DNA Damage and Neurodegeneration in the Aging Brain

Summary

Principal Investigator: Bruce A Yankner
Abstract: DESCRIPTION (provided by applicant): The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for neurodegenerative diseases. An exciting recent development is the elucidation of a pattern of DMA damage in the aging human brain that is associated with reduced expression of genes that mediate synaptic plasticity, vesicular transport and mitochondrial function. Our finding of a "genetic signature" of brain aging that can be explained, at least in part, by oxidative DNA damage to vulnerable gene promoters provides a novel conceptual framework for understanding how the brain ages. Furthermore, we have begun to define the mechanism by which damaged genes are silenced by obtaining evidence for the involvement of a nuclear protein complex that contains the longevity gene Sirtl, the transcriptional co-repressor NCOR1, and the DNA repair enzyme hOGG1. Our preliminary studies also raise the possibility that age-related .DNA damage and gene silencing may predispose to the pathology of Alzheimer's disease. This hypothesis is further supported by the development of the Ck-p25 transgenic mouse model of Cdk5 dysregulation that shows markedly increased DNA damage and features of the pathology of Alzheimer's disease. These findings provide the basis for our hypothesis that DNA damage contributes to reduced expression of important neuronal genes in the aging brain, and that this process may underlie cognitive decline and vulnerability to neurodegeneration. The studies in this proposal will establish a genome-wide database of gene expression and DNA damage in the normal aging human brain, and will investigate the role of a newly defined DNA damage silencing complex involving the longevity gene Sirt 1. Transgenic mice that overexpress DNA repair enzymes will be generated and mated with: APPsw and Ck-p25 transgenic mouse models to determine the role of age-related DNA damage in the cognitive decline of aging and the pathology of Alzheimer's disease. Moreover, the role of impaired autophagy as a mechanism of oxidative DNA damage and protein aggregation in the aging brain will be investigated. Finally, a novel set of potentially therapeutic Sirtl-activating compounds will be tested in normal aging mice and in mouse models of human neurodegenerative diseases. These studies may provide new insights into brain aging, with potentially significant therapeutic implications.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons
    Matthew M Dobbin
    Massachusetts Institute of Technology MIT, Cambridge, Massachusetts, USA
    Nat Neurosci 16:1008-15. 2013
  2. pmc A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex
    Sean 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
  3. pmc SIRT1 is essential for normal cognitive function and synaptic plasticity
    Shaday Michan
    Paul F Glenn Laboratories, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Neurosci 30:9695-707. 2010
  4. pmc Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity
    Bjoern Schwer
    Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 107:21790-4. 2010
  5. pmc Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy
    Angela 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
  6. pmc REST and stress resistance in ageing and Alzheimer's disease
    Tao Lu
    Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 507:448-54. 2014
  7. pmc SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function
    Nathan L Price
    Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 15:675-90. 2012
  8. pmc The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction
    Brenda Rascón
    Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, As, Norway
    Aging (Albany NY) 4:499-508. 2012
  9. pmc A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration
    Johannes Graff
    Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    J Neurosci 33:8951-60. 2013
  10. pmc A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse
    R W Stottmann
    Present address Divisions of Human Genetics and Developmental Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Hum Mol Genet 22:4053-63. 2013

Scientific Experts

  • Marcia Haigis
  • Junying Yuan
  • Li Huei Tsai
  • Sanjay Pimplikar
  • Lei Jin
  • STEPHEN JOHN HAGGARTY
  • David A Sinclair
  • Shaday Michan
  • Tao Lu
  • Bruce A Yankner
  • Dohoon Kim
  • Sean M Armour
  • Marta M Lipinski
  • Bénédicte F Py
  • Jun Gao
  • Hongying Yang
  • Junli Liu
  • Matthew M Dobbin
  • Brian J North
  • Joseph A Baur
  • Johannes Graff
  • Basil P Hubbard
  • Giorgio Ramadori
  • Xiuquan Ma
  • Tsuyoshi Furuya
  • Rafael De Cabo
  • Christopher L Frank
  • Philipp Oberdoerffer
  • R W Stottmann
  • Yangqing Xu
  • Nathan L Price
  • Brenda Rascón
  • Ling Pan
  • Roberto Coppari
  • Jing Hua
  • Yu Cai
  • Ying Pan
  • Hongguang Xia
  • Bogdan Beirowski
  • Carlos M Palmeira
  • Ana P Gomes
  • Dawei Ma
  • Johan Auwerx
  • Lois E H Smith
  • Karen I Guerin
  • Mingzhi Jin
  • Jing Chen
  • Ying Li
  • Hiroyasu Yamamoto
  • Lihong Zhang
  • Tao Zhang
  • Minsu Kim
  • Yongjie Yang
  • Aylwin Ng
  • Hong Guang Xia
  • Bjoern Schwer
  • Nicholas A Bishop
  • Ramnik J Xavier
  • Jarno Rutanen
  • Angela Hafner
  • Angela V Hafner
  • Cheng Li
  • Ji Song Guan
  • Frederick W Alt
  • Anthony Rosenzweig
  • Konrad T Howitz
  • Tomas A Prolla
  • Patrick M Loerch
  • Patrick Loerch
  • Jill C Milne
  • Siva Lavu
  • Haeyoung Kim
  • Joseph Zullo
  • David A Bennett
  • Hyun Min Kim
  • MONICA P COLAIACOVO
  • Liviu Aron
  • Yiwen Chen
  • Derek Drake
  • X Shirley Liu
  • Tun Hsiang Yang
  • Damien Rei
  • Steven B McMahon
  • Xiao Yong Zhang
  • Eric J Bennett
  • Craig R Braun
  • Yue Chen
  • A Bernard
  • A Hafner
  • Biafra Ahanonu

