Photo of David A. Sinclair,  PhD

David A. Sinclair, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-3931
Fax: (617) 432-6225


david_sinclair@hms.harvard.edu

David A. Sinclair, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Professor, Genetics, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Publications

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  • Zhang QS, Deater M, Schubert K, Marquez-Loza L, Pelz C, Sinclair DA, Grompe M. The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. 2015; 15:130-140. PubMed
  • Gomes AP, Sinclair DA. Measuring PGC-1留 and its acetylation status in mouse primary myotubes. Methods Mol Biol 2014; 1241:49-57. PubMed
  • Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, Oláh J, Ladwein KI, Schmidtkunz K, Gajer M, Pannek M, Steegborn C, Sinclair DA, Gerhardt S, Ovádi J, Schutkowski M, Sippl W, Einsle O, Jung M. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat Commun 2015; 6:6263. PubMed
  • Moroz N, Carmona JJ, Anderson E, Hart AC, Sinclair DA, Blackwell TK. Dietary restriction involves NAD(+) -dependent mechanisms and a shift toward oxidative metabolism. Aging Cell 2014. PubMed
  • Rimmelé P, Bigarella CL, Liang R, Izac B, Dieguez-Gonzalez R, Barbet G, Donovan M, Brugnara C, Blander JM, Sinclair DA, Ghaffari S. Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem Cell Reports 2014; 3:44-59. PubMed
  • North BJ, Rosenberg MA, Jeganathan KB, Hafner AV, Michan S, Dai J, Baker DJ, Cen Y, Wu LE, Sauve AA, van Deursen JM, Rosenzweig A, Sinclair DA. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J 2014. PubMed
  • Yoon JC, Ling AJ, Isik M, Lee DY, Steinbaugh MJ, Sack LM, Boduch AN, Blackwell TK, Sinclair DA, Elledge SJ. GLTSCR2/PICT1 links mitochondrial stress and Myc signaling. Proc Natl Acad Sci U S A 2014; 111:3781-6. PubMed
  • Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 2014; 35:146-54. PubMed
  • Wu LE, Gomes AP, Sinclair DA. Geroncogenesis: metabolic changes during aging as a driver of tumorigenesis. Cancer Cell 2014; 25:12-9. PubMed
  • Sinclair DA, Guarente L. Small-molecule allosteric activators of sirtuins. Annu Rev Pharmacol Toxicol 2014; 54:363-80. PubMed
  • Schmeisser K, Mansfeld J, Kuhlow D, Weimer S, Priebe S, Heiland I, Birringer M, Groth M, Segref A, Kanfi Y, Price NL, Schmeisser S, Schuster S, Pfeiffer AF, Guthke R, Platzer M, Hoppe T, Cohen HY, Zarse K, Sinclair DA, Ristow M. Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat Chem Biol 2013; 9:693-700. PubMed
  • Hubbard BP, Loh C, Gomes AP, Li J, Lu Q, Doyle TL, Disch JS, Armour SM, Ellis JL, Vlasuk GP, Sinclair DA. Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism. Cell Cycle 2013; 12:2233-40. PubMed
  • Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun 2013; 4:2192. PubMed
  • Hubbard BP, Sinclair DA. Measurement of sirtuin enzyme activity using a substrate-agnostic fluorometric nicotinamide assay. Methods Mol Biol 2013; 1077:167-77. PubMed
  • Sinclair DA. Studying the replicative life span of yeast cells. Methods Mol Biol 2013; 1048:49-63. PubMed
  • Nakamura K, Kosugi I, Lee DY, Hafner A, Sinclair DA, Ryo A, Lu KP. Prolyl isomerase Pin1 regulates neuronal differentiation via 硫-catenin. Mol Cell Biol 2012; 32:2966-78. PubMed
  • Bernier M, Paul RK, Martin-Montalvo A, Scheibye-Knudsen M, Song S, He HJ, Armour SM, Bohr VA, Wang L, Zong Y, Sinclair DA, de Cabo R. Negative regulation of STAT3-mediated cellular respiration by SirT1. J Biol Chem 2011. PubMed
  • Yang Y, Hubbard BP, Sinclair DA, Tong Q. Characterization of murine SIRT3 transcript variants and corresponding protein products. J Cell Biochem 2010; 111:1051-8. PubMed
  • Baur JA, Chen D, Chini EN, Chua K, Cohen HY, de Cabo R, Deng C, Dimmeler S, Gius D, Guarente LP, Helfand SL, Imai S, Itoh H, Kadowaki T, Koya D, Leeuwenburgh C, McBurney M, Nabeshima Y, Neri C, Oberdoerffer P, Pestell RG, Rogina B, Sadoshima J, Sartorelli V, Serrano M, Sinclair DA, Steegborn C, Tatar M, Tissenbaum HA, Tong Q, Tsubota K, Vaquero A, Verdin E. Dietary restriction: standing up for sirtuins. Science 2010; 329:1012-3; author reply 1013-4. PubMed
  • Michán S, Li Y, Chou MM, Parrella E, Ge H, Long JM, Allard JS, Lewis K, Miller M, Xu W, Mervis RF, Chen J, Guerin KI, Smith LE, McBurney MW, Sinclair DA, Baudry M, de Cabo R, Longo VD. SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci 2010; 30:9695-707. PubMed
