      • Wang R.H.
      • Lahusen T.
      • Xu X.
      • Vassilopoulos A.
      • Vazquez-Ortiz G.
      • Jeong W.I.
      • Park O.
      • Ki S.H.
      • Gao B.
      • Deng C.X.
      Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis.
      ). Mice with a liver-specific deletion of Sirt6 develop a fatty liver, and primary hepatocytes from these mice show relatively low levels of fatty acid oxidation. By contrast, mice with transgenic overexpression of SIRT6 show down-regulation of genes associated with lipid storage and are somewhat protected against the accumulation of visceral fat when placed on a high-fat diet (
      • Kanfi Y.
      • Peshti V.
      • Gil R.
      • Naiman S.
      • Nahum L.
      • Levin E.
      • Kronfeld-Schor N.
      • Cohen H.Y.
      SIRT6 protects against pathological damage caused by diet-induced obesity.
      ). These studies cast Sirt6 as an important promoter of fat utilization.
      Roles are beginning to be described for the other sirtuins in lipid metabolism and adipose biology. SIRT2 seems to fall in line with other family members described above: it inhibits adipocyte differentiation (
      • Jing E.
      • Gesta S.
      • Kahn C.R.
      SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation.
      ), possibly by deacetylating FoxO1 (
      • Wang F.
      • Tong Q.
      SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARγ.
      ), and its transcription is suppressed in obese mice by hypoxia-inducible factor 1α (HIF-1α) (
      • Krishnan J.
      • Danzer C.
      • Simka T.
      • Ukropec J.
      • Walter K.M.
      • Kumpf S.
      • Mirtschink P.
      • Ukropcova B.
      • Gasperikova D.
      • Pedrazzini T.
      • Krek W.
      Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system.
      ). However, not all sirtuins act in the same direction: knocking down Sirt4 increases fatty acid oxidation, suggesting that this sirtuin opposes its mitochondrial counterpart SIRT3 (
      • Nasrin N.
      • Wu X.
      • Fortier E.
      • Feng Y.
      • Bare′ O.C.
      • Chen S.
      • Ren X.
      • Wu Z.
      • Streeper R.S.
      • Bordone L.
      SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells.
      ). This induction goes away when Sirt1 is knocked down at the same time, indicating that there may be cross-talk between these sirtuins. The precise molecular mechanisms for such cross-regulation remain unclear.

      Glucose Metabolism

      Most of the work done so far on how sirtuins regulate glucose metabolism has focused on SIRT1, which is known to modulate gluconeogenesis in liver mainly through its substrate peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1α (
      • Houtkooper R.H.
      • Pirinen E.
      • Auwerx J.
      Sirtuins as regulators of metabolism and healthspan.
      ). Recently, other sirtuins have appeared on the stage as key regulators of glucose homeostasis. SIRT6 has come to the fore as an important regulator of glucose uptake and metabolism (Fig. 1). Sirt6 knock-out mice die early in life from a fatal hypoglycemia. These animals exhibit increased expression of the glucose transporter GLUT1, leading to increased glucose uptake in skeletal muscle and brown adipose tissue (
      • Zhong L.
      • D'Urso A.
      • Toiber D.
      • Sebastian C.
      • Henry R.E.
      • Vadysirisack D.D.
      • Guimaraes A.
      • Marinelli B.
      • Wikstrom J.D.
      • Nir T.
      • Clish C.B.
      • Vaitheesvaran B.
      • Iliopoulos O.
      • Kurland I.
      • Dor Y.
      • Weissleder R.
      • Shirihai O.S.
      • Ellisen L.W.
      • Espinosa J.M.
      • Mostoslavsky R.
      The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α.
      ). Sirt6-deficient embryonic stem cells similarly show lower oxygen consumption and greater lactate production than controls. In part, this phenotype appears to be related to the ability of SIRT6 to lower expression of glycolytic genes, such as Pfk1 and Glut1, through deacetylation of histone H3K9. In this context, SIRT6 works as a co-repressor of HIF-1α, and the increased glucose uptake seen in Sirt6 knock-outs is reversed by treatment with a HIF-1α inhibitor (
      • Zhong L.
      • D'Urso A.
      • Toiber D.
      • Sebastian C.
      • Henry R.E.
      • Vadysirisack D.D.
      • Guimaraes A.
      • Marinelli B.
      • Wikstrom J.D.
      • Nir T.
      • Clish C.B.
      • Vaitheesvaran B.
      • Iliopoulos O.
      • Kurland I.
      • Dor Y.
      • Weissleder R.
      • Shirihai O.S.
      • Ellisen L.W.
      • Espinosa J.M.
      • Mostoslavsky R.
      The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α.
      ). These results indicate that SIRT6 may function as a critical modulator of glucose homeostasis. Recently, SIRT2 has also been found to take part in glucose metabolism by promoting gluconeogenesis through deacetylation and stabilization of the rate-limiting enzyme phosphoenolpyruvate carboxykinase (
      • Jiang W.
      • Wang S.
      • Xiao M.
      • Lin Y.
      • Zhou L.
      • Lei Q.
      • Xiong Y.
      • Guan K.L.
      • Zhao S.
      Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase.
      ), adding this protein to the list of sirtuins that control glucose homeostasis.

