Sirtuins in mammals: insights into their biological function.

Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.

[1]  J. Wands,et al.  Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[2]  Oscar M. Aparicio,et al.  Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae , 1991, Cell.

[3]  J. Kato,et al.  Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae , 1997, Nature.

[4]  Madeleine Lemieux,et al.  Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells , 2005, PLoS biology.

[5]  S. Austad Life extension by dietary restriction in the bowl and doily spider, Frontinella pyramitela , 1989, Experimental Gerontology.

[6]  R. Weindruch,et al.  The retardation of aging by caloric restriction: its significance in the transgenic era , 2003, Experimental Gerontology.

[7]  Y. Terauchi,et al.  The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity , 2001, Nature Medicine.

[8]  J. Boeke,et al.  An unusual form of transcriptional silencing in yeast ribosomal DNA. , 1997, Genes & development.

[9]  小林 洋介 SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress , 2006 .

[10]  L. Guarente,et al.  Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans , 2001, Nature.

[11]  Antonino Cattaneo,et al.  Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate , 2006, Current Biology.

[12]  Matt Kaeberlein,et al.  Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients , 2005, Science.

[13]  L. Guarente,et al.  Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. , 2006, Genes & development.

[14]  D. Shore,et al.  Characterization of two genes required for the position‐effect control of yeast mating‐type genes. , 1984, The EMBO journal.

[15]  Wilhelm Haas,et al.  Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1 , 2005, Nature.

[16]  D. Accili,et al.  FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. , 2005, Cell metabolism.

[17]  T. Uzu,et al.  Silent information regulator 2 (SIRT1) attenuates oxidative stress-induced mesangial cell apoptosis via p53 deacetylation. , 2006, Free radical biology & medicine.

[18]  M. Permutt,et al.  Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. , 2005, Cell metabolism.

[19]  L. Mucke,et al.  SIRT1 Protects against Microglia-dependent Amyloid-β Toxicity through Inhibiting NF-κB Signaling* , 2005, Journal of Biological Chemistry.

[20]  W. Gu,et al.  Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage , 2006, Nature Cell Biology.

[21]  J. Denu,et al.  Conserved Enzymatic Production and Biological Effect of O-Acetyl-ADP-ribose by Silent Information Regulator 2-like NAD+-dependent Deacetylases* , 2002, The Journal of Biological Chemistry.

[22]  A. Fukamizu,et al.  The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity. , 2006, The Journal of clinical investigation.

[23]  Jiandie D. Lin,et al.  Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators , 2006, Cell.

[24]  Michael A. Tainsky,et al.  Role for Human SIRT2 NAD-Dependent Deacetylase Activity in Control of Mitotic Exit in the Cell Cycle , 2003, Molecular and Cellular Biology.

[25]  Li-Huei Tsai,et al.  Aberrant Cdk5 Activation by p25 Triggers Pathological Events Leading to Neurodegeneration and Neurofibrillary Tangles , 2003, Neuron.

[26]  J. Hicks,et al.  Map positions of yeast genes SIR1, SIR3 and SIR4. , 1985, Genetics.

[27]  M. Mayo,et al.  Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase , 2004, The EMBO journal.

[28]  H. Scrable,et al.  Progressive loss of SIRT1 with cell cycle withdrawal , 2006, Aging cell.

[29]  C M McCay,et al.  The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. , 1935, Nutrition.

[30]  J. Milner,et al.  Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. , 2005, Cancer research.

[31]  M. McVey,et al.  The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. , 1999, Genes & development.

[32]  C. Bäckesjö,et al.  Activation of Sirt1 Decreases Adipocyte Formation during Osteoblast Differentiation of Mesenchymal Stem Cells , 2008, Cells Tissues Organs.

[33]  F. Alt,et al.  SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells , 2006, Cell.

[34]  W. C. Hallows,et al.  Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases , 2006, Proceedings of the National Academy of Sciences.

[35]  Dudley Lamming,et al.  HST2 Mediates SIR2-Independent Life-Span Extension by Calorie Restriction , 2005, Science.

[36]  Namjin Chung,et al.  Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ , 2004, Nature.

[37]  J. Milbrandt,et al.  Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration , 2004, Science.

[38]  J. M. Sherman,et al.  The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. , 1995, Genes & development.

[39]  B. Lakowski,et al.  The genetics of caloric restriction in Caenorhabditis elegans. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Jinping Li,et al.  Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway , 2005, Oncogene.

