Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans

Apr 11, 2017Free radical biology & medicine

Long-lived mitochondrial mutants in C. elegans show separate changes in stress resistance and lifespan

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Abstract

The long-lived mitochondrial mutant isp-1 worms exhibit increased oxidative stress resistance.

Increased levels of reactive oxygen species (ROS) are observed in isp-1 worms, contrary to initial hypotheses.
Elevated ROS levels activate multiple stress-response pathways in isp-1 worms, including specific mitochondrial and hypoxia responses.
Isp-1 worms show increased expression of antioxidant enzymes, particularly superoxide dismutase genes sod-3 and sod-5.
Loss of sod-3 or sod-5 genes increases oxidative stress resistance but decreases lifespan in isp-1 worms.
The findings indicate that enhanced resistance to oxidative stress does not explain the longevity of isp-1 worms.

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Mutations affecting components of the mitochondrial electron transport chain have been shown to increase lifespan in multiple species including the worm Caenorhabditis elegans. While it was originally proposed that decreased generation of reactive oxygen species (ROS) resulting from lower rates of electron transport could account for the observed increase in lifespan, recent evidence indicates that ROS levels are increased in at least some of these long-lived mitochondrial mutants. Here, we show that the long-lived mitochondrial mutant isp-1 worms have increased resistance to oxidative stress. Our results suggest that elevated ROS levels in isp-1 worms cause the activation of multiple stress-response pathways including the mitochondrial unfolded protein response, the SKN-1-mediated stress response, and the hypoxia response. In addition, these worms have increased expression of specific antioxidant enzymes, including a marked upregulation of the inducible superoxide dismutase genes sod-3 and sod-5. Examining the contribution of sod-3 and sod-5 to the oxidative stress resistance in isp-1 worms revealed that loss of either of these genes increased resistance to oxidative stress, but not other forms of stress. Deletion of sod-3 or sod-5 decreased the lifespan of isp-1 worms and further exacerbated their slow physiologic rates. Thus, while deletion of sod-3 and sod-5 genes has little impact on stress resistance, physiologic rates or lifespan in wild-type worms, these genes are required for the longevity of isp-1 worms. Overall, this work shows that the increased resistance to oxidative stress in isp-1 worms does not account for their longevity, and that resistance to oxidative stress can be experimentally dissociated from lifespan.

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Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans

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