      Other Metabolic Processes

      Sirtuins have important functions in additional metabolic pathways that promote adaptation to periods of low-energy input. For example, SIRT3 activates ketone body synthesis via HMGCS2 (
      • Shimazu T.
      • Hirschey M.D.
      • Hua L.
      • Dittenhafer-Reed K.E.
      • Schwer B.
      • Lombard D.B.
      • Li Y.
      • Bunkenborg J.
      • Alt F.W.
      • Denu J.M.
      • Jacobson M.P.
      • Verdin E.
      SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 and regulates ketone body production.
      ). It also up-regulates the electron transport chain via SDHA (
      • Finley L.W.
      • Haas W.
      • Desquiret-Dumas V.
      • Wallace D.C.
      • Procaccio V.
      • Gygi S.P.
      • Haigis M.C.
      Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity.
      ) and the urea cycle via ornithine transcarbamoylase (
      • Hallows W.C.
      • Yu W.
      • Smith B.C.
      • Devries M.K.
      • Ellinger J.J.
      • Someya S.
      • Shortreed M.R.
      • Prolla T.
      • Markley J.L.
      • Smith L.M.
      • Zhao S.
      • Guan K.L.
      • Denu J.M.
      Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction.
      ). SIRT5 enhances the urea cycle through CPS1 (carbamoyl phosphate synthetase 1), the first step of the cycle. Indeed, Sirt5 knock-out mice show reduced basal CPS1 activity and lack the increase in activity normally seen with fasting (
      • Nakagawa T.
      • Lomb D.J.
      • Haigis M.C.
      • Guarente L.
      SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle.
      ). SIRT5 has been shown to deacetylate CPS1 (
      • Nakagawa T.
      • Lomb D.J.
      • Haigis M.C.
      • Guarente L.
      SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle.
      ), and a recent study indicates that SIRT5 may demalonylate and desuccinylate CPS1 as well (
      • Du J.
      • Zhou Y.
      • Su X.
      • Yu J.J.
      • Khan S.
      • Jiang H.
      • Kim J.
      • Woo J.
      • Kim J.H.
      • Choi B.H.
      • He B.
      • Chen W.
      • Zhang S.
      • Cerione R.A.
      • Auwerx J.
      • Hao Q.
      • Lin H.
      Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase.
      ). Suggestively, in the absence of SIRT5, the levels of succinylation of CPS1 were increased, indicating that SIRT5 may function as a bona fide deacylase. All together, these studies highlight that we are yet learning about the enzymatic functions of sirtuins, and future studies will surely investigate the mechanisms through which sirtuins might work together to coordinate metabolic responses.

