title: Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans.
abstract: Mutations affecting components of the mitochondrial electron transport chain have been shown to increase lifespan in multiple species including the worm Caenorhabditis elegans. While it was originally proposed that decreased generation of reactive oxygen species (ROS) resulting from lower rates of electron transport could account for the observed increase in lifespan, recent evidence indicates that ROS levels are increased in at least some of these long-lived mitochondrial mutants. Here, we show that the long-lived mitochondrial mutant isp-1 worms have increased resistance to oxidative stress. Our results suggest that elevated ROS levels in isp-1 worms cause the activation of multiple stress-response pathways including the mitochondrial unfolded protein response, the SKN-1-mediated stress response, and the hypoxia response. In addition, these worms have increased expression of specific antioxidant enzymes, including a marked upregulation of the inducible superoxide dismutase genes sod-3 and sod-5. Examining the contribution of sod-3 and sod-5 to the oxidative stress resistance in isp-1 worms revealed that loss of either of these genes increased resistance to oxidative stress, but not other forms of stress. Deletion of sod-3 or sod-5 decreased the lifespan of isp-1 worms and further exacerbated their slow physiologic rates. Thus, while deletion of sod-3 and sod-5 genes has little impact on stress resistance, physiologic rates or lifespan in wild-type worms, these genes are required for the longevity of isp-1 worms. Overall, this work shows that the increased resistance to oxidative stress in isp-1 worms does not account for their longevity, and that resistance to oxidative stress can be experimentally dissociated from lifespan.
authors.affiliation: Laboratory of Aging and Neurodegenerative Disease (LAND), Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Dues
authors.affiliation: Laboratory of Aging and Neurodegenerative Disease (LAND), Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Schaar
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Johnson
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Bowman
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Winn
authors.affiliation: Laboratory of Aging and Neurodegenerative Disease (LAND), Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Senchuk
authors.affiliation: Laboratory of Aging and Neurodegenerative Disease (LAND), Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Department of Genetics, Michigan State University, East Lansing, MI 48824, USA. Electronic address: jeremy.vanraamsdonk@vai.org.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Van Raamsdonk
mesh_terms: D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia; D008136:Longevity; D008928:Mitochondria / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D056811:Unfolded Protein Response
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; C443102:Isp-1 protein, Caenorhabditis elegans; C525107:Sod-3 protein, C elegans; D013482:Superoxide Dismutase; C000626855:sod-5 protein, C elegans; D014450:Electron Transport Complex III
keywords: Aging; Caenorhabditis elegans; Genetics; Lifespan; Mitochondria; Oxidative stress; Reactive oxygen species; Superoxide dismutase; isp-1