Environmental stresses and cell damage play a role in the longevity of humans and simple soil-dwelling nematodes. But new research from Stanford University shows that in the short-lived worm Caenorhabditis elegans, such stresses have no effect on the changes in gene expression that accompany worm aging, hinting that another process is at work.
The study suggests that in the worms, the transition to old age is perhaps triggered by a regulatory system gone awry, says Stuart Kim, a Stanford biologist who led the research. It’s not yet clear if the same processes are at work in humans (or mammals in general). But if they are, the relevant gene circuits could provide an easy target for drugs to boost longevity.
Scientists generally conceive of aging as a sort of cellular wear and tear. Stresses from the environment, such as oxidation (also the cause of rust), as well as from within the cell, such as errors in DNA, accumulate over time, eventually wearing out the tissue. Scores of scientific studies support this idea in mammals and, to a lesser extent, in nematodes. Protecting worms from oxidative damage can extend their life span, for example.
Kim’s team used DNA microarrays to track gene-expression changes in C. elegans,a microscopic worm commonly studied in the lab that typically lives for about two weeks. “We found a mechanism that was pretty different and pretty surprising,” he says.
Scientists identified three genes that appear to control the majority of changes in gene expression that accompany aging. They then exposed the worms to a range of environmental stressors, including heat, DNA damage, and oxidative stress, and found that expression of the controller genes was largely unaffected. The results were reported today in the journal Cell.
A possible interpretation of the findings, says Kim, is that aging in worms may in part be due to developmental pathways gone awry. In the wild, worms die from predation rather than from old age. So there’s little evolutionary pressure to stop damaging genetic mutations from taking root, a concept known as developmental drift. “It’s not environmental accumulation; it’s a developmental clock,” says Kim.
To see if they could fix the problem, Kim and his collaborators tried “rebalancing” the regulatory network in middle-aged worms by making their gene-expression pattern resemble that of younger organisms. Those animals lived longer.
“It’s a fundamental finding,” says Huber Warner, associate dean for research at the University of Minnesota, in St. Paul, and editor of the Journal of Gerontology. But it’s far from clear if this drift is also at work in people, he says. “The most important conclusion from this paper is that the basic mechanism of aging in these two kinds of species is fundamentally different,” says Warner. “If it does apply to mammals, it’s not as important as it is in nematodes.”
Mammals may be more susceptible to accumulated wear and tear, he says, because cells are continually damaged and replaced from a pool of stem cells present in most tissues. Too much stress destroys the ability of stem-cell pools to replace tissue. Worms, on the other hand, are generally stuck with the cells that they’ve got once they hit adulthood: most cells are no longer capable of proliferating.
Kim’s team is now studying the human versions of these genes. While it’s unlikely that the same genes are involved in human aging, he says, “I think that the conceptual idea that known human-developmental controls are not maintained as people grow older is attractive and theoretically possible.” However, “there is no direct evidence for developmental drift in mammals yet,” he says.
If developmental drift does turn out to play a role in human aging, it could be good news for drug developers. Scientists are currently trying to mimic the effects of some life-extending interventions–most notably, caloric restriction (a diet low in total calories but with adequate nutrition)–with drugs. But when it comes to longevity and the diseases of aging, new drug targets are always welcome.
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