Detail Information

Publications49

  1. ncbi SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons
    Matthew M Dobbin
    Massachusetts Institute of Technology MIT, Cambridge, Massachusetts, USA
    Nat Neurosci 16:1008-15. 2013
    ..We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration. ..
  2. pmc A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex
    Sean 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...
  3. pmc SIRT1 is essential for normal cognitive function and synaptic plasticity
    Shaday 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...
  4. pmc Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity
    Bjoern Schwer
    Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 107:21790-4. 2010
    ..On the basis of these findings, we propose that Sirt6 functions as a central regulator of somatic growth and plays an important role in preventing obesity by modulating neural chromatin structure and gene activity...
  5. pmc Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy
    Angela 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
    ....
  6. pmc REST and stress resistance in ageing and Alzheimer's disease
    Tao Lu
    Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 507:448-54. 2014
    ..Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain. ..
  7. pmc SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function
    Nathan 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...
  8. pmc The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction
    Brenda Rascón
    Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, As, Norway
    Aging (Albany NY) 4:499-508. 2012
    ..We also discovered that individuals fed a high dose of resveratrol-compared to controls-ingested fewer quantities of food under ad libitum feeding conditions...
  9. pmc A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration
    Johannes Graff
    Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    J Neurosci 33:8951-60. 2013
    ..Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments...
  10. pmc A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse
    R W Stottmann
    Present address Divisions of Human Genetics and Developmental Biology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Hum Mol Genet 22:4053-63. 2013
    ..This allele of Tubb2b represents the most severely affected mouse tubulin phenotype reported to date and this is the first report of a tubulin mutation affecting neuronal proliferation and survival. ..
  11. pmc Live imaging and single-cell analysis reveal differential dynamics of autophagy and apoptosis
    Yangqing Xu
    Department of Systems Biology Harvard Medical School Boston, MA USA
    Autophagy 9:1418-30. 2013
    ..We anticipate that our single-cell approach will be a powerful tool for gaining a quantitative understanding of the complex regulation of autophagy, its influence on cell fate decisions and its relationship with other cellular pathways. ..
  12. pmc 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
    ....
  13. pmc Evolution of the aging brain transcriptome and synaptic regulation
    Patrick M Loerch
    Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
    PLoS ONE 3:e3329. 2008
    ..Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes...
  14. pmc SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging
    Philipp 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...
  15. pmc Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity
    Dohoon Kim
    Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Neuron 60:803-17. 2008
    ..This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death...
  16. ncbi The aging brain
    Bruce A Yankner
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Annu Rev Pathol 3:41-66. 2008
    ..This review discusses potential approaches to unifying the systems biology of the aging brain with the pathogenesis of neurodegeneration...
  17. pmc Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival
    Hongying 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...
  18. pmc Xenohormesis: sensing the chemical cues of other species
    Konrad T Howitz
    BIOMOL International, LP, 5120 Butler Pike, Plymouth Meeting, PA 19462, USA
    Cell 133:387-91. 2008
    ..These cues provide advance warning about deteriorating environmental conditions, allowing the heterotrophs to prepare for adversity while conditions are still favorable...
  19. 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...
  20. pmc Sirtuins in mammals: insights into their biological function
    Shaday Michan
    Department of Pathology, Paul F Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA, USA
    Biochem J 404:1-13. 2007
    ....
  21. ncbi Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection
    Bénédicte F Py
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Autophagy 3:117-25. 2007
    ....
  22. pmc Sirtuins: a conserved key unlocking AceCS activity
    Brian 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...
  23. pmc 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...
  24. 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...
  25. pmc Resveratrol inhibits pathologic retinal neovascularization in Vldlr(-/-) mice
    Jing 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...
  26. pmc Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity
    Stephen J Haggarty
    Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Neurobiol Learn Mem 96:41-52. 2011
    ..Finally, open questions, challenges, and critical needs for the field of 'neuroepigenetics' in the years to come will be summarized...
  27. pmc Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling
    Bogdan 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...
  28. pmc Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13
    Junli Liu
    State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
    Cell 147:223-34. 2011
    ....
  29. pmc Mitochondrial electron transport chain complex III is required for antimycin A to inhibit autophagy
    Xiuquan Ma
    State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China
    Chem Biol 18:1474-81. 2011
    ..These data suggest that antimycin A inhibits autophagy through its inhibitory activity on mETC complex III. Our data suggest that mETC complex III may have a role in mediating autophagy induction...
  30. pmc A novel pathway regulates memory and plasticity via SIRT1 and miR-134
    Jun Gao
    Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Nature 466:1105-9. 2010
    ....
  31. pmc A critical role of eEF-2K in mediating autophagy in response to multiple cellular stresses
    Bénédicte F Py
    Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
    Autophagy 5:393-6. 2009
    ....
  32. pmc Amyloid-independent mechanisms in Alzheimer's disease pathogenesis
    Sanjay W Pimplikar
    Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA
    J Neurosci 30:14946-54. 2010
    ..A view of AD pathogenesis that encompasses both the amyloid-dependent and -independent mechanisms will help fill the gaps in our knowledge and reconcile the findings that cannot be explained solely by the amyloid hypothesis...
  33. pmc Biochemical characterization, localization, and tissue distribution of the longer form of mouse SIRT3
    Lei Jin
    Sirtris, a GSK Company, 200 Technology Square, Cambridge, MA 02139, USA
    Protein Sci 18:514-25. 2009
    ..Thus, identification and characterization of the actual SIRT3 sequence should help resolve the debate about the nature of mouse SIRT3 and identify new mechanisms to modulate enzymatic activity...
  34. pmc Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke
    Junying Yuan
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Apoptosis 14:469-77. 2009
    ....
  35. pmc Alternative functions of core cell cycle regulators in neuronal migration, neuronal maturation, and synaptic plasticity
    Christopher L Frank
    Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, Howard Hughes Medical Institute, Cambridge, MA 02139, USA
    Neuron 62:312-26. 2009
    ....
  36. pmc Control of basal autophagy by calpain1 mediated cleavage of ATG5
    Hong Guang Xia
    State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
    Autophagy 6:61-6. 2010
    ..We conclude that calpain1 plays an important role in controlling the levels of autophagy in normal living cells by regulating the levels of a key signaling molecule, ATG12-ATG5 conjugate...
  37. 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
    ..This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years...
  38. pmc SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity
    Jarno Rutanen
    Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
    Diabetes 59:829-35. 2010
    ..No studies are available in humans to demonstrate that SIRT1 expression in insulin-sensitive tissues is associated with energy expenditure and insulin sensitivity...
  39. pmc Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy
    Sean 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...
  40. pmc Neural mechanisms of ageing and cognitive decline
    Nicholas A Bishop
    Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 464:529-35. 2010
    ..Recent advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline...
  41. pmc Negative regulation of Vps34 by Cdk mediated phosphorylation
    Tsuyoshi Furuya
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell 38:500-11. 2010
    ..We propose that phosphorylation of Thr159 in Vps34 is a key regulatory mechanism that controls the class III PtdIns3 kinase activity in cell-cycle progression, development, and human diseases including neurodegeneration and cancers...
  42. pmc A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions
    Marta M Lipinski
    Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
    Dev Cell 18:1041-52. 2010
    ....
  43. pmc Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease
    Marta M Lipinski
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 107:14164-9. 2010
    ..Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death...
  44. pmc Characterization of murine SIRT3 transcript variants and corresponding protein products
    Yongjie Yang
    USDA ARS Children s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA
    J Cell Biochem 111:1051-8. 2010
    ....
  45. pmc The aging stress response
    Marcia C Haigis
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell 40:333-44. 2010
    ..The systems biology of stress response signaling thus provides a new approach to the understanding and potential treatment of age-related diseases...
  46. pmc SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance
    Giorgio Ramadori
    Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Cell Metab 14:301-12. 2011
    ..Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance...