Advertisement

Sirtuins in Multiple Sclerosis: The crossroad of neurodegeneration, autoimmunity and metabolism

  • Forough Foolad
    Affiliations
    Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
    Search for articles by this author
  • Fariba Khodagholi
    Affiliations
    Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
    Search for articles by this author
  • Mohammad Javan
    Correspondence
    Corresponding author at: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
    Affiliations
    Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
    Search for articles by this author

      Highlights

      • Sirtuins have critical roles in the central nervous system, immune system and metabolism.
      • Based on animal experiments SIRTs seems as novel candidates of therapeutic targets in MS.
      • Here some rational for selecting sirtuins as therapeutic targets in MS disease are presented.
      • The lack of clinical evidence for the role of some sirtuins in MS is highlighted.

      Abstract

      Multiple Sclerosis (MS) is a challenging and disabling condition particularly in the secondary progressive (SP) phase of this disease. The available treatments cannot ameliorate or stop disease progression in this phase, and there is an urgent need to focus on effective therapies and the molecular pathways involved SPMS. Given the significant impact of neurodegeneration, autoimmunity and metabolic alterations in MS, focusing on the molecules that target these different pathways could help in finding new treatments. Sirtuins (SIRTs) are NAD+ dependent epigenetic and metabolic regulators, which have critical roles in the physiology of central nervous system, immune system and metabolism. Based on these facts, SIRTs are crucial candidates of therapeutic targets in MS and collecting the information related to MS disease for each SIRT individually is noteworthy and highlights the lack of investigation in each part. In this review we summarized the role of different sirtuins as key regulator in neurodegeneration, autoimmunity and metabolism pathways. We also clarify the rationale behind selecting SIRTs as therapeutic targets in MS disease by collecting the researches showing alteration of these proteins in human samples of MS patients and animal model of MS, and also the improvement of modeled animals after SIRT-directed treatments.

      Keywords

      1. Introduction

      Multiple Sclerosis (MS), as an autoimmune inflammatory disorder of central nervous system (CNS), is a complex condition which is characterized by demyelination and axonal loss. It mostly appears in the early adult life of individuals, and has a great influence on the patients’ life quality. Costs are noticeable and rise with progression of disease and disability (
      • Brundin L.
      • Kobelt G.
      • Berg J.
      • Capsa D.
      • Eriksson J.
      New insights into the burden and costs of multiple sclerosis in Europe: results for Sweden.
      ). MS is the major cause of disability in young adults (
      • Kister I.
      • Chamot E.
      • Salter A.R.
      • Cutter G.R.
      • Bacon T.E.
      • Herbert J.
      Disability in multiple sclerosis: a reference for patients and clinicians.
      ,
      • Orton S.-M.
      • Herrera B.M.
      • Yee I.M.
      • Valdar W.
      • Ramagopalan S.V
      • Sadovnick A.D.
      • Ebers G.C.
      Sex ratio of multiple sclerosis in Canada: a longitudinal study.
      ), and its incidence in young women (between ages 20 and 40 years) is higher than men.
      MS has complex etiology and its causes are still not fully understood, though various mechanisms have been suggested to be involved in pathology of MS progression. The disease shows both aspect of inflammation and neural degeneration (
      • Compston A.
      • Coles A.
      Multiple sclerosis.
      ); while the CNS lesions are driven by inflammatory processes, after several years of chronic inflammation, neurodegeneration and axonal damage cause disease progression (
      • Lassmann H.
      • van Horssen J.
      • Mahad D.
      Progressive multiple sclerosis: pathology and pathogenesis.
      ). Furthermore, recent studies show that metabolic changes in either immune cells or the neurons/axons affect disease progression and the pathology (
      • Tannahill G.M.
      • Iraci N.
      • Gaude E.
      • Frezza C.
      • Pluchino S.
      Metabolic reprograming of mononuclear phagocytes in progressive multiple sclerosis.
      ).
      Although, multiple biological approaches and assessing the different molecules have yielded important insights into MS pathology, the treatment are insufficient especially in SP form of the disease. The need for effective treatments has created an emergence for diagnostic biomarkers to show transition from relapsing-remitting (RR) to SP phase.
      Mammalian sirtuins are nicotinamide adenine dinucleotide (NAD) dependent deacetylases which are widely conserved proteins from bacteria to humans. These proteins are known as lifespan regulators that inhibit genomic instability through chromatin modifications. There are seven homologs of sirtuins named SIRT1 to SIRT7 which possess various enzymatic activity and subcellular localization that affect their cellular functions. The major function of this family is related to protein acetylation state as a type of post-translational modifications. Members of sirtuin family are involved in several different molecular pathways including aging (
      • Sack M.N.
      • Finkel T.
      Mitochondrial metabolism, sirtuins, and aging.
      ), inflammation (
      • Haigis M.C.
      • Sinclair D.A.
      Mammalian sirtuins: biological insights and disease relevance.
      ), neurodegeneration (
      • Donmez G.
      The neurobiology of sirtuins and their role in neurodegeneration.
      ), metabolism (
      • Houtkooper R.H.
      • Pirinen E.
      • Auwerx J.
      Sirtuins as regulators of metabolism and healthspan.
      ) and cancer (
      • Brooks C.L.
      • Gu W.
      How does SIRT1 affect metabolism, senescence and cancer?.
      ). Neurodegeneration, autoimmunity and altered metabolism are three different aspects of MS pathology. On the other hand, sirtuins have been reported as a key regulator in these pathways. Therefore reviewing the available information related to MS disease and the sirtuins seems helpful via creating a better understanding leading to future studies and shedding light on the lack of investigation in each part. In this review we have summarized the role of different sirtuins as key regulator in neurodegeneration, autoimmunity and metabolism pathways involved in MS pathology and progression. We have also discussed the diagnostic perspective and the possible therapeutic application of sirtuins in MS.

      2. Sirtuins: SIRT1-SIRT7

      About 20 years ago, Guarente and colleagues showed that Silent Information Regular 2 (SIR2) gene could affect the life span in budding yeast via repressing of genomic instability (
      • Kaeberlein M.
      • McVey M.
      • Guarente L.
      The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms.
      ,
      • Sinclair D.A.
      • Guarente L.
      Extrachromosomal rDNA circles–a cause of aging in yeast.
      ). In most organisms such as the plants, bacteria and animals, SIR2-like genes, known as sirtuins have a crucial role in health and survival (
      • Sinclair D.A.
      • Guarente L.
      Unlocking the secrets of longevity genes.
      ). Several studies have focused on these roles and showed that sirtuins act at the molecular level as sensors for the amounts of energy, day light and stress. Additionally, they can respond to such signals and promote cell survival and health. Humans have seven sirtuin proteins (SIRT1-SIRT7) (
      • Frye R.A.
      Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins.
      ) that phylogenetically belong to the class III of histone deacetylase (HDAC) family (
      • Gray S.G.
      • Ekstrom T.J.
      The human histone deacetylase family.
      ). Other classes of HDACs enzymes including I, II and IV, are zinc dependent, but in contrast SIRTs have been recognized as nicotinamide adenine dinucleotide (NAD+) dependent enzymes. This feature characterizing SIRTs as a sensor of cellular energy status represented by NAD+, hence the enzymes activity can generate some by-products as like as 1-O-acetyl-ADP-ribose (
      • Chen B.
      • Zang W.
      • Wang J.
      • Huang Y.
      • He Y.
      • Yan L.
      • Liu J.
      • Zheng W.
      The chemical biology of sirtuins.
      ,
      • Imai S.
      • Armstrong C.M.
      • Kaeberlein M.
      • Guarente L.
      Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase.
      ,
      • Tanner K.G.
      • Landry J.
      • Sternglanz R.
      • Denu J.M.
      Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose.
      ). Other type of enzymatic activities have been reported for each member of the sirtuins family. Overall, SIRT1, SIRT2, SIRT3 and SIRT7 are deacetylases (
      • Bao X.
      • Wang Y.
      • Li X.
      • Li X.-M.
      • Liu Z.
      • Yang T.
      • Wong C.F.
      • Zhang J.
      • Hao Q.
      • Li X.D.
      Identification of “erasers” for lysine crotonylated histone marks using a chemical proteomics approach.
      ,
      • 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.
      ,
      • Chang H.-C.
      • Guarente L.
      SIRT1 and other sirtuins in metabolism.
      ,
      • Donmez G.
      • Outeiro T.F.
      SIRT1 and SIRT2: emerging targets in neurodegeneration.
      ). SIRT4 and SIRT6 has been reported to have deacetylase and ADP-ribosyltransferase functions. SIRT5 has been identified as a deacetylase, desuccinylase and demalonylase (
      • 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.
      ,
      • Nakamura Y.
      • Ogura M.
      • Ogura K.
      • Tanaka D.
      • Inagaki N.
      SIRT5 deacetylates and activates urate oxidase in liver mitochondria of mice.
      ) (Table 1). Besides, different cellular localization, target effectors and physiological function have been evaluated for these proteins (Table 1). SIRT1, SIRT6 and SIRT7 are nuclear enzymes, SIRT2 is localized in cytoplasm, while SIRT3, SIRT4 and SIRT5 are mitochondrial proteins. Based on several studies that assessed the effect of sirtuins family over the last two decades, these proteins have been implicated in the regulation of energy metabolism in a variety of tissues. Among the member of this family, SIRT1 has been detected in important metabolic centers of the brain, liver, pancreas, heart, muscle, and adipose tissue (
      • Lavu S.
      • Boss O.
      • Elliott P.J.
      • Lambert P.D.
      Sirtuins–novel therapeutic targets to treat age-associated diseases.
      ,
      • Ramadori G.
      • Lee C.E.
      • Bookout A.L.
      • Lee S.
      • Williams K.W.
      • Anderson J.
      • Elmquist J.K.
      • Coppari R.
      Brain SIRT1: anatomical distribution and regulation by energy availability.
      ,
      • Yu J.
      • Auwerx J.
      The role of sirtuins in the control of metabolic homeostasis.
      ). Also studies carried out with quantitative RT-PCR in different tissues show the highest expression of SIRT3 in kidney, brain, and heart, followed by liver and testes, with lower expression in lung, ovary, spleen, and thymus (
      • Su A.I.
      • Wiltshire T.
      • Batalov S.
      • Lapp H.
      • Ching K.A.
      • Block D.
      • Zhang J.
      • Soden R.
      • Hayakawa M.
      • Kreiman G.
      • Cooke M.P.
      • Walker J.R.
      • Hogenesch J.B.
      A gene atlas of the mouse and human protein-encoding transcriptomes.
      ,
      • Wu C.
      • Orozco C.
      • Boyer J.
      • Leglise M.
      • Goodale J.
      • Batalov S.
      • Hodge C.L.
      • Haase J.
      • Janes J.
      • Huss 3rd, J.W.
      • Su A.I.
      BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources.
      ).
      Table 1Subcellular localization, enzymatic activity, gene target and function of sirtuins in CNS, immune system (IS), metabolism (Met.) and both metabolism and Immune response.
      NameLocationEnzymatic activityTarget moleculesFunctionReference(s)
      SIRT1NucleusDeacetylaseCNS:ERK1/2, presenilin, BDNF, P53Learning, memory and emotions(
      • Abe-Higuchi N.
      • Uchida S.
      • Yamagata H.
      • Higuchi F.
      • Hobara T.
      • Hara K.
      • Kobayashi A.
      • Watanabe Y.
      Hippocampal Sirtuin 1 signaling mediates depression-like behavior.
      ,
      • Donmez G.
      • Outeiro T.F.
      SIRT1 and SIRT2: emerging targets in neurodegeneration.
      ,
      • Gao J.
      • Wang W.-Y.
      • Mao Y.-W.
      • Graff J.
      • Guan J.-S.
      • Pan L.
      • Mak G.
      • Kim D.
      • Su S.C.
      • Tsai L.-H.
      A novel pathway regulates memory and plasticity via SIRT1 and miR-134.
      ,
      • Herskovits A.Z.
      • Guarente L.
      SIRT1 in neurodevelopment and brain senescence.
      ,
      • Lisachev P.D.
      • Pustylnyak V.O.
      • Shtark M.B.
      Sirt1 Regulates p53 Stability and Expression of Its Target S100B during Long-Term Potentiation in Rat Hippocampus.
      ,
      • Michan S.
      • Li Y.
      • Chou M.M.-H.
      • 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.H.
      • McBurney M.W.
      • Sinclair D.A.
      • Baudry M.
      • de Cabo R.
      • Longo V.D.
      SIRT1 is essential for normal cognitive function and synaptic plasticity.
      ,
      • Zocchi L.
      • Sassone-Corsi P.
      SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression.
      )
      CREB binding protein
      IS:NF- κβ, FOXO3, AP-1Decrease microglia activation in the brain

