How to live long and prosper: autophagy, mitochondria, and aging.

Autophagy is a process of cellular self-degradation in which portions of the cytoplasm are sequestered within cytosolic double-membrane vesicles and delivered to the lysosome/vacuole. This process occurs in all eukaryotic cells and is partly a stress response; autophagy is induced during starvation and hypoxia. However, autophagy also plays a role during development and is associated with a range of diseases. Accumulating data also suggest the involvement of autophagy in aging. For example, the role of various hormones and nutrient sensing pathways in life span extension may involve autophagy. Similarly, autophagy is the primary mechanism for removing damaged organelles, such as mitochondria, which may have a direct impact on aging. Here, we review the role of autophagy, with an emphasis on the signaling pathways that are involved in regulation, and the consequences of autophagy induction with regard to aging.

[1]  D. Klionsky,et al.  Atg8 controls phagophore expansion during autophagosome formation. , 2008, Molecular biology of the cell.

[2]  I. Varela,et al.  Premature aging in mice activates a systemic metabolic response involving autophagy induction. , 2008, Human molecular genetics.

[3]  H. Sandoval,et al.  Essential role for Nix in autophagic maturation of erythroid cells , 2008, Nature.

[4]  G. Semenza Mitochondrial autophagy: Life and breath of the cell , 2008, Autophagy.

[5]  G. Semenza,et al.  Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia* , 2008, Journal of Biological Chemistry.

[6]  M. Sohrmann,et al.  Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease , 2008, Nature Cell Biology.

[7]  C. Mammucari,et al.  Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle , 2008, Autophagy.

[8]  Antonia P. Sagona,et al.  Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain , 2008, The Journal of cell biology.

[9]  P. Canonico,et al.  Characterization of NAD Uptake in Mammalian Cells* , 2008, Journal of Biological Chemistry.

[10]  Nicholas E. Bruns,et al.  A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy , 2008, Proceedings of the National Academy of Sciences.

[11]  Daniel J. Klionsky,et al.  Autophagy fights disease through cellular self-digestion , 2008, Nature.

[12]  A. Brech,et al.  Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila , 2008, Autophagy.

[13]  P. Codogno,et al.  In vivo effect of an antilipolytic drug (3,5'-dimethylpyrazole) on autophagic proteolysis and autophagy-related gene expression in rat liver. , 2008, Biochemical and biophysical research communications.

[14]  Zheng‐gang Liu,et al.  Autophagy plays a protective role during zVAD-induced necrotic cell death , 2008, Autophagy.

[15]  T. Vellai,et al.  Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans , 2008, Autophagy.

[16]  R. Billington,et al.  NAD depletion by FK866 induces autophagy , 2008, Autophagy.

[17]  Min Wu,et al.  Fission and selective fusion govern mitochondrial segregation and elimination by autophagy , 2008, The EMBO journal.

[18]  M. Driscoll,et al.  A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans , 2008, PLoS genetics.

[19]  Chao Cheng,et al.  Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9 , 2007, PLoS genetics.

[20]  E. Arriaga,et al.  Giant mitochondria do not fuse and exchange their contents with normal mitochondria. , 2008, Experimental cell research.

[21]  Yongqiang Chen,et al.  Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells , 2008, Cell Death and Differentiation.

[22]  L. Saltz,et al.  The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor , 2008, Investigational New Drugs.

[23]  W. Heideman,et al.  Protein Kinase A, TOR, and Glucose Transport Control the Response to Nutrient Repletion in Saccharomyces cerevisiae , 2007, Eukaryotic Cell.

[24]  A. Goldberg,et al.  FoxO3 controls autophagy in skeletal muscle in vivo. , 2007, Cell metabolism.

[25]  J. Opferman,et al.  NIX is required for programmed mitochondrial clearance during reticulocyte maturation , 2007, Proceedings of the National Academy of Sciences.

[26]  T. P. Neufeld,et al.  Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. , 2007, Genes & development.

[27]  Yongqiang Chen,et al.  Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species , 2007, Journal of Cell Science.

[28]  J. Broach,et al.  Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. , 2007, Molecular biology of the cell.

[29]  E. Bergamini,et al.  The Role of Autophagy in Aging , 2007, Annals of the New York Academy of Sciences.

