Sirtuins mediate mammalian metabolic responses to nutrient availability

Metabolic diseases are an increasing threat in developed countries. Dysregulation of metabolic pathways, caused by imbalances in energy homeostasis, leads to obesity, diabetes and cardiovascular disease with devastating results for both individuals and societies. Sirtuins, a conserved family of NAD+-dependent deacetylase enzymes found in many species, regulate various metabolic pathways and have emerged as important sensors of energy status in mammals. The nuclear sirtuins, SIRT1, SIRT6 and SIRT7, regulate the activity of key transcription factors and cofactors of numerous metabolic pathways in almost all tissues by linking nutrient signals with the cellular responses to energy demands. The mitochondrial sirtuins, SIRT3, SIRT4 and SIRT5, regulate the activity of important mitochondrial enzymes and drive metabolic cycles in response to fasting and calorie restriction. Accumulating evidence indicates that sirtuins can be beneficial in the prevention of metabolic and age-related diseases and suggests that they can be pharmacologically activated to ameliorate such diseases. This Review describes the latest advances in the understanding of the function of sirtuins as regulators of mammalian metabolism and focuses on the role of these enzymes as mediators of nutrient availability.

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

[2]  F. Dequiedt,et al.  Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase , 2011, Nature.

[3]  M. Dietrich,et al.  STAT3 inhibition of gluconeogenesis is downregulated by SirT1 , 2009, Nature Cell Biology.

[4]  D. Leprince,et al.  Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex , 2007, Proceedings of the National Academy of Sciences.

[5]  Nicholas E. Bruns,et al.  A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy , 2008, Proceedings of the National Academy of Sciences.

[6]  Corby K. Martin,et al.  Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. , 2009, Atherosclerosis.

[7]  Junjie Chen,et al.  Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. , 2010, Molecular cell.

[8]  C. Deng,et al.  Liver Steatosis and Increased ChREBP Expression in Mice Carrying a Liver Specific SIRT1 Null Mutation under a Normal Feeding Condition , 2010, International journal of biological sciences.

[9]  Joseph L Goldstein,et al.  SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. , 2002, The Journal of clinical investigation.

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

[11]  Jef D. Boeke,et al.  Structure of a Sir2 enzyme bound to an acetylated p53 peptide. , 2002, Molecular cell.

[12]  Emilio Clementi,et al.  Calorie Restriction Promotes Mitochondrial Biogenesis by Inducing the Expression of eNOS , 2005, Science.

[13]  R. de Cabo,et al.  JNK1 Phosphorylates SIRT1 and Promotes Its Enzymatic Activity , 2009, PloS one.

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

[15]  L. Guarente,et al.  The SirT3 divining rod points to oxidative stress. , 2011, Molecular cell.

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

[17]  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.

[18]  C. Vaslet,et al.  Hypothalamic Sirt1 Regulates Food Intake in a Rodent Model System , 2009, PloS one.

[19]  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.

[20]  Robert V Farese,et al.  SIRT 3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation , 2010 .

[21]  M. Montminy,et al.  The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism , 2005, Nature.

[22]  S. Fields,et al.  Substrate-specific Activation of Sirtuins by Resveratrol* , 2005, Journal of Biological Chemistry.

[23]  S. J. Berger,et al.  Effects of nicotinamide on NAD and poly(ADP-ribose) metabolism in DNA-damaged human lymphocytes. , 1981, Journal of supramolecular structure and cellular biochemistry.

[24]  N. Pavletich,et al.  Structure of the histone deacetylase SIRT2 , 2001, Nature Structural Biology.

[25]  G. Gores,et al.  Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice. , 2010, The Journal of clinical investigation.

[26]  D. Gigot,et al.  Pre‐B‐cell colony‐enhancing factor, whose expression is up‐regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis , 2002, European journal of immunology.

[27]  Qing Xu,et al.  Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. , 2009, Cell metabolism.

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

[29]  S. Nemoto,et al.  Nutrient Availability Regulates SIRT1 Through a Forkhead-Dependent Pathway , 2004, Science.

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

[31]  T. Veenstra,et al.  FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. , 2009, Cell metabolism.

