sirtuins

Summary

Summary: A homologous family of proteins that includes the NAD-dependent protein deacetylases which deacetylate proteins by catalyzing the formation of O-acetyl-ADP-ribose from the ADP-RIBOSE moiety (of NAD) and the acetyl group that is being removed from the protein. Sir2p, from Saccharomyces cerevisiae, is the founding member and the family includes other homologs (HSTs - homologs of Sir Two). Some HISTONE DEACETYLASES (the Sir2-like HDACs) belong to this family of proteins.

Top Publications

  1. ncbi Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5
    Christine Schlicker
    Laboratory of Biochemistry, Department of Physiological Chemistry, Ruhr University Bochum, Universitaetsstrasse 150, 44801 Bochum, Germany
    J Mol Biol 382:790-801. 2008
  2. ncbi Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
    Anne Brunet
    Division of Neuroscience, Children s Hospital, and Department of Neurobiology, Center for Blood Research CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA
    Science 303:2011-5. 2004
  3. ncbi Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha
    Marie Lagouge
    Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS INSERM ULP, 67404 Illkirch, France
    Cell 127:1109-22. 2006
  4. ncbi Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
    Konrad T Howitz
    BIOMOL Research Laboratories, Inc, 5120 Butler Pike, Plymouth Meeting, Pennsylvania 19462, USA
    Nature 425:191-6. 2003
  5. ncbi hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase
    H Vaziri
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
    Cell 107:149-59. 2001
  6. ncbi Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
    S Imai
    Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA
    Nature 403:795-800. 2000
  7. ncbi Sirtuins as regulators of metabolism and healthspan
    Riekelt H Houtkooper
    Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
    Nat Rev Mol Cell Biol 13:225-38. 2012
  8. pmc Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase
    Fan Yeung
    Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA 22908, USA
    EMBO J 23:2369-80. 2004
  9. ncbi Negative control of p53 by Sir2alpha promotes cell survival under stress
    J Luo
    Institute of Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, 1150 St Nicholas Avenue, New York, NY 10032, USA
    Cell 107:137-48. 2001
  10. ncbi Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1
    Joseph T Rodgers
    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    Nature 434:113-8. 2005

Detail Information

Publications307 found, 100 shown here

  1. ncbi Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5
    Christine Schlicker
    Laboratory of Biochemistry, Department of Physiological Chemistry, Ruhr University Bochum, Universitaetsstrasse 150, 44801 Bochum, Germany
    J Mol Biol 382:790-801. 2008
    ..Mammalian mitochondria contain three Sirtuins, Sirt3, Sirt4, and Sirt5...
  2. ncbi Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
    Anne Brunet
    Division of Neuroscience, Children s Hospital, and Department of Neurobiology, Center for Blood Research CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA
    Science 303:2011-5. 2004
    ..Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance...
  3. ncbi Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha
    Marie Lagouge
    Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS INSERM ULP, 67404 Illkirch, France
    Cell 127:1109-22. 2006
    ..These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis...
  4. ncbi Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
    Konrad T Howitz
    BIOMOL Research Laboratories, Inc, 5120 Butler Pike, Plymouth Meeting, Pennsylvania 19462, USA
    Nature 425:191-6. 2003
    ..Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of ..
  5. ncbi hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase
    H Vaziri
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
    Cell 107:149-59. 2001
    ..In contrast, expression of a catalytically inactive hSir2 protein potentiates p53-dependent apoptosis and radiosensitivity. We propose that hSir2 is involved in the regulation of p53 function via deacetylation...
  6. ncbi Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
    S Imai
    Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA
    Nature 403:795-800. 2000
    ..These findings provide a molecular framework of NAD-dependent histone deacetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes...
  7. ncbi Sirtuins as regulators of metabolism and healthspan
    Riekelt H Houtkooper
    Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
    Nat Rev Mol Cell Biol 13:225-38. 2012
    ..b>Sirtuins act in different cellular compartments: they deacetylate histones and several transcriptional regulators in the ..
  8. pmc Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase
    Fan Yeung
    Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA 22908, USA
    EMBO J 23:2369-80. 2004
    ....
  9. ncbi Negative control of p53 by Sir2alpha promotes cell survival under stress
    J Luo
    Institute of Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, 1150 St Nicholas Avenue, New York, NY 10032, USA
    Cell 107:137-48. 2001
    ..These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy...
  10. ncbi Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1
    Joseph T Rodgers
    Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    Nature 434:113-8. 2005
    ..Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan...
  11. pmc Recent progress in the biology and physiology of sirtuins
    Toren Finkel
    Translational Medicine Branch, National Heart Lung and Blood Institute, US National Institutes of Health, Bethesda, Maryland 20892, USA
    Nature 460:587-91. 2009
    The sirtuins are a highly conserved family of NAD(+)-dependent enzymes that regulate lifespan in lower organisms...
  12. ncbi The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase
    Brian J North
    Department of Physiology, University of California, San Francisco, 94141, San Francisco, CA, USA
    Mol Cell 11:437-44. 2003
    ..These observations establish SIRT2 as a bona fide tubulin deacetylase...
  13. pmc Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila
    Camilla Burnett
    Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, UK
    Nature 477:482-5. 2011
    Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster...
  14. pmc Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase
    Jintang Du
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
    Science 334:806-9. 2011
    Silent information regulator 2 (Sir2) proteins (sirtuins) are nicotinamide adenine dinucleotide-dependent deacetylases that regulate important biological processes. Mammals have seven sirtuins, Sirt1 to Sirt7...
  15. ncbi Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress
    Tim J Schulz
    Department of Human Nutrition, Institute of Nutrition, University of Jena, D 07743 Jena, Germany
    Cell Metab 6:280-93. 2007
    ....
  16. pmc Mammalian sirtuins: biological insights and disease relevance
    Marcia C Haigis
    Glenn Laboratories for the Molecular Biology of Aging, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Annu Rev Pathol 5:253-95. 2010
    ..Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms...
  17. ncbi Are sirtuins viable targets for improving healthspan and lifespan?
    Joseph A Baur
    Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Drug Discov 11:443-61. 2012
    ..Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing...
