Research Topics
Genomes and Genes
| David A SinclairSummaryAffiliation: Harvard University Country: USA Publications
Research Grants
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Detail Information
Publications
TPE or not TPE? It's no longer a questionJason G Wood
Dept of Pathology, Harvard Medical School, Boston, MA 02115
Trends Pharmacol Sci 23:1-4. 2002
The longevity of sirtuinsDavid Sinclair
Glenn Laboratories for the Molecular Biology of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Cell Rep 2:1473-4. 2012..In this issue of Cell Reports, Banerjee et al. demonstrate that Drosophila Sir2 is necessary for life span extension in response to dietary restriction and that its overexpression in the fat body increases the life span...- Paradigms and pitfalls of yeast longevity researchDavid A Sinclair
Department of Pathology, Harvard Medical School, Boston MA 02115, USA
Mech Ageing Dev 123:857-67. 2002..Characterizing this and other mechanisms of yeast aging should help identify additional components of longevity pathways in higher organisms... 
The ageing epigenome: damaged beyond repair?David A Sinclair
The Paul F Glenn Laboratories for the Biological Mechanisms of Ageing, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
Ageing Res Rev 8:189-98. 2009....- Is DNA cut out for a long life?David Sinclair
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
Sci Aging Knowledge Environ 2003:PE8. 2003..In this Perspective, I discuss results presented in this month's issue of Aging Cell that address whether the types of DNA damage repaired by the base excision repair pathway cause aging in yeast... - Toward a unified theory of caloric restriction and longevity regulationDavid A Sinclair
Department of Pathology, Harvard Medical School, 77 Avenue Louis Paster, Boston, MA 02115, USA
Mech Ageing Dev 126:987-1002. 2005..This has important implications for how we might develop novel medicines that can harness these newly discovered innate mechanisms of disease resistance and survival... - Cell biology. An age of instabilityDavid A Sinclair
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
Science 301:1859-60. 2003..As yeast cells age there is a marked increase in their genetic instability (a hallmark of cancer), which is independent of the mechanism that determines their life-span... - HST2 mediates SIR2-independent life-span extension by calorie restrictionDudley W Lamming
Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Science 309:1861-4. 2005..These findings demonstrate that the maintenance of DNA stability is critical for yeast life-span extension by CR and suggest that, in higher organisms, multiple members of the Sir2 family may regulate life span in response to diet... - Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiaeRozalyn M Anderson
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
Nature 423:181-5. 2003..We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms... - Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylaseHaim 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... - Yeast life-span extension by calorie restriction is independent of NAD fluctuationRozalyn M Anderson
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston MA 02115, USA
Science 302:2124-6. 2003..Moreover, the activity of Sir2 and its human homologue SIRT1 are not affected by physiological alterations in the NAD+:NADH ratio. These data implicate alternate mechanisms of Sir2 regulation by CR... - Design and synthesis of compounds that extend yeast replicative lifespanHongying Yang
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
Aging Cell 6:35-43. 2007..These studies show that it is possible to improve upon naturally occurring STACs based on a number of criteria including lifespan extension... - Nutrient-sensitive mitochondrial NAD+ levels dictate cell survivalHongying Yang
Department of Pathology, Paul F Glenn Laboratories, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Cell 130:1095-107. 2007..We discuss the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis... - Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1Kevin J Bitterman
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
J Biol Chem 277:45099-107. 2002..We discuss the possibility that nicotinamide is a physiologically relevant regulator of Sir2 enzymes... - Unlocking the secrets of longevity genesDavid A Sinclair
Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, USA
Sci Am 294:48-51, 54-7. 2006 - MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiaeOliver Medvedik
Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America
PLoS Biol 5:e261. 2007..These findings suggest that TOR and sirtuins may be part of the same longevity pathway in higher organisms, and that they may promote genomic stability during aging... - The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growthRon 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... - SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during agingPhilipp Oberdoerffer
Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, MA 02115, USA
Cell 135:907-18. 2008..Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes... - Nampt/PBEF/Visfatin: a regulator of mammalian health and longevity?Hongying Yang
Department of Pathology, Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA, USA
Exp Gerontol 41:718-26. 2006..We propose that there is a functional equivalent of PNC1 in mammals called Nampt (a.k.a. PBEF/Visfatin), a stress-responsive gene that would coordinately regulate metabolism, cell defenses, and resistance to diseases of aging... - Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatinKevin J Bitterman
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
Microbiol Mol Biol Rev 67:376-99, table of contents. 2003..We also present the specific methods used to study aging and longevity regulation in S. cerevisiae... - The role of protein arginine methylation in the formation of silent chromatinMichael C Yu
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
Genes Dev 20:3249-54. 2006..These data suggest a model whereby protein arginine methylation affects the establishment and maintenance of silent chromatin... - Small molecules that regulate lifespan: evidence for xenohormesisDudley W Lamming
Harvard Medical School, Department of Pathology, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Mol Microbiol 53:1003-9. 2004..In this way, organisms can prepare in advance for a deteriorating environment and/or loss of food supply... - SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial functionNathan L Price
Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA
Cell Metab 15:675-90. 2012..Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo... - Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylaseAnne 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... - Caloric restriction and life span determination of yeast cellsOliver Medvedik
Pharmacology Department, Harvard Medical School, Boston, MA, USA
Methods Mol Biol 371:97-109. 2007..cerevisiae (6-8)... - SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosisDohoon 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... - The intersection between aging and cardiovascular diseaseBrian J North