[30]  D. Klionsky,et al.  Autophagosome formation: core machinery and adaptations , 2007, Nature Cell Biology.

[31]  C. Leeuwenburgh,et al.  Autophagy in the heart and liver during normal aging and calorie restriction. , 2007, Rejuvenation research.

[32]  Zvulun Elazar,et al.  ROS, mitochondria and the regulation of autophagy. , 2007, Trends in cell biology.

[33]  D. Klionsky,et al.  Autophagy and Human Disease , 2007, Cell cycle.

[34]  Lin Yan,et al.  Type 5 Adenylyl Cyclase Disruption Increases Longevity and Protects Against Stress , 2007, Cell.

[35]  Eun Hee Kim,et al.  Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. , 2007, Cancer research.

[36]  S. Rodríguez-Enríquez,et al.  Selective degradation of mitochondria by mitophagy. , 2007, Archives of biochemistry and biophysics.

[37]  Daniel J Klionsky,et al.  Eating the endoplasmic reticulum: quality control by autophagy. , 2007, Trends in cell biology.

[38]  K. Nowikovsky,et al.  Mdm38 protein depletion causes loss of mitochondrial K+/H+ exchange activity, osmotic swelling and mitophagy , 2007, Cell Death and Differentiation.

[39]  Z. Elazar,et al.  Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4 , 2007, The EMBO journal.

[40]  Nicholas D Bonawitz,et al.  Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression. , 2007, Cell metabolism.

[41]  D. Klionsky,et al.  A Cycling Protein Complex Required for Selective Autophagy , 2007, Autophagy.

[42]  Richard Weindruch,et al.  Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss , 2007, Hearing Research.

[43]  B. Kennedy,et al.  Ruminations on dietary restriction and aging , 2007, Cellular and Molecular Life Sciences.

[44]  T. Asano,et al.  Distinct Roles of Autophagy in the Heart During Ischemia and Reperfusion: Roles of AMP-Activated Protein Kinase and Beclin 1 in Mediating Autophagy , 2007, Circulation research.

[45]  Chengcheng Hu,et al.  Autophagy Regulates Ageing in C. elegans , 2007, Autophagy.

[46]  T. P. Neufeld,et al.  Gene expression profiling identifies FKBP39 as an inhibitor of autophagy in larval Drosophila fat body , 2007, Cell Death and Differentiation.

[47]  Daniel J. Klionsky,et al.  Aup1p, a Yeast Mitochondrial Protein Phosphatase Homolog, Is Required for Efficient Stationary Phase Mitophagy and Cell Survival* , 2007, Journal of Biological Chemistry.

[48]  Gordon B. Mills,et al.  The energy sensing LKB1–AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis , 2007, Nature Cell Biology.

[49]  I. Dilova,et al.  Calorie restriction and the nutrient sensing signaling pathways , 2007, Cellular and Molecular Life Sciences.

[50]  K. Arden FoxOs in Tumor Suppression and Stem Cell Maintenance , 2007, Cell.

[51]  E. Bergamini,et al.  Evidence for Selective Mitochondrial Autophagy and Failure in Aging , 2007, Autophagy.

[52]  M. Prescott,et al.  Different Fates of Mitochondria: Alternative Ways for Degradation? , 2007, Autophagy.

[53]  B. Thiers Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6 , 2007 .

[54]  D. Klionsky,et al.  Aup 1 p , a Yeast Mitochondrial Protein Phosphatase Homolog , Is Required for Efficient Stationary Phase Mitophagy and Cell Survival * , 2007 .

[55]  郑俊 Maintenance , 2002, The Islamic Law of Personal Status.

[56]  J. Bessoule,et al.  Lipid oxidation and autophagy in yeast. , 2006, Free radical biology & medicine.

[57]  C. Schneider,et al.  Calpain is required for macroautophagy in mammalian cells , 2006, The Journal of cell biology.

[58]  P. Puigserver,et al.  Resveratrol improves health and survival of mice on a high-calorie diet , 2006, Nature.

[59]  C. Bauvy,et al.  NF-κB Activation Represses Tumor Necrosis Factor-α-induced Autophagy* , 2006, Journal of Biological Chemistry.

[60]  R. Testi,et al.  Long-lived C. elegans Mitochondrial mutants as a model for human mitochondrial-associated diseases , 2006, Experimental Gerontology.

[61]  P. Schumacker,et al.  Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia , 2006, Experimental physiology.

[62]  E. Bergamini,et al.  Stimulation of macroautophagy can rescue older cells from 8-OHdG mtDNA accumulation: a safe and easy way to meet goals in the SENS agenda. , 2006, Rejuvenation research.

[63]  Jiahuai Han,et al.  Autophagy Contributes to Caspase-independent Macrophage Cell Death* , 2006, Journal of Biological Chemistry.

[64]  S. Moreno,et al.  Glucose-dependent activation of protein kinase A activity in Saccharomyces cerevisiae and phosphorylation of its TPK1 catalytic subunit. , 2006, Cellular signalling.

[65]  J. Curb,et al.  Caloric restriction and human longevity: what can we learn from the Okinawans? , 2006, Biogerontology.

[66]  Masaaki Komatsu,et al.  Loss of autophagy in the central nervous system causes neurodegeneration in mice , 2006, Nature.

[67]  Hideyuki Okano,et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice , 2006, Nature.

[68]  A. Cuervo,et al.  Autophagic Defects in Aging: Looking for an “Emergency Exit"? , 2006, Cell cycle.

[69]  Andrzej Bartke,et al.  Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[70]  L. Partridge,et al.  The effects of exogenous antioxidants on lifespan and oxidative stress resistance in Drosophila melanogaster , 2006, Mechanisms of Ageing and Development.

[71]  Sudeshna Dutta,et al.  Autophagic programmed cell death by selective catalase degradation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[72]  P. Morgan,et al.  Mitochondrial respiration and reactive oxygen species in mitochondrial aging mutants , 2006, Experimental Gerontology.

[73]  G. Santangelo,et al.  Glucose Signaling in Saccharomyces cerevisiae , 2006, Microbiology and Molecular Biology Reviews.

[74]  Antonino Cattaneo,et al.  Resveratrol Prolongs Lifespan and Retards the Onset of Age-Related Markers in a Short-Lived Vertebrate , 2006, Current Biology.

[75]  Matt Kaeberlein,et al.  Extension of chronological life span in yeast by decreased TOR pathway signaling. , 2006, Genes & development.

[76]  Andrew D. Steele,et al.  Increase in Activity During Calorie Restriction Requires Sirt1 , 2005, Science.

[77]  Terje Johansen,et al.  p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death , 2005, The Journal of cell biology.

[78]  Matt Kaeberlein,et al.  Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients , 2005, Science.

[79]  Chao Cheng,et al.  Sir2 Blocks Extreme Life-Span Extension , 2005, Cell.

[80]  D. Wallace A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine , 2005, Annual review of genetics.

[81]  K. Rosenblatt,et al.  Regulation of Oxidative Stress by the Anti-aging Hormone Klotho*♦ , 2005, Journal of Biological Chemistry.

[82]  D. Klionsky,et al.  Autophagy: molecular machinery for self-eating , 2005, Cell Death and Differentiation.

[83]  K. Hughes,et al.  Gene expression patterns associated with queen honey bee longevity , 2005, Mechanisms of Ageing and Development.

[84]  T. O'Connor,et al.  Antioxidants do not explain the disparate longevity between mice and the longest-living rodent, the naked mole-rat , 2005, Mechanisms of Ageing and Development.

[85]  S. Rea Metabolism in the Caenorhabditis elegans Mit mutants , 2005, Experimental Gerontology.

[86]  S. Fields,et al.  Increased Life Span due to Calorie Restriction in Respiratory-Deficient Yeast , 2005, PLoS Genetics.

[87]  R. S. Sohal,et al.  Enhanced catabolism of mitochondrial superoxide/hydrogen peroxide and aging in transgenic Drosophila. , 2005, The Biochemical journal.

[88]  Junying Yuan,et al.  Autophagy in cell death: an innocent convict? , 2005, The Journal of clinical investigation.

[89]  K. Jacobsen,et al.  The Sirt1 deacetylase modulates the insulin-like growth factor signaling pathway in mammals , 2005, Mechanisms of Ageing and Development.

[90]  S. J. Deminoff,et al.  An evolutionary proteomics approach identifies substrates of the cAMP-dependent protein kinase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[91]  Michael D. Schneider,et al.  Bcl-2 Antiapoptotic Proteins Inhibit Beclin 1-Dependent Autophagy , 2005, Cell.

