Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans

Abstract

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 ...

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

“…Superoxides are converted to hydrogen peroxide by superoxide dismutases (SOD) followed by a conversion to water by catalases (CTL) or peroxiredoxins (PRDX) (Sies, 2014). The C. elegans genome encodes 5 different superoxide dismutases ( sod‐1 to sod‐5 ), three different catalases ( ctl‐1 to ctl‐3 ), and three peroxiredoxins that are named according to their homology to the mammalian peroxiredoxins, prdx‐2 , prdx‐3, and prdx‐6 (Doonan et al ., 2008; Olahova et al ., 2008; Kumsta et al ., 2011). …”

Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans

“…5a). Expression of sod‐1 and the genes encoding heat‐shock proteins is induced in the presence of oxidative stress (Park et al ., 2009), with SOD‐1 contributing to 80% of the total SOD activity in C. elegans (Doonan et al ., 2008). We observed that SOD activity was increased in LG2055‐fed worms compared with that in OP50‐fed worms (Fig.…”

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

“…In worms, insulin/IGF mutants have an increase in free-radical resistance (Gredilla et al 2001;Honda and Honda 1999). Although free radicals have been correlated with senescence, in both mice and worms, there is increasing evidence that they may not be the causative agent (Doonan et al 2008;Ran et al 2007;Van Raamsdonk and Hekimi 2009;Van Remmen et al 2003;Yen et al 2009). The target of rapamycin pathway, which may also link DR and insulin/IGF signaling, regulates autophagy, and this is important for both DR and insulin/IGF mediated longevity (Hansen et al 2008;Kaeberlein et al 2005;Kapahi et al 2004;Melendez et al 2003).…”