  • Le Couteur DG, Sinclair DA. A blueprint for developing therapeutic approaches that increase healthspan and delay death. J Gerontol A Biol Sci Med Sci 2010; 65:693-4. PubMed
  • Rutanen J, Yaluri N, Modi S, Pihlajamäki J, Vänttinen M, Itkonen P, Kainulainen S, Yamamoto H, Lagouge M, Sinclair DA, Elliott P, Westphal C, Auwerx J, Laakso M. SIRT1 mRNA Expression May Be Associated with Energy Expenditure and Insulin Sensitivity. Diabetes 2010; 59:829-35. PubMed
  • Blagosklonny MV, Campisi J, Sinclair DA, Bartke A, Blasco MA, Bonner WM, Bohr VA, Brosh RM, Brunet A, Depinho RA, Donehower LA, Finch CE, Finkel T, Gorospe M, Gudkov AV, Hall MN, Hekimi S, Helfand SL, Karlseder J, Kenyon C, Kroemer G, Longo V, Nussenzweig A, Osiewacz HD, Peeper DS, Rando TA, Rudolph KL, Sassone-Corsi P, Serrano M, Sharpless NE, Skulachev VP, Tilly JL, Tower J, Verdin E, Vijg J. Impact papers on aging in 2009. Aging (Albany NY) 2010; 2:111-21. PubMed
  • Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 2010; 5:253-95. PubMed
  • Sinclair DA,Oberdoerffer P. The ageing epigenome: damaged beyond repair? Ageing Res Rev 2009; 8:189-98. PubMed
  • Armour SM, Baur JA, Hsieh SN, Land-Bracha A, Thomas SM, Sinclair DA. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging (Albany NY) 2010; 1:515-28. PubMed
  • Jimenez-Hidalgo M,Santos-Ocana C,Padilla S,Villalba JM,Lopez-Lluch G,Martin-Montalvo A,Minor RK,Sinclair DA,de Cabo R,Navas P. NQR1 controls lifespan by regulating the promotion of respiratory metabolism in yeast. Aging Cell 2009; 8:140-51. PubMed
  • Jin L,Galonek H,Israelian K,Choy W,Morrison M,Xia Y,Wang X,Xu Y,Yang Y,Smith JJ,Hoffmann E,Carney DP,Perni RB,Jirousek MR,Bemis JE,Milne JC,Sinclair DA,Westphal CH. Biochemical characterization, localization, and tissue distribution of the longer form of mouse SIRT3. Protein Sci 2009; 18:514-25. PubMed
  • Oberdoerffer P,Michan S,McVay M,Mostoslavsky R,Vann J,Park SK,Hartlerode A,Stegmuller J,Hafner A,Loerch P,Wright SM,Mills KD,Bonni A,Yankner BA,Scully R,Prolla TA,Alt FW,Sinclair DA. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 2008; 135:907-18. PubMed
  • Pearson KJ,Baur JA,Lewis KN,Peshkin L,Price NL,Labinskyy N,Swindell WR,Kamara D,Minor RK,Perez E,Jamieson HA,Zhang Y,Dunn SR,Sharma K,Pleshko N,Woollett LA,Csiszar A,Ikeno Y,Le Couteur D,Elliott PJ,Becker KG,Navas P,Ingram DK,Wolf NS,Ungvari Z,Sinclair DA,de Cabo R. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8:157-68. PubMed
  • Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, Hahn WC, Guarente LP, Sinclair DA. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE 2008; 3:e2020. PubMed
  • Li Y, Yokota T, Gama V, Yoshida T, Gomez JA, Ishikawa K, Sasaguri H, Cohen HY, Sinclair DA, Mizusawa H, Matsuyama S. Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation. Cell Death Differ 2007; 14:2058-67. PubMed
  • Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007; 450:712-6. PubMed
  • Barbosa MT, Soares SM, Novak CM, Sinclair D, Levine JA, Aksoy P, Chini EN. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J 2007; 21:3629-39. PubMed
  • Medvedik O, Lamming DW, Kim KD, Sinclair DA. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol 2007; 5:e261. PubMed
  • Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 2007; 130:1095-107. PubMed
  • Oberdoerffer P, Sinclair DA. The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol 2007; 8:692-702. PubMed
  • Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J 2007; 26:3169-79. PubMed
  • Calabrese EJ, Bachmann KA, Bailer AJ, Bolger PM, Borak J, Cai L, Cedergreen N, Cherian MG, Chiueh CC, Clarkson TW, Cook RR, Diamond DM, Doolittle DJ, Dorato MA, Duke SO, Feinendegen L, Gardner DE, Hart RW, Hastings KL, Hayes AW, Hoffmann GR, Ives JA, Jaworowski Z, Johnson TE, Jonas WB, Kaminski NE, Keller JG, Klaunig JE, Knudsen TB, Kozumbo WJ, Lettieri T, Liu SZ, Maisseu A, Maynard KI, Masoro EJ, McClellan RO, Mehendale HM, Mothersill C, Newlin DB, Nigg HN, Oehme FW, Phalen RF, Philbert MA, Rattan SI, Riviere JE, Rodricks J, Sapolsky RM, Scott BR, Seymour C, Sinclair DA, Smith-Sonneborn J, Snow ET, Spear L, Stevenson DE, Thomas Y, Tubiana M, Williams GM, Mattson MP. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol 2007; 222:122-8. PubMed