[92]  Animesh Nandi,et al.  Suppression of Aging in Mice by the Hormone Klotho , 2005, Science.

[93]  L. Partridge,et al.  Dietary restriction in Drosophila , 2005, Mechanisms of Ageing and Development.

[94]  Edward J. Masoro,et al.  Overview of caloric restriction and ageing , 2005, Mechanisms of Ageing and Development.

[95]  Ana Maria Cuervo,et al.  Autophagy and Aging: The Importance of Maintaining "Clean" Cells , 2005, Autophagy.

[96]  A. Hsu,et al.  New Genes Tied to Endocrine, Metabolic, and Dietary Regulation of Lifespan from a Caenorhabditis elegans Genomic RNAi Screen , 2005, PLoS genetics.

[97]  Michael M. Murphy,et al.  Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. , 2005, Cell metabolism.

[98]  J. Lemasters Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis. , 2005, Gastroenterology.

[99]  D. Klionsky,et al.  Atg17 regulates the magnitude of the autophagic response. , 2005, Molecular biology of the cell.

[100]  L. Partridge,et al.  Counting the calories: the role of specific nutrients in extension of life span by food restriction. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[101]  M. Smith-Wheelock,et al.  Methionine‐deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF‐I and insulin levels, and increases hepatocyte MIF levels and stress resistance , 2005, Aging cell.

[102]  K. Nair,et al.  Decline in skeletal muscle mitochondrial function with aging in humans. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[103]  J. Lemasters Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. , 2005, Rejuvenation research.

[104]  L. Guarente,et al.  Calorie Restriction— the SIR2 Connection , 2005, Cell.

[105]  I. Germano,et al.  Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3 , 2005, Oncogene.

[106]  S. Helfand,et al.  Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. , 2005, Cell metabolism.

[107]  Kathleen Marchal,et al.  PKA and Sch9 control a molecular switch important for the proper adaptation to nutrient availability , 2004, Molecular microbiology.

[108]  J. Vanfleteren,et al.  Dietary restriction in the nematode Caenorhabditis elegans. , 2007, Interdisciplinary topics in gerontology.

[109]  G. Bjørkøy,et al.  p 62 / SQSTM 1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death , 2005 .

[110]  D. Leroith,et al.  Skeletal muscle. , 2005, Advances in experimental medicine and biology.

[111]  Takeshi Tokuhisa,et al.  The role of autophagy during the early neonatal starvation period , 2004, Nature.

[112]  J. Apfeld,et al.  The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. , 2004, Genes & development.

[113]  John J Lemasters,et al.  Role of mitochondrial permeability transition pores in mitochondrial autophagy. , 2004, The international journal of biochemistry & cell biology.

[114]  Yiping Gu,et al.  Effect of IGF‐1 on the balance between autophagy of dysfunctional mitochondria and apoptosis , 2004, FEBS letters.

[115]  B. Rogina,et al.  Sir2 mediates longevity in the fly through a pathway related to calorie restriction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[116]  S. Manon,et al.  Uth1p: a yeast mitochondrial protein at the crossroads of stress, degradation and cell death. , 2004, FEMS yeast research.

[117]  M. Tyers,et al.  A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. , 2004, Genes & development.

[118]  K. Hirokawa,et al.  coq7/clk‐1 regulates mitochondrial respiration and the generation of reactive oxygen species via coenzyme Q , 2004, Aging cell.

[119]  S. Ledoux,et al.  Mitochondrial DNA and aging. , 2004, Clinical science.

[120]  Stéphen Manon,et al.  Uth1p Is Involved in the Autophagic Degradation of Mitochondria* , 2004, Journal of Biological Chemistry.

[121]  Mary Ann Ottinger,et al.  Aging in Rhesus Monkeys: Relevance to Human Health Interventions , 2004, Science.

[122]  S. Subramani,et al.  Peroxisome turnover by micropexophagy: an autophagy-related process. , 2004, Trends in cell biology.

[123]  Di Chen,et al.  The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span , 2004, Development.

[124]  J. Milbrandt,et al.  Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration , 2004, Science.

[125]  Satoko Aratani,et al.  Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[126]  Namjin Chung,et al.  Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ , 2004, Nature.

[127]  Ajjai Alva,et al.  Regulation of an ATG7-beclin 1 Program of Autophagic Cell Death by Caspase-8 , 2004, Science.

[128]  M. Tatar,et al.  Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body , 2004, Nature.

[129]  L. Partridge,et al.  Lack of Correlation between Mitochondrial Reactive Oxygen Species Production and Life Span in Drosophila , 2004, Annals of the New York Academy of Sciences.

[130]  E. Kayser,et al.  The effects of complex I function and oxidative damage on lifespan and anesthetic sensitivity in Caenorhabditis elegans , 2004, Mechanisms of Ageing and Development.

[131]  U. Ruegg,et al.  Role of superoxide as a signaling molecule. , 2004, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[132]  S. Benzer,et al.  Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway , 2004, Current Biology.

[133]  D. Klionsky,et al.  The Ras/cAMP-dependent Protein Kinase Signaling Pathway Regulates an Early Step of the Autophagy Process in Saccharomyces cerevisiae* , 2004, Journal of Biological Chemistry.

[134]  U. Brunk,et al.  Myocyte aging and mitochondrial turnover , 2004, Experimental Gerontology.

[135]  Daniel J Klionsky,et al.  Development by self-digestion: molecular mechanisms and biological functions of autophagy. , 2004, Developmental cell.

[136]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.

[137]  Nicolas Hulo,et al.  The Novel Yeast PAS Kinase Rim15 Orchestrates G0-Associated Antioxidant Defense Mechanisms , 2004, Cell cycle.

[138]  R. Anson,et al.  Mitochondrial influence on aging rate in Caenorhabditis elegans , 2004, Aging cell.

[139]  J. Vaupel,et al.  Chronological aging‐independent replicative life span regulation by Msn2/Msn4 and Sod2 in Saccharomyces cerevisiae , 2004, FEBS letters.

[140]  M. Matsui,et al.  In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. , 2003, Molecular biology of the cell.

[141]  R. Morimoto,et al.  Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. , 2003, Molecular biology of the cell.

[142]  C. Epstein,et al.  Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. , 2003, Physiological genomics.

[143]  Tibor Vellai,et al.  Genetics: Influence of TOR kinase on lifespan in C. elegans , 2003, Nature.

[144]  Ivo Pedruzzi,et al.  TOR and PKA signaling pathways converge on the protein kinase Rim15 to control entry into G0. , 2003, Molecular cell.

[145]  Max Hasmann,et al.  FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. , 2003, Cancer research.

[146]  D. Hall,et al.  Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans , 2003, Science.

[147]  E. Ravussin,et al.  Calorie restriction and aging: review of the literature and implications for studies in humans. , 2003, The American journal of clinical nutrition.

[148]  V. Longo The Ras and Sch9 pathways regulate stress resistance and longevity , 2003, Experimental Gerontology.

[149]  A. Akatsuka,et al.  A Complex II Defect Affects Mitochondrial Structure, Leading to ced-3- and ced-4-dependent Apoptosis and Aging* , 2003, Journal of Biological Chemistry.

[150]  Gary Ruvkun,et al.  DAF-16 Target Genes That Control C. elegans Life-Span and Metabolism , 2003, Science.

[151]  R. S. Sohal,et al.  Does overexpression of Cu,Zn-SOD extend life span in Drosophila melanogaster? , 2003, Experimental Gerontology.

[152]  E. Hafen,et al.  Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. , 2003, Trends in cell biology.

[153]  L. Guarente,et al.  How does calorie restriction work? , 2003, Genes & development.

[154]  Matthias Blüher,et al.  Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue , 2003, Science.

[155]  J. Vanfleteren,et al.  Metabolism and life span determination in C. elegans , 2003 .

[156]  D. Goldfarb,et al.  Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. , 2003, Molecular biology of the cell.

[157]  Gary Ruvkun,et al.  A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity , 2003, Nature Genetics.

[158]  Andrew G Fraser,et al.  Rates of Behavior and Aging Specified by Mitochondrial Function During Development , 2002, Science.

[159]  J. Franklin,et al.  Loss of cardiolipin and mitochondria during programmed neuronal death: evidence of a role for lipid peroxidation and autophagy , 2002, Neuroscience.

[160]  P. Roach,et al.  Nutrient-Regulated Protein Kinases in Budding Yeast , 2002, Cell.

