Rethinking aging

Aging may not be caused by the accumulation of cellular damage, as a linkurl:prominent theory;http://www.the-scientist.com/blog/display/54281/ suggests. Instead, the process may result from the deterioration of crucial developmental pathways, according to a study published tomorrow in Cell. "What we found is, I think, a different way to think about aging," linkurl:Stuart Kim;http://cmgm.stanford.edu/~kimlab/ of Stanford University, main author of the study, told The Scientist. Kim and his colleagues used microarray gene chips to compare the genes being expressed in old and young C. elegans worms. They found 1254 genes that had different expression levels between the two groups. Almost all of these genes were developmental genes, necessary for proper intestinal and skin development in young worms. Kim's team also found a set of three transcription factors that had different expression levels in old worms. Two of the transcription factors -- called ELT-5 and ELT-6 -- were overexpressed in old worms. In turn, those two suppressed the expression of the third transcription factor -- called ELT-3. When ELT-3 was suppressed by the other two, the 1254 developmental genes were turned off. When the researchers blocked ELT-5 and ELT-6 in RNA interference experiments, ELT-3 expression went up, expression of the 1254 genes went up, and the worms lived 50% longer. This suggests that ELT-3 controls the continued expression of the developmental genes and might be the crucial link between aging and development. The researchers don't yet know what is pushing the transcription factors off balance, but their results suggest the culprit is not environmental factors of cellular damage such as oxidative stress. Exposing young worms to extreme oxidative stress didn't induce overexpression of ELT-5 and ELT-6. Kim's team is now looking into what unbalances the transcription factors in the first place. "People have been looking for gene expression changes in aging for a while," linkurl:Brian Kennedy,;http://depts.washington.edu/biowww/faculty/kennedy.html from the University of Washington, told The Scientist. "To have it linked to a specific set of transcription factors is definitely a step forward; now there's a potential mechanism by which those changes in gene expression occur." According to Kim's theory, oxidative damage to cells still occurs over the course of an organism's lifetime, but it's not the only cause of aging. Oxidative damage is like rust accumulating on a car, said Kim. In this new model of aging, the rusting still happens, but internal mechanisms in the car -- like the gas or break pedals -- start breaking down. The proportion of aging attributed to environmental factors versus this internal mechanism is still a mystery, said Kim. "I think Dr. Kim is right to raise this hypothesis," Kennedy said. "A lot of linkurl:previous studies;http://www.the-scientist.com/news/display/52925/ were done at the organism level. Now people are trying to ask what specific tissues are these genes having their effect in that causes increased lifespan. So looking at tissue specificity [like intestine and skin development] is very informative." Kim added that an internal aging mechanism might explain why some organisms live for two weeks (C. elegans), some 80 years (humans), and some 200 (sea turtles). Under Kim's theory, different organisms' developmental pathways degrade at different rates. Depending on natural selection, degradation might set in much earlier for some organisms than others, he said. "That could be contributing to why some animals live to 40, and others to 80."

Rethinking aging

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