  18. ncbi Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS
    Enzo Nisoli
    Integrated Laboratories Network, Department of Preclinical Sciences, Luigi Sacco Hospital, Milan University, 20157 Milan, Italy
    Science 310:314-7. 2005
    ..These effects were strongly attenuated in eNOS null-mutant mice. Thus, nitric oxide plays a fundamental role in the processes induced by calorie restriction and may be involved in the extension of life span in mammals...
  19. ncbi SIRT1 transgenic mice show phenotypes resembling calorie restriction
    Laura Bordone
    Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Aging Cell 6:759-67. 2007
    ..Our findings suggest that increased expression of SIRT1 in mice elicits beneficial phenotypes that may be relevant to human health and longevity...
  20. pmc Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice
    Rui Hong Wang
    Genetics of Development and Disease Branch, 10 9N105, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Cancer Cell 14:312-23. 2008
    ..Finally, we show that many human cancers exhibit reduced levels of SIRT1 compared to normal controls. Thus, SIRT1 may act as a tumor suppressor through its role in DNA damage response and genome integrity...
  21. pmc SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase
    Ilwola Mattagajasingh
    Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
    Proc Natl Acad Sci U S A 104:14855-60. 2007
    ..Furthermore, our results provide a possible molecular mechanism connecting the effects of CR on the endothelium and vascular tone to SIRT1-mediated deacetylation of eNOS...
  22. ncbi Mammalian SIRT1 represses forkhead transcription factors
    Maria Carla Motta
    Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Cell 116:551-63. 2004
    ..We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction...
  23. ncbi Genomic instability and aging-like phenotype in the absence of mammalian SIRT6
    Raul Mostoslavsky
    Howard Hughes Medical Institute, The Children s Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA
    Cell 124:315-29. 2006
    ..We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes...
  24. pmc The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control
    Yasukazu Nakahata
    Department of Pharmacology, University of California, Irvine, CA 92697, USA
    Cell 134:329-40. 2008
    ..We propose that SIRT1 functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock...
  25. pmc SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation
    Matthew F Barber
    Department of Biology, Stanford University, Stanford, California 94305, USA
    Nature 487:114-8. 2012
    ..Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs and tumour formation in vivo...
  26. ncbi Mechanism of human SIRT1 activation by resveratrol
    Margie T Borra
    Department of Biomolecular Chemistry, University of Wisconsin Madison, Madison, Wisconsin 53706, USA
    J Biol Chem 280:17187-95. 2005
    The NAD+-dependent protein deacetylase family, Sir2 (or sirtuins), is important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and life span extension...
  27. ncbi SIRT1 regulates circadian clock gene expression through PER2 deacetylation
    Gad Asher
    Department of Molecular Biology, Sciences III, University of Geneva, 30, Quai Ernest Ansermet, CH 1211 Geneva 4, Switzerland
    Cell 134:317-28. 2008
    ..Given the NAD(+) dependence of SIRT1 deacetylase activity, it is likely that SIRT1 connects cellular metabolism to the circadian core clockwork circuitry...
  28. pmc The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha
    Lei Zhong
    The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
    Cell 140:280-93. 2010
    ..Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity...
  29. pmc A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis
    Bong Hyun Ahn
    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
    Proc Natl Acad Sci U S A 105:14447-52. 2008
    ..These results implicate protein acetylation as an important regulator of Complex I activity and demonstrate that Sirt3 functions in vivo to regulate and maintain basal ATP levels...
  30. pmc SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine
    Hong Jiang
    Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA
    Nature 496:110-3. 2013
    The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases and have been implicated in the regulation of transcription, genome stability, metabolism and lifespan...
  31. ncbi SIRT6 promotes DNA repair under stress by activating PARP1
    Zhiyong Mao
    Department of Biology, University of Rochester, Rochester, NY 14627, USA
    Science 332:1443-6. 2011
    ....
  32. pmc SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
    Eriko Michishita
    Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA
    Nature 452:492-6. 2008
    ..Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome...
  33. pmc A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy
    In Hye Lee
    Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
    Proc Natl Acad Sci U S A 105:3374-9. 2008
    ..These results suggest that the Sirt1 deacetylase is an important in vivo regulator of autophagy and provide a link between sirtuin function and the overall cellular response to limited nutrients...
  34. pmc Human SIRT6 promotes DNA end resection through CtIP deacetylation
    Abderrahmane Kaidi
    Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
    Science 329:1348-53. 2010
    ..These findings further clarify how SIRT6 promotes genome stability...
  35. pmc SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis
    Dohoon Kim
    Howard Hughes Medical Institute, Picower Insitute for Learning and Memory, RIKEN MIT Neuroscience Research Center, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Boston, MA, USA
    EMBO J 26:3169-79. 2007
    ..Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention...
  36. ncbi Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins
    R A Frye
    Pittsburgh V A Medical Center 132L, University, Pittsburgh, Pennsylvania 15240, USA
    Biochem Biophys Res Commun 273:793-8. 2000
    b>Sirtuins (Sir2-like proteins) are present in prokaryotes and eukaryotes. Here, two new human sirtuins (SIRT6 and SIRT7) are found to be similar to a particular subset of insect, nematode, plant, and protozoan sirtuins...
  37. ncbi Sirt1 regulates aging and resistance to oxidative stress in the heart
    Ralph R Alcendor
    Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA
    Circ Res 100:1512-21. 2007
    ..These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1...
  38. pmc Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation
    Aparna Purushotham
    Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
    Cell Metab 9:327-38. 2009
    ..Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases...
  39. pmc The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms
    M Kaeberlein
    Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Genes Dev 13:2570-80. 1999
    ..Sir2p is a limiting component in promoting yeast longevity, and increasing the gene dosage extends the life span in wild-type cells. A possible role of the conserved SIR2 in mammalian aging is discussed...
  40. ncbi SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells
    Marcia C Haigis
    Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
    Cell 126:941-54. 2006
    ..These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR...
  41. pmc SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism
    Seung Min Jeong
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 23:450-63. 2013
    ..Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression...
  42. pmc Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
    Jill C Milne
    Sirtris Pharmaceuticals Inc, 790 Memorial Drive, Cambridge, Massachusetts 02139, USA
    Nature 450:712-6. 2007
    ..Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes...
