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Aging May Be Controlled by Brake and Accelerator Genes

Study in worms challenges the "rust" theory of senescence
aging worm



COURTESY OF STUART KIM

Can we tweak certain genes to stave off the aging process—or, conversely, to speed it up? New research indicates that it may one day be possible.

Scientists have discovered genetic switches in roundworms (Caenorhabditis elegans)—whose genetic makeup is remarkably similar to that of humans—that apparently cause the spineless critters to grow old when flicked on but, when off, may extend their lives.

"This is a new and potentially powerful circuit that has just been discovered," says Brown University biologist Marc Tatar, who was not involved in the study. "The take-home message is that aging can be slowed and managed by manipulating signaling circuits within cells."

The new finding challenges the prevailing theory of aging, which is that our bodies wear out, or "rust," in much the same way as cars and other machines due to damage inflicted on our cellular DNA (genetic material) by factors such as smoking, disease, the sun's ultraviolet rays and chemically reactive molecules called free radicals, which are produced when our cells make energy. It suggests instead that a combination of factors is at play—that in addition to rusting, there are also certain genes that may carry instructions to start the aging process.

Stanford University School of Medicine biologist Stuart Kim, who co-authored the new study published in the journal Cell, says the results may explain different why species have different life spans: For example, worms can live up to two weeks, whereas humans stick around for an average of 66 years (78 in the U.S.) and tortoises can lumber along for 200 years.

His theory: there are certain master genes tasked with directing and maintaining body functions. These genes make proteins called "transcription factors" that influence the activity of other genes by switching them on or off. According to Kim, these master genes are programmed to shift gears—that is to make either more or less of these transcription factors—which in turn changes the function of their charges, jump-starting the aging process.

Kim believes that it is possible to slow—or even reverse—senescence if scientists can figure out how to keep the master genes from changing course. "What we found was this developmental regulatory system [that keeps worms young] had become unbalanced in old age," Kim says.

Kim studied the activity of all 20,000 genes in worms from the time they were about three days old (about 20 years in a human lifetime) until they were 18 days old (80 to 90 human years), which is when most of them died.

As the worms aged, researchers observed changes in the level of activity of more than 1,200 genes, with some turning on and others switching off. Most of these genes are controlled by a transcription factor made by the gene elt3, which is known to be involved in the development of roundworms' skin and intestines.

Over time, elt3 began to shut down and its transcription factor production waned. According to Kim, elt3's shift was caused by the increased activity of two other genes: elt5 and elt6, also involved in skin and intestine development.

Kim likens elt5 and elt6 to brake pedals and elt3 to the accelerator in a car. As the brakes are applied and exert greater force, the car decelerates—and several genes that depend on the gas pedal for cues on how to behave stop functioning properly.

When Kim and his team blocked both elt5 and elt6 in adult worms, they were able to keep elt3 from turning off in the animals. As a result, the worms lived up to a week longer than normal.

Kim believes the newly discovered process, along with DNA damage are responsible for aging, noting that the worms died when exposed to high levels of radiation, although there was no change in the elt genes or those that control them.

So the best way to prevent avoid it? Avoid factors known to cause DNA damage, manipulate the so-called master genes—and come up with a way to repair already hobbled cells. "It's partly rust and it's partly the gas pedal and brakes," he says, referring to the condition of a 10-year old car that has seen better days. "If I wanted to fix it up so I could keep driving it, I'd want to wax it to prevent rust and then I'd fix the gas pedal and the brakes, as well."

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