      Reduce the mRNA level of COX-2
      (
      • Brunet A.
      • Sweeney L.B.
      • Sturgill J.F.
      • Chua K.F.
      • Greer P.L.
      • Lin Y.
      • Tran H.
      • Ross S.E.
      • Mostoslavsky R.
      • Cohen H.Y.
      • Hu L.S.
      • Cheng H.-L.
      • Jedrychowski M.P.
      • Gygi S.P.
      • Sinclair D.A.
      • Alt F.W.
      • Greenberg M.E.
      Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.
      ,
      • Jiang D.-Q.
      • Wang Y.
      • Li M.-X.
      • Ma Y.-J.
      • Wang Y.
      SIRT3 in neural stem cells attenuates microglia activation-induced oxidative stress injury through mitochondrial pathway.
      ,
      • Li L.
      • Sun Q.
      • Li Y.
      • Yang Y.
      • Yang Y.
      • Chang T.
      • Man M.
      • Zheng L.
      Overexpression of SIRT1 induced by resveratrol and inhibitor of miR-204 suppresses activation and proliferation of microglia.
      ,
      • Motta M.C.
      • Divecha N.
      • Lemieux M.
      • Kamel C.
      • Chen D.
      • Gu W.
      • Bultsma Y.
      • McBurney M.
      • Guarente L.
      Mammalian SIRT1 represses forkhead transcription factors.
      ,
      • Pais T.F.
      • Szego E.M.
      • Marques O.
      • Miller-Fleming L.
      • Antas P.
      • Guerreiro P.
      • de Oliveira R.M.
      • Kasapoglu B.
      • Outeiro T.F.
      The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation.
      ,
      • Rangarajan P.
      • Karthikeyan A.
      • Lu J.
      • Ling E.-A.
      • Dheen S.T.
      Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia.
      ,
      • Viswanathan M.
      • Kim S.K.
      • Berdichevsky A.
      • Guarente L.
      A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span.
      ,
      • Yeung F.
      • Hoberg J.E.
      • Ramsey C.S.
      • Keller M.D.
      • Jones D.R.
      • Frye R.A.
      • Mayo M.W.
      Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.
      ,
      • Zhang R.
      • Chen H.-Z.
      • Liu J.-J.
      • Jia Y.-Y.
      • Zhang Z.-Q.
      • Yang R.-F.
      • Zhang Y.
      • Xu J.
      • Wei Y.-S.
      • Liu D.-P.
      • Liang C.-C.
      SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages.
      )
      Met.: CRTC2, FOXO1, PGC-1α, HIF-1α, PGAM-1Gluconeogenesis, glycolysis and insulin secretion(
      • Hallows W.C.
      • Yu W.
      • Denu J.M.
      Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation.
      ,
      • Houtkooper R.H.
      • Pirinen E.
      • Auwerx J.
      Sirtuins as regulators of metabolism and healthspan.
      ,
      • Liu Y.
      • Dentin R.
      • Chen D.
      • Hedrick S.
      • Ravnskjaer K.
      • Schenk S.
      • Milne J.
      • Meyers D.J.
      • Cole P.
      • Yates J.3rd
      • Olefsky J.
      • Guarente L.
      • Montminy M.
      A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.
      ,
      • Wang F.
      • Tong Q.
      SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARgamma.
      )
      SREBP-1 and 2, AMPK, PPARγ, SMRTLipid synthesis(
      • Frescas D.
      • Valenti L.
      • Accili D.
      Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes.
      ,
      • 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.
      • Naar A.M.
      Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.
      ,
      • Wang F.
      • Tong Q.
      SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARgamma.
      )
      IS & Met.: PGC-1α and 1βLipolysis switch toward fatty acid oxidation.(
      • Kelly T.J.
      • Lerin C.
      • Haas W.
      • Gygi S.P.
      • Puigserver P.
      GCN5-mediated transcriptional control of the metabolic coactivator PGC-1beta through lysine acetylation.
      ,
      • Rodgers J.T.
      • Lerin C.
      • Haas W.
      • Gygi S.P.
      • Spiegelman B.M.
      • Puigserver P.
      Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.
      )
      Differentiation of activated CD8+ lymphocytes into memory cells
      SIRT2CytoplasmDeacetylaseCNS: ERK, CREBLearning, memory and emotions(
      • Donmez G.
      • Outeiro T.F.
      SIRT1 and SIRT2: emerging targets in neurodegeneration.
      )
      α-TubulinNeuronal differentiation(
      • Jeong S.-G.
      • Cho G.-W.
      The tubulin deacetylase sirtuin-2 regulates neuronal differentiation through the ERK/CREB signaling pathway.
      )
      IS: NF- κβReduces several cytokines(
      • Pais T.F.
      • Szego E.M.
      • Marques O.
      • Miller-Fleming L.
      • Antas P.
      • Guerreiro P.
      • de Oliveira R.M.
      • Kasapoglu B.
      • Outeiro T.F.
      The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation.
      )
      FOXO3Decrease microglia activation in the brain(
      • Jiang D.-Q.
      • Wang Y.
      • Li M.-X.
      • Ma Y.-J.
      • Wang Y.
      SIRT3 in neural stem cells attenuates microglia activation-induced oxidative stress injury through mitochondrial pathway.
      ,
      • Li L.
      • Sun Q.
      • Li Y.
      • Yang Y.
      • Yang Y.
      • Chang T.
      • Man M.
      • Zheng L.
      Overexpression of SIRT1 induced by resveratrol and inhibitor of miR-204 suppresses activation and proliferation of microglia.
      ,
      • Pais T.F.
      • Szego E.M.
      • Marques O.
      • Miller-Fleming L.
      • Antas P.
      • Guerreiro P.
      • de Oliveira R.M.
      • Kasapoglu B.
      • Outeiro T.F.
      The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation.
      ,
      • Rangarajan P.
      • Karthikeyan A.
      • Lu J.
      • Ling E.-A.
      • Dheen S.T.
      Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia.
      )
      Met.: PEPCK-CGluconeogenesis(
      • 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.
      ,
      • Wang F.
      • Tong Q.
      SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARgamma.
      )
      PPARγInhibition of adipogenesis
      SIRT3MitochondriaDeacetylaseIS: NF- κβ, FOXO3Decrease microglia activation in the brain(
      • Jiang D.-Q.
      • Wang Y.
      • Li M.-X.
      • Ma Y.-J.
      • Wang Y.
      SIRT3 in neural stem cells attenuates microglia activation-induced oxidative stress injury through mitochondrial pathway.
      ,
      • Li L.
      • Sun Q.
      • Li Y.
      • Yang Y.
      • Yang Y.
      • Chang T.
      • Man M.
      • Zheng L.
      Overexpression of SIRT1 induced by resveratrol and inhibitor of miR-204 suppresses activation and proliferation of microglia.
      ,
      • Pais T.F.
      • Szego E.M.
      • Marques O.
      • Miller-Fleming L.
      • Antas P.
      • Guerreiro P.
      • de Oliveira R.M.
      • Kasapoglu B.
      • Outeiro T.F.
      The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation.
      ,
      • Rangarajan P.
      • Karthikeyan A.
      • Lu J.
      • Ling E.-A.
      • Dheen S.T.
      Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia.
      )
      Met.: Subunits of the ETC and ATP synthase

      AceCS2, LCAD, IDH2, GDH
      Modulation of complex I proteins and mitochondrial translation(
      • Ahn B.-H.
      • Kim H.-S.
      • Song S.
      • Lee I.H.
      • Liu J.
      • Vassilopoulos A.
      • Deng C.-X.
      • Finkel T.
      A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis.
      ,
      • Cimen H.
      • Han M.-J.
      • Yang Y.
      • Tong Q.
      • Koc H.
      • Koc E.C.
      Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria.
      ,
      • Law I.K.M.
      • Liu L.
      • Xu A.
      • Lam K.S.L.
      • Vanhoutte P.M.
      • Che C.-M.
      • Leung P.T.Y.
      • Wang Y.
      Identification and characterization of proteins interacting with SIRT1 and SIRT3: implications in the anti-aging and metabolic effects of sirtuins.
      ,
      • Yang Y.
      • Cimen H.
      • Han M.-J.
      • Shi T.
      • Deng J.-H.
      • Koc H.
      • Palacios O.M.
      • Montier L.
      • Bai Y.
      • Tong Q.
      • Koc E.C.
      NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10.
      )
      Influence the Krebs cycle(
      • Cimen H.
      • Han M.-J.
      • Yang Y.
      • Tong Q.
      • Koc H.
      • Koc E.C.
      Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria.
      ,
      • Hallows W.C.
      • Lee S.
      • Denu J.M.
      Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases.
      ,
      • Lombard D.B.
      • Alt F.W.
      • Cheng H.-L.
      • Bunkenborg J.
      • Streeper R.S.
      • Mostoslavsky R.
      • Kim J.
      • Yancopoulos G.
      • Valenzuela D.
      • Murphy A.
      • Yang Y.
      • Chen Y.
      • Hirschey M.D.
      • Bronson R.T.
      • Haigis M.
      • Guarente L.P.
      • Farese R.V.J.
      • Weissman S.
      • Verdin E.
      • Schwer B.
      Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation.
      ,
      • Schlicker C.
      • Gertz M.
      • Papatheodorou P.
      • Kachholz B.
      • Becker C.F.W.
      • Steegborn C.
      Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5.
      ,
      • Schwer B.
      • Eckersdorff M.
      • Li Y.
      • Silva J.C.
      • Fermin D.
      • Kurtev M.V
      • Giallourakis C.
      • Comb M.J.
      • Alt F.W.
      • Lombard D.B.
      Calorie restriction alters mitochondrial protein acetylation.
      )
      IS & Met.:Contribute in an immune response(
      • Finley L.W.S.
      • 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 HIF1alpha destabilization.
      ,
      • 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 R.V.J.
      • Alt F.W.
      • Kahn C.R.
      • Verdin E.
      SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.
      )
      SIRT4MitochondriaADP-ribosyltransferaseMet.:

      GDH
      Insulin secretion in pancreatic β cells(
      • Haigis M.C.
      • Mostoslavsky R.
      • Haigis K.M.
      • Fahie K.
      • Christodoulou D.C.
      • Murphy A.J.
      • Valenzuela D.M.
      • Yancopoulos G.D.
      • Karow M.
      • Blander G.
      • Wolberger C.
      • Prolla T.A.
      • Weindruch R.
      • Alt F.W.
      • Guarente L.
      SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
      )
      DeacetylaseLipid metabolism(
      • Laurent G.
      • de Boer V.C.J.
      • Finley L.W.S.
      • Sweeney M.
      • Lu H.
      • Schug T.T.
      • Cen Y.
      • Jeong S.M.
      • Li X.
      • Sauve A.A.
      • Haigis M.C.
      SIRT4 represses peroxisome proliferator-activated receptor alpha activity to suppress hepatic fat oxidation.
      )
      Krebs cycle(
      • Haigis M.C.
      • Mostoslavsky R.
      • Haigis K.M.
      • Fahie K.
      • Christodoulou D.C.
      • Murphy A.J.
      • Valenzuela D.M.
      • Yancopoulos G.D.
      • Karow M.
      • Blander G.
      • Wolberger C.
      • Prolla T.A.
      • Weindruch R.
      • Alt F.W.
      • Guarente L.
      SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
      )
      SIRT5MitochondriaDeacetylase, Desuccinylase DemalonylaseMet.: CPSIUrea cycle

      Modulation of cytochrome C
      (
      • Nakagawa T.
      • Lomb D.J.
      • Haigis M.C.
      • Guarente L.
      SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle.
      )

