Free Radic Biol Med. 2011 Oct 15;51(8):1575-82. doi: 10.1016/j.freeradbiomed.2011.07.020. Epub 2011 Jul 31.

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

Cabreiro F, Ackerman D, Doonan R, Araiz C, Back P, Papp D, Braeckman BP, Gems D.

Source

Institute of Healthy Ageing and Research Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.

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.