  43. pmc SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways
    Jeongsoon Park
    Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
    Mol Cell 50:919-30. 2013
    ..Our data reveal widespread roles for lysine succinylation in regulating metabolism and potentially other cellular functions. ..
  44. ncbi Asymmetric inheritance of oxidatively damaged proteins during cytokinesis
    Hugo Aguilaniu
    Department of Cell and Molecular Biology Microbiology, Goteborg University, Goteborg, Sweden
    Science 299:1751-3. 2003
    ..These findings suggest that a genetically determined, Sir2p-dependent asymmetric inheritance of oxidatively damaged proteins may contribute to free-radical defense and the fitness of newborn cells...
  45. pmc Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation
    David B Lombard
    Howard Hughes Medical Institute, The Children s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell Biol 27:8807-14. 2007
    Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems...
  46. ncbi SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}
    Shino Nemoto
    Cardiovascular Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892 1454, USA
    J Biol Chem 280:16456-60. 2005
    ..These results provide a direct link between the sirtuins, a family of proteins linked to lifespan determination and PGC-1alpha, a coactivator that regulates cellular ..
  47. pmc SIRT1 controls endothelial angiogenic functions during vascular growth
    Michael Potente
    Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, 60590 Frankfurt, Germany
    Genes Dev 21:2644-58. 2007
    ..Mammalian homologs of Sir2 are called sirtuins (SIRT1-SIRT7)...
  48. ncbi Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase
    Haim Y Cohen
    Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Science 305:390-2. 2004
    ..Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells...
  49. ncbi Substrate-specific activation of sirtuins by resveratrol
    Matt Kaeberlein
    Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
    J Biol Chem 280:17038-45. 2005
    ..In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined...
  50. ncbi Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration
    Toshiyuki Araki
    Department of Pathology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Science 305:1010-3. 2004
    ..These findings suggest that novel therapeutic strategies directed at increasing the supply of NAD and/or Sir2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration...
  51. pmc Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha
    Zachary Gerhart-Hines
    Dana Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA
    EMBO J 26:1913-23. 2007
    ..These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes...
  52. ncbi The Sir2 family of protein deacetylases
    Gil Blander
    Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Annu Rev Biochem 73:417-35. 2004
    ..We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging...
  53. ncbi Sirtuins: critical regulators at the crossroads between cancer and aging
    L R Saunders
    Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA, USA
    Oncogene 26:5489-504. 2007
    b>Sirtuins (SIRTs 1-7), or class III histone deacetylases (HDACs), are protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational ..
  54. ncbi DBC1 is a negative regulator of SIRT1
    Ja Eun Kim
    Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Nature 451:583-6. 2008
    ..Our results shed new light on the regulation of SIRT1 and have important implications in understanding the molecular mechanism of ageing and cancer...
  55. ncbi The sirtuin SIRT6 regulates lifespan in male mice
    Yariv Kanfi
    The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 52900, Israel
    Nature 483:218-21. 2012
    ..To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies...
  56. pmc SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span
    Tiara L A Kawahara
    Program in Epithelial Biology, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cell 136:62-74. 2009
    ..We propose that SIRT6 attenuates NF-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging...
  57. pmc SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase
    Xiuyun Hou
    Vascular Biology Unit and Molecular Cardiology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, and Section of Endocrinology, Boston University, Boston, MA 02118, USA
    J Biol Chem 283:20015-26. 2008
    ..Targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases...
  58. pmc Histone H4 lysine 16 acetylation regulates cellular lifespan
    Weiwei Dang
    Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA
    Nature 459:802-7. 2009
    ..b>Sirtuins, a group of conserved NAD(+)-dependent deacetylases or ADP-ribosyltransferases, promote longevity in diverse ..
  59. ncbi Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons
    J Alex Parker
    Institut National de la Sante et de la Recherche Medicale, Avenir Group, Laboratory of Genomic Biology, Centre Paul Broca, 75014 Paris, France
    Nat Genet 37:349-50. 2005
    ..Additionally, resveratrol rescued mutant polyglutamine-specific cell death in neuronal cells derived from HdhQ111 knock-in mice. We conclude that Sir2 activation may protect against mutant polyglutamines...
  60. pmc SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle
    Takashi Nakagawa
    Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, USA
    Cell 137:560-70. 2009
    b>Sirtuins are NAD-dependent protein deacetylases that connect metabolism and aging. In mammals, there are seven sirtuins (SIRT1-7), three of which are associated with mitochondria...
  61. ncbi Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly
    G Rose
    Department of Cell Biology, University of Calabria, Rende 87030, Italy
    Exp Gerontol 38:1065-70. 2003
    ..The disequilibrium was not significant in any case, thus suggesting that SIRT3 itself, or a gene strictly linked to SIRT3, may have a role in human longevity...
  62. ncbi Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease
    Tiago Fleming Outeiro
    Alzheimer s Research Unit, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA
    Science 317:516-9. 2007
    The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging...
  63. ncbi Sirt1 modulates premature senescence-like phenotype in human endothelial cells
    Hidetaka Ota
    Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 8655, Japan
    J Mol Cell Cardiol 43:571-9. 2007
    ..Our data suggest that Sirt1 may exert protective effects against endothelial dysfunction by preventing stress-induced premature senescence and deranged expression of PAI-1 and eNOS...
  64. ncbi SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction
    Fei Wang
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
    Aging Cell 6:505-14. 2007
    ..Furthermore, as Bim is a pro-apoptotic factor, SIRT2 promotes cell death when cells are under severe stress. Therefore, mammalian SIRT2 responds to caloric restriction and oxidative stress to deacetylate FOXO transcription factors...
  65. pmc Sirt1 protects against high-fat diet-induced metabolic damage
    Paul T Pfluger
    Department of Psychiatry, Obesity Research Center, Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
    Proc Natl Acad Sci U S A 105:9793-8. 2008
    ..Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet...