      (
      • Huang J.-Y.
      • Hirschey M.D.
      • Shimazu T.
      • Ho L.
      • Verdin E.
      Mitochondrial sirtuins.
      )
      SIRT6NucleusADP-ribosyltransferaseCNS: Oct4, Sox2, NanogNeural Stem cell differentiation(
      • Etchegaray J.-P.
      • Chavez L.
      • Huang Y.
      • Ross K.N.
      • Choi J.
      • Martinez-Pastor B.
      • Walsh R.M.
      • Sommer C.A.
      • Lienhard M.
      • Gladden A.
      • Kugel S.
      • Silberman D.M.
      • Ramaswamy S.
      • Mostoslavsky G.
      • Hochedlinger K.
      • Goren A.
      • Rao A.
      • Mostoslavsky R.
      The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.
      )
      Deacetylase
      IS: NF- κβpromoters of NF-κB target genes(
      • Kawahara T.L.A.
      • Michishita E.
      • Adler A.S.
      • Damian M.
      • Berber E.
      • Lin M.
      • McCord R.A.
      • Ongaigui K.C.L.
      • Boxer L.D.
      • Chang H.Y.
      • Chua K.F.
      SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.
      )
      Met.:
      AKt, IR, IRSLipid homeostasis(
      • Xiao C.
      • Kim H.-S.
      • Lahusen T.
      • Wang R.-H.
      • Xu X.
      • Gavrilova O.
      • Jou W.
      • Gius D.
      • Deng C.-X.
      SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice.
      )
      GLUT1, GLUT4Glucose metabolism, down-regulates glycolysis(
      • Wu M.
      • Seto E.
      • Zhang J.
      E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells.
      )
      SREBP, FOXO3, Srebp2Cholesterol homeostasis(
      • Tao R.
      • Xiong X.
      • DePinho R.A.
      • Deng C.-X.
      • Dong X.C.
      Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6.
      )
      IS & Met.: HIF-1αRegulate the expression of different cytokines(
      • Fang H.-Y.
      • Hughes R.
      • Murdoch C.
      • Coffelt S.B.
      • Biswas S.K.
      • Harris A.L.
      • Johnson R.S.
      • Imityaz H.Z.
      • Simon M.C.
      • Fredlund E.
      • Greten F.R.
      • Rius J.
      • Lewis C.E.
      Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.
      ,
      • Greer S.N.
      • Metcalf J.L.
      • Wang Y.
      • Ohh M.
      The updated biology of hypoxia-inducible factor.
      ,
      • Kohler T.
      • Reizis B.
      • Johnson R.S.
      • Weighardt H.
      • Forster I.
      Influence of hypoxia-inducible factor 1alpha on dendritic cell differentiation and migration.
      ,
      • Zhang W.
      • Petrovic J.-M.
      • Callaghan D.
      • Jones A.
      • Cui H.
      • Howlett C.
      • Stanimirovic D.
      Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures.
      )
      SIRT7NucleusDeacetylaseMet.:Energy metabolism(
      • Ryu D.
      • Jo Y.S.
      • Lo Sasso G.
      • Stein S.
      • Zhang H.
      • Perino A.
      • Lee J.U.
      • Zeviani M.
      • Romand R.
      • Hottiger M.O.
      • Schoonjans K.
      • Auwerx J.
      A SIRT7-dependent acetylation switch of GABPbeta1 controls mitochondrial function.
      ,
      • Shin J.
      • He M.
      • Liu Y.
      • Paredes S.
      • Villanova L.
      • Brown K.
      • Qiu X.
      • Nabavi N.
      • Mohrin M.
      • Wojnoonski K.
      • Li P.
      • Cheng H.-L.
      • Murphy A.J.
      • Valenzuela D.M.
      • Luo H.
      • Kapahi P.
      • Krauss R.
      • Mostoslavsky R.
      • Yancopoulos G.D.
      • Alt F.W.
      • Chua K.F.
      • Chen D.
      SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease.
      ,
      • Yoshizawa T.
      • Karim M.F.
      • Sato Y.
      • Senokuchi T.
      • Miyata K.
      • Fukuda T.
      • Go C.
      • Tasaki M.
      • Uchimura K.
      • Kadomatsu T.
      • Tian Z.
      • Smolka C.
      • Sawa T.
      • Takeya M.
      • Tomizawa K.
      • Ando Y.
      • Araki E.
      • Akaike T.
      • Braun T.
      • Oike Y.
      • Bober E.
      • Yamagata K.
      SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway.
      )
      Hepatic lipid metabolism
      In addition, sirtuins are acting as a mediator in many other biological functions including longevity, learning and memory, circadian rhythm, sleep, DNA repair, stress response, cell survival, telomere and chromatin regulation, cancer metabolism and autophagy (
      • Haigis M.C.
      • Sinclair D.A.
      Mammalian sirtuins: biological insights and disease relevance.
      ,
      • Houtkooper R.H.
      • Pirinen E.
      • Auwerx J.
      Sirtuins as regulators of metabolism and healthspan.
      ,
      • Min S.-W.
      • Sohn P.D.
      • Cho S.-H.
      • Swanson R.A.
      • Gan L.
      Sirtuins in neurodegenerative diseases: an update on potential mechanisms.
      ).

      3. Involvement of sirtuins in physiological and pathological functions

      3.1 Role of sirtuins in central nervous system

      All sirtuins are detected in adult mammalian brains with various RNA and protein expression levels. While SIRT2 is widely expressed throughout the CNS, SIRT4 is only detected in minimal amounts (
      • Sidorova-Darmos E.
      • Wither R.G.
      • Shulyakova N.
      • Fisher C.
      • Ratnam M.
      • Aarts M.
      • Lilge L.
      • Monnier P.P.
      • Eubanks J.H.
      Differential expression of sirtuin family members in the developing, adult, and aged rat brain.
      ). Moreover, the sirtuins protein expression has a distinct distribution in different regions of the adult CNS that may indicate specific role of individual sirtuins in specific brain regions. The highest level of SIRT1 has been observed in the cortex, hippocampus, cerebellum and hypothalamus, and the lowest level in spinal cord and white matter (
      • Ramadori G.
      • Lee C.E.
      • Bookout A.L.
      • Lee S.
      • Williams K.W.
      • Anderson J.
      • Elmquist J.K.
      • Coppari R.
      Brain SIRT1: anatomical distribution and regulation by energy availability.
      ,
      • Sidorova-Darmos E.
      • Wither R.G.
      • Shulyakova N.
      • Fisher C.
      • Ratnam M.
      • Aarts M.
      • Lilge L.
      • Monnier P.P.
      • Eubanks J.H.
      Differential expression of sirtuin family members in the developing, adult, and aged rat brain.
      ). SIRT2 is abundant in hippocampus, striatum, spinal cord, and brain stem, while elevated levels of SIRT5 are revealed in the cerebellum and brain stem (
      • Sidorova-Darmos E.
      • Wither R.G.
      • Shulyakova N.
      • Fisher C.
      • Ratnam M.
      • Aarts M.
      • Lilge L.
      • Monnier P.P.
      • Eubanks J.H.
      Differential expression of sirtuin family members in the developing, adult, and aged rat brain.
      ). Besides, this protein is highly expressed in the cortex of the human brain, especially in layer II (
      • Glorioso C.
      • Oh S.
      • Douillard G.G.
      • Sibille E.
      Brain molecular aging, promotion of neurological disease and modulation by sirtuin 5 longevity gene polymorphism.
      ).
      On the other hand, these proteins have various level of expression in different cell types of CNS. For example SIRT1 is predominantly expressed in neurons (
      • Hisahara S.
      • Chiba S.
      • Matsumoto H.
      • Tanno M.
      • Yagi H.
      • Shimohama S.
      • Sato M.
      • Horio Y.
      Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation.
      ,
      • Ramadori G.
      • Lee C.E.
      • Bookout A.L.
      • Lee S.
      • Williams K.W.
      • Anderson J.
      • Elmquist J.K.
      • Coppari R.
      Brain SIRT1: anatomical distribution and regulation by energy availability.
      ,
      • Sakamoto J.
      • Miura T.
      • Shimamoto K.
      • Horio Y.
      Predominant expression of Sir2alpha, an NAD-dependent histone deacetylase, in the embryonic mouse heart and brain.
      ), while SIRT2 as a cytoplasmic protein has a high expression level in oligodendrocytes and plays a crucial role in myelin sheath formation and the interaction between myelin and axon (
      • 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 alpha-tubulin.
      ,
      • 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.
      ). Oligodendrocytes express SIRT2 primarily and this protein is incorporated into the myelin sheath near paranodal loops (
      • 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 alpha-tubulin.
      ,
      • Werner H.B.
      • Kuhlmann K.
      • Shen S.
      • Uecker M.
      • Schardt A.
      • Dimova K.
      • Orfaniotou F.
      • Dhaunchak A.
      • Brinkmann B.G.
      • Mobius W.
      • Guarente L.
      • Casaccia-Bonnefil P.
      • Jahn O.
      • Nave K.-A.
      Proteolipid protein is required for transport of sirtuin 2 into CNS myelin.
      ). SIRT2 expression promotes process formation and induces myelin gene expression during differentiation of oligodendrocytes in vitro (
      • Ji S.
      • Doucette J.R.
      • Nazarali A.J.
      Sirt2 is a novel in vivo downstream target of Nkx2.2 and enhances oligodendroglial cell differentiation.
      ). Loss of SIRT2 in the peripheral nervous system causes a delay in Schwann cell myelin formation (
      • Beirowski B.
      • Gustin J.
      • Armour S.M.
      • Yamamoto H.
      • Viader A.
      • North B.J.
      • Michan 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.
      ), but its role in CNS myelination remains speculative.
      As a matter of fact, sirtuins have been shown to have distinct roles in the higher-order brain functions including feeding behavior, endocrine regulation, physiological rhythms, and emotion (Fig. 1). These physiological functions have been particularly attributed to the hypothalamic sirtuins. Among all the family members, SIRT1 and SIRT2 are known as mediators in learning, memory and emotions (
      • Donmez G.
      • Outeiro T.F.
      SIRT1 and SIRT2: emerging targets in neurodegeneration.
      ,
      • Herskovits A.Z.
      • Guarente L.
      SIRT1 in neurodevelopment and brain senescence.
      ). It seems that these proteins influence the physiological function through various neurological processes involving in dendritic arborization, synaptic plasticity, and adult neurogenesis. Deletion of SIRT1 could cause deficits in short- and long-term associative memory, and spatial learning (
      • Michan S.
      • Li Y.
      • Chou M.M.-H.
      • 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.H.
      • McBurney M.W.
      • Sinclair D.A.
      • Baudry M.
      • de Cabo R.
      • Longo V.D.
      SIRT1 is essential for normal cognitive function and synaptic plasticity.
      ). This alteration can occur in an ERK1/2-dependent manner (
      • Abe-Higuchi N.
      • Uchida S.
      • Yamagata H.
      • Higuchi F.
      • Hobara T.
      • Hara K.
      • Kobayashi A.
      • Watanabe Y.
      Hippocampal Sirtuin 1 signaling mediates depression-like behavior.
      ,
      • Michan S.
      • Li Y.
      • Chou M.M.-H.
      • 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.H.
      • McBurney M.W.
      • Sinclair D.A.
      • Baudry M.
      • de Cabo R.
      • Longo V.D.
      SIRT1 is essential for normal cognitive function and synaptic plasticity.
      ). It is noteworthy that SIRT1 could increase presenilin (
      • Torres G.
      • Dileo J.N.
      • Hallas B.H.
      • Horowitz J.M.
      • Leheste J.R.
      Silent information regulator 1 mediates hippocampal plasticity through presenilin1.
      ) and brain-derived neurotrophic factor (BDNF) (
      • Zocchi L.
      • Sassone-Corsi P.
      SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression.
      ) expression, regulates p53 stability, and increases the induction of LTP (
      • Lisachev P.D.
      • Pustylnyak V.O.
      • Shtark M.B.
      Sirt1 Regulates p53 Stability and Expression of Its Target S100B during Long-Term Potentiation in Rat Hippocampus.
      ). In addition, it induces the expression of CREB-binding protein-dependent genes (
      • Gao J.
      • Wang W.-Y.
      • Mao Y.-W.
      • Graff J.
      • Guan J.-S.
      • Pan L.
      • Mak G.
      • Kim D.
      • Su S.C.
      • Tsai L.-H.
      A novel pathway regulates memory and plasticity via SIRT1 and miR-134.
      ) through the regulation of microRNAs (
      • van Ham T.J.
      • Thijssen K.L.
      • Breitling R.
      • Hofstra R.M.W.
      • Plasterk R.H.A.
      • Nollen E.A.A.
      C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging.
      ).
      Fig 1
      Fig. 1Different roles of sirtuins in central nervous system, immune system, and metabolism.
      It has been reported that both SIRT1 and SIRT2 can mediate fate decisions of neural stem and/or progenitor cells into oligodendrocytes (
      • Stein L.R.
      • Imai S.
      Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging.
      ). SIRT2 seems to play a positive role in neuronal differentiation and it was reported that SIRT2 promotes neuronal differentiation of mesenchymal stem cells through its tubulin deacetylase activity and stimulation of the extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB) signaling pathway (
      • Jeong S.-G.
      • Cho G.-W.
      The tubulin deacetylase sirtuin-2 regulates neuronal differentiation through the ERK/CREB signaling pathway.
      ). SIRT1, SIRT2, and SIRT3 decrease microglia activation and inflammatory responses (
      • Jiang D.-Q.
      • Wang Y.
      • Li M.-X.
      • Ma Y.-J.
      • Wang Y.
      SIRT3 in neural stem cells attenuates microglia activation-induced oxidative stress injury through mitochondrial pathway.
      ,
      • Li L.
      • Sun Q.
      • Li Y.
      • Yang Y.
      • Yang Y.
      • Chang T.
      • Man M.
      • Zheng L.
      Overexpression of SIRT1 induced by resveratrol and inhibitor of miR-204 suppresses activation and proliferation of microglia.
      ,
      • Pais T.F.
      • Szego E.M.
      • Marques O.
      • Miller-Fleming L.
      • Antas P.
      • Guerreiro P.
      • de Oliveira R.M.
      • Kasapoglu B.
      • Outeiro T.F.
      The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation.
      ). Besides, SIRT6 could affect stem cell differentiation and modulated the expression of core pluripotent genes (Oct4, Sox2, and Nanog) by H3 deacetylation (
      • Etchegaray J.-P.
      • Chavez L.
      • Huang Y.
      • Ross K.N.
      • Choi J.
      • Martinez-Pastor B.
      • Walsh R.M.
      • Sommer C.A.
      • Lienhard M.
      • Gladden A.
      • Kugel S.
      • Silberman D.M.
      • Ramaswamy S.
      • Mostoslavsky G.
      • Hochedlinger K.
      • Goren A.
      • Rao A.
      • Mostoslavsky R.
      The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine.
      ).
      These studies have demonstrated that sirtuins family members play an essential role in maintaining neural health and their alterations may be involved in several neurodegenerative disease pathogenesis including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS) and MS (
      • Fujita Y.
      • Yamashita T.
      Sirtuins in neuroendocrine regulation and neurological diseases.
      ,
      • Szegő É.M.
      • Outeiro T.F.
      • Kazantsev A.G.
      Sirtuins in brain and neurodegenerative disease.
      ,
      • Zhang F.
      • Wang S.
      • Gan L.
      • Vosler P.S.
      • Gao Y.
      • Zigmond M.J.
      • Chen J.
      Protective effects and mechanisms of sirtuins in the nervous system.
      ).

