From Sirtuin Biology to Human Diseases: An Update*

Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD+-dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas.

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[2]  A. Akhmedov,et al.  Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction. , 2013, Antioxidants & redox signaling.

[3]  R. Pi,et al.  Sirtuin 6 protects cardiomyocytes from hypertrophy in vitro via inhibition of NF‐κB‐dependent transcriptional activity , 2013, British journal of pharmacology.

[4]  A. Regev,et al.  The Histone Deacetylase SIRT6 Is a Tumor Suppressor that Controls Cancer Metabolism , 2012, Cell.

[5]  Lei Zhong,et al.  The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun , 2012, Nature Medicine.

[6]  Kevin Struhl,et al.  SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation , 2012, Nature.

[7]  Y. Cai,et al.  Nmnat2 protects cardiomyocytes from hypertrophy via activation of SIRT6 , 2012, FEBS letters.

[8]  Ming-Cheh Liu,et al.  Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure. , 2012, Blood.

[9]  D. Lombard,et al.  Ageing: Sorting out the sirtuins , 2012, Nature.

[10]  Johan Auwerx,et al.  Sirtuins as regulators of metabolism and healthspan , 2012, Nature Reviews Molecular Cell Biology.

[11]  Ziv Bar-Joseph,et al.  The sirtuin SIRT6 regulates lifespan in male mice , 2012, Nature.

[12]  Wilhelm Krek,et al.  Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. , 2012, Genes & development.

[13]  Qing Xu,et al.  Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high‐fat‐diet feeding , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  L. Guarente,et al.  SIRT1 Protects against α-Synuclein Aggregation by Activating Molecular Chaperones , 2012, The Journal of Neuroscience.

[15]  Bárbara Martínez-Pastor,et al.  Sirtuins, Metabolism, and Cancer , 2011, Front. Pharmacol..

[16]  Lin Du,et al.  Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets , 2011, Nature Medicine.

[17]  D. Accili,et al.  Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation. , 2011, Cell metabolism.

[18]  John R. Yates,et al.  Sirt1 mediates neuroprotection from mutant huntingtin by activation of TORC1 and CREB transcriptional pathway , 2011, Nature Medicine.

[19]  Shaoping Ji,et al.  Sirt2 is a novel in vivo downstream target of Nkx2.2 and enhances oligodendroglial cell differentiation. , 2011, Journal of molecular cell biology.

[20]  Takeshi Kimura,et al.  Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice. , 2011, Journal of molecular and cellular cardiology.

[21]  M. Sack.  Emerging characterization of the role of SIRT3-mediated mitochondrial protein deacetylation in the heart. , 2011, American journal of physiology. Heart and circulatory physiology.

[22]  Alexander S. Banks,et al.  SirT1 Regulates Adipose Tissue Inflammation , 2011, Diabetes.

[23]  Johan Auwerx,et al.  Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase , 2011, Science.

[24]  A. Shen,et al.  Interferon gamma (IFN-γ) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription , 2011, Nucleic acids research.

[25]  Tongsheng Chen,et al.  Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling , 2011, Journal of neuroscience research.

[26]  Robert V Farese,et al.  SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. , 2011, Molecular cell.

[27]  X. Wang,et al.  SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. , 2011, Cancer cell.

[28]  E. Weiss,et al.  Caloric restriction: powerful protection for the aging heart and vasculature. , 2011, American journal of physiology. Heart and circulatory physiology.

[29]  J. Auwerx,et al.  Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling , 2011, Proceedings of the National Academy of Sciences.

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

[31]  V. Ganapathy,et al.  SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer. , 2011, Cancer research.

[32]  A. Seluanov,et al.  SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells , 2011, Cell cycle.

[33]  De-Pei Liu,et al.  Repression of P66Shc Expression by SIRT1 Contributes to the Prevention of Hyperglycemia-Induced Endothelial Dysfunction , 2011, Circulation research.

[34]  L. Qiang,et al.  SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL[S] , 2011, Journal of Lipid Research.

[35]  S. Gygi,et al.  Succinate Dehydrogenase Is a Direct Target of Sirtuin 3 Deacetylase Activity , 2011, PloS one.

[36]  K. Jang,et al.  Expression and role of SIRT1 in hepatocellular carcinoma. , 2011, Oncology reports.

[37]  Matt Kaeberlein,et al.  Absence of effects of Sir2 over-expression on lifespan in C. elegans and Drosophila , 2011, Nature.

[38]  John M. Cunningham,et al.  The Deacetylase SIRT1 Promotes Membrane Localization and Activation of Akt and PDK1 During Tumorigenesis and Cardiac Hypertrophy , 2011, Science Signaling.

[39]  Y. Xiong,et al.  Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. , 2011, Molecular cell.

[40]  Q. Zhai,et al.  Overexpression of SIRT1 in Mouse Forebrain Impairs Lipid/Glucose Metabolism and Motor Function , 2011, PloS one.

