An Unexpected Result

I noticed an open access paper today that describes an unexpected effect on life span of genetic manipulation in the nematode worm species Caenorhabditis elegans. It's a good illustration that metabolism is complicated - much more so than we'd like.

In this paper, we examine the oxidative stress theory of aging using C. elegans as a model system. This theory proposes that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS). To test this theory, we examined the effect of deleting each of the five individual superoxide dismutase (SOD) genes on lifespan and sensitivity to oxidative stress. Since SOD acts to detoxify ROS, the oxidative stress theory predicts that deletion of sod genes should increase oxidative stress and decrease lifespan.

However, in contrast to yeast, flies, and mice, where loss of either cytoplasmic or mitochondrial SOD results in decreased lifespan, we find that none of the sod deletion mutants in C. elegans exhibits a shortened lifespan despite increased sensitivity to oxidative stress. Surprisingly, we find that sod-2 mutant worms have extended lifespan and even worms with the primary cytoplasmic, mitochondrial, and extracellular sod genes deleted can live longer than wild-type worms. By examining genetic interactions with other genes known to extend lifespan and by comparing the phenotype of worms lacking sod-2 to that of known long-lived mitochondrial mutants such as clk-1 or isp-1, we provide evidence that the loss of sod-2 extends lifespan through alteration of mitochondrial function.

It looks like a case of the unexpected effect - the slowed mitochondrial function, and thus less generation of mitochondrial ROS, a noted cause of aging - far outweighing the deliberate effect, the engineered lack of the antioxidant SOD. This doesn't happen in higher animals: we can learn a lot from worms, flies, and the like, but there are always lurking differences. If we're lucky, as here, those differences will illustrate or support other important points about the way in which aging occurs.

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