      Cancer

      Tumorigenesis is a multistep process that involves the acquisition of several mutations leading to cell transformation and cancer initiation. Among the hallmarks of cancer cells, metabolic reprogramming is also an important regulator of tumor growth, allowing tumor cells to fulfill their energetic and anabolic demands (
      • Vander Heiden M.G.
      • Cantley L.C.
      • Thompson C.B.
      Understanding the Warburg effect: the metabolic requirements of cell proliferation.
      ). In addition to their role in regulating metabolism, sirtuins are important in the regulation of genomic stability, making them excellent candidates to control tumorigenesis (Fig. 2).
      Figure thumbnail gr2
      FIGURE 2Mammalian sirtuins in carcinogenesis. The roles of sirtuins in initiation and tumor progression are summarized. For molecular targets, see text. ERα, estrogen receptor-α.
      A large amount of data generated over the last decade has involved SIRT1 in tumorigenesis by modulating cellular stress responses and DNA repair (
      • Martinez-Pastor B.
      • Mostoslavsky R.
      Sirtuins, metabolism, and cancer.
      ). However, the ability of SIRT1 to promote or suppress tumorigenesis seems to depend on the specific tumor type, cellular context, and signaling pathway affected. Several studies support a role for SIRT1 as a tumor suppressor. SIRT1 opposes Myc-dependent transformation by interacting with and deacetylating this proto-oncogene (
      • Yuan J.
      • Minter-Dykhouse K.
      • Lou Z.
      A c-Myc-SIRT1 feedback loop regulates cell growth and transformation.
      ). Furthermore, overexpression of SIRT1 in vivo protects against metabolic syndrome-associated liver cancer by reducing DNA damage and inflammation. Importantly, a moderate increase of SIRT1 in these mice protects from spontaneous and aging-associated cancers (
      • Herranz D.
      • Muñoz-Martin M.
      • Cañamero M.
      • Mulero F.
      • Martinez-Pastor B.
      • Fernandez-Capetillo O.
      • Serrano M.
      Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer.
      ). Moreover, recent work has demonstrated that SIRT1 interacts with HIF-1α and represses its activity, thereby inhibiting growth and angiogenesis of xenograft tumors (
      • Lim J.H.
      • Lee Y.M.
      • Chun Y.S.
      • Chen J.
      • Kim J.E.
      • Park J.W.
      Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α.
      ). Finally, a recent study reported increased levels of acetylated H3K56, a substrate for SIRT1 and SIRT2, in human tumors (
      • Das C.
      • Lucia M.S.
      • Hansen K.C.
      • Tyler J.K.
      CBP/p300-mediated acetylation of histone H3 on lysine 56.
      ). Although the influence of SIRT1 and SIRT2 in modulating this histone mark specifically in tumors has not been addressed, it is tempting to speculate that decreased levels or activity of these sirtuins could have an impact on tumorigenesis by increasing the levels of H3K56 acetylation. Notably, H3K56 acetylation has been shown to be a primary substrate for SIRT6, thereby raising the possibility that the modulation of this particular histone mark in tumors may depend on this chromatin deacetylase rather than SIRT1/2, as proposed.
      In contrast with the above observations, recently published data have added evidence for a tumor-promoting function of SIRT1. A new positive feedback loop involving N-Myc and SIRT1 has been described to promote tumorigenesis in a mouse model of neuroblastoma (
      • Marshall G.M.
      • Liu P.Y.
      • Gherardi S.
      • Scarlett C.J.
      • Bedalov A.
      • Xu N.
      • Iraci N.
      • Valli E.
      • Ling D.
      • Thomas W.
      • van Bekkum M.
      • Sekyere E.
      • Jankowski K.
      • Trahair T.
      • Mackenzie K.L.
      • Haber M.
      • Norris M.D.
      • Biankin A.V.
      • Perini G.
      • Liu T.
      SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.
      ). N-Myc induces the expression of Sirt1, which in turn deacetylates and stabilizes N-Myc, thereby promoting tumor growth. Furthermore, a complex between SIRT1 and estrogen receptor-α has been found to be essential to promote the expression of prosurvival genes and to inactivate tumor suppressor genes in breast cancer cells (
      • Elangovan S.
      • Ramachandran S.
      • Venkatesan N.
      • Ananth S.
      • Gnana-Prakasam J.P.
      • Martin P.M.
      • Browning D.D.
      • Schoenlein P.V.
      • Prasad P.D.
      • Ganapathy V.
      • Thangaraju M.
      SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer.
      ). Sirt1 expression also appears to be up-regulated in hepatocellular carcinomas, where it inhibits senescence and apoptosis and leads to tumor growth (
      • Chen J.
      • Zhang B.
      • Wong N.
      • Lo A.W.
      • To K.F.
      • Chan A.W.
      • Ng M.H.
      • Ho C.Y.
      • Cheng S.H.
      • Lai P.B.
      • Yu J.
      • Ng H.K.
      • Ling M.T.
      • Huang A.L.
      • Cai X.F.
      • Ko B.C.
      Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth.
      ,
      • Choi H.N.
      • Bae J.S.
      • Jamiyandorj U.
      • Noh S.J.
      • Park H.S.
      • Jang K.Y.
      • Chung M.J.
      • Kang M.J.
      • Lee D.G.
      • Moon W.S.
      Expression and role of SIRT1 in hepatocellular carcinoma.
      ). However, the precise molecular mechanism through which SIRT1 exerts this tumor-promoting function remains unclear.
      As mentioned above, metabolic reprogramming is a key feature of cancer cells. Although differentiated cells under normal conditions obtain energy by oxidizing fuels such as glucose through mitochondrial oxidative phosphorylation, Warburg observed that rapidly proliferating cancer cells often up-regulate glycolysis, which we now understand allows cells to generate macromolecules needed for cellular proliferation. Recent studies reported that SIRT3 normally counteracts this metabolic switch by destabilizing HIF-1α through down-regulation of ROS (
      • Finley L.W.
      • Carracedo A.
      • Lee J.
      • Souza A.