[41]  Jun Yu,et al.  Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth. , 2011, Cancer research.

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[43]  Howard Y. Chang,et al.  Dynamic Chromatin Localization of Sirt6 Shapes Stress- and Aging-Related Transcriptional Networks , 2011, PLoS genetics.

[44]  A. Biankin,et al.  SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability , 2011, PLoS genetics.

[45]  F. Villarroya,et al.  Sirt1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. , 2011, Cardiovascular research.

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

[47]  S. H. Kim,et al.  Neuronal Sirt3 Protects against Excitotoxic Injury in Mouse Cortical Neuron Culture , 2011, PloS one.

[48]  C. Kahn,et al.  Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. , 2011, The Biochemical journal.

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

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

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

[52]  B. Lüscher,et al.  SIRT2 regulates NF-κB-dependent gene expression through deacetylation of p65 Lys310 , 2010, Journal of Cell Science.

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

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

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

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

[57]  F. Alt,et al.  Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity , 2010, Proceedings of the National Academy of Sciences.

[58]  V. Haroutunian,et al.  Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy , 2010, Neuron.

[59]  Stephen F. Lowry,et al.  Roles of SIRT1 in the Acute and Restorative Phases following Induction of Inflammation* , 2010, The Journal of Biological Chemistry.

[60]  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.

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

[62]  Olivia Baré,et al.  SIRT4 Regulates Fatty Acid Oxidation and Mitochondrial Gene Expression in Liver and Muscle Cells , 2010, The Journal of Biological Chemistry.

[63]  Lois E. H. Smith,et al.  SIRT1 Is Essential for Normal Cognitive Function and Synaptic Plasticity , 2010, The Journal of Neuroscience.

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

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

[66]  L. Guarente,et al.  RETRACTED: SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10 , 2010, Cell.

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

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

[69]  Christian Neri,et al.  SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis , 2010, Proceedings of the National Academy of Sciences.

[70]  Y. Kanfi,et al.  SIRT6 protects against pathological damage caused by diet‐induced obesity , 2010, Aging cell.

[71]  J. Olefsky,et al.  SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. , 2010, American journal of physiology. Endocrinology and metabolism.

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

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

[74]  D. Sinclair,et al.  Mammalian sirtuins: biological insights and disease relevance. , 2010, Annual review of pathology.

[75]  N. Sundaresan,et al.  Exogenous NAD Blocks Cardiac Hypertrophic Response via Activation of the SIRT3-LKB1-AMP-activated Kinase Pathway* , 2009, The Journal of Biological Chemistry.

[76]  A. Ballestrero,et al.  Catastrophic NAD+ Depletion in Activated T Lymphocytes through Nampt Inhibition Reduces Demyelination and Disability in EAE , 2009, PloS one.

[77]  Gene Kim,et al.  Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. , 2009, The Journal of clinical investigation.

[78]  J. Auwerx,et al.  Caloric restriction, SIRT1 and longevity , 2009, Trends in Endocrinology & Metabolism.

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

[80]  J. Tyler,et al.  CBP/p300-mediated acetylation of histone H3 on lysine 56 , 2009, Nature.

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

[82]  Z. Lou,et al.  A c-Myc–SIRT1 feedback loop regulates cell growth and transformation , 2009, The Journal of cell biology.

[83]  Véronique Kruys,et al.  Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner , 2009, Nature Medicine.

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

[85]  Q. Tong,et al.  SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1's repressive interaction with PPARgamma. , 2008, Molecular biology of the cell.

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

[87]  T. Lüscher,et al.  Final common molecular pathways of aging and cardiovascular disease: role of the p66Shc protein. , 2008, Arteriosclerosis, thrombosis, and vascular biology.

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

[89]  C. Kahn,et al.  SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. , 2007, Cell metabolism.

[90]  S. Vatner,et al.  Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart , 2007, Circulation research.

[91]  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.

[92]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[93]  D. Yan,et al.  Ageing and hearing loss , 2007, The Journal of pathology.

[94]  L. Guarente,et al.  Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. , 2006, Genes & development.

[95]  Pingfang Liu,et al.  Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6 , 2006, Cell.

[96]  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.

[97]  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.

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

[99]  H. Leong,et al.  Glycolysis and pyruvate oxidation in cardiac hypertrophy--why so unbalanced? , 2003, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[100]  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.

[101]  J. Ross,et al.  Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[102]  D. Lang.  Cardiac hypertrophy and oxidative stress: a leap of faith or stark reality? , 2002, Heart.

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

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

[105]  K. Arima,et al.  Immunoelectron-microscopic demonstration of NACP/α-synuclein-epitopes on the filamentous component of Lewy bodies in Parkinson's disease and in dementia with Lewy bodies , 1998, Brain Research.

[106]  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.

[107]  Robert V Farese,et al.  SIRT 3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome , 2011 .

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

[109]  B. Lüscher,et al.  SIRT 2 regulates NFk B-dependent gene expression through deacetylation of p 65 Lys 310 , 2010 .