The Aging Stress Response

Molecular Cell - Tập 40 - Trang 333-344 - 2010
Marcia C. Haigis1, Bruce A. Yankner1
1Department of Pathology, Harvard Medical School, Boston, MA 02115 USA

Tài liệu tham khảo

Abu-Elheiga, 2001, Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2, Science, 291, 2613, 10.1126/science.1056843 Banks, 2008, SirT1 gain of function increases energy efficiency and prevents diabetes in mice, Cell Metab., 8, 333, 10.1016/j.cmet.2008.08.014 Baur, 2006, Resveratrol improves health and survival of mice on a high-calorie diet, Nature, 444, 337, 10.1038/nature05354 Ben-Zvi, 2009, Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging, Proc. Natl. Acad. Sci. USA, 106, 14914, 10.1073/pnas.0902882106 Bennett, 2005, Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation, Mol. Cell, 17, 351, 10.1016/j.molcel.2004.12.021 Bennett, 2007, Global changes to the ubiquitin system in Huntington's disease, Nature, 448, 704, 10.1038/nature06022 Bishop, 2007, Two neurons mediate diet-restriction-induced longevity in C. elegans, Nature, 447, 545, 10.1038/nature05904 Bishop, 2010, Neural mechanisms of ageing and cognitive decline, Nature, 464, 529, 10.1038/nature08983 Bjedov, 2010, Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster, Cell Metab., 11, 35, 10.1016/j.cmet.2009.11.010 Boily, 2008, SirT1 regulates energy metabolism and response to caloric restriction in mice, PLoS ONE, 3, e1759, 10.1371/journal.pone.0001759 Bonawitz, 2007, Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression, Cell Metab., 5, 265, 10.1016/j.cmet.2007.02.009 Bonkowski, 2009, Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity, PLoS ONE, 4, e4567, 10.1371/journal.pone.0004567 Bordone, 2005, Calorie restriction, SIRT1 and metabolism: understanding longevity, Nat. Rev. Mol. Cell Biol., 6, 298, 10.1038/nrm1616 Bordone, 2007, SIRT1 transgenic mice show phenotypes resembling calorie restriction, Aging Cell, 6, 759, 10.1111/j.1474-9726.2007.00335.x Broadley, 2008, Mitochondrial stress signaling: a pathway unfolds, Trends Cell Biol., 18, 1, 10.1016/j.tcb.2007.11.003 Brown, 2007, The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes, Metabolism, 56, 1500, 10.1016/j.metabol.2007.06.016 Buchberger, 2010, Protein quality control in the cytosol and the Endoplasmic Reticulum: Brothers in Arms, Mol. Cell, 40, 238, 10.1016/j.molcel.2010.10.001 Chen, 2007, Longevity determined by developmental arrest genes in Caenorhabditis elegans, Aging Cell, 6, 525, 10.1111/j.1474-9726.2007.00305.x Ciccia, 2010, The DNA Damage Response: Making it safe to play with knives, Mol. Cell, 40, 179, 10.1016/j.molcel.2010.09.019 Cohen, 2006, Opposing activities protect against age-onset proteotoxicity, Science, 313, 1604, 10.1126/science.1124646 Comfort, 1963, Effect of Delayed and Resumed Growth on the Longevity of a Fish (Lebistes Reticulatus, Peters) in Captivity, Gerontologia, 49, 150, 10.1159/000211216 Cuervo, 2010, Protein degradation, aggregation, and misfolding, Mov. Disord., 25, S49, 10.1002/mds.22718 Cunningham, 2007, mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex, Nature, 450, 736, 10.1038/nature06322 Dai, 2010, Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria, Aging Cell, 9, 536, 10.1111/j.1474-9726.2010.00581.x David, 2010, Widespread protein aggregation as an inherent part of aging in C. elegans, PLoS Biol., 8, e1000450, 10.1371/journal.pbio.1000450 De Strooper, 2010, Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process, Physiol. Rev., 90, 465, 10.1152/physrev.00023.2009 Dillin, 2002, Rates of behavior and aging specified by mitochondrial function during development, Science, 298, 2398, 10.1126/science.1077780 Fabrizio, 2010, Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation, PLoS Genet., 6, e1001024, 10.1371/journal.pgen.1001024 Fan, 2010, SIRT1 regulates UV-induced DNA repair through deacetylating XPA, Mol. Cell, 39, 247, 10.1016/j.molcel.2010.07.006 Feige, 