  66. pmc SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70
    Nagalingam R Sundaresan
    University of Chicago Medical Center, Committee on Cellular and Molecular Physiology, Biological Science Division, University of Chicago, Chicago, Illinois 60637, USA
    Mol Cell Biol 28:6384-401. 2008
    ..These studies underscore an essential role of SIRT3 in the survival of cardiomyocytes in stress situations...
  67. ncbi Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin
    Alejandro Vaquero
    Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
    Mol Cell 16:93-105. 2004
    ..We propose a model for SirT1-mediated heterochromatin formation that includes deacetylation of histone tails, recruitment and deacetylation of histone H1, and spreading of hypomethylated H3-K79 with resultant silencing...
  68. ncbi Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells
    H Ota
    Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    Oncogene 25:176-85. 2006
    ..These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol...
  69. pmc Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator
    Sonia Lain
    Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK
    Cancer Cell 13:454-63. 2008
    ..This underscores the utility of these compounds as biological tools for the study of sirtuin function as well as their potential therapeutic interest...
  70. pmc SirT1 gain of function increases energy efficiency and prevents diabetes in mice
    Alexander S Banks
    Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell Metab 8:333-41. 2008
    ..increases metabolic efficiency, as does administration of polyphenols like resveratrol, thought to act through Sirtuins. But evidence that Sirtuin gain of function results in increased metabolic efficiency in mammals is limited...
  71. ncbi Aging and disease: connections to sirtuins
    Gizem Donmez
    Paul F Glenn Laboratory and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Aging Cell 9:285-90. 2010
    The sirtuins are highly conserved NAD-dependent deacetylases that were shown to regulate lifespan in lower organisms and affect diseases of aging in mammals, such as diabetes, cancer, and inflammation...
  72. pmc Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2
    Bjoern Schwer
    Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 103:10224-9. 2006
    ..Because the activity of a bacterial ortholog of AceCS2, called ACS, is controlled via deacetylation by a bacterial sirtuin protein, our observation highlights the conservation of a metabolic regulatory pathway from bacteria to humans...
  73. pmc Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases
    William C Hallows
    Department of Biomolecular Chemistry, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706, USA
    Proc Natl Acad Sci U S A 103:10230-5. 2006
    Silent Information Regulator 2 (Sir2) enzymes (or sirtuins) are NAD(+)-dependent deacetylases that modulate gene silencing, aging and energy metabolism. Previous work has implicated several transcription factors as sirtuin targets...
  74. pmc Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins
    Eriko Michishita
    Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
    Mol Biol Cell 16:4623-35. 2005
    ....
  75. pmc Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice
    Qing Jun Zhang
    National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, PR China
    Cardiovasc Res 80:191-9. 2008
    ..Recent studies suggest that class III deacetylase SIRT1 may promote cell survival via novel antioxidative mechanisms. The current study tested the hypothesis that SIRT1, specifically overexpressed in the endothelium, is atheroprotective...
  76. pmc Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage
    Jonathan M Solomon
    Elixir Pharmaceuticals, Inc, One Kendall Square, Cambridge, MA 02139, USA
    Mol Cell Biol 26:28-38. 2006
    ..These results show that, although SIRT1 deacetylates p53, this does not play a role in cell survival following DNA damage in certain cell lines and primary human mammary epithelial cells...
  77. ncbi Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans
    H A Tissenbaum
    Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA
    Nature 410:227-30. 2001
    ..1 transgene functions upstream of daf-16 in the insulin-like signalling pathway. Our findings suggest that Sir2 proteins may couple longevity to nutrient availability in many eukaryotic organisms...
  78. pmc Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity
    Hiroaki Daitoku
    Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1 1 1 Ten noudai, Tsukuba, Ibaraki 305 8577, Japan
    Proc Natl Acad Sci U S A 101:10042-7. 2004
    ..Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems...
  79. ncbi SIRT1 deacetylates and positively regulates the nuclear receptor LXR
    Xiaoling Li
    Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
    Mol Cell 28:91-106. 2007
    ..Our findings suggest that deacetylation of LXRs by SIRT1 may be a mechanism that affects atherosclerosis and other aging-associated diseases...
  80. ncbi SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling
    Jennifer Chen
    Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA
    J Biol Chem 280:40364-74. 2005
    ..They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease...
  81. pmc Structure-based development of novel sirtuin inhibitors
    Christine Schlicker
    Department of Biophysics, Ruhr University Bochum, Germany
    Aging (Albany NY) 3:852-72. 2011
    b>Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes...
  82. pmc Negative regulation of the deacetylase SIRT1 by DBC1
    Wenhui Zhao
    Institute for Cancer Genetics, and Department of Pathology College of Physicians and Surgeons, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA
    Nature 451:587-90. 2008
    ..Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1...
  83. ncbi Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses
    Wen Yong Chen
    Cancer Biology Program, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland 21231, USA
    Cell 123:437-48. 2005
    ....
  84. pmc Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence
    Emma Langley
    Wellcome Institute Cancer Research UK and Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QR, UK
    EMBO J 21:2383-96. 2002
    ..Taken together, our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence...
  85. pmc The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth
    Ron Firestein
    Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 3:e2020. 2008
    ..Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies...
  86. ncbi Sirtuins mediate mammalian metabolic responses to nutrient availability
    Angeliki Chalkiadaki
    Paul F Glenn Laboratory, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 68, Cambridge, MA 02139, USA
    Nat Rev Endocrinol 8:287-96. 2012
    ..b>Sirtuins, a conserved family of NAD(+)-dependent deacetylase enzymes found in many species, regulate various metabolic ..
  87. ncbi Sirtuin activators mimic caloric restriction and delay ageing in metazoans
    Jason G Wood
    Department of Pathology, Harvard Medical School, 77 Ave Louis Pasteur, Boston, Massachusetts 02115, USA
    Nature 430:686-9. 2004
    ..Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without ..
  88. ncbi Nutrient availability regulates SIRT1 through a forkhead-dependent pathway
    Shino Nemoto
    Cardiovascular Branch, National Heart, Lung, and Blood Institute NHLBI, Bethesda, MD 20892, USA
    Science 306:2105-8. 2004
    ..SIRT1 expression was not induced in starved p53-deficient mice. Thus, in mammalian cells, p53, Foxo3a, and SIRT1, three proteins separately implicated in aging, constitute a nutrient-sensing pathway...
