Deletion of the Mitochondrial Superoxide Dismutase sod-2 Extends Lifespan in Caenorhabditis elegans

Abstract

The oxidative stress theory of aging postulates that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS) generated during normal metabolism. Superoxide dismutases (SODs) counteract this process by detoxifying superoxide. It has previously been shown that elimination of either cytoplasmic or mitochondrial SOD in yeast, flies, and mice results in decreased lifespan. In this experiment, we examine the effect of eliminating each of the five individual sod genes present in Caenorhabditis elegans. In contrast to what is observed in other model organisms, none of the sod deletion mutants shows decreased lifespan compared to wild-type worms, despite a clear increase in sensitivity to paraquat- and juglone-induced oxidative stress. In fact, even mutants lacking combinations of two or three sod genes survive at least as long as wild-type worms. Examination of gene expression in these mutants reveals mild compensatory up-regulation of other sod genes. Interestingly, we find that sod-2 mutants are long-lived despite a significant increase in oxidatively damaged proteins. Testing the effect of sod-2 deletion on known pathways of lifespan extension reveals a clear interaction with genes that affect mitochondrial function: sod-2 deletion markedly increases lifespan in clk-1 worms while clearly decreasing the lifespan of isp-1 worms. Combined with the mitochondrial localization of SOD-2 and the fact that sod-2 mutant worms exhibit phenotypes that are characteristic of long-lived mitochondrial mutants—including slow development, low brood size, and slow defecation—this suggests that deletion of sod-2 extends lifespan through a similar mechanism. This conclusion is supported by our demonstration of decreased oxygen consumption in sod-2 mutant worms. Overall, we show that increased oxidative stress caused by deletion of sod genes does not result in decreased lifespan in C. elegans and that deletion of sod-2 extends worm lifespan by altering mitochondrial function.

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

“…As previously seen, mutations in many of the sod , ctl, or prdx genes decreased the survival of water‐treated animals (Fig. 2B, Table S3), confirming the requirement of these genes for wild‐type resistance to oxidative stress (Van Raamsdonk & Hekimi, 2009). In contrast, Mianserin protected most mutants from oxidative stress, except sod‐1(tm776), sod‐1(tm783), ctl‐1(ok1242), and prdx‐2(gk169) animals (Fig.…”

Antioxidants reveal an inverted U‐shaped dose‐response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans

“…As expected, these mutants are hypersensitive to lifespan‐shortening treatments with various pro‐oxidants (Van Raamsdonk & Hekimi, 2009). Here, we tested an eightfold lower dosage (0.0125 m m ) of the mitochondrial pro‐oxidant PQ than that is required for its maximum pro‐longevity effect, and this still resulted in significant lifespan shortening for these mutants (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).…”