2008, Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation, Cell Metab., 8, 347, 10.1016/j.cmet.2008.08.017 Flachsbart, 2009, Association of FOXO3A variation with human longevity confirmed in German centenarians, Proc. Natl. Acad. Sci. USA, 106, 2700, 10.1073/pnas.0809594106 Frye, 2000, Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins, Biochem. Biophys. Res. Commun., 273, 793, 10.1006/bbrc.2000.3000 García-Cao, 2002, “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally, EMBO J., 21, 6225, 10.1093/emboj/cdf595 Geisler, 2010, PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1, Nat. Cell Biol., 12, 119, 10.1038/ncb2012 Giannakou, 2008, Role of dFOXO in lifespan extension by dietary restriction in Drosophila melanogaster: not required, but its activity modulates the response, Aging Cell, 7, 187, 10.1111/j.1474-9726.2007.00362.x Gidalevitz, 2006, Progressive disruption of cellular protein folding in models of polyglutamine diseases, Science, 311, 1471, 10.1126/science.1124514 Greer, 2009, Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans, Aging Cell, 8, 113, 10.1111/j.1474-9726.2009.00459.x Guarente, 2006, Sirtuins as potential targets for metabolic syndrome, Nature, 444, 868, 10.1038/nature05486 Guertin, 2007, Defining the role of mTOR in cancer, Cancer Cell, 12, 9, 10.1016/j.ccr.2007.05.008 Haigis, 2010, Mammalian sirtuins: biological insights and disease relevance, Annu. Rev. Pathol., 5, 253, 10.1146/annurev.pathol.4.110807.092250 Hansen, 2007, Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans, Aging Cell, 6, 95, 10.1111/j.1474-9726.2006.00267.x Hansen, 2008, A role for autophagy in the extension of lifespan by dietary restriction in C. elegans, PLoS Genet., 4, e24, 10.1371/journal.pgen.0040024 Hara, 2006, Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice, Nature, 441, 885, 10.1038/nature04724 Harman, 1956, Aging: a theory based on free radical and radiation chemistry, J. Gerontol., 11, 298, 10.1093/geronj/11.3.298 Harrison, 2009, Rapamycin fed late in life extends lifespan in genetically heterogeneous mice, Nature, 460, 392, 10.1038/nature08221 Hartwig, 2009, Feeding a ROS-generator to Caenorhabditis elegans leads to increased expression of small heat shock protein HSP-16.2 and hormesis, Genes Nutr., 4, 59, 10.1007/s12263-009-0113-x Herranz, 2010, Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer, Nature Communications, 1, 1, 10.1038/ncomms1001 Hsu, 2003, Regulation of aging and age-related disease by DAF-16 and heat-shock factor, Science, 300, 1142, 10.1126/science.1083701 Hunt, 2006, Bioenergetics of aging and calorie restriction, Ageing Res. Rev., 5, 125, 10.1016/j.arr.2006.03.006 Ishii, 1998, A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes, Nature, 394, 694, 10.1038/29331 Jäger, 2007, AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha, Proc. Natl. Acad. Sci. USA, 104, 12017, 10.1073/pnas.0705070104 Jang, 2009, Overexpression of Mn superoxide dismutase does not increase life span in mice, J. Gerontol. A Biol. Sci. Med. Sci., 64, 1114, 10.1093/gerona/glp100 Juhász, 2007, Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila, Genes Dev., 21, 3061, 10.1101/gad.1600707 Kaeberlein, 1999, The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms, Genes Dev., 13, 2570, 10.1101/gad.13.19.2570 Kaganovich, 2008, Misfolded proteins partition between two distinct quality control compartments, Nature, 454, 1088, 10.1038/nature07195 Kahn, 2005, AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism, Cell Metab., 1, 15, 10.1016/j.cmet.2004.12.003 Kapahi, 2004, Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway, Curr. Biol., 14, 885, 10.1016/j.cub.2004.03.059 Kelly, 2004, Transcriptional regulatory circuits controlling mitochondrial biogenesis and function, Genes Dev., 18, 357, 10.1101/gad.1177604 Kenyon, 2010, The genetics of ageing, Nature, 464, 504, 10.1038/nature08980 Kenyon, 1993, A C. elegans mutant that lives twice as long as wild type, Nature, 366, 461, 