  89. pmc SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria
    Patrick Onyango
    Institute of Genetic Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, 1064 Ross, 720 Rutland Avenue, Baltimore, MD 21205, USA
    Proc Natl Acad Sci U S A 99:13653-8. 2002
    ..Human homologues, termed sirtuins, are highly conserved but are of unknown function...
  90. pmc Phosphorylation of HuR by Chk2 regulates SIRT1 expression
    Kotb Abdelmohsen
    Laboratory of Cellular and Molecular Biology, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
    Mol Cell 25:543-57. 2007
    ..Our findings demonstrate that HuR regulates SIRT1 expression, underscore functional links between the two stress-response proteins, and implicate Chk2 in these processes...
  91. pmc SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair
    Ronald A McCord
    Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    Aging (Albany NY) 1:109-21. 2009
    ....
  92. ncbi Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state
    Marcella Fulco
    Muscle Gene Expression Group, Laboratory of Muscle Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Mol Cell 12:51-62. 2003
    ..In response to exercise, food intake, and starvation, Sir2 may sense modifications of the redox state and promptly modulate gene expression...
  93. pmc Phosphorylation regulates SIRT1 function
    Tsutomu Sasaki
    Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia, United States of America
    PLoS ONE 3:e4020. 2008
    ..However, other than a recent report on sumoylation [10] and identification of SIRT1 as a nuclear phospho-protein by mass spectrometry [11], post-translational modifications of this important protein have not been reported...
  94. pmc Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose
    K G Tanner
    Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, OR 97201 3098, USA
    Proc Natl Acad Sci U S A 97:14178-82. 2000
    ..We suggest that the reported histone/protein ADP-ribosyltransferase activity is a low-efficiency side reaction that can be explained through the partial uncoupling of the intrinsic deacetylation and acetate transfer to ADP-ribose...
  95. ncbi Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae
    S J Lin
    Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Science 289:2126-8. 2000
    ..These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD...
  96. ncbi FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction
    Yukari Ido Kitamura
    Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, New York 10032, USA
    Cell Metab 2:153-63. 2005
    ..The findings provide a mechanism linking glucose- and growth factor receptor-activated pathways to protect beta cells against oxidative damage via FoxO proteins...
  97. pmc The first identification of lysine malonylation substrates and its regulatory enzyme
    Chao Peng
    Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
    Mol Cell Proteomics 10:M111.012658. 2011
    ..Our results therefore reveal a new type of PTM pathway and identify the first enzyme that can regulate lysine malonylation and lysine succinylation status...
  98. ncbi Evidence that a complex of SIR proteins interacts with the silencer and telomere-binding protein RAP1
    P Moretti
    Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, New York 10032
    Genes Dev 8:2257-69. 1994
    ..These data are consistent with a model in which SIR3 and SIR4 play a structural role in the maintenance of silent chromatin and indicate that their action is initiated at the silencer itself...
  99. pmc Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression
    Thanaset Senawong
    Laboratory of Molecular Pharmacology, Department of Pharmaceutical Sciences, College of Pharmacy, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA
    J Biol Chem 278:43041-50. 2003
    ..These findings implicate SIRT1 as a histone H3/H4 deacetylase in mammalian cells and in transcriptional repression mediated by CTIP2...
  100. ncbi Functions of site-specific histone acetylation and deacetylation
    Mona D Shahbazian
    Department of Biological Chemistry, Geffen School of Medicine and the Molecular Biology Institute, University of California, Los Angeles, California 90095, USA
    Annu Rev Biochem 76:75-100. 2007
    ..Determining how these enzymes create distinct acetylation patterns and regulate the functional outcome is an important challenge...
  101. ncbi Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1
    Yasukazu Nakahata
    Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
    Science 324:654-7. 2009
    ..Our findings in mouse embryo fibroblasts reveal an interlocked transcriptional-enzymatic feedback loop that governs the molecular interplay between cellular metabolism and circadian rhythms...

Research Grants69

  1. THE ROLE OF ACETYLATION IN MITOCHONDRIAL FUNCTION
    Gary Cecchini; Fiscal Year: 2013
    ..One such family is the NAD+dependent family of deacetylases referred to as sirtuins. SIRT3 is a member of this family and appears to be a global deacetylase within the mitochondrion...
  2. Sirtuin/FOXO Signaling in the Regulation of Bone Mass
    Stavroula Kousteni; Fiscal Year: 2012
    ..Cellular fate in response to FOXO1 dephosphorylation depends on Sirtuins. Sirtuins are NAD-dependent protein deacetylases which attenuate stress-induced apoptosis and extend lifespan in ..
  3. ROLE OF SIRTUIN IN CIGARETTE SMOKE-INDUCED LUNG INFLAMMATION AND INJURY
    Irfan Rahman; Fiscal Year: 2013
    ..The NAD+dependent protein deacetylases (sirtuins) have recently emerged as important regulators of aging (apoptosis/senescence), chronic inflammatory diseases and ..
  4. NAD Metabolism and Signaling
    Frances E Lund; Fiscal Year: 2011
    ..showing that NAD is consumed by enzymes that deacetylate lysine and generate putative signaling metabolites (sirtuins), that post-translationally modify protein targets by ADP-ribosylation via poly ADP ribose polymerases (PARPs) ..
  5. Deacetylation of mitochondrial proteins protect neurons from ischemic injury
    Conrad Alano; Fiscal Year: 2013
    ..Removal of the acetyl group (or deacetylation) is catalyzed by deacetylases, including the sirtuins. Sirtuins are a family of NAD-dependent deacetylases that have been implicated in metabolism, cell survival ..
  6. SIRT1 as a regulator of health and lifespan of mammals
    David A Sinclair; Fiscal Year: 2013
    DESCRIPTION (provided by applicant): Sirtuins are a family of NAD+-dependent deacetylases that are thought to have evolved to increase an organism's chances of surviving adversity...