[41]  J. Boeke,et al.  A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Broach,et al.  Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. , 1993, Genes & development.

[43]  C. Harris,et al.  ING1 represses transcription by direct DNA binding and through effects on p53. , 2003, Cancer research.

[44]  R. Medema,et al.  FOXO4 Is Acetylated upon Peroxide Stress and Deacetylated by the Longevity Protein hSir2SIRT1* , 2004, Journal of Biological Chemistry.

[45]  P. Distefano,et al.  Inhibition of SIRT1 Catalytic Activity Increases p53 Acetylation but Does Not Alter Cell Survival following DNA Damage , 2006, Molecular and Cellular Biology.

[46]  P. Sassone-Corsi,et al.  Control of AIF-mediated Cell Death by the Functional Interplay of SIRT1 and PARP-1 in Response to DNA Damage , 2006, Cell cycle.

[47]  J. Murnane,et al.  Characterization of a human gene with sequence homology to Saccharomyces cerevisiae SIR2. , 1999, Gene.

[48]  M. Beal,et al.  Mitochondria take center stage in aging and neurodegeneration , 2005, Annals of neurology.

[49]  R. Sternglanz,et al.  Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[50]  L. Guarente Calorie restriction and SIR2 genes—Towards a mechanism , 2005, Mechanisms of Ageing and Development.

[51]  R. Frye,et al.  Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. , 2000, Biochemical and biophysical research communications.

[52]  S. Wang,et al.  SIRT1 interacts with p73 and suppresses p73‐dependent transcriptional activity , 2007, Journal of cellular physiology.

[53]  P. Puigserver,et al.  Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α , 2006, Cell.

[54]  R. E. Esposito,et al.  Direct evidence for SIR2 modulation of chromatin structure in yeast rDNA , 1997, The EMBO journal.

[55]  H. Tissenbaum,et al.  Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO , 2006, Mechanisms of Ageing and Development.

[56]  Danish Sayed,et al.  Histone H2A.z Is Essential for Cardiac Myocyte Hypertrophy but Opposed by Silent Information Regulator 2α* , 2006, Journal of Biological Chemistry.

[57]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.

[58]  F. Alt,et al.  Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[59]  P. Lansdorp,et al.  The Mammalian SIR2α Protein Has a Role in Embryogenesis and Gametogenesis , 2003, Molecular and Cellular Biology.

[60]  Arthur Mangun Banta,et al.  A study of longevity, growth, reproduction and heart rate in Daphnia longispina as influenced by limitations in quantity of food , 1937 .

[61]  L. Guarente,et al.  Extrachromosomal rDNA Circles— A Cause of Aging in Yeast , 1997, Cell.

[62]  B. Kennedy,et al.  Localization of Sir2p: the nucleolus as a compartment for silent information regulators , 1997, The EMBO journal.

[63]  S. Imai,et al.  Poly(ADP-ribose) Polymerase-1-dependent Cardiac Myocyte Cell Death during Heart Failure Is Mediated by NAD+ Depletion and Reduced Sir2α Deacetylase Activity* , 2005, Journal of Biological Chemistry.

[64]  N. Pattabiraman,et al.  Hormonal Control of Androgen Receptor Function through SIRT1 , 2006, Molecular and Cellular Biology.

[65]  Q. Tong,et al.  SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in Brown Adipocytes* , 2005, Journal of Biological Chemistry.

[66]  J. Wood,et al.  Sirtuin activators mimic caloric restriction and delay ageing in metazoans , 2004, Nature.

[67]  G. Tomasevic,et al.  Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma , 2003, Nature Medicine.

[68]  D. Reinberg,et al.  Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. , 2004, Molecular cell.

[69]  M. Tainsky,et al.  Microtubule Deacetylases, SirT2 and HDAC6, in the Nervous System , 2007, Neurochemical Research.

[70]  R. Frye ‘SIRT8’ expressed in thyroid cancer is actually SIRT7 , 2002, British Journal of Cancer.

[71]  R. Sternglanz,et al.  Role of NAD(+) in the deacetylase activity of the SIR2-like proteins. , 2000, Biochemical and biophysical research communications.

[72]  M. Miura,et al.  Caspase‐mediated changes in Sir2α during apoptosis , 2006 .

[73]  Jeremy C. McIntyre,et al.  Differentially expressed transcripts from phenotypically identified olfactory sensory neurons , 2005, The Journal of comparative neurology.