      3.2 Role of sirtuins in immune system

      Sirtuins play a role in the control of immune responses and their effects on inflammation may be considered as a double-edged sword. These proteins appear to exert both pro- and anti-inflammatory roles (Fig. 1). Sirtuins regulate two major pathways, nuclear factor kappa β (NF-κβ) and AP-1, which are involved in the immune responses, both innate and adaptive ones.
      One of the master regulators in immune responses and inflammation is NF-κβ (
      • Hayden M.S.
      • Ghosh S.
      NF-kappaB, the first quarter-century: remarkable progress and outstanding questions.
      ) which can be modulated by sirtuin proteins. Expression of pro-inflammatory genes, such as growth factors, chemokines, and cytokines occurs via activation of NF-κβ (
      • Mattson M.P.
      • Meffert M.K.
      Roles for NF-kappaB in nerve cell survival, plasticity, and disease.
      ). In addition, a decrease in NF-κβ transcription activity happened by deacetylation of NF-κβ subunit p65, consequently, cytokines and anti-apoptotic genes products were reduced (
      • Yeung F.
      • Hoberg J.E.
      • Ramsey C.S.
      • Keller M.D.
      • Jones D.R.
      • Frye R.A.
      • Mayo M.W.
      Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.
      ). This molecule was revealed to be correlated with the synthesis of various cytokines, such as TNF-α, IL-1β, interleukin-6 (IL-6) and interleukin-8 (IL-8) (
      • Di Maggio F.M.
      • Minafra L.
      • Forte G.I.
      • Cammarata F.P.
      • Lio D.
      • Messa C.
      • Gilardi M.C.
      • Bravata V.
      Portrait of inflammatory response to ionizing radiation treatment.
      ,
      • Hoesel B.
      • Schmid J.A.
      The complexity of NF-kappaB signaling in inflammation and cancer.
      ). Physical interaction of SIRT1 with the RelA/p65 subunit of NF- κβ, causes a deacetylation of RelA/p65 at lysine 310 and results in transcription inhibition (
      • Yeung F.
      • Hoberg J.E.
      • Ramsey C.S.
      • Keller M.D.
      • Jones D.R.
      • Frye R.A.
      • Mayo M.W.
      Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.
      ). Furthermore, SIRT2 acts as a deacetylator of the p65 subunit of NF-κβ (
      • Pais T.F.
      • Szego E.M.
      • Marques O.
      • Miller-Fleming L.
      • Antas P.
      • Guerreiro P.
      • de Oliveira R.M.
      • Kasapoglu B.
      • Outeiro T.F.
      The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation.
      ). Studies on cells obtained from SIRT2 knockout mice show hyper-acetylation of p65 and increased expression of NF-κβ-dependent genes induced by TNF. Deacetylation of p65 subunit of NF-κβ by SIRT2 resulted in reduced expression of IL-1β, IL-6, matrix metalloproteinase 9 (MMP-9), MMP-13 and monocyte chemo attractant protein 1 (MCP-1) (
      • Lin J.
      • Sun B.
      • Jiang C.
      • Hong H.
      • Zheng Y.
      Sirt2 suppresses inflammatory responses in collagen-induced arthritis.
      ,
      • Rothgiesser K.M.
      • Erener S.
      • Waibel S.
      • Luscher B.
      • Hottiger M.O.
      SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310.
      ). Moreover, SIRT6 has interaction with the RelA/p65 component of the NF-κB complex which recruits some promoters of NF-κB target genes (
      • Kawahara T.L.A.
      • Michishita E.
      • Adler A.S.
      • Damian M.
      • Berber E.
      • Lin M.
      • McCord R.A.
      • Ongaigui K.C.L.
      • Boxer L.D.
      • Chang H.Y.
      • Chua K.F.
      SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.
      ).
      It is noteworthy that sirtuins may also activate NF- κβ signaling by regulating FOXO proteins. FOXO3 can inhibit the TNFα-induced activation of NF- κβ, and modulate apoptosis (
      • Peng S.L.
      Immune regulation by Foxo transcription factors.
      ). Deacetylation of FOXO proteins via SIRT1 is reported by several studies in different cell types and systems (
      • Brunet A.
      • Sweeney L.B.
      • Sturgill J.F.
      • Chua K.F.
      • Greer P.L.
      • Lin Y.
      • Tran H.
      • Ross S.E.
      • Mostoslavsky R.
      • Cohen H.Y.
      • Hu L.S.
      • Cheng H.-L.
      • Jedrychowski M.P.
      • Gygi S.P.
      • Sinclair D.A.
      • Alt F.W.
      • Greenberg M.E.
      Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.
      ,
      • Motta M.C.
      • Divecha N.
      • Lemieux M.
      • Kamel C.
      • Chen D.
      • Gu W.
      • Bultsma Y.
      • McBurney M.
      • Guarente L.
      Mammalian SIRT1 represses forkhead transcription factors.
      ,
      • Viswanathan M.
      • Kim S.K.
      • Berdichevsky A.
      • Guarente L.
      A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span.
      ). Some other studies showed that SIRT1, SIRT2, and SIRT3 decrease microglia activation, as the innate immune cells of the brain, as well as the inflammatory responses. These responses have been attributed to the inhibition of NF- κβ signaling or FOXO3 activation (
      • Jiang D.-Q.
      • Wang Y.
      • Li M.-X.
      • Ma Y.-J.
      • Wang Y.
      SIRT3 in neural stem cells attenuates microglia activation-induced oxidative stress injury through mitochondrial pathway.
      ,
      • Li L.
      • Sun Q.
      • Li Y.
      • Yang Y.
      • Yang Y.
      • Chang T.
      • Man M.
      • Zheng L.
      Overexpression of SIRT1 induced by resveratrol and inhibitor of miR-204 suppresses activation and proliferation of microglia.
      ,
      • Pais T.F.
      • Szego E.M.
      • Marques O.
      • Miller-Fleming L.
      • Antas P.
      • Guerreiro P.
      • de Oliveira R.M.
      • Kasapoglu B.
      • Outeiro T.F.
      The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation.
      ,
      • Rangarajan P.
      • Karthikeyan A.
      • Lu J.
      • Ling E.-A.
      • Dheen S.T.
      Sirtuin 3 regulates Foxo3a-mediated antioxidant pathway in microglia.
      ).
      In addition to the NF- κβ pathway, evidence demonstrated the interaction between SIRT1 and AP-1 in macrophages (
      • Zhang R.
      • Chen H.-Z.
      • Liu J.-J.
      • Jia Y.-Y.
      • Zhang Z.-Q.
      • Yang R.-F.
      • Zhang Y.
      • Xu J.
      • Wei Y.-S.
      • Liu D.-P.
      • Liang C.-C.
      SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages.
      ). In macrophages, SIRT1 overexpression could reduce the mRNA level of COX-2 as a target gene of AP-1 and reduce the production of prostaglandin E.
      Although recent investigations have revealed that sirtuins are an important regulator of both innate and adaptive immune response (
      • Kong S.
      • McBurney M.W.
      • Fang D.
      Sirtuin 1 in immune regulation and autoimmunity.
      ,
      • Szegő É.M.
      • Outeiro T.F.
      • Kazantsev A.G.
      Sirtuins in brain and neurodegenerative disease.
      ) and alteration in their functions are presumably related to autoimmune diseases, information regarding the mechanisms of their involvement in inflammatory signaling pathways and mechanisms are still insufficient.