10.1038/366461a0 Kimura, 1997, daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans, Science, 277, 942, 10.1126/science.277.5328.942 Komatsu, 2006, Loss of autophagy in the central nervous system causes neurodegeneration in mice, Nature, 441, 880, 10.1038/nature04723 Kroemer, 2010, Autophagy and the integrated stress response, Mol. Cell, 40, 280, 10.1016/j.molcel.2010.09.023 Kujoth, 2005, Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging, Science, 309, 481, 10.1126/science.1112125 Kume, 2010, Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney, J. Clin. Invest., 120, 1043, 10.1172/JCI41376 Kyng, 2005, Gene expression and DNA repair in progeroid syndromes and human aging, Ageing Res. Rev., 4, 579, 10.1016/j.arr.2005.06.008 Lagouge, 2006, Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha, Cell, 127, 1109, 10.1016/j.cell.2006.11.013 Lapointe, 2008, Early mitochondrial dysfunction in long-lived Mclk1+/- mice, J. Biol. Chem., 283, 26217, 10.1074/jbc.M803287200 Lapointe, 2010, When a theory of aging ages badly, Cell. Mol. Life Sci., 67, 1, 10.1007/s00018-009-0138-8 Le Bacquer, 2007, Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2, J. Clin. Invest., 117, 387, 10.1172/JCI29528 Lee, 2009, Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia, J. Neurosci., 29, 8506, 10.1523/JNEUROSCI.0924-09.2009 Lee, 1999, Gene expression profile of aging and its retardation by caloric restriction, Science, 285, 1390, 10.1126/science.285.5432.1390 Lee, 2000, Gene-expression profile of the ageing brain in mice, Nat. Genet., 25, 294, 10.1038/77046 Lee, 2002, Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts, Proc. Natl. Acad. Sci. USA, 99, 14988, 10.1073/pnas.232308999 Lee, 2003, A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity, Nat. Genet., 33, 40, 10.1038/ng1056 Lee, 2008, A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy, Proc. Natl. Acad. Sci. USA, 105, 3374, 10.1073/pnas.0712145105 Lee, 2010, Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations, Cell, 141, 1146, 10.1016/j.cell.2010.05.008 Lin, 2000, Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae, Science, 289, 2126, 10.1126/science.289.5487.2126 Loerch, 2008, Evolution of the aging brain transcriptome and synaptic regulation, PLoS ONE, 3, 10.1371/journal.pone.0003329 Lombard, 2005, DNA repair, genome stability, and aging, Cell, 120, 497, 10.1016/j.cell.2005.01.028 Long, 2005, Role of AMP-activated protein kinase in the coordinated expression of genes controlling glucose and lipid metabolism in mouse white skeletal muscle, Diabetologia, 48, 2354, 10.1007/s00125-005-1962-5 López-Lluch, 2006, Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency, Proc. Natl. Acad. Sci. USA, 103, 1768, 10.1073/pnas.0510452103 Lu, 2004, Gene regulation and DNA damage in the ageing human brain, Nature, 429, 883, 10.1038/nature02661 Maier, 2004, Modulation of mammalian life span by the short isoform of p53, Genes Dev., 18, 306, 10.1101/gad.1162404 Majmundar, 2010, Hypoxia inducible factors and the response to hypoxic stress, Mol. Cell, 40, 294, 10.1016/j.molcel.2010.09.022 Martin, 2005, Genetic modulation of senescent phenotypes in Homo sapiens, Cell, 120, 523, 10.1016/j.cell.2005.01.031 Martin, 2009, Sod2 knockdown in the musculature has whole-organism consequences in Drosophila, Free Radic. Biol. Med., 47, 803, 10.1016/j.freeradbiomed.2009.06.021 Martinez-Vicente, 2010, Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease, Nat. Neurosci., 13, 567, 10.1038/nn.2528 Matsuoka, 2007, ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage, Science, 316, 1160, 10.1126/science.1140321 Mattagajasingh, 2007, SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase, Proc. Natl. Acad. Sci. USA, 104, 14855, 10.1073/pnas.0704329104 McCarty, 2004, Chronic activation of AMP-activated kinase as a strategy for slowing aging, Med. Hypotheses, 63, 334, 10.1016/j.mehy.2004.01.043 McCay, 1989, The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935, Nutrition, 