      • Egia A.
      • Zhang J.
      • Teruya-Feldstein J.
      • Moreira P.I.
      • Cardoso S.M.
      • Clish C.B.
      • Pandolfi P.P.
      • Haigis M.C.
      SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.
      ,
      • Bell E.L.
      • Emerling B.M.
      • Ricoult S.J.
      • Guarente L.
      SirT3 suppresses hypoxia-inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production.
      ). Overexpressing SIRT3 also suppresses the Warburg effect in various cancer cell lines lacking SIRT3 (
      • Finley L.W.
      • Carracedo A.
      • Lee J.
      • Souza A.
      • Egia A.
      • Zhang J.
      • Teruya-Feldstein J.
      • Moreira P.I.
      • Cardoso S.M.
      • Clish C.B.
      • Pandolfi P.P.
      • Haigis M.C.
      SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.
      ,
      • Bell E.L.
      • Emerling B.M.
      • Ricoult S.J.
      • Guarente L.
      SirT3 suppresses hypoxia-inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production.
      ), suggesting that SIRT3 may be a tumor suppressor. Consistent with this role, Sirt3 expression is down-regulated in human breast cancers, and Sirt3 knock-out mice have a higher incidence of spontaneous mammary tumors (
      • Kim H.S.
      • Patel K.
      • Muldoon-Jacobs K.
      • Bisht K.S.
      • Aykin-Burns N.
      • Pennington J.D.
      • van der Meer R.
      • Nguyen P.
      • Savage J.
      • Owens K.M.
      • Vassilopoulos A.
      • Ozden O.
      • Park S.H.
      • Singh K.K.
      • Abdulkadir S.A.
      • Spitz D.R.
      • Deng C.X.
      • Gius D.
      SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress.
      ). As noted above, SIRT6 is a key regulator of glucose metabolism, and lack of this chromatin factor leads to a phenotype that is reminiscent of the Warburg effect (
      • Zhong L.
      • D'Urso A.
      • Toiber D.
      • Sebastian C.
      • Henry R.E.
      • Vadysirisack D.D.
      • Guimaraes A.
      • Marinelli B.
      • Wikstrom J.D.
      • Nir T.
      • Clish C.B.
      • Vaitheesvaran B.
      • Iliopoulos O.
      • Kurland I.
      • Dor Y.
      • Weissleder R.
      • Shirihai O.S.
      • Ellisen L.W.
      • Espinosa J.M.
      • Mostoslavsky R.
      The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α.
      ). Indeed, SIRT6 has been recently described as a tumor suppressor that regulates cancer metabolism (
      • Sebastian C.
      • Zwaans B.M.
      • Silberman D.M.
      • Gymrek M.A.
      • Goren A.
      • Zhong L.
      • Ran O.
      • Truelove J.
      • Guimaraes A.R.
      • Toiber D.
      • Cosentino C.
      • Greenson J.K.
      • MacDonald A.I.
      • McGlynn L.
      • Maxwell F.
      • Edwards J.
      • Giacosa S.
      • Guccione E.
      • Weisledder R.
      • Bernstein B.E.
      • Regev A.
      • Shiels P.G.
      • Lombard D.B.
      • Mostoslavsky R.
      The Histone Deacetylase SIRT6 is a novel tumor suppressor that controls cancer metabolism.
      ). Mechanistically, SIRT6 suppresses aerobic glycolysis and Myc-dependent ribosome biosynthesis, and lack of this sirtuin leads to robust metabolic reprogramming, sufficient to promote tumorigenesis. In line with this, Sirt6 expression is down-regulated in human pancreatic and colorectal cancers, and conditional deletion of Sirt6 promotes intestinal tumorigenesis in vivo (
      • Sebastian C.
      • Zwaans B.M.
      • Silberman D.M.
      • Gymrek M.A.
      • Goren A.
      • Zhong L.
      • Ran O.
      • Truelove J.
      • Guimaraes A.R.
      • Toiber D.
      • Cosentino C.
      • Greenson J.K.
      • MacDonald A.I.
      • McGlynn L.
      • Maxwell F.
      • Edwards J.
      • Giacosa S.
      • Guccione E.
      • Weisledder R.
      • Bernstein B.E.
      • Regev A.
      • Shiels P.G.
      • Lombard D.B.
      • Mostoslavsky R.
      The Histone Deacetylase SIRT6 is a novel tumor suppressor that controls cancer metabolism.
      ). Consistent with a tumor-suppressive function, it has recently been shown that overexpression of SIRT6 induces apoptosis in cancer cell lines (
      • Van Meter M.
      • Mao Z.
      • Gorbunova V.
      • Seluanov A.
      SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells.
      ). However, the mechanism and physiological relevance of this observation remain as yet unexplored.
      The roles of other sirtuins in cancer development have just started to emerge (Fig. 2). Because SIRT2 regulates normal mitotic progression by controlling the activity of the anaphase-promoting complex/cyclosome (
      • Dryden S.C.
      • Nahhas F.A.
      • Nowak J.E.
      • Goustin A.S.
      • Tainsky M.A.
      Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.
      ), SIRT2 was proposed to be a tumor suppressor by preventing chromosomal instability during mitosis. Indeed, Sirt2-deficient mice develop spontaneous and gender-specific tumors, with females primarily developing mammary tumors, whereas hepatocellular carcinomas arise in males (
      • Kim H.S.
      • Vassilopoulos A.
      • Wang R.H.
      • Lahusen T.
      • Xiao Z.
      • Xu X.
      • Li C.
      • Veenstra T.D.
      • Li B.
      • Yu H.
      • Ji J.
      • Wang X.W.
      • Park S.H.
      • Cha Y.I.
      • Gius D.
      • Deng C.X.
      SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity.
      ). Finally, a recent study has demonstrated that SIRT7 functions as an H3K18 deacetylase, repressing transcription of multiple genes involved in anchorage-independent growth and contact inhibition (
      • Barber M.F.
      • Michishita-Kioi E.
      • Xi Y.
      • Tasselli L.
      • Kioi M.
      • Moqtaderi Z.
      • Tennen R.I.
      • Paredes S.
      • Young N.L.
      • Chen K.
      • Struhl K.
      • Garcia B.A.
      • Gozani O.
      • Li W.
      • Chua K.F.
      SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.
      ). In this context, SIRT7 depletion markedly reduced tumorigenicity of cancer cells, suggesting that SIRT7 may play a critical role in maintaining oncogenic transformation.

