Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage

• Published in: Free radical biology & medicine Vol. 51; no. 8; pp. 1575 - 1582
• Main Authors: Cabreiro, Filipe, Ackerman, Daniel, Doonan, Ryan, Araiz, Caroline, Back, Patricia, Papp, Diana, Braeckman, Bart P., Gems, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-10-2011; Elsevier Science
• Subjects: Aging; Animals; Animals, Genetically Modified; antioxidants; Caenorhabditis elegans; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; catalase; Catalase - metabolism; Cells, Cultured; daf-16/FoxO; endoplasmic reticulum; ER stress; Forkhead Transcription Factors; Free radicals; gene overexpression; glycation; heat shock response; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; homeostasis; hydrogen peroxide; Hydrogen Peroxide - metabolism; lipid peroxidation; longevity; Original Contribution; oxidation; Oxidation-Reduction; Oxidative damage; Oxidative Stress - genetics; protein folding; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; superoxide anion; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; transcription factors; Transcription Factors - metabolism; Transcriptional Activation; Transgenes - genetics; HSF-1; RNAi; CML; O2; Free radicals; Oxidative damage; ER stress; SOD; Superoxide dismutase; co-OE; NAC; Caenorhabditis elegans; IIS; OE; ROS; daf-16/FoxO; Aging; AMPK; HNE
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2011.07.020

The superoxide free radical (O2•−) has been viewed as a likely major contributor to aging. If this is correct, then superoxide dismutase (SOD), which removes O2•−, 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 (H2O2) levels in vivo. However, co-overexpression of catalase did not suppress the life-span extension, arguing against H2O2 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 O2•−, but instead by activating longevity-promoting transcription factors.
► sod-1 over-expression increases levels of cellular ROS and of molecular damage. ► sod-1 over-expression effects on lifespan are dependent on DAF-16 (FoxO) and HSF-1. ► Increased lifespan is partially suppressed by inactivation of ER stress mediators. ► sod-2 (MnSOD) over-expression effects on lifespan are dependent on DAF-16.