The superoxide radical (O 2 − ) has long been considered a major cause of aging. O 2 − in cytosolic, extracellular, and mitochondrial pools is detoxified by dedicated superoxide dismutase (SOD) isoforms. We tested the impact of each SOD isoform in Caenorhabditis elegans by manipulating its five sod genes and saw no major effects on life span. sod genes are not required for daf-2 insulin/ IGF-1 receptor mutant longevity. However, loss of the extracellular Cu/ZnSOD sod-4 enhances daf-2 longevity and constitutive diapause, suggesting a signaling role for sod-4. Overall, these findings imply that O 2 − is not a major determinant of aging in C. elegans.Supplemental material is available at http://www.genesdev.org.Received April 11, 2008; revised version accepted September 29, 2008. Many forms of pathology lead to elevated levels of damage to biological macromolecules (Halliwell and Gutteridge 2007). This is also true of aging, the poorly understood biological process that leads to progressive deterioration and death. One strategy to discover the underlying mechanisms of aging has been to seek the causes of its associated molecular damage. An important early theory, proposed by Harman (1956), postulates that the cause might be oxygen free radicals. Harman later developed the theory, proposing a central role for the superoxide (O 2 − ) radical, issuing from the mitochondrial electron transport chain (Harman 1972). During the last few decades, much effort has been invested in tests of this nexus of theories (for review, see Muller et al. 2007 (Fujii et al. 1998). Two mitochondrial MnSOD isoforms are encoded by sod-2 and sod-3 (Giglio et al. 1994;Suzuki et al. 1996;Hunter et al. 1997).This superabundance of SOD isoforms has been a technical hurdle to investigations of the role of SOD and O 2 − in aging in C. elegans, and some of the sod genes have been barely studied. In situ gel SOD activity assays of a sod-1 deletion mutant imply that this gene encodes the major cytosolic Cu/ZnSOD (Jensen and Culotta 2005), leaving the function of sod-5 unclear. sod-3 mRNA levels are elevated in the dauer larva (Honda and Honda 1999), suggesting that this gene may play a special role in antioxidant defense in this long-lived, stress-resistant diapausal stage, but the role of sod-2 has remained obscure. In this study, we describe in detail the function of each of the five sod genes, characterizing their expression, and the phenotypic effects of manipulating their expression. This has allowed us to assess the effect on life history, especially aging, of each of the three major O 2 − pools, thereby critically testing the role of SOD and, by inference, O 2 − , in longevity assurance and aging. O 2 − can affect living organisms in a variety of ways. It can cause molecular damage that might contribute to aging; thus, one expectation of our study was that lowering SOD activity and increasing O 2 − levels might accelerate aging, and vice versa. H 2 O 2 derived from O 2 − can also act a secondary messenger-for example, in receptor tyrosine ...

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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.

Many insights into the mechanisms and signaling pathways underlying aging have resulted from research on the nematode Caenorhabditis elegans. In this paper, we discuss the recent findings that emerged using this model organism concerning the role of reactive oxygen species (ROS) in the aging process. The accrual of oxidative stress and damage has been the predominant mechanistic explanation for the process of aging for many years, but reviewing the recent studies in C. elegans calls this theory into question. Thus, it becomes more and more evident that ROS are not merely toxic byproducts of the oxidative metabolism. Rather it seems more likely that tightly controlled concentrations of ROS and fluctuations in redox potential are important mediators of signaling processes. We therefore discuss some theories that explain how redox signaling may be involved in aging and provide some examples of ROS functions and signaling in C. elegans metabolism. To understand the role of ROS and the redox status in physiology, stress response, development, and aging, there is a rising need for accurate and reversible in vivo detection. Therefore, we comment on some methods of ROS and redox detection with emphasis on the implementation of genetically encoded biosensors in C. elegans.

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