5, 155 Medvedik, 2007, MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae, PLoS Biol., 5, e261, 10.1371/journal.pbio.0050261 Moreira, 2008, Nucleic acid oxidation in Alzheimer disease, Free Radic. Biol. Med., 44, 1493, 10.1016/j.freeradbiomed.2008.01.002 Morimoto, 2008, Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging, Genes Dev., 22, 1427, 10.1101/gad.1657108 Morley, 2004, Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones, Mol. Biol. Cell, 15, 657, 10.1091/mbc.E03-07-0532 Morley, 2002, The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans, Proc. Natl. Acad. Sci. USA, 99, 10417, 10.1073/pnas.152161099 Morris, 1996, A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans, Nature, 382, 536, 10.1038/382536a0 Mostoslavsky, 2006, Genomic instability and aging-like phenotype in the absence of mammalian SIRT6, Cell, 124, 315, 10.1016/j.cell.2005.11.044 Narendra, 2008, Parkin is recruited selectively to impaired mitochondria and promotes their autophagy, J. Cell Biol., 183, 795, 10.1083/jcb.200809125 Niedernhofer, 2006, A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis, Nature, 444, 1038, 10.1038/nature05456 Nilsson, 2006, Opposite transcriptional regulation in skeletal muscle of AMP-activated protein kinase gamma3 R225Q transgenic versus knock-out mice, J. Biol. Chem., 281, 7244, 10.1074/jbc.M510461200 Nisoli, 2005, Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS, Science, 310, 314, 10.1126/science.1117728 Oberdoerffer, 2008, SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging, Cell, 135, 907, 10.1016/j.cell.2008.10.025 Olsen, 2006, Lifespan extension of Caenorhabditis elegans following repeated mild hormetic heat treatments, Biogerontology, 7, 221, 10.1007/s10522-006-9018-x Osler, 2008, Adenosine 5′-monophosphate-activated protein kinase regulation of fatty acid oxidation in skeletal muscle, Endocrinology, 149, 935, 10.1210/en.2007-1441 Pan, 2007, Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans, Aging Cell, 6, 111, 10.1111/j.1474-9726.2006.00266.x Pawlikowska, 2009, Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity, Aging Cell, 8, 460, 10.1111/j.1474-9726.2009.00493.x Pickford, 2008, The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice, J. Clin. Invest., 118, 2190 Powell, 2000, The impact of media composition and petite mutation on the longevity of a polyploid brewing yeast strain, Lett. Appl. Microbiol., 31, 46, 10.1046/j.1472-765x.2000.00766.x Qiang, 2007, Aging impairs insulin-stimulated glucose uptake in rat skeletal muscle via suppressing AMPKalpha, Exp. Mol. Med., 39, 535, 10.1038/emm.2007.59 Ramsey, 2008, Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice, Aging Cell, 7, 78, 10.1111/j.1474-9726.2007.00355.x Rea, 2007, Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans, PLoS Biol., 5, e259, 10.1371/journal.pbio.0050259 Richter, 2010, Life on the verge of death: The heat shock response revisited, Mol. Cell, 40, 253, 10.1016/j.molcel.2010.10.006 Rodgers, 2005, Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1, Nature, 434, 113, 10.1038/nature03354 Rodier, 2009, Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nat. Cell Biol., 11, 973, 10.1038/ncb1909 Rogina, 2004, Sir2 mediates longevity in the fly through a pathway related to calorie restriction, Proc. Natl. Acad. Sci. USA, 101, 15998, 10.1073/pnas.0404184101 Ron, 2007, Signal integration in the endoplasmic reticulum unfolded protein response, Nat. Rev. Mol. Cell Biol., 8, 519, 10.1038/nrm2199 Rossi, 2010, Roles of Werner syndrome protein in protection of genome integrity, DNA Repair (Amst.), 9, 331, 10.1016/j.dnarep.2009.12.011 Saggerson, 2008, Malonyl-CoA, a key signaling molecule in mammalian cells, Annu. Rev. Nutr., 28, 253, 10.1146/annurev.nutr.28.061807.155434 Sasaki, 2006, Progressive loss of SIRT1 with cell cycle withdrawal, Aging Cell, 5, 413, 10.1111/j.1474-9726.2006.00235.x Schriner, 2005, Extension of murine life