The oxidative damage theory of aging proposes that accumulation of molecular damage caused by reactive oxygen species (ROS), particularly superoxide (O2-), contributes significantly to aging. Accordingly, the enzyme superoxide dismutase (SOD), which catalytically eliminates O2-, should contribute to longevity assurance. Thus, a prediction of the theory is that experimentally induced increases in SOD activity should lead to retardation of aging. This prediction has been tested in several model organisms, with mixed results. A common weakness of such studies is a lack of direct measurements of ROS levels or distribution in vivo, or measurements of oxidative damage and/or effects on cell physiology, such as redox state. This is important, since redox state can influence multiple signal transduction pathways, and mild oxidative insults can trigger protective hormetic effects. Moreover, elevation of SOD can markedly increase net ROS production1. In short, it is naive to think that effects of SOD overexpression on lifespan simply reflect protection from ROS-mediated damage. Given these concerns, we ask whether SOD overexpression can deliver what it promises as a means of testing the oxidative damage theory of aging in C. elegans. Ubiquitous overexpression of SOD-1, the major cytosolic Cu/ZnSOD, results in a small, but significant increase in lifespan2. We are now characterizing further the biochemical and cellular consequences of SOD overexpression in C. elegans. We find that it increases H2O2 production as predicted1. However, simultaneous overexpression of catalase does not suppress the extended lifespan, implying that H2O2 over-production is not a driver of longevity here. Strikingly, we find that the increase in lifespan is dependent on the FoxO transcription factor DAF-16. This suggests that elevated SOD results in a hormetic effect, mediated by activation of stress-sensitive signalling pathways. We also find that SOD overexpression lowers protein oxidation, and are now testing whether this effect is DAF-16 dependent too. We are also testing whether the increased lifespan is
aak-2,
hsf-1, and/or
skn-1 dependent, and will present our findings at the meeting. 1. Buettner et al. Free Radic Biol Med 41, 1338 (2006). 2. Doonan et al. Genes Dev 22, 3236 (2008).