[32]  L. Qiang,et al.  Identification of a Domain within Peroxisome Proliferator-Activated Receptor γ Regulating Expression of a Group of Genes Containing Fibroblast Growth Factor 21 That Are Selectively Repressed by SIRT1 in Adipocytes , 2007, Molecular and Cellular Biology.

[33]  L. Guarente,et al.  Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes , 2011, Nature.

[34]  P. Puigserver,et al.  Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. , 2010, Genes & development.

[35]  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.

[36]  Howard Y. Chang,et al.  SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-κB-Dependent Gene Expression and Organismal Life Span , 2009, Cell.

[37]  R. Coppari,et al.  SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. , 2010, Cell metabolism.

[38]  W. Kraus,et al.  The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. , 2010, Molecular cell.

[39]  Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. , 2007, Molecular cell.

[40]  L. Guarente,et al.  SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production , 2011, Oncogene.

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

[42]  Danica Chen,et al.  Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. , 2010, Cell metabolism.

[43]  Lloyd M. Smith,et al.  Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. , 2011, Molecular cell.

[44]  F. Alt,et al.  SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. , 2010, Cell metabolism.

[45]  Andrew D. Steele,et al.  SIRT1 transgenic mice show phenotypes resembling calorie restriction , 2007, Aging cell.

[46]  P. Sassone-Corsi,et al.  Circadian Control of the NAD+ Salvage Pathway by CLOCK-SIRT1 , 2009, Science.

[47]  Florian Kreppel,et al.  SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation , 2008, Cell.

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

[49]  F. Alt,et al.  SIRT1 controls endothelial angiogenic functions during vascular growth. , 2007, Genes & development.

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

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

[52]  J. Takahashi,et al.  Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis , 2009, Science.

[53]  Satoko Aratani,et al.  Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[56]  Y. Mo,et al.  A Pathway Involving Farnesoid X Receptor and Small Heterodimer Partner Positively Regulates Hepatic Sirtuin 1 Levels via MicroRNA-34a Inhibition* , 2010, The Journal of Biological Chemistry.

[57]  Diana Wang,et al.  SIRT1 Suppresses b-Amyloid Production by Activating the a-Secretase Gene ADAM10 , 2010 .

[58]  E. Hoffman,et al.  Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. , 2008, Developmental cell.

[59]  George F Cahill,et al.  Fuel metabolism in starvation. , 2006, Annual review of nutrition.

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

[61]  J. Kyriakis.  Faculty Opinions recommendation of SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator. , 2010 .

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

[63]  H. Fried.  Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival , 2007 .

[64]  Eric Verdin,et al.  Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation , 2007, Molecular and Cellular Biology.

[65]  M. Ziegler,et al.  Subcellular Compartmentation and Differential Catalytic Properties of the Three Human Nicotinamide Mononucleotide Adenylyltransferase Isoforms* , 2005, Journal of Biological Chemistry.

[66]  Fan Lan,et al.  SIRT1 Regulates Hepatocyte Lipid Metabolism through Activating AMP-activated Protein Kinase* , 2008, Journal of Biological Chemistry.

[67]  David P. Carney,et al.  SIRT1 Activation by Small Molecules , 2010, The Journal of Biological Chemistry.

[68]  M. Karin,et al.  Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity , 2008, Cell.

[69]  L. Guarente,et al.  Sir2 links chromatin silencing, metabolism, and aging. , 2000, Genes & development.

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

[71]  W. Minor,et al.  Phosphorylation Regulates SIRT1 Function , 2008, PLoS ONE.

[72]  I. Shimomura,et al.  Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[73]  P Bailey,et al.  Double Edged Sword , 2002 .

[74]  G. Reaven.  The insulin resistance syndrome: definition and dietary approaches to treatment. , 2005, Annual review of nutrition.

[75]  Jerry Donovan,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. , 2003, Nature.

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

[77]  Ana Maria Cuervo,et al.  Autophagy in the cellular energetic balance. , 2011, Cell metabolism.

[78]  D. Sinclair,et al.  SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. , 2011, Cell metabolism.

[79]  Michael W Young,et al.  Interplay of circadian clocks and metabolic rhythms. , 2006, Annual review of genetics.