      3.3 Role of sirtuins in metabolic regulation

      Several studies have demonstrated that sirtuins regulate the pathways involved in the control of metabolism and calorie restriction (
      • Chang H.-C.
      • Guarente L.
      SIRT1 and other sirtuins in metabolism.
      ,
      • Guarente L.
      Sir2 links chromatin silencing, metabolism, and aging.
      ). As a supporting fact, various proteins which play critical roles in metabolism, such as acetyl coenzyme A synthetase 2 (AceCS2) and PGC-1α are deacylated by sirtuins (
      • Hallows W.C.
      • Lee S.
      • Denu J.M.
      Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases.
      ,
      • Nemoto S.
      • Fergusson M.M.
      • Finkel T.
      SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}.
      ,
      • Rodgers J.T.
      • Lerin C.
      • Haas W.
      • Gygi S.P.
      • Spiegelman B.M.
      • Puigserver P.
      Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.
      ,
      • Schwer B.
      • Bunkenborg J.
      • Verdin R.O.
      • Andersen J.S.
      • Verdin E.
      Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.
      ).
      SIRT1, as the most studied member of this family, mediates metabolic effects in various tissues and cell types including liver, heart, adipose tissue, CNS and the immune cells (
      • Chang H.-C.
      • Guarente L.
      SIRT1 and other sirtuins in metabolism.
      ,
      • Kong S.
      • McBurney M.W.
      • Fang D.
      Sirtuin 1 in immune regulation and autoimmunity.
      ). These proteins have pivotal actions in the maintenance of glucose and lipid homeostasis, control of insulin secretion and sensitivity, the promotion of fat mobilization and the control of oxidative stress (Fig. 1). As a regulator of glucose metabolism, SIRT1 affects several pathways including gluconeogenesis, glycolysis and insulin secretion through influencing several proteins as like as CREB-regulated transcription co-activator 2 (CRTC2) (
      • Liu Y.
      • Dentin R.
      • Chen D.
      • Hedrick S.
      • Ravnskjaer K.
      • Schenk S.
      • Milne J.
      • Meyers D.J.
      • Cole P.
      • Yates J.3rd
      • Olefsky J.
      • Guarente L.
      • Montminy M.
      A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.
      ), FOXO1 and PGC-1α (
      • Wang F.
      • Tong Q.
      SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARgamma.
      ), hypoxia-inducible factor 1α (HIF-1α) (
      • Houtkooper R.H.
      • Pirinen E.
      • Auwerx J.
      Sirtuins as regulators of metabolism and healthspan.
      ) and phosphoglycerate mutase-1(PGAM-1) (
      • Hallows W.C.
      • Yu W.
      • Denu J.M.
      Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation.
      ). It can modulate gluconeogenesis and inhibit the process of glycolysis. On the other hand, SIRT1 is involved in the pathway of lipid synthesis by affecting sterol regulatory element-binding protein-1 (SREBP-1) and SREBP-2 proteins (
      • 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.
      • Naar A.M.
      Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.
      ), AMP-activated protein kinase (AMPK) (
      • Wang F.
      • Tong Q.
      SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARgamma.
      ), lipolysis via PPARγ activity, silencing mediator for retinoid and thyroid hormone receptor (SMRT) (
      • Frescas D.
      • Valenti L.
      • Accili D.
      Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes.
      ), and cholesterol transport.
      Another member of the sirtuins family, SIRT2, mediates gluconeogenesis by affecting the activity of a rate-limiting enzyme in this process, phosphoenolpyruvate carboxykinase (PEPCK-C) (
      • 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.
      ) and by blocking PPARγ can inhibit adipogenesis (
      • Wang F.
      • Tong Q.
      SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARgamma.
      ).
      SIRT3, a major mitochondrial deacetylase, acts as a metabolic sensor responding to the alteration of energy status in the cells. This protein is responsible for epigenetic modulation of complex I proteins in the respiratory chain (
      • Ahn B.-H.
      • Kim H.-S.
      • Song S.
      • Lee I.H.
      • Liu J.
      • Vassilopoulos A.
      • Deng C.-X.
      • Finkel T.
      A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis.
      ,
      • Cimen H.
      • Han M.-J.
      • Yang Y.
      • Tong Q.
      • Koc H.
      • Koc E.C.
      Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria.
      ,
      • Law I.K.M.
      • Liu L.
      • Xu A.
      • Lam K.S.L.
      • Vanhoutte P.M.
      • Che C.-M.
      • Leung P.T.Y.
      • Wang Y.
      Identification and characterization of proteins interacting with SIRT1 and SIRT3: implications in the anti-aging and metabolic effects of sirtuins.
      ), and regulation of mitochondrial translation (
      • Yang Y.
      • Cimen H.
      • Han M.-J.
      • Shi T.
      • Deng J.-H.
      • Koc H.
      • Palacios O.M.
      • Montier L.
      • Bai Y.
      • Tong Q.
      • Koc E.C.
      NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10.
      ).
      SIRT3 can influence the Krebs cycle directly (
      • Cimen H.
      • Han M.-J.
      • Yang Y.
      • Tong Q.
      • Koc H.
      • Koc E.C.
      Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria.
      ,
      • Schlicker C.
      • Gertz M.
      • Papatheodorou P.
      • Kachholz B.
      • Becker C.F.W.
      • Steegborn C.
      Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5.
      ) and indirectly (
      • Hallows W.C.
      • Lee S.
      • Denu J.M.
      Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases.
      ,
      • Lombard D.B.
      • Alt F.W.
      • Cheng H.-L.
      • Bunkenborg J.
      • Streeper R.S.
      • Mostoslavsky R.
      • Kim J.
      • Yancopoulos G.
      • Valenzuela D.
      • Murphy A.
      • Yang Y.
      • Chen Y.
      • Hirschey M.D.
      • Bronson R.T.
      • Haigis M.
      • Guarente L.P.
      • Farese R.V.J.
      • Weissman S.
      • Verdin E.
      • Schwer B.
      Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation.
      ,
      • Schlicker C.
      • Gertz M.
      • Papatheodorou P.
      • Kachholz B.
      • Becker C.F.W.
      • Steegborn C.
      Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5.
      ,
      • Schwer B.
      • Eckersdorff M.
      • Li Y.
      • Silva J.C.
      • Fermin D.
      • Kurtev M.V
      • Giallourakis C.
      • Comb M.J.
      • Alt F.W.
      • Lombard D.B.
      Calorie restriction alters mitochondrial protein acetylation.
      ). It has different acetylation targets that all are involved in metabolic status of cells including AceCS2 (
      • Schwer B.
      • Bunkenborg J.
      • Verdin R.O.
      • Andersen J.S.
      • Verdin E.
      Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.
      ), long-chain acyl CoA dehydrogenase (LCAD) (
      • 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 R.V.J.
      • Alt F.W.
      • Kahn C.R.
      • Verdin E.
      SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.
      ), isocitrate dehydrogenase 2 (IDH2) (
      • Yu W.
      • Dittenhafer-Reed K.E.
      • Denu J.M.
      SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status.
      ) and glutamate dehydrogenase (GDH) (
      • Frescas D.
      • Valenti L.
      • Accili D.
      Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes.
      ).
      It seems that SIRT4 is involved in insulin secretion in pancreatic β cells (
      • Haigis M.C.
      • Mostoslavsky R.
      • Haigis K.M.
      • Fahie K.
      • Christodoulou D.C.
      • Murphy A.J.
      • Valenzuela D.M.
      • Yancopoulos G.D.
      • Karow M.
      • Blander G.
      • Wolberger C.
      • Prolla T.A.
      • Weindruch R.
      • Alt F.W.
      • Guarente L.
      SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
      ) as well as lipid metabolism (
      • Laurent G.
      • de Boer V.C.J.
      • Finley L.W.S.
      • Sweeney M.
      • Lu H.
      • Schug T.T.
      • Cen Y.
      • Jeong S.M.
      • Li X.
      • Sauve A.A.
      • Haigis M.C.
      SIRT4 represses peroxisome proliferator-activated receptor alpha activity to suppress hepatic fat oxidation.
      ) and in the transport of ATP. An indirect role in the Krebs cycle through GDH inhibition by ADP-ribosylation is also suggested (
      • Haigis M.C.
      • Mostoslavsky R.
      • Haigis K.M.
      • Fahie K.
      • Christodoulou D.C.
      • Murphy A.J.
      • Valenzuela D.M.
      • Yancopoulos G.D.
      • Karow M.
      • Blander G.
      • Wolberger C.
      • Prolla T.A.
      • Weindruch R.
      • Alt F.W.
      • Guarente L.
      SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
      ).
      SIRT5 regulates the first and rate-limiting step (carbamoyl phosphate synthetase) of the urea cycle. Also, deacetylation activity of SIRT5 toward the mitochondrial protein, cytochrome C (
      • Huang J.-Y.
      • Hirschey M.D.
      • Shimazu T.
      • Ho L.
      • Verdin E.
      Mitochondrial sirtuins.
      ), plays a central role in oxidative metabolism and apoptosis initiation.
      SIRT6 is reported to regulate lipid homeostasis and glucose metabolism. It was demonstrated that SIRT6 negatively regulates AKT, IR, insulin receptor substrate (IRS), glucose transporter-1 (GLUT1) and GLUT4 that result in the suppression of insulin/IGF-1 like signaling (
      • Xiao C.
      • Kim H.-S.
      • Lahusen T.
      • Wang R.-H.
      • Xu X.
      • Gavrilova O.
      • Jou W.
      • Gius D.
      • Deng C.-X.
      SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice.
      ). SIRT6 also inhibits the expression of several genes that are key modulators in glycolytic pathways and down-regulates glycolysis (
      • Wu M.
      • Seto E.
      • Zhang J.
      E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells.
      ). In the cholesterol homeostasis pathway, SIRT6 can regulate the SREBP and FoxO3 and Srebp2 genes promoter by deacetylation (
      • Tao R.
      • Xiong X.
      • DePinho R.A.
      • Deng C.-X.
      • Dong X.C.
      Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6.
      ).
      Recent studies have shown that the function of SIRT7 is associated with energy metabolism especially in hepatic cells lipid metabolism (
      • Ryu D.
      • Jo Y.S.
      • Lo Sasso G.
      • Stein S.
      • Zhang H.
      • Perino A.
      • Lee J.U.
      • Zeviani M.
      • Romand R.
      • Hottiger M.O.
      • Schoonjans K.
      • Auwerx J.
      A SIRT7-dependent acetylation switch of GABPbeta1 controls mitochondrial function.
      ,
      • Shin J.
      • He M.
      • Liu Y.
      • Paredes S.
      • Villanova L.
      • Brown K.
      • Qiu X.
      • Nabavi N.
      • Mohrin M.
      • Wojnoonski K.
      • Li P.
      • Cheng H.-L.
      • Murphy A.J.
      • Valenzuela D.M.
      • Luo H.
      • Kapahi P.
      • Krauss R.
      • Mostoslavsky R.
      • Yancopoulos G.D.
      • Alt F.W.
      • Chua K.F.
      • Chen D.
      SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease.
      ,
      • Yoshizawa T.
      • Karim M.F.
      • Sato Y.
      • Senokuchi T.
      • Miyata K.
      • Fukuda T.
      • Go C.
      • Tasaki M.
      • Uchimura K.
      • Kadomatsu T.
      • Tian Z.
      • Smolka C.
      • Sawa T.
      • Takeya M.
      • Tomizawa K.
      • Ando Y.
      • Araki E.
      • Akaike T.
      • Braun T.
      • Oike Y.
      • Bober E.
      • Yamagata K.
      SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway.
      ).

      3.4 Sirtuins as a link between metabolism and immune response

      Considering the role of sirtuins in metabolic pathways, their activity is undoubtedly most prominent in immune cells. Changes in the metabolic status of these cells contributes in different facets of inflammation, including pro- or anti-inflammatory pathways (Fig. 1). The important role of cell metabolism in regulating an innate and adaptive immune response have been proven by several studies. These studies suggest a connection of inflammation with glycolysis and fatty acids that provide nutritional needs for immune cells in phase shifts after sensing the stress (
      • Liu T.F.
      • Brown C.M.
      • El Gazzar M.
      • McPhail L.
      • Millet P.
      • Rao A.
      • Vachharajani V.T.
      • Yoza B.K.
      • McCall C.E.
      Fueling the flame: bioenergy couples metabolism and inflammation.
      ). Before T cells activation, ATP is generated by tricarboxylic acid cycle and fatty acid β-oxidation in these cells (
      • Michalek R.D.
      • Gerriets V.A.
      • Jacobs S.R.
      • Macintyre A.N.
      • MacIver N.J.
      • Mason E.F.
      • Sullivan S.A.
      • Nichols A.G.
      • Rathmell J.C.
      Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.
      ,
      • Wang R.
      • Dillon C.P.
      • Shi L.Z.
      • Milasta S.
      • Carter R.
      • Finkelstein D.
      • McCormick L.L.
      • Fitzgerald P.
      • Chi H.
      • Munger J.
      • Green D.R.
      The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.
      ). Whereas after antigen stimulation, T cells markedly increase their glucose uptake and switch to a glycolytic mode. It can result in more intracellular ATP generation. Evidence have shown that pharmacological blockage of glycolysis reduces the differentiation of T cells into effector lymphocytes (
      • Shi L.Z.
      • Wang R.
      • Huang G.
      • Vogel P.
      • Neale G.
      • Green D.R.
      • Chi H.
      HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
      ). Although the reason of this switch is still unclear, some studies suggested that it may be related to the capacity of glycolytic intermediates to fuel anabolic reactions in activated cells (
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      ). In addition, switching to fatty acid oxidation is required for several processes including CD8+ memory T cells differentiation and the resolution/adaptation phase induction of an inflammatory response (
      • Pearce E.L.
      Metabolism in T cell activation and differentiation.
      ). It is reported by some studies that SIRT1 and SIRT6 have the crucial role to link immune cell response to changes in metabolism (
      • Liu T.F.
      • Vachharajani V.T.
      • Yoza B.K.
      • McCall C.E.
      NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response.
      ). Sirt6 has been shown to physically interact with HIF-1α which plays a crucial role in the immune cells by regulating the different pathways. It regulates the expression of different cytokines, such as IL-1β and IL-22 (
      • Fang H.-Y.
      • Hughes R.
      • Murdoch C.
      • Coffelt S.B.
      • Biswas S.K.
      • Harris A.L.
      • Johnson R.S.
      • Imityaz H.Z.
      • Simon M.C.
      • Fredlund E.
      • Greten F.R.
      • Rius J.
      • Lewis C.E.
      Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.
      ,
      • Kohler T.
      • Reizis B.
      • Johnson R.S.
      • Weighardt H.
      • Forster I.
      Influence of hypoxia-inducible factor 1alpha on dendritic cell differentiation and migration.
      ,
      • Zhang W.
      • Petrovic J.-M.
      • Callaghan D.
      • Jones A.
      • Cui H.
      • Howlett C.
      • Stanimirovic D.
      Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures.
      ) and modulates T cells differentiation by targeting FOXO3 transcription factor (
      • Greer S.N.
      • Metcalf J.L.
      • Wang Y.
      • Ohh M.
      The updated biology of hypoxia-inducible factor.
      ). Moreover, SIRT1 mediates deacetylation which results in increased transcriptional activity of PGC-1α and PGC-1β (
      • Kelly T.J.
      • Lerin C.
      • Haas W.
      • Gygi S.P.
      • Puigserver P.
      GCN5-mediated transcriptional control of the metabolic coactivator PGC-1beta through lysine acetylation.
      ,
      • Rodgers J.T.
      • Lerin C.
      • Haas W.
      • Gygi S.P.
      • Spiegelman B.M.
      • Puigserver P.
      Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.
      ). It modulates switch toward fatty acid oxidation, as a determinative phase of inflammatory responses, and the differentiation of activated CD8+ lymphocytes into memory cells (
      • Lunt S.Y.
      • Vander Heiden M.G.
      Aerobic glycolysis: meeting the metabolic requirements of cell proliferation.
      ). Also mitochondrial SIRT3, as an important metabolism mediator, contributes to the immune response via recovering of oxidative metabolism during the resolution/memory phase (
      • Finley L.W.S.
      • 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 HIF1alpha destabilization.
      ,
      • 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 R.V.J.
      • Alt F.W.
      • Kahn C.R.
      • Verdin E.
      SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.
      ).

      4. Sirtuins in Multiple Sclerosis

      Although a notable number of studies have focused on sirtuins functions in health and diseases, the relevance of sirtuins in MS is not clear. Most of the studies just indicated a possible role for SIRT1 while the role of other members of this family needs more consideration. We just summarize the available reports on sirtuins and MS related studies.