span by overexpression of catalase targeted to mitochondria, Science, 308, 1909, 10.1126/science.1106653 Schulz, 2007, Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress, Cell Metab., 6, 280, 10.1016/j.cmet.2007.08.011 Schwer, 2008, Conserved metabolic regulatory functions of sirtuins, Cell Metab., 7, 104, 10.1016/j.cmet.2007.11.006 Sengupta, 2010, Regulation of the mTor complex 1 by nutrients, growth factors and stress, Mol. Cell, 40, 310, 10.1016/j.molcel.2010.09.026 Sharp, 2005, Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice, J. Gerontol. A Biol. Sci. Med. Sci., 60, 293, 10.1093/gerona/60.3.293 Shibata, 2006, Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1, J. Biol. Chem., 281, 14474, 10.1074/jbc.M600364200 Simonsen, 2008, Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila, Autophagy, 4, 176, 10.4161/auto.5269 Singh, 2009, Autophagy regulates lipid metabolism, Nature, 458, 1131, 10.1038/nature07976 Singh, 2009, Autophagy regulates adipose mass and differentiation in mice, J. Clin. Invest., 119, 3329 Sipula, 2006, Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation, Metabolism, 55, 1637, 10.1016/j.metabol.2006.08.002 Sohal, 1996, Oxidative stress, caloric restriction, and aging, Science, 273, 59, 10.1126/science.273.5271.59 Spilman, 2010, Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease, PLoS ONE, 5, e9979, 10.1371/journal.pone.0009979 Steffen, 2008, Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4, Cell, 133, 292, 10.1016/j.cell.2008.02.037 Suh, 2008, Functionally significant insulin-like growth factor I receptor mutations in centenarians, Proc. Natl. Acad. Sci. USA, 105, 3438, 10.1073/pnas.0705467105 Sun, 1999, FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies, Mol. Cell. Biol., 19, 216, 10.1128/MCB.19.1.216 Tissenbaum, 2001, Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans, Nature, 410, 227, 10.1038/35065638 Trifunovic, 2004, Premature ageing in mice expressing defective mitochondrial DNA polymerase, Nature, 429, 417, 10.1038/nature02517 Tyner, 2002, p53 mutant mice that display early ageing-associated phenotypes, Nature, 415, 45, 10.1038/415045a Um, 2004, Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity, Nature, 431, 200, 10.1038/nature02866 Van Raamsdonk, 2009, Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans, PLoS Genet., 5, e1000361, 10.1371/journal.pgen.1000361 Vermulst, 2007, Mitochondrial point mutations do not limit the natural lifespan of mice, Nat. Genet., 39, 540, 10.1038/ng1988 Vermulst, 2008, DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice, Nat. Genet., 40, 392, 10.1038/ng.95 Weindruch, 1988 Wellen, 2010, Cellular metabolic stress: Considering what happens when cells overeat, Mol. Cell, 40, 323, 10.1016/j.molcel.2010.10.004 Wenz, 2008, Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype, Cell Metab., 8, 249, 10.1016/j.cmet.2008.07.006 Wenz, 2009, Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging, Proc. Natl. Acad. Sci. USA, 106, 20405, 10.1073/pnas.0911570106 Westerheide, 2009, Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1, Science, 323, 1063, 10.1126/science.1165946 Willcox, 2008, FOXO3A genotype is strongly associated with human longevity, Proc. Natl. Acad. Sci. USA, 105, 13987, 10.1073/pnas.0801030105 Wong, 2010, Autophagy gone awry in neurodegenerative diseases, Nat. Neurosci., 13, 805, 10.1038/nn.2575 Wullschleger, 2006, TOR signaling in growth and metabolism, Cell, 124, 471, 10.1016/j.cell.2006.01.016 Yankner, 2008, The aging brain, Annu. Rev. Pathol., 3, 41, 10.1146/annurev.pathmechdis.2.010506.092044 Yu, 2005, Macroautophagy—a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease, J. Cell Biol., 171, 87, 10.1083/jcb.200505082 Yuan, 2007, SIRT1 regulates the function of the Nijmegen breakage syndrome protein, Mol. Cell, 27, 149, 10.1016/j.molcel.2007.05.029 Zhang, 2008, Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function, Nat. Med., 14, 959, 10.1038/nm.1851