[80]  L. Guarente,et al.  Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction. , 2009, Genes & development.

[81]  Hong Wang,et al.  Adiponectin Secretion Is Regulated by SIRT1 and the Endoplasmic Reticulum Oxidoreductase Ero1-Lα , 2007, Molecular and Cellular Biology.

[82]  J. Auwerx,et al.  Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. , 2008, Cell metabolism.

[83]  Bin Zhang,et al.  Sirtuin 2, a Mammalian Homolog of Yeast Silent Information Regulator-2 Longevity Regulator, Is an Oligodendroglial Protein That Decelerates Cell Differentiation through Deacetylating α-Tubulin , 2007, The Journal of Neuroscience.

[84]  J. Auwerx,et al.  Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. , 2010, Cell metabolism.

[85]  T. Uzu,et al.  Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. , 2010, The Journal of clinical investigation.

[86]  Takeshi Tokuhisa,et al.  The role of autophagy during the early neonatal starvation period , 2004, Nature.

[87]  Takashi Nakagawa,et al.  SIRT5 Deacetylates Carbamoyl Phosphate Synthetase 1 and Regulates the Urea Cycle , 2009, Cell.

[88]  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.

[89]  Howard Y. Chang,et al.  SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin , 2008, Nature.

[90]  D. Garfinkel,et al.  Transcriptional silencing of Ty1 elements in the RDN1 locus of yeast. , 1997, Genes & development.

[91]  E. Verdin,et al.  Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. , 2010, Trends in biochemical sciences.

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

[93]  F. Alt,et al.  Tissue-specific regulation of SIRT1 by calorie restriction. , 2008, Genes & development.

[94]  Peter Carmeliet,et al.  Regulation of angiogenesis by oxygen and metabolism. , 2009, Developmental cell.

[95]  Q. Tong,et al.  Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. , 2010, Biochemistry.

[96]  Junjie Chen,et al.  DBC1 is a negative regulator of SIRT1 , 2008, Nature.

[97]  P. Pandolfi,et al.  SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. , 2011, Cancer cell.

[98]  P. Carmeliet,et al.  Oxygen sensors at the crossroad of metabolism. , 2009, Cell metabolism.

[99]  Bruce M. Spiegelman,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction , 2003, Nature.

[100]  W. Wong,et al.  Hypoxia-inducible factors and the response to hypoxic stress. , 2010, Molecular cell.

[101]  L. Guarente,et al.  SIRT1 deacetylates and positively regulates the nuclear receptor LXR. , 2007, Molecular cell.

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

[103]  Andrew D. Steele,et al.  Increase in Activity During Calorie Restriction Requires Sirt1 , 2005, Science.

[104]  Venkataraman Thanabal,et al.  SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1♦ , 2010, The Journal of Biological Chemistry.

[105]  Paolo Sassone-Corsi,et al.  The NAD+-Dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian Control , 2008, Cell.

[106]  P. Lansdorp,et al.  The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. , 2003, Molecular and cellular biology.

[107]  S. Park,et al.  Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. , 2010, Molecular cell.

[108]  J. Auwerx,et al.  PARP-2 regulates SIRT1 expression and whole-body energy expenditure. , 2011, Cell metabolism.

[109]  C. Steegborn,et al.  Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. , 2008, Journal of molecular biology.

[110]  L. Guarente,et al.  Calorie Restriction— the SIR2 Connection , 2005, Cell.

[111]  D. Hardie,et al.  AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy , 2007, Nature Reviews Molecular Cell Biology.

[112]  J. Auwerx,et al.  PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. , 2011, Cell metabolism.

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

[114]  Cuk-Seong Kim,et al.  SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase , 2007, Proceedings of the National Academy of Sciences.

[115]  Shiwei Song,et al.  A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis , 2008, Proceedings of the National Academy of Sciences.

[116]  G. Shulman,et al.  AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[117]  D. Holtzman,et al.  SIRT1 Promotes the Central Adaptive Response to Diet Restriction through Activation of the Dorsomedial and Lateral Nuclei of the Hypothalamus , 2010, The Journal of Neuroscience.