[74]  Angelika Pedal,et al.  SIRT1 Regulates HIV Transcription via Tat Deacetylation , 2005, PLoS biology.

[75]  S. Nicosia,et al.  Suppression of FOXO1 activity by FHL2 through SIRT1‐mediated deacetylation , 2005, The EMBO journal.

[76]  A. Klar,et al.  MAR1-a Regulator of the HMa and HMalpha Loci in SACCHAROMYCES CEREVISIAE. , 1979, Genetics.

[77]  F. Ishikawa,et al.  Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression. , 2003, Biochemical and biophysical research communications.

[78]  Jun Wang,et al.  Neuronal SIRT1 Activation as a Novel Mechanism Underlying the Prevention of Alzheimer Disease Amyloid Neuropathology by Calorie Restriction* , 2006, Journal of Biological Chemistry.

[79]  S. Minucci,et al.  Human SIR2 deacetylates p53 and antagonizes PML/p53‐induced cellular senescence , 2002, The EMBO journal.

[80]  P. Shiels,et al.  Altered sirtuin expression is associated with node-positive breast cancer , 2006, British Journal of Cancer.

[81]  J. Denu,et al.  The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. , 2003, Molecular cell.

[82]  P. Defossez,et al.  Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. , 2000, Science.

[83]  M. Swanson,et al.  Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10. , 2004, Journal of biochemistry.

[84]  Phuong Chung,et al.  Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan , 2003, Nature.

[85]  R. Frye,et al.  Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. , 1999, Biochemical and biophysical research communications.

[86]  L. Guarente,et al.  Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase , 2000, Nature.

[87]  S. Jazwinski,et al.  An intervention resembling caloric restriction prolongs life span and retards aging in yeast , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[88]  D A Sinclair,et al.  Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. , 1997, Science.

[89]  J. Murray,et al.  DNA damage triggers disruption of telomeric silencing and Mec1p-dependent relocation of Sir3p , 1999, Current Biology.

[90]  D. Ingram,et al.  Dietary restriction in aging nonhuman primates. , 2007, Interdisciplinary topics in gerontology.

[91]  Delin Chen,et al.  Mammalian SIRT1 Represses Forkhead Transcription Factors , 2004, Cell.

[92]  R. Sternglanz,et al.  The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[93]  J. Strathern,et al.  HST1, a new member of the SIR2 family of genes , 1996, Yeast.

[94]  Pamela Maher,et al.  Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6‐methyl‐phenyl‐tetrahydropyridine toxicity , 2005, Journal of neurochemistry.

[95]  Delin Chen,et al.  Negative Control of p53 by Sir2α Promotes Cell Survival under Stress , 2001, Cell.

[96]  I. Rahman,et al.  Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[97]  D. Sinclair,et al.  Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae , 2003, Nature.

[98]  C. Kamel,et al.  SirT1 fails to affect p53‐mediated biological functions , 2006, Aging cell.

[99]  E. Yeh,et al.  Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFκB-dependent transcription , 2006, Nature Cell Biology.

[100]  L. Guarente,et al.  The Sir2 family of protein deacetylases. , 2004, Annual review of biochemistry.

[101]  Po Zhao,et al.  Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. , 2003, Molecular cell.

[102]  D. Goldfarb,et al.  A novel assay for replicative lifespan in Saccharomyces cerevisiae. , 2004, FEMS yeast research.

[103]  J. Shao,et al.  SIRT1 Regulates Adiponectin Gene Expression through Foxo1-C/Enhancer-binding Protein α Transcriptional Complex* , 2006, Journal of Biological Chemistry.

[104]  Sophie G. Martin,et al.  Relocalization of Telomeric Ku and SIR Proteins in Response to DNA Strand Breaks in Yeast , 1999, Cell.

[105]  K. Shimamoto,et al.  Predominant expression of Sir2α, an NAD‐dependent histone deacetylase, in the embryonic mouse heart and brain 1 , 2004 .

[106]  L. Guarente,et al.  Mouse Sir2 Homolog SIRT6 Is a Nuclear ADP-ribosyltransferase* , 2005, Journal of Biological Chemistry.

[107]  L. Guarente,et al.  SIRT1 Inhibits Transforming Growth Factor β-Induced Apoptosis in Glomerular Mesangial Cells via Smad7 Deacetylation* , 2007, Journal of Biological Chemistry.

[108]  B. Thiers Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6 , 2007 .

[109]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[110]  Z. Ungvari,et al.  Vascular dysfunction in aging: potential effects of resveratrol, an anti-inflammatory phytoestrogen. , 2006, Current medicinal chemistry.