  7. Transcriptional Regulation by a Deacetylase, CobB, in a Periodontopathogen
    DAVID J KOLODRUBETZ; Fiscal Year: 2013
    ..Importantly, since CobB is an NAD+-dependent deacetylase, our results would also suggest that there is a possible new connection between physiology (NAD levels) and transcriptional regulation (acetylation) in bacteria. ..
  8. Chemical approaches for studying the biology of CD38
    Hening Lin; Fiscal Year: 2013
    ..CD38 can have a significant impact on other NAD-dependent enzymes, particularly the NAD-dependent deacetylases (sirtuins) and poly(ADP-ribose) polymerases (PARPs)...
  9. Exercise, Breast Cancer Prevention, and Mechanisms
    Henry J Thompson; Fiscal Year: 2013
    ..If mTOR-IGF-1 is not explanatory, alternative hypothesis centers on sirtuins and forkhead transcription factors (FOXO) by IL-6;and 3) How does PA affect the expansion of tumor mass in ..
  10. Regulation of mitochondrial metabolism by lysine acetylation
    Eric S Goetzman; Fiscal Year: 2013
    ..Specific Aim 1 will investigate interactions between the mitochondrial sirtuins Sirt3, Sirt4, and Sirt5 and the enzymes very long-chain acyl-CoA dehydrogenase (VLCAD), medium chain-acyl-CoA ..
  11. Novel Role for Sirtuin Signaling Mechanisms and Downstream Targets in Depression
    Deveroux Ferguson; Fiscal Year: 2013
    ..protein is the founding member of a family of NAD+-dependent deacetylases and ADP-ribosyltransferases, termed sirtuins. In this grant we propose to test the hypothesis that modulation of SIRT1 constitutes a novel candidate ..
  12. Mammalian SIRT6 Is A Master Regulator Of Glucose Homeostasis
    Raul Mostoslavsky; Fiscal Year: 2013
    ..adapt the cellular metabolic activity;while recent studies indicate that some of the mammalian homologs (termed sirtuins) play a role in stress resistance and metabolic homeostasis, their precise molecular functions remain to be fully ..
  13. The role of the deacetylase Sirt1 in the maintenance of adult neural stem cells
    VICTORIA RAFALSKI; Fiscal Year: 2010
    ..Importantly, the enzymatic activity of Sirt1 can be targeted with small molecule activators or inhibitors, providing a valuable avenue for therapeutic interventions for neurological disorders that may be treated with neural stem cells. ..
  14. FASEB SRC on HDACs, Sirtuins and Reversible Acetylation in Signaling and Disease
    Scott W Hiebert; Fiscal Year: 2013
    ..In addition, the Sirtuins, a subclass of HDACs, were fingered in yeast genetic studies as regulating lifespan, and these enzymes might be ..
  15. Regulation of yeast cellular aging through chromatin and novel pathways
    Weiwei Dang; Fiscal Year: 2013
    ..studies, and our previous research in this area have focused on only a few known histone modification targets of Sirtuins. It is of tremendous interest to discover new histone targets of Sirtuins and other chromatin-mediated aging ..
  16. Mechanisms of SIRT2 Function in the Replication Stress Response
    David Yu; Fiscal Year: 2013
    ..Prior work has implicated sirtuins in both aging and tumor suppression...
  17. Regulation of insulin sensitivity by TUG acetylation
    JONATHAN BOGAN; Fiscal Year: 2013
    ..How aging affects insulin action in fat and muscle is not well understood. Sirtuins comprise a family of NAD+-dependent lysine deacetylases, which are implicated in various aspects of aging and ..
  18. SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION
    Shin Ichiro Imai; Fiscal Year: 2013
    ..SIR2 (silent information regulator 2) family of NAD-dependent deacetylases/ADP-ribosyltransferases, also called "sirtuins," as a critical regulator that coordinates physiological responses to DR...
  19. Differential Impact of Resveratrol and Resveratrol Mimetics Upon Aging Bone
    Bruce R Troen; Fiscal Year: 2013
    ..b>Sirtuins have been implicated in metabolism, longevity, and healthspan...
  20. The Role of SIRT6 in Modulating Circadian Gene Expression
    Selma Masri; Fiscal Year: 2012
    ..The goal of this proposal is to elucidate the mechanisms of regulation of the mammalian sirtuins, class III histone deacetylases (HDACs), on circadian gene expression and biological rhythmicity in vivo...
  21. Novel mechanisms of mitochondrial regulation by sirtuin deacetylases
    DAVID BENNER LOMBARD; Fiscal Year: 2013
    ..This application focuses on novel roles for sirtuin proteins in regulating key mitochondrial functions. Sirtuins are a family of deacetylases that promote increased longevity in invertebrate models and modulate diverse ..
  22. Blocking cardiac toxicity of anticancer drugs
    Mahesh P Gupta; Fiscal Year: 2013
    ..My laboratory has specific interest in sirtuins, which are capable of protecting the heart from variou pathological stimuli...
  23. EXERCISE AND FUEL METABOLISM
    David H Wasserman; Fiscal Year: 2013
    ..Speciic Aims will test in lean and high fat fed mice whether (a) the activation of hepatic energy sensors (AMPK, sirtuins, hypoxia inducible factors) are protective against insulin resistance; (b) the extracellular matrix conveys a ..
  24. Activation of sirtuins to prevent adverse cardiac remodeling after CABG
    Mahesh P Gupta; Fiscal Year: 2013
    ..My laboratory has specific interest in sirtuins, which are capable of activating intracellular anti-oxidant defense mechanisms and extending life-span of species...
  25. The role of nicotinamide N-methyltransferase in glucose and lipid homeostasis
    Pavlos Pissios; Fiscal Year: 2013
    ..Nicotinamide is a potent inhibitor of sirtuins, recently recognized important metabolic regulators in the liver and other tissues...
  26. Sirtuins in Glaucomatous Optic Neuropathy
    Robert N Weinreb; Fiscal Year: 2013
    ..protection against the normal age-related loss of retinal ganglion cells by Sirt1 activation suggests that the sirtuins are highly relevant to glaucoma...