[118]  Alexander S Banks,et al.  SirT1 gain of function increases energy efficiency and prevents diabetes in mice. , 2008, Cell metabolism.

[119]  T. Schug,et al.  DYRK1A and DYRK3 Promote Cell Survival through Phosphorylation and Activation of SIRT1* , 2010, The Journal of Biological Chemistry.

[120]  Wei Yu,et al.  Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction , 2010, Cell.

[121]  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.

[122]  P. Pfluger,et al.  Sirt1 protects against high-fat diet-induced metabolic damage , 2008, Proceedings of the National Academy of Sciences.

[123]  R. Busse,et al.  Endothelial aging. , 2005, Cardiovascular research.

[124]  D. Cai,et al.  Uncoupling Obesity-related Hypertension by Targeting Hypothalamic IKKβ/NF-κB , 2011, Nature Medicine.

[125]  F. Mulero,et al.  Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. , 2010, Nature communications.

[126]  P. Puigserver,et al.  Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1α , 2007, The EMBO journal.

[127]  R. DePinho,et al.  Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in Cardiac Myocytes , 2010, Circulation research.

[128]  D. Herranz,et al.  SIRT1: recent lessons from mouse models , 2010, Nature Reviews Cancer.

[129]  S. Schinner.  AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity , 2009 .

[130]  Guido Kroemer,et al.  Autophagy in the Pathogenesis of Disease , 2008, Cell.

[131]  M. Yamakuchi,et al.  miR-34a repression of SIRT1 regulates apoptosis , 2008, Proceedings of the National Academy of Sciences.

[132]  T. Veenstra,et al.  SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism* , 2010, The Journal of Biological Chemistry.

[133]  Xiaoling Xu,et al.  Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. , 2010, Cell metabolism.

[134]  J. Olefsky,et al.  Insulin sensitivity: modulation by nutrients and inflammation. , 2008, The Journal of clinical investigation.

[135]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[136]  B. Spiegelman,et al.  AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α , 2007, Proceedings of the National Academy of Sciences.

[137]  Johan Auwerx,et al.  Histone methyl transferases and demethylases; can they link metabolism and transcription? , 2010, Cell metabolism.

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

[139]  Orian S. Shirihai,et al.  The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α , 2010, Cell.

[140]  N. Ruderman,et al.  SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1 , 2008, Journal of Biological Chemistry.

[141]  C. Deng,et al.  SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. , 2010, Cancer cell.

[142]  Y. Ouchi,et al.  Cilostazol Inhibits Oxidative Stress–Induced Premature Senescence Via Upregulation of Sirt1 in Human Endothelial Cells , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[143]  Qing Xu,et al.  Myeloid Deletion of SIRT1 Induces Inflammatory Signaling in Response to Environmental Stress , 2010, Molecular and Cellular Biology.

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

[145]  J. Yates,et al.  A Fasting Inducible Switch Modulates Gluconeogenesis Via Activator-Coactivator Exchange , 2008, Nature.

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

[147]  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.

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

[149]  E. Bober,et al.  Sirt7 Increases Stress Resistance of Cardiomyocytes and Prevents Apoptosis and Inflammatory Cardiomyopathy in Mice , 2008, Circulation research.

[150]  S. Imai,et al.  The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells* , 2004, Journal of Biological Chemistry.

[151]  Daniel J. Klionsky,et al.  Autophagy in Health and Disease: A Double-Edged Sword , 2004, Science.

[152]  Y. Hayashi,et al.  Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1 , 2010, Nature.

[153]  B. Staels,et al.  FXR: a promising target for the metabolic syndrome? , 2007, Trends in pharmacological sciences.

[154]  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.

[155]  Amy V. Lynch,et al.  Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes , 2007, Nature.

[156]  J. Qin,et al.  Negative regulation of the deacetylase SIRT1 by DBC1 , 2008, Nature.

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

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

[159]  L. Guarente.  Franklin H. Epstein Lecture: Sirtuins, aging, and medicine. , 2011, The New England journal of medicine.

[160]  F. Zipp,et al.  Sirt1 contributes critically to the redox-dependent fate of neural progenitors , 2008, Nature Cell Biology.