      Inflammation

      Inflammation plays a central role in the pathogenesis of many diseases, including cancer, diabetes, and cardiac disease. Current research points to an anti-inflammatory role for sirtuins, especially SIRT1 and SIRT3. Several studies have shown SIRT1 to be protective against inflammation (e.g. Ref.
      • Gillum M.P.
      • Kotas M.E.
      • Erion D.M.
      • Kursawe R.
      • Chatterjee P.
      • Nead K.T.
      • Muise E.S.
      • Hsiao J.J.
      • Frederick D.W.
      • Yonemitsu S.
      • Banks A.S.
      • Qiang L.
      • Bhanot S.
      • Olefsky J.M.
      • Sears D.D.
      • Caprio S.
      • Shulman G.I.
      SirT1 regulates adipose tissue inflammation.
      ), a function that may counteract the effects of inflammatory factors such as NF-κB (
      • Schug T.T.
      • Xu Q.
      • Gao H.
      • Peres-da-Silva A.
      • Draper D.W.
      • Fessler M.B.
      • Purushotham A.
      • Li X.
      Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress.
      ) and TNF-α (
      • Yoshizaki T.
      • Schenk S.
      • Imamura T.
      • Babendure J.L.
      • Sonoda N.
      • Bae E.J.
      • Oh D.Y.
      • Lu M.
      • Milne J.C.
      • Westphal C.
      • Bandyopadhyay G.
      • Olefsky J.M.
      SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity.
      ). SIRT1 is also important for preventing lung inflammation following exposure to airborne particulate matter (
      • Wu Z.
      • Liu M.C.
      • Liang M.
      • Fu J.
      Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure.
      ). Furthermore, suppression of SIRT1 is seen during inflammation (
      • Li P.
      • Zhao Y.
      • Wu X.
      • Xia M.
      • Fang M.
      • Iwasaki Y.
      • Sha J.
      • Chen Q.
      • Xu Y.
      • Shen A.
      Interferon γ (IFN-γ) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription.
      ), but one study prevented these effects by pretreating mice with the SIRT1-activating compound resveratrol (
      • Zhang Z.
      • Lowry S.F.
      • Guarente L.
      • Haimovich B.
      Roles of SIRT1 in the acute and restorative phases following induction of inflammation.
      ).
      Other sirtuins may also negatively regulate inflammation. SIRT2, for instance, may down-regulate the immune response through deacetylation of the NF-κB subunit p65 at Lys-310 (
      • Rothgiesser K.M.
      • Erener S.
      • Waibel S.
      • Lüscher B.
      • Hottiger M.O.
      SIRT2 regulates NF-κB-dependent gene expression through deacetylation of p65 Lys310.
      ). Lys-310 is hyperacetylated in Sirt2 knock-out mouse embryonic fibroblasts following TNF-α stimulation, leading to an increase in the expression of NF-κB target genes. These results suggest that SIRT2 is a negative regulator of NF-κB gene expression and therefore potentially of inflammation as well. SIRT6 binds many of the same promoters in the mouse genome as NF-κB subunit RelA (
      • Kawahara T.L.
      • Rapicavoli N.A.
      • Wu A.R.
      • Qu K.
      • Quake S.R.
      • Chang H.Y.
      Dynamic chromatin localization of Sirt6 shapes stress- and aging-related transcriptional networks.
      ), and it deacetylates Lys-9 of histone H3, leading to RelA destabilization and cessation of gene expression (
      • Kawahara T.L.
      • Michishita E.
      • Adler A.S.
      • Damian M.
      • Berber E.
      • Lin M.
      • McCord R.A.
      • Ongaigui K.C.
      • Boxer L.D.
      • Chang H.Y.
      • Chua K.F.
      SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span.
      ). Like SIRT2, SIRT6 may also have an anti-inflammatory role through suppression of NF-κB target gene expression. However, Sirt6-deficient T cells exhibit reduced interferon-γ secretion upon activation (
      • Bruzzone S.
      • Fruscione F.
      • Morando S.
      • Ferrando T.
      • Poggi A.
      • Garuti A.
      • D'Urso A.
      • Selmo M.
      • Benvenuto F.
      • Cea M.
      • Zoppoli G.
      • Moran E.
      • Soncini D.
      • Ballestrero A.
      • Sordat B.
      • Patrone F.
      • Mostoslavsky R.
      • Uccelli A.
      • Nencioni A.
      Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.
      ), and SIRT6 also enhances TNF-α translation in dendritic cells (
      • Van Gool F.
      • Gallí M.
      • Gueydan C.
      • Kruys V.
      • Prevot P.P.
      • Bedalov A.
      • Mostoslavsky R.
      • Alt F.W.
      • De Smedt T.
      • Leo O.
      Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner.
      ), so the picture is not entirely clear. Finally, in one study, Sirt7 knock-out mice had elevated myocardial levels of several cytokines compared with controls, demonstrating that SIRT7 may help fight inflammation (
      • Vakhrusheva O.
      • Smolka C.
      • Gajawada P.
      • Kostin S.
      • Boettger T.
      • Kubin T.
      • Braun T.
      • Bober E.
      Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice.
      ).