      4.1 Sirtuin-1

      Related to MS disease, SIRT1 is the most investigated member of this family in different animal models including experimental autoimmune encephalomyelitis (EAE), cuprizone fed animals, and in samples obtained from individuals suffering from MS (Table 2). EAE is one of the best available animal models for MS. There are some contradictory results about SIRT1 activation in this model; some studies have reported the protective function of SIRT1 in the EAE mice. Shindler and colleagues demonstrated that treating with SIRT1 activators, SRT501 and SRT647, reduced retinal ganglion cells death in optic neuritis following induction relapsing-remitting EAE. Besides, sirtinol as a SIRT1 inhibitor could block this neuroprotective effect (
      • Shindler K.S.
      • Ventura E.
      • Rex T.S.
      • Elliott P.
      • Rostami A.
      SIRT1 activation confers neuroprotection in experimental optic neuritis.
      ). In 2010, Shindler and colleagues continued their work and showed that SRT501 preserved the axons in the spinal cord (
      • Shindler K.S.
      • Ventura E.
      • Dutt M.
      • Elliott P.
      • Fitzgerald D.C.
      • Rostami A.
      Oral resveratrol reduces neuronal damage in a model of multiple sclerosis.
      ). In addition, genetically overexpression of SIRT1 in EAE mice had similar effects. Suppressed EAE symptoms compared to wild-type EAE mice have been shown in EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide in transgenic mice with neuron-specific overexpression of SIRT1 (
      • Nimmagadda V.K.
      • Bever C.T.
      • Vattikunta N.R.
      • Talat S.
      • Ahmad V.
      • Nagalla N.K.
      • Trisler D.
      • Judge S.I.V
      • Royal W.3rd
      • Chandrasekaran K.
      • Russell J.W.
      • Makar T.K.
      Overexpression of SIRT1 protein in neurons protects against experimental autoimmune encephalomyelitis through activation of multiple SIRT1 targets.
      ).
      Table 2The role of sirtuins in human pathologies or animal models of MS.
      NameHuman/MouseManipulationMain findingsReference(s)
      SIRT1EAE mouseSRT501 and SRT647 (SIRT1 activators)Reduction of retinal ganglion cell death in optic neuritis(
      • Shindler K.S.
      • Ventura E.
      • Rex T.S.
      • Elliott P.
      • Rostami A.
      SIRT1 activation confers neuroprotection in experimental optic neuritis.
      )
      EAE mouseSRT501Preservation of axonal density in the spinal cord(
      • Shindler K.S.
      • Ventura E.
      • Dutt M.
      • Elliott P.
      • Fitzgerald D.C.
      • Rostami A.
      Oral resveratrol reduces neuronal damage in a model of multiple sclerosis.
      )
      EAE mouseGenetically SIRT1 overexpressionSuppression of EAE symptoms(
      • Nimmagadda V.K.
      • Bever C.T.
      • Vattikunta N.R.
      • Talat S.
      • Ahmad V.
      • Nagalla N.K.
      • Trisler D.
      • Judge S.I.V
      • Royal W.3rd
      • Chandrasekaran K.
      • Russell J.W.
      • Makar T.K.
      Overexpression of SIRT1 protein in neurons protects against experimental autoimmune encephalomyelitis through activation of multiple SIRT1 targets.
      )
      EAE mouseIntravitreal overexpression of SIRT1Neuroprotection of visual function and RGC survival(
      • McDougald D.S.
      • Dine K.E.
      • Zezulin A.U.
      • Bennett J.
      • Shindler K.S.
      SIRT1 and NRF2 gene transfer mediate distinct neuroprotective effects upon retinal ganglion cell survival and function in experimental optic neuritis.
      )
      EAE mouseIncrease of SIRT1 expression in GFAP-positive cells around inflammatory lesions(
      • Prozorovski T.
      • Schulze-Topphoff U.
      • Glumm R.
      • Baumgart J.
      • Schroter F.
      • Ninnemann O.
      • Siegert E.
      • Bendix I.
      • Brustle O.
      • Nitsch R.
      • Zipp F.
      • Aktas O.
      Sirt1 contributes critically to the redox-dependent fate of neural progenitors.
      )
      C57BL/6 miceResveratrol (SIRT1 activator)Suppression of proliferation in NPCs-differentiation toward astrocyte(
      • Prozorovski T.
      • Schulze-Topphoff U.
      • Glumm R.
      • Baumgart J.
      • Schroter F.
      • Ninnemann O.
      • Siegert E.
      • Bendix I.
      • Brustle O.
      • Nitsch R.
      • Zipp F.
      • Aktas O.
      Sirt1 contributes critically to the redox-dependent fate of neural progenitors.
      )
      C57BL/6 miceKnockout of SIRT1Elevated level in OPCs generation(
      • Rafalski V.A.
      • Ho P.P.
      • Brett J.O.
      • Ucar D.
      • Dugas J.C.
      • Pollina E.A.
      • Chow L.M.L.
      • Ibrahim A.
      • Baker S.J.
      • Barres B.A.
      • Steinman L.
      • Brunet A.
      Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain.
      )
      EAE mouseEx-527 (SIRT1 inhibitor)Induction of remyelination, delay in paralysis onset, inhibition of pro-inflammatory Th17 cells and reduction of infiltration of immune cells into the spinal cord(
      • Lim H.W.
      • Kang S.G.
      • Ryu J.K.
      • Schilling B.
      • Fei M.
      • Lee I.S.
      • Kehasse A.
      • Shirakawa K.
      • Yokoyama M.
      • Schnolzer M.
      • Kasler H.G.
      • Kwon H.-S.
      • Gibson B.W.
      • Sato H.
      • Akassoglou K.
      • Xiao C.
      • Littman D.R.
      • Ott M.
      • Verdin E.
      SIRT1 deacetylates RORgammat and enhances Th17 cell generation.
      )
      EAE mouseIncrease in level of transcription of SIRT1 in the CNS during chronic disease stages(
      • Prozorovski T.
      • Ingwersen J.
      • Lukas D.
      • Gottle P.
      • Koop B.
      • Graf J.
      • Schneider R.
      • Franke K.
      • Schumacher S.
      • Britsch S.
      • Hartung H.-P.
      • Kury P.
      • Berndt C.
      • Aktas O.
      Regulation of sirtuin expression in autoimmune neuroinflammation: induction of SIRT1 in oligodendrocyte progenitor cells.
      )
      Upregulated level of SIRT1 in nuclei of NG2+ or PDGFRα+ OPCs in demyelinated brain lesions.
      Ex527 (SIRT1 inhibitor)Expansion of the endogenous pool of OPCs without affecting their differentiation
      Human-MSDecrease of SIRT1 expression in PBMCs in Relapse phase(
      • Ciriello J.
      • Tatomir A.
      • Hewes D.
      • Boodhoo D.
      • Anselmo F.
      • Rus V.
      • Rus H.
      Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis.
      ,
      • Hewes D.
      • Tatomir A.
      • Kruszewski A.M.
      • Rao G.
      • Tegla C.A.
      • Ciriello J.
      • Nguyen V.
      • Royal W.3rd
      • Bever C.
      • Rus V.
      • Rus H.
      SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis.
      ,
      • Tegla C.A.
      • Azimzadeh P.
      • Andrian-Albescu M.
      • Martin A.
      • Cudrici C.D.
      • Trippe R.3rd
      • Sugarman A.
      • Chen H.
      • Boodhoo D.
      • Vlaicu S.I.
      • Royal W.3rd
      • Bever C.
      • Rus V.
      • Rus H.
      SIRT1 is decreased during relapses in patients with multiple sclerosis.
      )
      Human-MSIncrease of SIRT1 expression in acute and chronic lesion sites(
      • Tegla C.A.
      • Azimzadeh P.
      • Andrian-Albescu M.
      • Martin A.
      • Cudrici C.D.
      • Trippe R.3rd
      • Sugarman A.
      • Chen H.
      • Boodhoo D.
      • Vlaicu S.I.
      • Royal W.3rd
      • Bever C.
      • Rus V.
      • Rus H.
      SIRT1 is decreased during relapses in patients with multiple sclerosis.
      )
      Human-MSIncrease of SIRT1 level in plasma samples(
      • Pennisi G.
      • Cornelius C.
      • Cavallaro M.M.
      • Salinaro A.T.
      • Cambria M.T.
      • Pennisi M.
      • Bella R.
      • Milone P.
      • Ventimiglia B.
      • Migliore M.R.
      • Di Renzo L
      • De Lorenzo A.
      • Calabrese V.
      Redox regulation of cellular stress response in multiple sclerosis.
      )
      SIRT2Wistar ratsRNA knockdown of SIRT2Increase of tubulin acetylation, MBP expression, and cell arbor complexity of OPCs(
      • 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 alpha-tubulin.
      )
      Human-MSPresence of antibodies against SIRT2 in the CSF(
      • Lovato L.
      • Cianti R.
      • Gini B.
      • Marconi S.
      • Bianchi L.
      • Armini A.
      • Anghileri E.
      • Locatelli F.
      • Paoletti F.
      • Franciotta D.
      • Bini L.
      • Bonetti B.
      Transketolase and 2’,3’-cyclic-nucleotide 3’-phosphodiesterase type I isoforms are specifically recognized by IgG autoantibodies in multiple sclerosis patients.
      )
      EAE mouseDecrease in the level of SIRT2(
      • Jastorff A.M.
      • Haegler K.
      • Maccarrone G.
      • Holsboer F.
      • Weber F.
      • Ziemssen T.
      • Turck C.W.
      Regulation of proteins mediating neurodegeneration in experimental autoimmune encephalomyelitis and multiple sclerosis.
      )
      EAE mouseIncrease in level of transcription of SIRT2 in the CNS during chronic disease stages(
      • Prozorovski T.
      • Ingwersen J.
      • Lukas D.
      • Gottle P.
      • Koop B.
      • Graf J.
      • Schneider R.
      • Franke K.
      • Schumacher S.
      • Britsch S.
      • Hartung H.-P.
      • Kury P.
      • Berndt C.
      • Aktas O.
      Regulation of sirtuin expression in autoimmune neuroinflammation: induction of SIRT1 in oligodendrocyte progenitor cells.
      )
      Human-MSDecrease in level of several isoform of SIRT2 in MS lesions(
      • Jastorff A.M.
      • Haegler K.
      • Maccarrone G.
      • Holsboer F.
      • Weber F.
      • Ziemssen T.
      • Turck C.W.
      Regulation of proteins mediating neurodegeneration in experimental autoimmune encephalomyelitis and multiple sclerosis.
      )
      SIRT3Human-MSReduction in the level of SIRT3 expression in MS affected brain(
      • Rice C.M.
      • Sun M.
      • Kemp K.
      • Gray E.
      • Wilkins A.
      • Scolding N.J.
      Mitochondrial sirtuins–a new therapeutic target for repair and protection in multiple sclerosis.
      )
      SIRT4Human-MSChange in genetic variants(
      • Inkster B.
      • Strijbis E.M.M.
      • Vounou M.
      • Kappos L.
      • Radue E.-W.
      • Matthews P.M.
      • Uitdehaag B.M.J.
      • Barkhof F.
      • Polman C.H.
      • Montana G.
      • Geurts J.J.G.
      Histone deacetylase gene variants predict brain volume changes in multiple sclerosis.
      )
      SIRT5Human-MSChange in genetic variants(
      • Inkster B.
      • Strijbis E.M.M.
      • Vounou M.
      • Kappos L.
      • Radue E.-W.
      • Matthews P.M.
      • Uitdehaag B.M.J.
      • Barkhof F.
      • Polman C.H.
      • Montana G.
      • Geurts J.J.G.
      Histone deacetylase gene variants predict brain volume changes in multiple sclerosis.
      )
      SIRT6EAE mouseIncrease in level of transcription of SIRT6 in the CNS during chronic disease stages(
      • Prozorovski T.
      • Ingwersen J.
      • Lukas D.
      • Gottle P.
      • Koop B.
      • Graf J.
      • Schneider R.
      • Franke K.
      • Schumacher S.
      • Britsch S.
      • Hartung H.-P.
      • Kury P.
      • Berndt C.
      • Aktas O.
      Regulation of sirtuin expression in autoimmune neuroinflammation: induction of SIRT1 in oligodendrocyte progenitor cells.
      )
      SIRT7EAE mouseSIRT7 knockoutDecrease in cell differentiation and increase in cytokine production(
      • Burg N.
      • Bittner S.
      • Ellwardt E.
      Role of the epigenetic factor Sirt7 in neuroinflammation and neurogenesis.
      )
      As neuroprotective agents, simultaneous overexpression of NRF2 or SIRT1 within RGCs could prevent impairment of visual function and induced RGCs survival in EAE mice (
      • McDougald D.S.
      • Dine K.E.
      • Zezulin A.U.
      • Bennett J.
      • Shindler K.S.
      SIRT1 and NRF2 gene transfer mediate distinct neuroprotective effects upon retinal ganglion cell survival and function in experimental optic neuritis.
      ). Also, similar protective effects were reported in chronic EAE in C57BL/6 mice and in a virus-induced CNS demyelination model (
      • Fonseca-Kelly Z.
      • Nassrallah M.
      • Uribe J.
      • Khan R.S.
      • Dine K.
      • Dutt M.
      • Shindler K.S.
      Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis.
      ,
      • Khan R.S.
      • Dine K.
      • Das Sarma J.
      • Shindler K.S.
      SIRT1 activating compounds reduce oxidative stress mediated neuronal loss in viral induced CNS demyelinating disease.
      ).
      On the other hand, other studies have reported opposite effects for SIRT1. SIRT1 expression was increased in GFAP-positive cells around the EAE lesions, and also the induction of mild activation of SIRT1 using resveratrol, caused suppression of neuronal progenitor cells (NPCs) proliferation and leading to their differentiation into astrocytes (
      • Prozorovski T.
      • Schulze-Topphoff U.
      • Glumm R.
      • Baumgart J.
      • Schroter F.
      • Ninnemann O.
      • Siegert E.
      • Bendix I.
      • Brustle O.
      • Nitsch R.
      • Zipp F.
      • Aktas O.
      Sirt1 contributes critically to the redox-dependent fate of neural progenitors.
      ). The elevated level in the generation of oligodendrocyte progenitor cells (OPCs) was also reported in NPC-specific knockout of SIRT1 in mice (
      • Rafalski V.A.
      • Ho P.P.
      • Brett J.O.
      • Ucar D.
      • Dugas J.C.
      • Pollina E.A.
      • Chow L.M.L.
      • Ibrahim A.
      • Baker S.J.
      • Barres B.A.
      • Steinman L.
      • Brunet A.
      Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain.
      ). Furthermore, several studies have shown that SIRT1 inhibition leads to improvement of clinical scores in EAE. Lim and colleagues reported that inactivation of SIRT1 induced remyelination and caused a delay in paralysis onset in chronic EAE model. In addition, production of pro-inflammatory T helper 17 (Th17) cells was inhibited in SIRT1 knockout mice and EAE clinical scores were ameliorated in a Th17 cell-mediated autoimmune disease. Pharmacological inhibition of SIRT1 could prove these data since using Ex-527 reduced infiltration of immune cells into the spinal cord and reduced EAE scores. SIRT1 can physically interact with transcription factor RAR-related orphan receptor ɣ-t (RORɣt) as a regulator in Th17 cells and induces Th17 cells differentiation through deacetylation of RORɣt (
      • Lim H.W.
      • Kang S.G.
      • Ryu J.K.
      • Schilling B.
      • Fei M.
      • Lee I.S.
      • Kehasse A.
      • Shirakawa K.
      • Yokoyama M.
      • Schnolzer M.
      • Kasler H.G.
      • Kwon H.-S.
      • Gibson B.W.
      • Sato H.
      • Akassoglou K.
      • Xiao C.
      • Littman D.R.
      • Ott M.
      • Verdin E.
      SIRT1 deacetylates RORgammat and enhances Th17 cell generation.
      ). Prozorovski and colleagues in a recent study demonstrated that transcription of SIRT1, SIRT2 and SIRT6 is significantly increased in the CNS during chronic disease stages in EAE mice. Also, they showed upregulated levels of SIRT1 in nuclei of NG2+ or PDGFRα+ OPCs in demyelinated brain lesions. Their data using Ex527 suggest that SIRT1 inhibition may help to expand the endogenous pool of OPCs without affecting their differentiation (
      • Prozorovski T.
      • Ingwersen J.
      • Lukas D.
      • Gottle P.
      • Koop B.
      • Graf J.
      • Schneider R.
      • Franke K.
      • Schumacher S.
      • Britsch S.
      • Hartung H.-P.
      • Kury P.
      • Berndt C.
      • Aktas O.
      Regulation of sirtuin expression in autoimmune neuroinflammation: induction of SIRT1 in oligodendrocyte progenitor cells.
      ).
      In addition to the studies that directly targeted SIRT1 and assessed the role of this protein in animal models of MS, there are numerous investigations that used disease protective agents and measured SIRT1 level. The effects of some of these protective drugs have been attributed to SIRT1 alterations. In this way, Singh and colleagues used lovastatin as an inhibitor of RhoA and AICAR as mediators for activation of AMPK and reported enhanced expression of the transcription of SIRT1 and attenuated EAE scores at the same time (
      • Singh I.
      • Samuvel D.J.
      • Choi S.
      • Saxena N.
      • Singh A.K.
      • Won J.
      Combination therapy of lovastatin and AMP-activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model.
      ). Another report studied a cuprizone-induced demyelination model and reveal the neuroprotective effect of linagliptin on behavioral dysfunction in mice, and the modulatory role of AMPK/SIRT1 signaling pathway in this effect was demonstrated (
      • Elbaz E.M.
      • Senousy M.A.
      • El-Tanbouly D.M.
      • Sayed R.H.
      Neuroprotective effect of linagliptin against cuprizone-induced demyelination and behavioural dysfunction in mice: a pivotal role of AMPK/SIRT1 and JAK2/STAT3/NF-kappaB signalling pathway modulation.
      ). Moreover, AMPK/SIRT1 signaling pathway could be targeted by NAD+ inhibitor, methylene blue, and Adiponectin treatment, and resulted in the modulation of Th1/Th17 immune responses in EAE models (
      • Wang J.
      • Zhao C.
      • Kong P.
      • Sun H.
      • Sun Z.
      • Bian G.
      • Sun Y.
      • Guo L.
      Treatment with NAD(+) inhibited experimental autoimmune encephalomyelitis by activating AMPK/SIRT1 signaling pathway and modulating Th1/Th17 immune responses in mice.
      ,
      • Wang J.
      • Zhao C.
      • Kong P.
      • Bian G.
      • Sun Z.
      • Sun Y.
      • Guo L.
      • Li B.
      Methylene blue alleviates experimental autoimmune encephalomyelitis by modulating AMPK/SIRT1 signaling pathway and Th17/Treg immune response.
      ,
      • Zhang K.
      • Guo Y.
      • Ge Z.
      • Zhang Z.
      • Da Y.
      • Li W.
      • Zhang Z.
      • Xue Z.
      • Li Y.
      • Ren Y.
      • Jia L.
      • Chan K.-H.
      • Yang F.
      • Yan J.
      • Yao Z.
      • Xu A.
      • Zhang R.
      Adiponectin suppresses T Helper 17 cell differentiation and limits autoimmune CNS inflammation via the SIRT1/PPARgamma/RORgammat pathway.
      ).
      Peripheral blood mononuclear cells (PBMCs) have been an important target for studies. Several studies demonstrated SIRT1 as a biomarker and reported that expression of this molecule in PBMCs obtained from MS patients in the relapse phase was decreased compared to healthy controls and patient with stable MS (
      • Ciriello J.
      • Tatomir A.
      • Hewes D.
      • Boodhoo D.
      • Anselmo F.
      • Rus V.
      • Rus H.
      Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis.
      ,
      • Hewes D.
      • Tatomir A.
      • Kruszewski A.M.
      • Rao G.
      • Tegla C.A.
      • Ciriello J.
      • Nguyen V.
      • Royal W.3rd
      • Bever C.
      • Rus V.
      • Rus H.
      SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis.
      ,
      • Tegla C.A.
      • Azimzadeh P.
      • Andrian-Albescu M.
      • Martin A.
      • Cudrici C.D.
      • Trippe R.3rd
      • Sugarman A.
      • Chen H.
      • Boodhoo D.
      • Vlaicu S.I.
      • Royal W.3rd
      • Bever C.
      • Rus V.
      • Rus H.
      SIRT1 is decreased during relapses in patients with multiple sclerosis.
      ). Tegla and colleagues also showed the elevated expression of SIRT1 in acute and chronic lesion sites when compared to normal brain tissue. The expression of this protein is rarely detected in healthy brain samples. Besides, SIRT1 protein in MS plaques co-localize with CD4+ and CD8+ inflammatory cells, oligodendrocytes, and GFAP-positive astrocytes (
      • Tegla C.A.
      • Azimzadeh P.
      • Andrian-Albescu M.
      • Martin A.
      • Cudrici C.D.
      • Trippe R.3rd
      • Sugarman A.
      • Chen H.
      • Boodhoo D.
      • Vlaicu S.I.
      • Royal W.3rd
      • Bever C.
      • Rus V.
      • Rus H.
      SIRT1 is decreased during relapses in patients with multiple sclerosis.
      ). A study by Pennisi et al. in 2011 reported an increase in SIRT1 plasma levels in MS patients when compared with healthy plasma samples (
      • Pennisi G.
      • Cornelius C.
      • Cavallaro M.M.
      • Salinaro A.T.
      • Cambria M.T.
      • Pennisi M.
      • Bella R.
      • Milone P.
      • Ventimiglia B.
      • Migliore M.R.
      • Di Renzo L
      • De Lorenzo A.
      • Calabrese V.
      Redox regulation of cellular stress response in multiple sclerosis.
      ). One of the rational approaches for investigating the effect of candidate drugs on MS is their effectiveness on PBMCs inflammatory response, isolated from MS patients. Some of these experiments explained a link between the beneficial effect of the treatments and the modulation of SIRT1 expression (
      • Emamgholipour S.
      • Hossein-Nezhad A.
      • Sahraian M.A.
      • Askarisadr F.
      • Ansari M.
      Evidence for possible role of melatonin in reducing oxidative stress in multiple sclerosis through its effect on SIRT1 and antioxidant enzymes.
      ).
      Altogether, the review of the evidence shows the importance of SIRT1 in health and MS disease. This protein acts as a key regulator in normal brain function, immune system and metabolism. Some studies revealed the neuroprotective effects of this protein on MS animal models, whereas in other experiments neuroprotection were showed following SIRT1 inhibition. Besides, alteration of this protein in plasma samples, PBMC and lesion sites of MS patient confirm the role of SIRT1 in MS disease. So based on all these findings, SIRT1 may serve as a potential target for the treatment as well as a biomarker for MS.