[111]  J. Escalante‐Semerena,et al.  CobB, a New Member of the SIR2 Family of Eucaryotic Regulatory Proteins, Is Required to Compensate for the Lack of Nicotinate Mononucleotide:5,6-Dimethylbenzimidazole Phosphoribosyltransferase Activity in cobT Mutants during Cobalamin Biosynthesis inSalmonella typhimurium LT2* , 1998, The Journal of Biological Chemistry.

[112]  J. Boeke,et al.  The biochemistry of sirtuins. , 2006, Annual review of biochemistry.

[113]  C. Franceschi,et al.  A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. , 2005, Genomics.

[114]  R. Weindruch,et al.  Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. , 1982, Science.

[115]  A. Perraud,et al.  Metabolite of SIR2 Reaction Modulates TRPM2 Ion Channel* , 2006, Journal of Biological Chemistry.

[116]  平塚 正治 Proteomics-based identification of differentially expressed genes in human gliomas : down-regulation of SIRT2 gene , 2004 .

[117]  R. Weinberg,et al.  hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase , 2001, Cell.

[118]  B. Rogina,et al.  Sir2 mediates longevity in the fly through a pathway related to calorie restriction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[119]  L. Guarente,et al.  MEC1-Dependent Redistribution of the Sir3 Silencing Protein from Telomeres to DNA Double-Strand Breaks , 1999, Cell.

[120]  M. Oshimura,et al.  SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress , 2007, Oncogene.

[121]  Y. Sadovsky,et al.  N-Myc Down-regulated Gene 1 Modulates the Response of Term Human Trophoblasts to Hypoxic Injury* , 2006, Journal of Biological Chemistry.

[122]  R. E. Esposito,et al.  A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA , 1989, Cell.

[123]  I. Grummt,et al.  Acetylation of TAFI68, a subunit of TIF‐IB/SL1, activates RNA polymerase I transcription , 2001, The EMBO journal.

[124]  R. Evans,et al.  Regulation of MEF2 by Histone Deacetylase 4- and SIRT1 Deacetylase-Mediated Lysine Modifications , 2005, Molecular and Cellular Biology.

[125]  W. Gu,et al.  SIRT1 Deacetylation and Repression of p300 Involves Lysine Residues 1020/1024 within the Cell Cycle Regulatory Domain 1* , 2005, Journal of Biological Chemistry.

[126]  P. Puigserver,et al.  Resveratrol improves health and survival of mice on a high-calorie diet , 2006, Nature.

[127]  Myriam Gorospe,et al.  Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase , 2004, Science.

[128]  D. Ingram,et al.  Circulating adiponectin levels increase in rats on caloric restriction: the potential for insulin sensitization , 2004, Experimental Gerontology.

[129]  T. Horvath,et al.  Mitochondrial uncoupling proteins in the cns: in support of function and survival , 2005, Nature Reviews Neuroscience.

[130]  I. Herskowitz,et al.  Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. , 1987, Genetics.

[131]  Eric Verdin,et al.  Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2 , 2006, Proceedings of the National Academy of Sciences.

[132]  Michael M. Murphy,et al.  Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. , 2005, Cell metabolism.

[133]  T. Anekonda Resveratrol—A boon for treating Alzheimer's disease? , 2006, Brain Research Reviews.

[134]  L. Partridge,et al.  Demography of Dietary Restriction and Death in Drosophila , 2003, Science.

[135]  Stuart K. Kim,et al.  A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. , 2005, Developmental cell.

[136]  Izumi Horikawa,et al.  Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. , 2005, Molecular biology of the cell.

[137]  M. Leid,et al.  BCL11A-dependent recruitment of SIRT1 to a promoter template in mammalian cells results in histone deacetylation and transcriptional repression. , 2005, Archives of biochemistry and biophysics.

[138]  S. Vatner,et al.  Silent Information Regulator 2&agr;, a Longevity Factor and Class III Histone Deacetylase, Is an Essential Endogenous Apoptosis Inhibitor in Cardiac Myocytes , 2004, Circulation research.

[139]  S. Baylin,et al.  Tumor Suppressor HIC1 Directly Regulates SIRT1 to Modulate p53-Dependent DNA-Damage Responses , 2005, Cell.

[140]  D. Moazed,et al.  An Enzymatic Activity in the Yeast Sir2 Protein that Is Essential for Gene Silencing , 1999, Cell.