title: Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage.
abstract: The superoxide free radical (O(2)(•-)) has been viewed as a likely major contributor to aging. If this is correct, then superoxide dismutase (SOD), which removes O(2)(•-), should contribute to longevity assurance. In Caenorhabditis elegans, overexpression (OE) of the major cytosolic Cu/Zn-SOD, sod-1, increases life span. But is this increase caused by enhanced antioxidant defense? sod-1 OE did not reduce measures of lipid oxidation or glycation and actually increased levels of protein oxidation. The effect of sod-1 OE on life span was dependent on the DAF-16/FoxO transcription factor (TF) and, partially, on the heat shock TF HSF-1. Similarly, overexpression of sod-2 (major mitochondrial Mn-SOD) resulted in life-span extension that was daf-16 dependent. sod-1 OE increased steady-state hydrogen peroxide (H(2)O(2)) levels in vivo. However, co-overexpression of catalase did not suppress the life-span extension, arguing against H(2)O(2) as a cause of longevity. sod-1 OE increased hsp-4 expression, suggesting increased endoplasmic reticulum (ER) stress. Moreover, longevity was partially suppressed by inactivation of ire-1 and xbp-1, mediators of the ER stress response. This suggests that high levels of SOD-1 protein may challenge protein-folding homeostasis, triggering a daf-16- and hsf-1-dependent stress response that extends life span. These findings imply that SOD overexpression increases C. elegans life span, not by removal of O(2)(•-), but instead by activating longevity-promoting transcription factors.
authors.affiliation: Institute of Healthy Ageing and Research Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
authors.forename: Filipe
authors.initials: F
authors.lastname: Cabreiro
authors.forename: Daniel
authors.initials: D
authors.lastname: Ackerman
authors.forename: Ryan
authors.initials: R
authors.lastname: Doonan
authors.forename: Caroline
authors.initials: C
authors.lastname: Araiz
authors.forename: Patricia
authors.initials: P
authors.lastname: Back
authors.forename: Diana
authors.initials: D
authors.lastname: Papp
authors.forename: Bart P
authors.initials: BP
authors.lastname: Braeckman
authors.forename: David
authors.initials: D
authors.lastname: Gems
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D019076:Transgenes / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins; C502196:Hsp-4 protein, C elegans; D014157:Transcription Factors; C548541:XBP-1 protein, C elegans; C108831:daf-16 protein, C elegans; C474710:heat shock factor-1, C elegans; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D017346:Protein Serine-Threonine Kinases; C541905:IRE-1 protein, C elegans