Mitochondria, reactive oxygen species, and chronological aging: A message from yeast

As a major intracellular source of reactive oxygen species (ROS), mitochondria are involved in aging and lifespan regulation. Using the yeast chronological aging model, researchers have identified conserved signaling pathways that affect lifespan by modulating mitochondrial functions. Caloric restriction and a genetic mimetic with reduced target of rapamycin signaling globally upregulate the mitochondrial proteome and respiratory functions. Recent discoveries support the notion that an altered mitochondrial proteome induces mitohormesis. Mitohormesis involves a variety of ROS during several growth stages and extends lifespan in yeast and other organisms. Here we recap recent advances in understanding of ROS as signals that decelerate chronological aging in yeast. We also discuss parallels between yeast and worm hypoxic signaling. In sum, this mini-review covers mitochondrial regulation by nutrient-sensing pathways and the complex underlying interactions of ROS, metabolic pathways, and chronological aging.

[1]  Caloric restriction. , 1998, Aging.

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

[3]  W. Burhans,et al.  Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H2O2 and superoxide dismutase activity , 2010, Proceedings of the National Academy of Sciences.

[4]  V. Longo,et al.  The chronological life span of Saccharomyces cerevisiae. , 2003, Aging cell.

[5]  William B. Mair,et al.  Aging and survival: the genetics of life span extension by dietary restriction. , 2008, Annual review of biochemistry.

[6]  B. Kennedy,et al.  Replicative aging in yeast: the means to the end. , 2008, Annual review of cell and developmental biology.

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

[8]  P. Piper,et al.  Preadaptation to efficient respiratory maintenance is essential both for maximal longevity and the retention of replicative potential in chronologically ageing yeast , 2006, Mechanisms of Ageing and Development.

[9]  M. Whiteway,et al.  Increased Respiration in the sch9Δ Mutant Is Required for Increasing Chronological Life Span but Not Replicative Life Span , 2008, Eukaryotic Cell.

[10]  Subhash D. Katewa,et al.  4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila , 2009, Cell.

[11]  Jeffrey S. Smith,et al.  Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins , 2007, Aging cell.

[12]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[13]  Matt Kaeberlein,et al.  Yeast Life Span Extension by Depletion of 60S Ribosomal Subunits Is Mediated by Gcn4 , 2008, Cell.

[14]  A. Diaspro,et al.  SOD2 functions downstream of Sch9 to extend longevity in yeast. , 2003, Genetics.

[15]  M. Kaeberlein,et al.  Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans , 2009, Science.

[16]  J. Cypser,et al.  Multiple stressors in Caenorhabditis elegans induce stress hormesis and extended longevity. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

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

[18]  N. Sonenberg,et al.  mRNAs containing extensive secondary structure in their 5′ non‐coding region translate efficiently in cells overexpressing initiation factor eIF‐4E. , 1992, The EMBO journal.

[19]  Eiichiro Fukusaki,et al.  Metabolomics‐based systematic prediction of yeast lifespan and its application for semi‐rational screening of ageing‐related mutants , 2010, Aging cell.

[20]  S. Haggarty,et al.  Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

[22]  T. Griffin,et al.  Hsf1 Activation Inhibits Rapamycin Resistance and TOR Signaling in Yeast Revealed by Combined Proteomic and Genetic Analysis , 2008, PloS one.

[23]  S. Schreiber,et al.  Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[25]  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.

[26]  Thomas Nyström,et al.  Perspectives on the mitochondrial etiology of replicative aging in yeast , 2010, Experimental Gerontology.

[27]  C. Epstein,et al.  Overexpression of Mn superoxide dismutase does not increase life span in mice. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[28]  P. Brown,et al.  Exploring the metabolic and genetic control of gene expression on a genomic scale. , 1997, Science.

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

[30]  Anja Voigt,et al.  Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. , 2007, Cell metabolism.

[31]  Siegfried Hekimi,et al.  A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis elegans , 2010, PLoS biology.

[32]  M. Toledano,et al.  ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis , 2007, Nature Reviews Molecular Cell Biology.

[33]  Thomas Nyström,et al.  Role of oxidative carbonylation in protein quality control and senescence , 2005, The EMBO journal.

[34]  H. Aguilaniu,et al.  The oncogenicRAS2val19 mutation locks respiration, independently of PKA, in a mode prone to generate ROS , 2003, The EMBO journal.

[35]  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.

[36]  G. Shadel,et al.  Repression of Mitochondrial Translation, Respiration and a Metabolic Cycle-Regulated Gene, SLF1, by the Yeast Pumilio-Family Protein Puf3p , 2011, PloS one.

[37]  Seung-Jae V. Lee,et al.  Inhibition of Respiration Extends C. elegans Life Span via Reactive Oxygen Species that Increase HIF-1 Activity , 2010, Current Biology.

[38]  G. Shadel,et al.  Extension of chronological life span by reduced TOR signaling requires down-regulation of Sch9p and involves increased mitochondrial OXPHOS complex density , 2009, Aging.

[39]  Robbie Loewith,et al.  Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. , 2007, Molecular cell.

[40]  Christopher J. Murakami,et al.  A molecular mechanism of chronological aging in yeast , 2009, Cell cycle.

[41]  G. Shadel,et al.  Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling. , 2011, Cell metabolism.