      4.2 Sirtuin-2

      As mentioned in the aforementioned sections, SIRT2 plays an important role in oligodendrocyte differentiation, formation of myelin sheath, and the interaction of myelin and axons. SIRT2 protein exerts this effects by promoting both arborization and the expression of myelin-specific genes (Table 2). In 2007 Li et al. investigated an interfering RNA mediated knockdown of SIRT2 and showed increased tubulin acetylation, myelin basic protein expression, and cell arbor complexity of OPCs, whereas SIRT2 overexpression had the opposite effects, and counteracted the cell arborization. SIRT2 mutation caused a reduction in its deacetylase action and its effect on OPCs arborization (
      • 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 alpha-tubulin.
      ). Studying of human cerebrospinal fluid (CSF) in patients suffering from MS and healthy control individuals showed that antibodies against SIRT2 were present in the CSF of more than 44% of patients with MS but not in control CSF (
      • Lovato L.
      • Cianti R.
      • Gini B.
      • Marconi S.
      • Bianchi L.
      • Armini A.
      • Anghileri E.
      • Locatelli F.
      • Paoletti F.
      • Franciotta D.
      • Bini L.
      • Bonetti B.
      Transketolase and 2’,3’-cyclic-nucleotide 3’-phosphodiesterase type I isoforms are specifically recognized by IgG autoantibodies in multiple sclerosis patients.
      ). Another experiment in 2009 showed a diminished level of SIRT2 in EAE animals. In addition, they reported in post-mortem tissue that the level of several isoforms of SIRT2 in MS lesion was decreased when compared with normal appearing white matter (non-affected white matter) in MS patient and/or healthy controls (
      • Jastorff A.M.
      • Haegler K.
      • Maccarrone G.
      • Holsboer F.
      • Weber F.
      • Ziemssen T.
      • Turck C.W.
      Regulation of proteins mediating neurodegeneration in experimental autoimmune encephalomyelitis and multiple sclerosis.
      ). Some effective treatments on chronic EAE could enhance SIRT2 expression and other agents leading to ameliorating neurological function as determined by diminished clinical signs, protection of axonal integrity, induction of oligodendrocyte maturation and repopulation of neurons (
      • Li X.
      • Zhang Y.
      • Yan Y.
      • Ciric B.
      • Ma C.-G.
      • Chin J.
      • Curtis M.
      • Rostami A.
      • Zhang G.-X.
      LINGO-1-Fc-transduced neural stem cells are effective therapy for chronic stage experimental autoimmune encephalomyelitis.
      ).