      Cardiovascular Disease

      Cardiovascular disease is one of the leading causes of death worldwide and involves the deterioration of heart and blood vessel function. Remarkably, early studies demonstrated that CR protects from cardiovascular disease by improving both endothelial and heart function (
      • Weiss E.P.
      • Fontana L.
      Caloric restriction: powerful protection for the aging heart and vasculature.
      ). Given the role of sirtuins in mediating, at least in part, some of the effects of CR, multiple studies have explored their function in cardiovascular disease. Most of this work described the role of SIRT1 in endothelial function, vessel inflammation, vascularization, and cholesterol metabolism and has been reviewed previously (
      • Haigis M.C.
      • Sinclair D.A.
      Mammalian sirtuins: biological insights and disease relevance.
      ). Here, we summarize recent findings regarding the role of sirtuins in cardiac function.
      SIRT1, SIRT7, and, more recently, SIRT3 and SIRT6 have been described as key regulators of cardiac hypertrophy, one of the main causes leading to heart failure. Early studies demonstrated that SIRT1 and SIRT7 play a protective role against cardiac hypertrophy by deacetylating and modulating p53 activity (
      • Vakhrusheva O.
      • Smolka C.
      • Gajawada P.
      • Kostin S.
      • Boettger T.
      • Kubin T.
      • Braun T.
      • Bober E.
      Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice.
      ,
      • Alcendor R.R.
      • Kirshenbaum L.A.
      • Imai S.
      • Vatner S.F.
      • Sadoshima J.
      Silent information regulator 2α, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes.
      ,
      • Pillai J.B.
      • Isbatan A.
      • Imai S.
      • Gupta M.P.
      Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2α deacetylase activity.
      ). Recently, the protective role of SIRT1 has been extended to its ability to regulate fatty acid oxidation (
      • Planavila A.
      • Iglesias R.
      • Giralt M.
      • Villarroya F.
      Sirt1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation.
      ). A normal healthy heart utilizes both fatty acids and glucose simultaneously to obtain energy. However, cardiac hypertrophy is accompanied by a metabolic shift similar to the Warburg effect that favors glycolysis and impairs fatty acid oxidation (
      • Leong H.S.
      • Brownsey R.W.
      • Kulpa J.E.
      • Allard M.F.
      Glycolysis and pyruvate oxidation in cardiac hypertrophy–why so unbalanced?.
      ). In a phenylephrine-induced cardiac hypertrophy model, SIRT1 prevented the development of cardiac hypertrophy by promoting fatty acid oxidation (
      • Planavila A.
      • Iglesias R.
      • Giralt M.
      • Villarroya F.
      Sirt1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation.
      ). Mechanistically, SIRT1 binds to PPARα, favoring the deacetylation of PPARγ coactivator 1α and preventing the down-regulation of fatty acid oxidation genes (
      • Planavila A.
      • Iglesias R.
      • Giralt M.
      • Villarroya F.
      Sirt1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation.
      ). In line with a protective role for SIRT1 in cardiovascular disease, it also protects mice from hyperglycemia-induced endothelial dysfunction by inhibiting the expression of p66Shc (
      • Zhou S.
      • Chen H.Z.
      • Wan Y.Z.
      • Zhang Q.J.
      • Wei Y.S.
      • Huang S.
      • Liu J.J.
      • Lu Y.B.
      • Zhang Z.Q.
      • Yang R.F.
      • Zhang R.
      • Cai H.
      • Liu D.P.
      • Liang C.C.
      Repression of P66Shc expression by SIRT1 contributes to the prevention of hyperglycemia-induced endothelial dysfunction.
      ). Mice deficient in p66Shc have increased resistance to oxidative stress and improved endothelial function and are protected against vascular and cardiac diseases (
      • Cosentino F.
      • Francia P.
      • Camici G.G.
      • Pelicci P.G.
      • Lüscher T.F.
      • Volpe M.
      Final common molecular pathways of aging and cardiovascular disease: role of the p66Shc protein.
      ). In contrast with these observations, transgenic mice overexpressing SIRT1 develop larger atherosclerotic lesions compared with control animals (
      • Qiang L.
      • Lin H.V.
      • Kim-Muller J.Y.
      • Welch C.L.
      • Gu W.
      • Accili D.
      Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation.
      ). A similar phenotype was observed in a different line of SIRT1 transgenic mice, where SIRT1 overexpression reduced cardiac function and was associated with impaired mitochondria (
      • Kawashima T.
      • Inuzuka Y.
      • Okuda J.
      • Kato T.
      • Niizuma S.
      • Tamaki Y.
      • Iwanaga Y.
      • Kawamoto A.
      • Narazaki M.
      • Matsuda T.
      • Adachi S.
      • Takemura G.
      • Kita T.
      • Kimura T.
      • Shioi T.
      Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice.
      ). Furthermore, a recent study using Sirt1-deficient mice also demonstrated a detrimental role for SIRT1 in cardiac function (
      • Sundaresan N.R.
      • Pillai V.B.
      • Wolfgeher D.
      • Samant S.
      • Vasudevan P.
      • Parekh V.
      • Raghuraman H.
      • Cunningham J.M.
      • Gupta M.
      • Gupta M.P.
      The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.
      ). In response to a hypertrophic stimulus, Sirt1-deficient mice failed to develop cardiac hypertrophy, a phenotype associated with impaired Akt signaling. Moreover, hearts of mice overexpressing SIRT1 exhibited increased phosphorylation and deacetylation of Akt and developed cardiac hypertrophy under basal conditions (
