Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 51, Issue 8, Pages 1575-1582Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.07.020
Keywords
Aging; Caenorhabditis elegans; daf-16/FoxO; ER stress; Oxidative damage; Superoxide dismutase; Free radicals
Funding
- Biotechnology and Biological Research Council (UK)
- European Union
- Fund for Scientific Research-Flanders [G.0025.06]
- FEBS Collaborative Experimental Scholarship for Central Eastern Europe
- Institute for the Promotion of Innovation through Science and Technology in Flanders
- Wellcome Trust
- National Institutes of Health Center for Research Resources
- Medical Research Council [G0700729B] Funding Source: researchfish
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The superoxide free radical (O-2(center dot-)) has been viewed as a likely major contributor to aging. If this is correct, then superoxide dismutase (SOD), which removes O-2(center dot-), 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 O-2(center dot-), but instead by activating longevity-promoting transcription factors. (C) 2011 Elsevier Inc. All rights reserved.
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