  27. Function of SIRT1 in Growth and Reproduction
    Leonard P Guarente; Fiscal Year: 2013
    DESCRIPTION (provided by applicant): Sirtuins are NAD-dependent deacetylases that have been implicated in aging and metabolism in organisms ranging from bacteria to mice. In mammals, there are seven sirtuins termed SIRT1-7...
  28. High-throughput assays for the development of SIRT5-specific inhibitors
    Hening Lin; Fiscal Year: 2012
    DESCRIPTION (provided by applicant): Sirtuins are a class of enzymes known as nicotinamide adenine dinucleotide (NAD)- dependent deacetylases...
  29. Regulation of mitochondrial metabolism by SIRT4
    Marcia Haigis; Fiscal Year: 2013
    ..Mammals have seven Sir2 homologs (sirtuins;SIRT1-7), which regulate distinct aspects of metabolism...
  30. Role of SIRT3 in Modulation of Lipotoxicity in Liver
    SEAN ALEC NEWSOM; Fiscal Year: 2013
    DESCRIPTION (provided by applicant): Sirtuins are NAD+-dependent protein deacetylases that mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress...
  31. MECHANISM OF ACTION OF YEAST SILENCING COMPLEXES
    Danesh Moazed; Fiscal Year: 2013
    ....
  32. REVIVE - Resveratrol to enhance vitality and vigor in elders
    Stephen D Anton; Fiscal Year: 2013
    ..decline in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and specific Sirtuins (i.e., SIRT3) in skeletal muscle, both of which are regulators of mitochondria biogenesis...
  33. NAD Biosynthesis and the Regulation of Sirtuins
    JEFFREY SCOTT SMITH; Fiscal Year: 2012
    The Sirtuins are a conserved family of NAD-dependent protein deacetylases that function in a wide variety of cellular processes, including repression of gene expression (silencing), apoptosis, and lifespan regulation...
  34. The role of astrocytes in memory consolidation
    Virginia Gao; Fiscal Year: 2013
    ..Proteins that are known to be regulated by redox state and reactive oxygen species include sirtuins, a class of deacetylases involved in a number of cellular functions, of which SIRT1 is known to play a role in ..
  35. Type-1 Diabetes: Zn2+ Potentiated Beta-Cell Death By Sirtuin-Mediated NAD+ Loss
    CHRISTIAN THOMAS SHELINE; Fiscal Year: 2010
    ..These experiments will test novel therapeutic compounds (pyruvate, sirtinol) and mechanisms (NAD+loss, sirtuins) involved in Zn2+ mediation of beta-cell death in type-1 diabetes.
  36. Role of Nrf2 in Ischemic Preconditioning-Induced Neuroprotection
    Srinivasan V Narayanan; Fiscal Year: 2013
    ..if Nrf2 activation and nuclear translocatio are regulated by protein kinase C[unreadable] (PKC[unreadable]) and sirtuins (family of protein/histone deacetylases), specifically sirtuin 1 (SIRT1), following IPC;(2) Determine the ..
  37. Intramitochondrial function of the deacetylase SIRT3
    JOSEPH DANIEL PENNINGTON; Fiscal Year: 2011
    ..A family of genes called the sirtuins exists in nearly every life form and has been closely associated with aging regulation...
  38. Probing functions of NAM and NAD+ salvage in development and aging in C. elegans
    Wendy Hanna-Rose; Fiscal Year: 2013
    ..the molecular mechanisms underlying organ pathologies caused by perturbations of NAD+ precursor deficiency and metabolism in humans and will shed light on key aspects of regulation of lifespan promotion by sirtuins.
  39. Sirtuin regulation of aging human primary adipose tissue
    Ivona Percec; Fiscal Year: 2013
    ..Based on these studies, I propose to validate the functional role of sirtuins in primary human adipose aging and to identify specific sirtuin regulators that reverse or induce age-associated ..
  40. Chemical Tools to Visualize Sirtuin Activity in Cells
    Anthony A Sauve; Fiscal Year: 2013
    DESCRIPTION (provided by applicant): The mammalian sirtuins (SIRT1-7) are NAD+-dependent deacetylase enzymes that regulate adaptations of cells to nutrient availability and are linked to the life-extending and health-providing benefits ..
  41. TWO NOVEL CPLA2 BINDING PROTEINS AND CELL DEATH
    JOSEPH VINCENT BONVENTRE; Fiscal Year: 2010
    ..SIRT2 shares large areas of homology with other class I sirtuins, including SIRT1...
  42. Reversible protein acetylation and sirtuin function
    John M Denu; Fiscal Year: 2013
    ..To accomplish these goals, we will investigate the biochemical and biological functions of sirtuins, NAD+dependent protein deacetylases, which are implicated in genome maintenance, metabolism, cell survival, and ..
  43. Functional Sir2-RNA Interactions
    JEFFREY SCOTT SMITH; Fiscal Year: 2013
    DESCRIPTION (provided by applicant): The Sirtuins are a conserved family of NAD+-dependent protein deacetylases that function in a wide variety of cellular processes related to aging and age-associated disease...
  44. SCA7 neurodegeneration: molecular epigenetic basis and therapy development
    Albert R La Spada; Fiscal Year: 2013
    ..and functional interaction between Sgf73 and Sir2, the original member of a family of proteins known as the "sirtuins", and noted a physical interaction between ataxin-7 and mammalian Sirt1...
  45. Nicotinamide Riboside and NAD+: Modulation of Sirtuins and Reactive Oxygen
    Anthony A Sauve; Fiscal Year: 2013
    DESCRIPTION (provided by applicant): The mammalian sirtuins (SIRT1-7) are NAD+-dependent deacetylase enzymes that deacetylate cellular proteins to regulate their target proteins...
  46. Investigating the biology of lysine succinylation
    PHILIP MERKSAMER; Fiscal Year: 2013
    ..cerevisiae sirtuins for desuccinylase activity Aim 2: To identify, characterize, and quantify the S...
  47. The role of Sirt1 in Huntington's Disease.
    Dimitri Krainc; Fiscal Year: 2013
    ..More generally, this work will further our understanding of the precise mechanistic link between the sirtuins and healthy brain aging, and potentiate development of drugs that delay and ameliorate neurodegenerative diseases. ..