      • Sundaresan N.R.
      • Pillai V.B.
      • Wolfgeher D.
      • Samant S.
      • Vasudevan P.
      • Parekh V.
      • Raghuraman H.
      • Cunningham J.M.
      • Gupta M.
      • Gupta M.P.
      The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.
      ). These conflicting results for SIRT1 may be influenced by differences in expression levels in the different mouse models (
      • Alcendor R.R.
      • Gao S.
      • Zhai P.
      • Zablocki D.
      • Holle E.
      • Yu X.
      • Tian B.
      • Wagner T.
      • Vatner S.F.
      • Sadoshima J.
      Sirt1 regulates aging and resistance to oxidative stress in the heart.
      ), suggesting that a beneficial effect of SIRT1 in the context of cardiac function, like the topic areas covered above, may be confined to a window of optimal activity.
      Due to its mitochondrial localization and ability to regulate cellular ROS levels, SIRT3 has also emerged as a critical regulator of cardiac function (
      • Sack M.N.
      Emerging characterization of the role of SIRT3-mediated mitochondrial protein deacetylation in the heart.
      ). Sirt3-deficient mice develop cardiac hypertrophy, whereas transgenic animals overexpressing SIRT3 in the heart are protected against agonist-mediated cardiac hypertrophy (
      • Sundaresan N.R.
      • Gupta M.
      • Kim G.
      • Rajamohan S.B.
      • Isbatan A.
      • Gupta M.P.
      Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice.
      ). At the molecular level, SIRT3 deacetylates and activates LKB1, thereby activating AMP-activated kinase, which suppresses Akt phosphorylation (
      • Pillai V.B.
      • Sundaresan N.R.
      • Kim G.
      • Gupta M.
      • Rajamohan S.B.
      • Pillai J.B.
      • Samant S.
      • Ravindra P.V.
      • Isbatan A.
      • Gupta M.P.
      Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway.
      ). Moreover, SIRT3-dependent deacetylation of FoxO3a leads to its nuclear localization and enhanced expression of antioxidant genes, such as manganese superoxide dismutase, reducing cellular ROS levels (
      • Sundaresan N.R.
      • Gupta M.
      • Kim G.
      • Rajamohan S.B.
      • Isbatan A.
      • Gupta M.P.
      Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice.
      ). Importantly, both Akt activation and increased ROS levels play a crucial role in the development of cardiac hypertrophy (
      • Lang D.
      Cardiac hypertrophy and oxidative stress: a leap of faith or stark reality?.
      ,
      • Condorelli G.
      • Drusco A.
      • Stassi G.
      • Bellacosa A.
      • Roncarati R.
      • Iaccarino G.
      • Russo M.A.
      • Gu Y.
      • Dalton N.
      • Chung C.
      • Latronico M.V.
      • Napoli C.
      • Sadoshima J.
      • Croce C.M.
      • Ross Jr., J.
      Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice.
      ). Thus, by regulating these two pathways, SIRT3 exerts a key antihypertrophic function in cardiomyocytes.
      SIRT6 is also involved in cardiac hypertrophy and myocardial infarction. In models of cardiac hypertrophy, Sirt6 expression is up-regulated, yet its deacetylase activity is reduced (
      • Yu S.S.
      • Cai Y.
      • Ye J.T.
      • Pi R.B.
      • Chen S.R.
      • Liu P.Q.
      • Shen X.Y.
      • Ji Y.
      Sirtuin 6 protects cardiomyocytes from hypertrophy in vitro via inhibition of NF-κB-dependent transcriptional activity.
      ). Increased activity of SIRT6 protects cardiomyocytes from a hypertrophic response in vitro by suppressing NF-κB activation (
      • Yu S.S.
      • Cai Y.
      • Ye J.T.
      • Pi R.B.
      • Chen S.R.
      • Liu P.Q.
      • Shen X.Y.
      • Ji Y.
      Sirtuin 6 protects cardiomyocytes from hypertrophy in vitro via inhibition of NF-κB-dependent transcriptional activity.
      ). Furthermore, increased NAD synthesis protects cardiomyocytes from hypertrophy, possibly through SIRT6 activation (
      • Cai Y.
      • Yu S.S.
      • Chen S.R.
      • Pi R.B.
      • Gao S.
      • Li H.
      • Ye J.T.
      • Liu P.Q.
      Nmnat2 protects cardiomyocytes from hypertrophy via activation of SIRT6.
      ). In line with this, a recent study reported that Sirt6 acts as a negative regulator of cardiac hypertrophy by repressing IGF/Akt signaling (
      • Sundaresan N.R.
      • Vasudevan P.
      • Zhong L.
      • Kim G.
      • Samant S.
      • Ravindra P.V.
      • Pillai V.B.
      • Gupta M.
      • Cunningham J.M.
      • Deng C.-X.
      • Lombard D.B.
      • Mostoslavsky R.
      • Gupta M.P.
      The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun.
      ). However, in contrast with these results, inhibition of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD synthesis, reduces myocardial infarction by inhibiting neutrophil infiltration and ROS production within the infarcted hearts (
      • Montecucco F.
      • Bauer I.
      • Braunersreuther V.
      • Bruzzone S.
      • Akhmedov A.
      • Luscher T.F.
      • Speer T.
      • Poggi A.
      • Mannino E.
      • Pelli G.
      • Galan K.
      • Bertolotto M.
      • Lenglet S.
      • Garuti A.
      • Montessuit C.
      • Lerch R.
      • Pellieux C.
      • Vuilleumier N.
      • Dallegri F.
      • Mage J.
      • Sebastian C.
      • Mostoslavsky R.
      • Gayet-Ageron A.
      • Patrone F.
      • Mach F.
      • Nencioni A.
      Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction.
      ). Interestingly, the same protective phenotype was observed when Sirt6 expression was silenced, implying that although SIRT6 may protect against cardiac hypertrophy, lower SIRT6 levels may be beneficial in the context of myocardial infarction.