      4.3 Sirtuin-3, 4 and 5

      Three sirtuins (SIRT3, SIRT4, and SIRT5) are known as mitochondrial sirtuins because they are located primarily within the mitochondria. Unlike SIRT1 and SIRT2, they have not been extensively studied in MS, but are thought to have important roles in energy production, cell signaling, and apoptosis (
      • Verdin E.
      • Hirschey M.D.
      • Finley L.W.S.
      • Haigis M.C.
      Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling.
      ). Evidence is beginning to describe a role for mitochondrial sirtuins in protection against oxidative stress and excitotoxicity, although the mechanisms underlying these effects have not yet been clearly understood (Table 2) (
      • Zhang F.
      • Wang S.
      • Gan L.
      • Vosler P.S.
      • Gao Y.
      • Zigmond M.J.
      • Chen J.
      Protective effects and mechanisms of sirtuins in the nervous system.
      ).
      In 2012, Rice et al. studied the role of mitochondrial sirtuins. They focused on these proteins as a new therapeutic target for repair and protection in MS. They performed immunohistochemistry studies on post-mortem human brain tissues that showed reduced levels of SIRT3 expression in MS affected brains compared to control samples (
      • Rice C.M.
      • Sun M.
      • Kemp K.
      • Gray E.
      • Wilkins A.
      • Scolding N.J.
      Mitochondrial sirtuins–a new therapeutic target for repair and protection in multiple sclerosis.
      ). Furthermore, Inkster and colleagues carried out a neuroimaging study on the brains of MS patients (
      • Inkster B.
      • Strijbis E.M.M.
      • Vounou M.
      • Kappos L.
      • Radue E.-W.
      • Matthews P.M.
      • Uitdehaag B.M.J.
      • Barkhof F.
      • Polman C.H.
      • Montana G.
      • Geurts J.J.G.
      Histone deacetylase gene variants predict brain volume changes in multiple sclerosis.
      ). They evaluated the predictive value of single nucleotide polymorphisms (SNPs) with several brain volumetric- and lesion-related measures in MS affected brains by advanced multivariate regression methods.
      Their SIRT4 and SIRT5 findings were interestingly consistent with the literature showing that MS is associated with mitochondrial dysfunction (
      • Inkster B.
      • Strijbis E.M.M.
      • Vounou M.
      • Kappos L.
      • Radue E.-W.
      • Matthews P.M.
      • Uitdehaag B.M.J.
      • Barkhof F.
      • Polman C.H.
      • Montana G.
      • Geurts J.J.G.
      Histone deacetylase gene variants predict brain volume changes in multiple sclerosis.
      ). SIRT4 contributed in the downregulation of GDH (
      • Haigis M.C.
      • Mostoslavsky R.
      • Haigis K.M.
      • Fahie K.
      • Christodoulou D.C.
      • Murphy A.J.
      • Valenzuela D.M.
      • Yancopoulos G.D.
      • Karow M.
      • Blander G.
      • Wolberger C.
      • Prolla T.A.
      • Weindruch R.
      • Alt F.W.
      • Guarente L.
      SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
      ), which reduced glutamate catabolism leading to increased glutamate levels. Several studies showed that MS has been linked with abnormal glutamate metabolism, excitotoxicity, and gene variants (
      • Baranzini S.E.
      • Srinivasan R.
      • Khankhanian P.
      • Okuda D.T.
      • Nelson S.J.
      • Matthews P.M.
      • Hauser S.L.
      • Oksenberg J.R.
      • Pelletier D.
      Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis.
      ,
      • Baranzini S.E.
      • Galwey N.W.
      • Wang J.
      • Khankhanian P.
      • Lindberg R.
      • Pelletier D.
      • Wu W.
      • Uitdehaag B.M.J.
      • Kappos L.
      • Polman C.H.
      • Matthews P.M.
      • Hauser S.L.
      • Gibson R.A.
      • Oksenberg J.R.
      • Barnes M.R.
      Pathway and network-based analysis of genome-wide association studies in multiple sclerosis.
      ,
      • Geurts J.J.G.
      • Wolswijk G.
      • Bo L.
      • Redeker S.
      • Ramkema M.
      • Troost D.
      • Aronica E.
      Expression patterns of Group III metabotropic glutamate receptors mGluR4 and mGluR8 in multiple sclerosis lesions.
      ,
      • Geurts J.J.G.
      • Wolswijk G.
      • Bo L.
      • van der Valk P.
      • Polman C.H.
      • Troost D.
      • Aronica E.
      Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis.
      ,
      • Matute C.
      • Alberdi E.
      • Domercq M.
      • Perez-Cerda F.
      • Perez-Samartin A.
      • Sanchez-Gomez M.V
      The link between excitotoxic oligodendroglial death and demyelinating diseases.
      ). Besides, the absence of GDH expression in MS lesions was shown in postmortems, results were unlike the healthy control subjects (
      • Werner P.
      • Pitt D.
      • Raine C.S.
      Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage.
      ). Inkster et al. demonstrated a relative link between mitochondrial-related gene variants in SIRT4 and SIRT5 and neurodegeneration in MS (
      • Inkster B.
      • Strijbis E.M.M.
      • Vounou M.
      • Kappos L.
      • Radue E.-W.
      • Matthews P.M.
      • Uitdehaag B.M.J.
      • Barkhof F.
      • Polman C.H.
      • Montana G.
      • Geurts J.J.G.
      Histone deacetylase gene variants predict brain volume changes in multiple sclerosis.
      ).

      4.4 Sirtuin-6

      Although the key regulatory role of SIRT6 in the metabolism pathways and the link between changes in the metabolism and immune cell response has been proved, there is no sufficient evidence to show any alteration or stability in the levels of this protein in animal models of MS or in post mortem brain samples. Although a recent study assessed the transcription level of SIRT6 in EAE mouse and showed that it is significantly increased in the CNS during the chronic disease stages (
      • Prozorovski T.
      • Ingwersen J.
      • Lukas D.
      • Gottle P.
      • Koop B.
      • Graf J.
      • Schneider R.
      • Franke K.
      • Schumacher S.
      • Britsch S.
      • Hartung H.-P.
      • Kury P.
      • Berndt C.
      • Aktas O.
      Regulation of sirtuin expression in autoimmune neuroinflammation: induction of SIRT1 in oligodendrocyte progenitor cells.
      ).

      4.5 Sirtuin-7

      A recent study by Burg and colleagues investigated the role of SIRT7 in EAE mice. They used SIRT7 knockout mice and EAE induction by myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. Based on their results, SIRT7 could regulate cell differentiation and cytokine production especially by causing the reduction in the level of peripheral IFN and failure in the accumulation of regulatory T cells in the CNS of EAE in knockout mice. The effect was not strong enough to affect the clinical course of EAE. Besides they demonstrated that SIRT7 positively regulates the survival of adult-born neurons but did not impact the proliferation of hippocampal neurons. They concluded that SIRT7 could influence the immune and nervous system, but it was too weak to modulate the clinical scores in EAE mice as an animal model of MS (
      • Burg N.
      • Bittner S.
      • Ellwardt E.
      Role of the epigenetic factor Sirt7 in neuroinflammation and neurogenesis.
      ).

      5. Therapeutic potentials of sirtuins in MS

      Current treatments for MS are mostly immunomodulation-based therapies that try to reduce inflammatory relapses (
      • Arnold A.C.
      Evolving management of optic neuritis and multiple sclerosis.
      ), but these do not prevent the progressive phase of neurodegeneration observed in MS patients. Sirtuins may be modulated by several activators and inhibitors that are natural or synthetic products (Table 3). Usually, activators can influence several targets besides SIRT1 and selective activators targeting the SIRT2-7 are very rare. On the other hand, most identified inhibitors for this family belongs to the SIRT1/2 isoform. Although none of the sirtuin modulators has received approval as a drug yet, some clinical trial using them are completed or recruiting for the treatment of cancer, diabetes and Huntington's disease (
      • Bonkowski M.S.
      • Sinclair D.A.
      Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds.
      ,
      • Sussmuth S.D.
      • Haider S.
      • Landwehrmeyer G.B.
      • Farmer R.
      • Frost C.
      • Tripepi G.
      • Andersen C.A.
      • Di Bacco M.
      • Lamanna C.
      • Diodato E.
      • Massai L.
      • Diamanti D.
      • Mori E.
      • Magnoni L.
      • Dreyhaupt J.
      • Schiefele K.
      • Craufurd D.
      • Saft C.
      • Rudzinska M.
      • Ryglewicz D.
      • Orth M.
      • Brzozy S.
      • Baran A.
      • Pollio G.
      • Andre R.
      • Tabrizi S.J.
      • Darpo B.
      • Westerberg G.
      An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease.
      ).To date, the most studied sirtuins in the context of neurodegeneration and MS are SIRT1 and SIRT2. Additionally, as awareness grows for the roles that the mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5 play in metabolic regulation and adaption their potential as therapeutic targets in MS become more promising. Increasing evidence suggests they may play different roles in neurodegeneration, autoimmunity, and metabolism with different protein targets, and provide different potentials for the development of therapeutic applications. Several experiments using drugs that target sirtuins and other HDACs show initial promise for treatment of the neurodegenerative and neurological part of MS (
      • Aljada A.
      • Dong L.
      • Mousa S.A.
      Sirtuin-targeting drugs: mechanisms of action and potential therapeutic applications.
      ,
      • Camelo S.
      • Iglesias A.H.
      • Hwang D.
      • Due B.
      • Ryu H.
      • Smith K.
      • Gray S.G.
      • Imitola J.
      • Duran G.
      • Assaf B.
      • Langley B.
      • Khoury S.J.
      • Stephanopoulos G.
      • De Girolami U.
      • Ratan R.R.
      • Ferrante R.J.
      • Dangond F.
      Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis.
      ,
      • Chuang D.-M.
      • Leng Y.
      • Marinova Z.
      • Kim H.-J.
      • Chiu C.-T.
      Multiple roles of HDAC inhibition in neurodegenerative conditions.
      ) and, therefore, these may be used as potential complementary therapeutic drugs with current immunotherapies (
      • Shindler K.S.
      • Ventura E.
      • Dutt M.
      • Elliott P.
      • Fitzgerald D.C.
      • Rostami A.
      Oral resveratrol reduces neuronal damage in a model of multiple sclerosis.
      ,
      • Shindler K.S.
      • Ventura E.
      • Rex T.S.
      • Elliott P.
      • Rostami A.
      SIRT1 activation confers neuroprotection in experimental optic neuritis.
      ).
      Table 3Sirtuins activators and inhibitors.
      NameCompound nameRelated informationUse in clinical trialsReference(s)
      SIRT1PiceatannolEffects on SIRT3 and SIRT5; Natural activator(
      • Gertz M.
      • Nguyen G.T.T.
      • Fischer F.
      • Suenkel B.
      • Schlicker C.
      • Franzel B.
      • Tomaschewski J.
      • Aladini F.
      • Becker C.
      • Wolters D.
      • Steegborn C.
      A molecular mechanism for direct sirtuin activation by resveratrol.
      ,
      • Howitz K.T.
      • Bitterman K.J.
      • Cohen H.Y.
      • Lamming D.W.
      • Lavu S.
      • Wood J.G.
      • Zipkin R.E.
      • Chung P.
      • Kisielewski A.
      • Zhang L.-L.
      • Scherer B.
      • Sinclair D.A.
      Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
      )
      ResveratrolEffects on SIRT3 and SIRT5; Natural activatorDiabetes (
      • Timmers S.
      • de Ligt M.
      • Phielix E.
      • van de Weijer T.
      • Hansen J.
      • Moonen-Kornips E.
      • Schaart G.
      • Kunz I.
      • Hesselink M.K.C.
      • Schrauwen-Hinderling V.B.
      • Schrauwen P.
      Resveratrol as add-on therapy in subjects with well-controlled type 2 diabetes: a randomized controlled trial.
      )

      Cognitive function and mood (
      • Evans H.M.
      • Howe P.R.C.
      • Wong R.H.X.
      Effects of resveratrol on cognitive performance, mood and cerebrovascular function in post-menopausal women; a 14-week randomised placebo-controlled intervention trial.
      )
      (
      • Gertz M.
      • Nguyen G.T.T.
      • Fischer F.
      • Suenkel B.
      • Schlicker C.
      • Franzel B.
      • Tomaschewski J.
      • Aladini F.
      • Becker C.
      • Wolters D.
      • Steegborn C.
      A molecular mechanism for direct sirtuin activation by resveratrol.
      ,
      • Howitz K.T.
      • Bitterman K.J.
      • Cohen H.Y.
      • Lamming D.W.
      • Lavu S.
      • Wood J.G.
      • Zipkin R.E.
      • Chung P.
      • Kisielewski A.
      • Zhang L.-L.
      • Scherer B.
      • Sinclair D.A.
      Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
      )
      Alzheimer's disease (
      • Turner R.S.
      • Thomas R.G.
      • Craft S.
      • van Dyck C.H.
      • Mintzer J.
      • Reynolds B.A.
      • Brewer J.B.
      • Rissman R.A.
      • Raman R.
      • Aisen P.S.
      A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.
      )
      SRT1720Synthetic activator(
      • Dai H.
      • Kustigian L.
      • Carney D.
      • Case A.
      • Considine T.
      • Hubbard B.P.
      • Perni R.B.
      • Riera T.V
      • Szczepankiewicz B.
      • Vlasuk G.P.
      • Stein R.L.
      SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator.
      ,
      • Milne J.C.
      • Lambert P.D.
      • Schenk S.
      • Carney D.P.
      • Smith J.J.
      • Gagne D.J.
      • Jin L.
      • Boss O.
      • Perni R.B.
      • Vu C.B.
      • Bemis J.E.
      • Xie R.
      • Disch J.S.
      • Ng P.Y.
      • Nunes J.J.
      • Lynch A.V
      • Yang H.
      • Galonek H.
      • Israelian K.
      • Choy W.
      • Iffland A.
      • Lavu S.
      • Medvedik O.
      • Sinclair D.A.
      • Olefsky J.M.
      • Jirousek M.R.
      • Elliott P.J.
      • Westphal C.H.
      Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.
      )
      SRT2104Highly specific; Synthetic activatorDiabetes (
      • Baksi A.
      • Kraydashenko O.
      • Zalevkaya A.
      • Stets R.
      • Elliott P.
      • Haddad J.
      • Hoffmann E.
      • Vlasuk G.P.
      • Jacobson E.W.
      A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes.
      )
      (
      • Hoffmann E.
      • Wald J.
      • Lavu S.
      • Roberts J.
      • Beaumont C.
      • Haddad J.
      • Elliott P.
      • Westphal C.
      • Jacobson E.
      Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man.
      ,
      • Krueger J.G.
      • Suarez-Farinas M.
      • Cueto I.
      • Khacherian A.
      • Matheson R.
      • Parish L.C.
      • Leonardi C.
      • Shortino D.
      • Gupta A.
      • Haddad J.
      • Vlasuk G.P.
      • Jacobson E.W.
      A randomized, placebo-controlled study of SRT2104, a SIRT1 activator, in patients with moderate to severe psoriasis.
      )
      1,4-DHP derivativeIn vitro and in vivo activator; Effect on SIRT2 and SIRT3(
      • Mai A.
      • Valente S.
      • Meade S.
      • Carafa V.
      • Tardugno M.
      • Nebbioso A.
      • Galmozzi A.
      • Mitro N.
      • De Fabiani E.
      • Altucci L.
      • Kazantsev A.
      Study of 1,4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors.
      ,