  • Syrzycka M, McEachern LA, Kinneard J, Prabhu K, Fitzpatrick K, Schulze S, Rawls JM, Lloyd VK, Sinclair DA, Honda BM. The pink gene encodes the Drosophila orthologue of the human Hermansky-Pudlak syndrome 5 (HPS5) gene. Genome 2007; 50:548-56. PubMed
  • Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004; 430:686-9. PubMed
  • Lamming DW, Wood JG, Sinclair DA. Small molecules that regulate lifespan: evidence for xenohormesis. Mol Microbiol 2004; 53:1003-9. PubMed
  • Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004; 305:390-2. PubMed
  • Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004; 303:2011-5. PubMed
  • Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 2004; 13:627-38. PubMed
  • Anderson RM, Latorre-Esteves M, Neves AR, Lavu S, Medvedik O, Taylor C, Howitz KT, Santos H, Sinclair DA. Yeast life-span extension by calorie restriction is independent of NAD fluctuation. Science 2003; 302:2124-6. PubMed
  • Sinclair DA. Cell biology. An age of instability. Science 2003; 301:1859-60. PubMed
  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425:191-6. PubMed
  • Bitterman KJ, Medvedik O, Sinclair DA. Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatin. Microbiol Mol Biol Rev 2003; 67:376-99, table of contents. PubMed
  • Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 2003; 423:181-5. PubMed
  • Sinclair D. Is DNA cut out for a long life? Sci Aging Knowledge Environ 2003; 2003:PE8. PubMed
  • Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 2002; 277:45099-107. PubMed
  • Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Cohen H, Lin SS, Manchester JK, Gordon JI, Sinclair DA. Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. J Biol Chem 2002; 277:18881-90. PubMed
  • Sinclair DA. Paradigms and pitfalls of yeast longevity research. Mech Ageing Dev 2002; 123:857-67. PubMed
  • Wood JG, Sinclair DA. TPE or not TPE? It's no longer a question. Trends Pharmacol Sci 2002; 23:1-4. PubMed
  • Cohen H, Sinclair DA. Recombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase. Proc Natl Acad Sci U S A 2001; 98:3174-9. PubMed
  • Sinclair DA. Yeast aging research: recent advances and medical relevance. Cell Mol Life Sci 2001; 56:807-16. PubMed
  • Ashrafi K, Sinclair D, Gordon JI, Guarente L. Passage through stationary phase advances replicative aging in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 1999; 96:9100-5. PubMed
  • Mills KD, Sinclair DA, Guarente L. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell 1999; 97:609-20. PubMed
  • Hong SP, Piper MD, Sinclair DA, Dawes IW. Control of expression of one-carbon metabolism genes of Saccharomyces cerevisiae is mediated by a tetrahydrofolate-responsive protein binding to a glycine regulatory region including a core 5'-CTTCTT-3' motif. J Biol Chem 1999; 274:10523-32. PubMed
  • Johnson FB, Sinclair DA, Guarente L. Molecular biology of aging. Cell 1999; 96:291-302. PubMed
  • Sinclair DA, Mills K, Guarente L. Molecular mechanisms of yeast aging. Trends Biochem Sci 1998; 23:131-4. PubMed
  • Sinclair D, Mills K, Guarente L. Aging in Saccharomyces cerevisiae. Annu Rev Microbiol 1999; 52:533-60. PubMed
  • Sinclair DA, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell 1998; 91:1033-42. PubMed
  • Sinclair DA, Mills K, Guarente L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 1997; 277:1313-6. PubMed
  • Kennedy BK, Gotta M, Sinclair DA, Mills K, McNabb DS, Murthy M, Pak SM, Laroche T, Gasser SM, Guarente L. Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 1997; 89:381-91. PubMed
  • Sinclair DA, Hong SP, Dawes IW. Specific induction by glycine of the gene for the P-subunit of glycine decarboxylase from Saccharomyces cerevisiae. Mol Microbiol 1996; 19:611-23. PubMed
  • Sinclair DA, Dawes IW. Genetics of the synthesis of serine from glycine and the utilization of glycine as sole nitrogen source by Saccharomyces cerevisiae. Genetics 1995; 140:1213-22. PubMed
  • Sinclair DA, Dawes IW, Dickinson JR. Purification and characterization of the branched chain alpha-ketoacid dehydrogenase complex from Saccharomyces cerevisiae. Biochem Mol Biol Int 1993; 31:911-22. PubMed
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