      Brain

      Important roles have been elucidated for SIRT1 and SIRT2 in the brain. SIRT1 in particular has shown itself to be beneficial in multiple models of neuropathology. Alzheimer disease is characterized by the accumulation of the β-amyloid peptide and the aggregation of tau protein (
      • Haass C.
      • Selkoe D.J.
      Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide.
      ). In a mouse model of Alzheimer disease, brain-specific knock-out of Sirt1 increased levels of β-amyloid plaque formation, whereas overexpression of SIRT1 decreased the plaque levels (
      • Donmez G.
      • Wang D.
      • Cohen D.E.
      • Guarente L.
      SIRT1 suppresses β-amyloid production by activating the α-secretase gene ADAM10.
      ). SIRT1 may contribute to this effect because it activates transcription of the ADAM10 gene, which encodes α-secretase, an enzyme whose activity helps the brain avoid plaque formation. SIRT1 also deacetylates and destabilizes tau protein, thereby suppressing its aggregation (
      • Min S.W.
      • Cho S.H.
      • Zhou Y.
      • Schroeder S.
      • Haroutunian V.
      • Seeley W.W.
      • Huang E.J.
      • Shen Y.
      • Masliah E.
      • Mukherjee C.
      • Meyers D.
      • Cole P.A.
      • Ott M.
      • Gan L.
      Acetylation of tau inhibits its degradation and contributes to tauopathy.
      ). Likewise, in a mouse model of α-synuclein pathology, which drives conditions such as Parkinson disease (
      • Arima K.
      • Ueda K.
      • Sunohara N.
      • Hirai S.
      • Izumiyama Y.
      • Tonozuka-Uehara H.
      • Kawai M.
      Immunoelectron-microscopic demonstration of NACP/α-synuclein-epitopes on the filamentous component of Lewy bodies in Parkinson's disease and in dementia with Lewy bodies.
      ), SIRT1 played a protective role by preventing protein aggregation (
      • Donmez G.
      • Arun A.
      • Chung C.Y.
      • McLean P.J.
      • Lindquist S.
      • Guarente L.
      SIRT1 protects against α-synuclein aggregation by activating molecular chaperones.
      ). One possible mechanism is that SIRT1 deacetylates HSF1 to increase levels of HSP70, a chaperone that could prevent aggregation by helping with protein folding. SIRT1 overexpression improved motor function in a mouse model of Huntington disease (
      • Jiang M.
      • Wang J.
      • Fu J.
      • Du L.
      • Jeong H.
      • West T.
      • Xiang L.
      • Peng Q.
      • Hou Z.
      • Cai H.
      • Seredenina T.
      • Arbez N.
      • Zhu S.
      • Sommers K.
      • Qian J.
      • Zhang J.
      • Mori S.
      • Yang X.W.
      • Tamashiro K.L.
      • Aja S.
      • Moran T.H.
      • Luthi-Carter R.
      • Martin B.
      • Maudsley S.
      • Mattson M.P.
      • Cichewicz R.H.
      • Ross C.A.
      • Holtzman D.M.
      • Krainc D.
      • Duan W.
      Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets.
      ), whereas brain-specific knock-out of Sirt1 worsened disease-related pathology (
      • Jeong H.
      • Cohen D.E.
      • Cui L.
      • Supinski A.
      • Savas J.N.
      • Mazzulli J.R.
      • Yates 3rd, J.R.
      • Bordone L.
      • Guarente L.
      • Krainc D.
      Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway.
      ). Sirt1 knock-out mice also have defective short- and long-term memory despite seemingly normal gross brain anatomy, an effect possibly due to a decrease in hippocampal synaptic plasticity (
      • Michán S.
      • Li Y.
      • Chou M.M.
      • Parrella E.
      • Ge H.
      • Long J.M.
      • Allard J.S.
      • Lewis K.
      • Miller M.
      • Xu W.
      • Mervis R.F.
      • Chen J.
      • Guerin K.I.
      • Smith L.E.
      • McBurney M.W.
      • Sinclair D.A.
      • Baudry M.
      • de Cabo R.
      • Longo V.D.
      SIRT1 is essential for normal cognitive function and synaptic plasticity.
      ).
      By contrast, models of neuropathology show protective effects when Sirt2 is knocked down, where inhibition of SIRT2 lowered toxicity in a striatal neuron model of Huntington disease (
      • Luthi-Carter R.
      • Taylor D.M.
      • Pallos J.
      • Lambert E.
      • Amore A.
      • Parker A.
      • Moffitt H.
      • Smith D.L.
      • Runne H.
      • Gokce O.
      • Kuhn A.
      • Xiang Z.
      • Maxwell M.M.
      • Reeves S.A.
      • Bates G.P.
      • Neri C.
      • Thompson L.M.
      • Marsh J.L.
      • Kazantsev A.G.
      SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis.
      ). Thus, although SIRT1 is protective against brain pathology, SIRT2 may have opposing effects.
      SIRT1 and SIRT2 are also important for differentiation and migration of certain types of brain cells. In primary neurons, SIRT1 promotes neurite outgrowth and increases cell survival, and it also decreases mTOR signaling (
      • Guo W.
      • Qian L.
      • Zhang J.
      • Zhang W.
      • Morrison A.
      • Hayes P.
      • Wilson S.
      • Chen T.
      • Zhao J.
      Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling.
      ). Other studies have found that SIRT2 both promotes (
      • Ji S.
      • Doucette J.R.
      • Nazarali A.J.
      Sirt2 is a novel in vivo downstream target of Nkx2.2 and enhances oligodendroglial cell differentiation.
      ) and inhibits (
      • Li W.
      • Zhang B.
      • Tang J.
      • Cao Q.
      • Wu Y.
      • Wu C.
      • Guo J.
      • Ling E.A.
      • Liang F.
      Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating α-tubulin.
      ) oligodendrocyte differentiation. SIRT2 also promotes myelin formation in Schwann cells by deacetylating Par-3, a regulator of cell polarity (
      • Beirowski B.
      • Gustin J.
      • Armour S.M.
      • Yamamoto H.
      • Viader A.
      • North B.J.
      • Michán S.
      • Baloh R.H.
      • Golden J.P.
      • Schmidt R.E.
      • Sinclair D.A.
      • Auwerx J.
      • Milbrandt J.
      Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling.
      ).
      Little is known about the activity of the remaining sirtuins in the brain. SIRT3 was important for neuron viability in a primary cell model that used NMDA to deplete NAD and induce excitotoxic injury (
      • Kim S.H.
      • Lu H.F.
      • Alano C.C.
      Neuronal Sirt3 protects against excitotoxic injury in mouse cortical neuron culture.
      ). Mice with a neuron-specific deletion of Sirt6 did not die of hypoglycemia like full-body knock-outs (
      • Schwer B.
      • Schumacher B.
      • Lombard D.B.
      • Xiao C.
      • Kurtev M.V.
      • Gao J.
      • Schneider J.I.
      • Chai H.
      • Bronson R.T.
      • Tsai L.H.
      • Deng C.X.
      • Alt F.W.
      Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity.
      ). Rather, they initially exhibited growth retardation, with lower levels of pituitary growth hormone and IGF-1, ultimately becoming obese, likely secondary to altered neuropeptide levels.

      Future Perspectives

      In the past few years, the function of mammalian sirtuins has been investigated in greater detail than ever before, and we now have a much better molecular understanding of the multiple roles that this unique family of enzymes plays in seemingly every biological process. There is little doubt that sirtuins have emerged as critical modulators of metabolic adaptive responses, and their activities have been linked to multiple diseases, including metabolic abnormalities, cancer, inflammation, cardiac hypertrophy, and neurodegeneration. However, key questions will keep investigators busy in the coming years. We still have a poor understanding of the molecular mechanisms regulating sirtuins' expression and activity and of the precise stimuli that regulate these proteins. Are the activities of different sirtuins regulated in a coordinated fashion? In other words, is there cross-talk between sirtuins? Will future studies cement the argument that sirtuins are indeed critical modulators of life span? The future “sirtainly” looks promising.

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