[161]  J. Crespo,et al.  Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. , 2002, Molecular cell.

[162]  D. Ingram,et al.  Biomarkers of Caloric Restriction May Predict Longevity in Humans , 2002, Science.

[163]  G. Fink,et al.  Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration , 2002, Nature.

[164]  J. Tower,et al.  Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. , 2002, Genetics.

[165]  Kurt Zatloukal,et al.  p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. , 2002, The American journal of pathology.

[166]  N. Oleinick,et al.  Photodynamic Therapy-induced Apoptosis in Epidermoid Carcinoma Cells , 2001, The Journal of Biological Chemistry.

[167]  Raymond Y. N. Lee,et al.  Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway , 2001, Current Biology.

[168]  E. Shoubridge,et al.  Ubiquinone Is Necessary for Mouse Embryonic Development but Is Not Essential for Mitochondrial Respiration* , 2001, The Journal of Biological Chemistry.

[169]  D. Hardie,et al.  AMP‐activated protein kinase: the energy charge hypothesis revisited , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[170]  S. Hekimi,et al.  Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. , 2001, Developmental cell.

[171]  Sherry F. Grissom,et al.  The mitochondrial permeability transition initiates autophagy in rat hepatocytes , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[172]  J. Hayashi,et al.  Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria , 2001, Nature Genetics.

[173]  M. Tatar,et al.  A Mutant Drosophila Insulin Receptor Homolog That Extends Life-Span and Impairs Neuroendocrine Function , 2001, Science.

[174]  E. Hafen,et al.  Extension of Life-Span by Loss of CHICO, a Drosophila Insulin Receptor Substrate Protein , 2001, Science.

[175]  V. Longo,et al.  Regulation of Longevity and Stress Resistance by Sch9 in Yeast , 2001, Science.

[176]  P. Piper,et al.  Chronological lifespan of stationary phase yeast cells; a model for investigating the factors that might influence the ageing of postmitotic tissues in higher organisms , 2001, Yeast.

[177]  J. Heitman,et al.  The TOR Kinases Link Nutrient Sensing to Cell Growth* , 2001, The Journal of Biological Chemistry.

[178]  L. Guarente,et al.  Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans , 2001, Nature.

[179]  S. Emr,et al.  Autophagy as a regulated pathway of cellular degradation. , 2000, Science.

[180]  E. Kominami,et al.  Autophagy in embryonic erythroid cells: its role in maturation. , 2000, European journal of cell biology.

[181]  Kazuya Nagano,et al.  Tor-Mediated Induction of Autophagy via an Apg1 Protein Kinase Complex , 2000, The Journal of cell biology.

[182]  J. Alimonti,et al.  BNIP3 and Genetic Control of Necrosis-Like Cell Death through the Mitochondrial Permeability Transition Pore , 2000, Molecular and Cellular Biology.

[183]  Richard Weindruch,et al.  Gene-expression profile of the ageing brain in mice , 2000, Nature Genetics.

[184]  D. Clemmons,et al.  Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. , 2000, Endocrinology.

[185]  J. D. de Winde,et al.  Nutrient-induced signal transduction through the protein kinase A pathway and its role in the control of metabolism, stress resistance, and growth in yeast. , 2000, Enzyme and microbial technology.

[186]  I. Pedruzzi,et al.  Saccharomyces cerevisiae Ras/cAMP pathway controls post‐diauxic shift element‐dependent transcription through the zinc finger protein Gis1 , 2000, The EMBO journal.

[187]  C J Epstein,et al.  Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. , 2000, The journals of gerontology. Series A, Biological sciences and medical sciences.

[188]  Pier Paolo Pandolfi,et al.  The p66shc adaptor protein controls oxidative stress response and life span in mammals , 1999, Nature.

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

[190]  C. K. Lee,et al.  Gene expression profile of aging and its retardation by caloric restriction. , 1999, Science.

[191]  Yusuke Nakamura,et al.  Bcl-2/E1B 19 kDa-interacting protein 3-like protein (Bnip3L) interacts with Bcl-2/Bcl-xL and induces apoptosis by altering mitochondrial membrane permeability , 1999, Oncogene.

[192]  Y Honda,et al.  The daf‐2 gene network for longevity regulates oxidative stress resistance and Mn‐superoxide dismutase gene expression in Caenorhabditis elegans , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[193]  C. Borland,et al.  The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[194]  G. Ruvkun,et al.  A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. , 1999, Genes & development.