  48. Mechanisms of tumor suppression by the chromatin deacetylase SIRT6
    DAVID BENNER LOMBARD; Fiscal Year: 2013
    ..The sirtuins are a family of protein deacetylases that promote many aspects of healthspan in mammals, among them tumor ..
  49. Mechanisms of Epigenetic Gene Silencing
    Kevin Pruitt; Fiscal Year: 2013
    ..This proposal will explore entirely new links between a relatively unexplored class of deacetylases (the sirtuins) and proteins that bind to methylated DNA (methyl-CpG binding proteins) in gene silencing...
  50. Mechanisms Specific to the Beneficial Effects of Dietary Restriction
    William B Mair; Fiscal Year: 2013
    ..Although nutrient- sensing mediators of DR have been identified, such as mTOR, FOXO/As and the sirtuins, these central nodes recapitulate the entirety of the response, making them sub-optimal therapeutic targets...
  51. Not Only SIRT1: A Role for Nuclear SIRT6 in Circadian Control
    Paolo Sassone-Corsi; Fiscal Year: 2013
    ..Recent results in our laboratory however indicate that SIRT1 can't be the whole story: other sirtuins operate in the nucleus and one of them, SIRT6, is tightly associated to chromatin and has been shown to play a ..
  52. NAD+ metabolism in prostate cancer
    Steven J Kridel; Fiscal Year: 2013
    ..Specifically, we posit that a trefoil of NAD+-dependent enzymes, namely Nampt, CD38 and the sirtuins control lipid metabolism to support prostate cancer cell survival, wherein the sirtuins act as the metabolic ..
  53. Homogenous NAD assay for ARDT activity measurement
    Karen Wu; Fiscal Year: 2013
    DESCRIPTION: Sirtuins and ADP ribosyltransferases (ARDTs) are two families of related enzymes that have important medically relevant functions...
  54. Sirtuins and Metabolic Pathway Integration
    JORGE C ESCALANTE; Fiscal Year: 2012
    ..Given the ubiquity of the SDPADS, advances in this research area will have broad impact on our understanding of the physiology of all cells. ..
  55. SIRT1 Overexpression in Cellular Mitochondrial Metabolism and Function
    James Russell; Fiscal Year: 2009
    ..Activation of the sirtuins offers the potential for a novel treatment of several human diseases that are related to oxidative injury and ..
  56. Histone Deacetylases and reversible acetylation in signaling and disease
    JOHN DENU; Fiscal Year: 2009
    ..Particularly, key topics will include the sirtuins deacetylases, which are NAD-dependent deacetylases involved in aging and metabolism...
  57. Understanding the mechanism of cell senescence delay by methylene blue
    Hani Atamna; Fiscal Year: 2011
    ..will investigate our hypothesis that MB delays cellular senescence by improving specific functions including, Sirtuins, AMPK, telomeres and by increasing the biogenesis of specific mitochondrial components...
  58. Role of Sirt3 in Aging and Caloric Restriction
    TOMAS ALBERTO PROLLA; Fiscal Year: 2013
    ..from the study will provide a detailed molecular understanding of mitochondrial adaptation to CR and the role of sirtuins in these pathways;Knowledge of the molecular mechanisms and key pathways regulated has potential for ..
  59. Sirtuins in Metabolism, Aging and Disease
    James Aiken; Fiscal Year: 2011
    DESCRIPTION (provided by applicant): This proposal requests support for a Keystone Symposia meeting entitled Sirtuins in Metabolism, Aging and Disease, organized by Alexsey G...
  60. Chemical/biochemical tools for studying novel protein acyl lysine modifications
    Hening Lin; Fiscal Year: 2013
    ..We have shown that these new acyl lysine modifications occur in mammalian cells and there are dedicated enzymes (sirtuins) that can remove them efficiently...
  61. Computational Studies of Histone Modifications
    Yingkai Zhang; Fiscal Year: 2013
    ..Aim 2: Elucidate inner workings of sirtuins, a novel family o class III histone deacetylases. Aim 3: Advance ab initio QM/MM methods...
  62. Function of Mammalian SIRT1 in Aging
    Leonard P Guarente; Fiscal Year: 2013
    ..PUBLIC HEALTH RELEVANCE: Sirtuins regulate life span in lower organisms and may mediate some of the effects of calorie restriction...
  63. NAD Metabolism and Signaling Conference
    JOHN DENU; Fiscal Year: 2009
    ..Topic areas will include the cellular pathways and medical implications of such NAD+- dependent enzymes as sirtuins, glycohydrolases, oxidoreductases, PARPs, PARGs, and ADP-ribosyl cyclases, as well as NAD+ synthesizing enzymes ..
  64. Protein Acetylation Signature of ES Cell Differentiation
    Alexey Terskikh; Fiscal Year: 2007
    ..acetylation profile between ES cells and their differentiated progeny, embryoid bodies and the role of individual Sirtuins in protein acetylation in ES cells...
  65. 2009 Molecular and Cellular Bioenergetics (Gordon Research Conference)
    David Nicholls; Fiscal Year: 2009
    ..of the mitochondrial theory of aging, the roles of mitochondrial mutations and the exciting possibilities of sirtuins and resveratrol...
  66. TRANSCRIPTIONAL SILENCING MECHANISMS
    JEF BOEKE; Fiscal Year: 2005
    ..We will use the tools of molecular genetics, biochemistry and structural biology to carry out a comprehensive analysis of the molecular mechanisms involved in silencing. ..
  67. Mechanism of Sir2 Family of NAD+-dependent Deacetylases
    Margie Borra; Fiscal Year: 2005
    ..The enzymatic function of Sir2 and its homologs, called sirtuins, were established just recently...
  68. Synergistic Nutraceutical Effects of DLPC and SAMe
    Charles Lieber; Fiscal Year: 2007
    ..unreadable] [unreadable] [unreadable]..
  69. ANTIVIRAL & ANTIFIBROTIC LIVER THERAPY OF HCV+ DRINKERS
    Charles Lieber; Fiscal Year: 2005
    ..Funds are requested for special laboratory tests, study nurses, travel to meetings, patient monitoring expenses and a core office. ..