It afflicts every creature on this planet, and everyone dreams of an antidote. But even after decades of research, aging largely remains a mystery. Now new research findings suggest there is a good reason for this impasse: scientists may have been thinking about the causes of aging all wrong. Instead of being the result of an accumulation of genetic and cellular damage, new evidence suggests that aging may occur when genetic programs for development go awry.

The idea that stress and reactive forms of oxygen—“free radicals” that are the normal by-products of metabolism—cause aging has dominated the field for 50 years. Studies on the worm Caenorhabditis elegans have shown that reducing exposure to reactive oxygen species increases life span, and worms that have been bred to live longer are also more resistant to stress. But few studies have definitively linked oxidative damage to altered cellular function.

Scientists have also noticed that intrinsic genetic changes accompany aging. As mice age, a gene called p16INK4a, which controls cell growth and regeneration, becomes more active in most tissues, preventing the cells from regenerating as easily as younger cells do in response to injury or disease. And compared with muscle stem cells in young mice, those in older mice accumulate a complex of proteins that, over time, transform muscle into fibrous, fatty tissue.

These findings did little, however, to challenge the idea that aging is the result of damage accumulation, because these genetic changes may simply be a consequence of aging rather than the culprit. “That’s always the challenge, to try to get cause and effect,” says Brian Kennedy, a biochemist at the University of Washington. And although studies have shown that changing the expression of certain genes can affect an organism’s life span, it is unclear whether these genes are actually involved in the normal aging process.

A recent paper published in the journal Cell, however, suggests that genetic programs do drive aging. Scientists at Stanford University and the University of Colorado at Boulder compared the genes that turn on in young nematode worms with those expressed in old worms. Although more than 1,000 genes differed, most of them were under the control of just three, called ELT-3, ELT-5 and ELT-6. These genes are transcription factors—molecular switches that turn other genes on and off. “There were hundreds of things that had gone awry, but they were all traced back to these three transcription factors,” which are known to be involved in the development of specialized membranous cells, explains Stanford developmental biologist and study co-author Stuart Kim. The expression of the three transcription factors also differed in young and old worms.

To see whether damage accumulation ultimately affected these transcription factors, the scientists exposed worms to oxidative stress, infection and radiation, but nothing affected the factors’ expression. The changes “seem to be intrinsic to the genome of the worm,” Kim says—not brought on by outside influences. In addition, when the researchers stopped the expression of ELT-5 and ELT-6, which typically become more active in old age, the worms lived 50 percent longer. “I was totally surprised,” Kim remarks.

The study’s findings also agree with conventional wisdom linking life span to reduced calorie intake. The researchers found that the three transcription factors are under the control of the insulinlike signaling pathway, which controls how an organism’s metabolism changes in response to famine. One of the things the insulinlike signaling pathway does during periods of caloric restriction, Kim says, is to reset the ELT transcription factors and their counterparts in other organisms “to a younger state.” Scientists believe that the plant compound resveratrol, which increases life span in some organisms, mimics the effects of caloric restriction and resets these pathways, too.

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Kim does not believe that the transcription factors are programmed to trigger aging. Instead, he speculates, their function becomes unbalanced as worms get older. Evolution, after all, selects for genes that help individuals reproduce, but once organisms have passed breeding age, they are no longer subject to its control. “Entire biological systems drift away when nature doesn’t care anymore,” Kim notes. ELT-3, ELT-5 and ELT-6 may play an important role in the development of young worms, but after their job is done, their function could go awry—and this “developmental drift,” as Kim calls it, could actually cause aging.

The study does not prove that aging in worms is driven only by developmental drift, Kennedy observes. Both damage accumulation and drift could play a role, and other genetic circuits could also be involved. But the paper certainly gives scientists “something else to think about with regards to what might be driving the aging process,” he points out. “It brings to the forefront a new hypothesis that can be tested in more detail.”

What could these findings mean for people? If aging is primarily a genetic process, conceivably it could one day be preventable. No one yet knows, however, whether the human counterparts to the ELT genes—called GATA transcription factors—might also be involved in normal aging, but it is a question Kim and his colleagues hope to address soon. “We know how human development works,” Kim says. “Now we just have to find out which of these pathways are not working as well in old humans.”

Note: This article was originally printed with the title, "Rethinking the Wrinkling".