[195]  M. Chalfie,et al.  A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants , 1999, Nature.

[196]  J. Labbé,et al.  CLK‐1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans , 1999, The EMBO journal.

[197]  今津 哲央 Bcl-2/E1B 19 kDa - interacting Protein 3 - like Protein (Bnip3L) Interacts with Bcl-2/Bcl-xL and Induces Apoptosis by Altering Mitochondrial Membrane Permeability , 1999 .

[198]  Lianfa Shi,et al.  Nix and Nip3 Form a Subfamily of Pro-apoptotic Mitochondrial Proteins* , 1999, The Journal of Biological Chemistry.

[199]  J. Tower,et al.  FLP Recombinase-Mediated Induction of Cu/Zn-Superoxide Dismutase Transgene Expression Can Extend the Life Span of Adult Drosophila melanogaster Flies , 1999, Molecular and Cellular Biology.

[200]  S. Benzer,et al.  Extended life-span and stress resistance in the Drosophila mutant methuselah. , 1998, Science.

[201]  Michio Tsuda,et al.  A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes , 1998, Nature.

[202]  M. Ward,et al.  Yeast PKA represses Msn2p/Msn4p‐dependent gene expression to regulate growth, stress response and glycogen accumulation , 1998, The EMBO journal.

[203]  A. Elia,et al.  Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons , 1998, Nature Genetics.

[204]  W. Fiers,et al.  Inhibition of Caspases Increases the Sensitivity of L929 Cells to Necrosis Mediated by Tumor Necrosis Factor , 1998, The Journal of experimental medicine.

[205]  A. Cuervo,et al.  How do intracellular proteolytic systems change with age? , 1998, Frontiers in bioscience : a journal and virtual library.

[206]  L. Guarente,et al.  Extrachromosomal rDNA Circles— A Cause of Aging in Yeast , 1997, Cell.

[207]  Lianfa Shi,et al.  The E1B 19K/Bcl-2–binding Protein Nip3 is a Dimeric Mitochondrial Protein that Activates Apoptosis , 1997, The Journal of experimental medicine.

[208]  Koutarou D. Kimura,et al.  daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. , 1997, Science.

[209]  J. D. de Winde,et al.  The Sch9 protein kinase in the yeast Saccharomyces cerevisiae controls cAPK activity and is required for nitrogen activation of the fermentable-growth-medium-induced (FGM) pathway. , 1997, Microbiology.

[210]  Andrzej Bartke,et al.  Dwarf mice and the ageing process , 1996, Nature.

[211]  D. Riddle,et al.  Genes that regulate both development and longevity in Caenorhabditis elegans. , 1995, Genetics.

[212]  B. Kennedy,et al.  Mutation in the silencing gene S/R4 can delay aging in S. cerevisiae , 1995, Cell.

[213]  R. S. Sohal,et al.  Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. , 1994, Science.

[214]  L. Gross,et al.  Prevention of spontaneous and radiation-induced tumors in rats by reduction of food intake. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[215]  Dice Jf Peptide sequences that target cytosolic proteins for lysosomal proteolysis , 1990 .

[216]  G. M. Tener,et al.  Overexpression of Cu-Zn superoxide dismutase in Drosophila does not affect life-span. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[217]  J. Dice,et al.  Peptide sequences that target cytosolic proteins for lysosomal proteolysis. , 1990, Trends in biochemical sciences.

[218]  R. E. Esposito,et al.  A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA , 1989, Cell.

[219]  B. Lardeux,et al.  Mechanism and regulation of protein degradation in liver. , 1989, Diabetes/metabolism reviews.

[220]  R. Weindruch,et al.  Influences of Aging and Dietary Restriction on Serum Thymosinαl Levels in Mice , 1988 .

[221]  R. Weindruch,et al.  Influences of aging and dietary restriction on serum thymosin alpha 1 levels in mice. , 1988, Journal of gerontology.

[222]  M. Ermini Ageing changes in mammalian skeletal muscle: biochemical studies. , 1976, Gerontology.

[223]  Denham Harman,et al.  The Biologic Clock: The Mitochondria? , 1972, Journal of the American Geriatrics Society.