Glenn Laboratories for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA, USA
Circ Res 110:1097-108. 2012.... - Resveratrol improves health and survival of mice on a high-calorie dietJoseph A Baur
Department of Pathology, Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
Nature 444:337-42. 2006..These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing... - SIRT1 is essential for normal cognitive function and synaptic plasticityShaday Michan
Paul F Glenn Laboratories, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
J Neurosci 30:9695-707. 2010..In contrast, mice with high levels of SIRT1 expression in brain exhibited regular synaptic plasticity and memory. We conclude that SIRT1 is indispensable for normal learning, memory, and synaptic plasticity in mice... - The role of nuclear architecture in genomic instability and ageingPhilipp Oberdoerffer
Department of Pathology, Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts, USA
Nat Rev Mol Cell Biol 8:692-702. 2007.... - Mammalian sirtuins: biological insights and disease relevanceMarcia 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..This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years... - Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosisHaim Y Cohen
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115 USA
Mol Cell 13:627-38. 2004..We demonstrate that increased acetylation of Ku70 disrupts the Ku70-Bax interaction and coincides with cytoplasmic accumulation of CBP. These results shed light on the role of acetyltransferases as tumor suppressors... - Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophyAngela V Hafner
Harvard Medical School, Department of Pathology and Glenn Labs for Aging Research, Boston, MA 02115, USA
Aging (Albany NY) 2:914-23. 2010.... - Evidence for a common mechanism of SIRT1 regulation by allosteric activatorsBasil P Hubbard
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Science 339:1216-9. 2013..In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs... - Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signalingBogdan Beirowski
Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, USA
Proc Natl Acad Sci U S A 108:E952-61. 2011..These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity... - Prolyl isomerase Pin1 regulates neuronal differentiation via β-cateninKazuhiro Nakamura
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Mol Cell Biol 32:2966-78. 2012.... - Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levelsRozalyn M Anderson
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
J Biol Chem 277:18881-90. 2002..We propose a model in which increased flux through the NAD(+) salvage pathway is responsible for the Sir2-dependent extension of life span... - Therapeutic potential of resveratrol: the in vivo evidenceJoseph A Baur
Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
Nat Rev Drug Discov 5:493-506. 2006..Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans... - Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesisAna P Gomes
Center for Neurosciences and Cell Biology, Department of Life Sciences, University of Coimbra 3004 517 Coimbra, Portugal
Biochim Biophys Acta 1822:185-95. 2012..Taken together, these data reveal an important role for SIRT1 and mitochondrial biogenesis in the preventive effects of BBR on diet-induced insulin resistance... - Sirtuins: a conserved key unlocking AceCS activityBrian J North
Department of Pathology, Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Trends Biochem Sci 32:1-4. 2007..These findings highlight a metabolic regulatory network controlled by sirtuins that has implications for the mechanisms of calorie restriction and modulation of mammalian lifespan... - Inhibition of mammalian S6 kinase by resveratrol suppresses autophagySean M Armour
Department of Pathology and Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA
Aging (Albany NY) 1:515-28. 2009..These data indicate that S6K1 is important for the full induction of autophagy in mammals and raise the possibility that some of the beneficial effects of resveratrol are due to modulation of S6K1 activity... - A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complexSean M Armour
Department of Genetics and The Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, Massachusetts, USA
Mol Cell Biol 33:1487-502. 2013..Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex... - Resveratrol inhibits pathologic retinal neovascularization in Vldlr(-/-) miceJing Hua
Department of Ophthalmology, Harvard Medical School, Children s Hospital, Boston, Massachusetts 02115, USA
Invest Ophthalmol Vis Sci 52:2809-16. 2011..In this study, the authors evaluate the therapeutic potential of resveratrol, a plant polyphenol, in Vldlr(-/-) mice as a model for MacTel... - Sirtuin activators mimic caloric restriction and delay ageing in metazoansJason G Wood
Department of Pathology, Harvard Medical School, 77 Ave Louis Pasteur, Boston, Massachusetts 02115, USA
Nature 430:686-9. 2004..Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction... - Life-span extension in yeastDavid A Sinclair
Science 312:195-7; author reply 195-7. 2006 - Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespanKonrad T Howitz
BIOMOL Research Laboratories, Inc, 5120 Butler Pike, Plymouth Meeting, Pennsylvania 19462, USA
Nature 425:191-6. 2003..We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators... - Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitorsAntonello Mai
Dipartimento di Studi Farmaceutici, Istituto Pasteur, Fondazione Cenci Bolognetti, Universita degli Studi di Roma La Sapienza, P le A Moro 5, 00185 Roma, Italy
J Med Chem 48:7789-95. 2005..3-13 times less potent than sirtinol, whereas the 2'-carboxamido analogue was totally inactive. Both (R)- and (S)-sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect... - Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetesJill 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... - Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life spanKevin J Pearson
Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA
Cell Metab 8:157-68. 2008..Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife... - David A. Sinclair, Ph.D is interviewed by Vicki GlaserDavid A Sinclair
Rejuvenation Res 11:265-8. 2008
Research Grants
- Yeast screens for genetic & chemical mimetics of CRDavid Sinclair; Fiscal Year: 2006..The longer-term goal is to test the genes and compounds we identify for their ability to extend life span in C. elegans. The knowledge gained should serve to guide searches for compounds that retard aging in mammals. ..
- NAD+ control of transcriptional silencing and longevityDavid Sinclair; Fiscal Year: 2007..As far as we are aware, our approach to understanding this fundamental regulatory network is unique. ..
- SIRT as a regulator of health and lifespan of mammalsDavid Sinclair; Fiscal Year: 2007....
- SIRT as a regulator of health and lifespan of mammalsDavid A Sinclair; Fiscal Year: 2010....
- Role of Sgs1 DNA helicase in telomere maintenanceDavid Sinclair; Fiscal Year: 2005....
- Role of Chromatin in Genomic MaintenanceDavid A Sinclair; Fiscal Year: 2010....