Harvard Prof. Finds Brain Regulates Aging

In the beginning, there was insulin.

It was a billion years ago, before the Flintstones split off from jellyfish, that nature first found the crucial hormone that regulates life-span and metabolism from worms to man.

But insulin, for all its virtues, also helps keep life spans short, a recent study shows.

Scientists have known for a while that roundworms insensitive to insulin live up to three times their species' average life span of 10 days.

This month, Harvard researchers reported that it is in the brain of the roundworm that insulin-like signaling controls life span.

The findings, published by Professor of Genetics Gary Ruvkun in the Oct. 6 issue of the journal Science, suggest that the brain may have a bigger role in controlling aging than was previously thought.

Roundworms that have longer than normal life spans have been kicking around in genetics laboratories for more than 20 years, first made by severely inbreeding families of worms and by exposing worms to harmful chemicals that cause mutations.

But only in recent years did researchers, using powerful new tools of molecular biology, learn that it is a defect in these worms' insulin systems that causes their long life.

Ruvkun and other scientists choose to work with the laboratory roundworm, a tiny bacteria-eating soil-dweller, because the sequence of its entire genome is known and its 302-neuron nervous system has been described in detail.

But though it looks very different from most humans, the worm shares 40 percent of its genes with man, including almost its entire insulin pathway.

In their recent study, Ruvkun and his colleagues first used genetic tricks to deactivate genes that encode the proteins--known as receptors--that respond to insulin signaling in many worm tissues, creating a group of long-lived individuals.

What they did is like yanking parts out of an electrical appliance, explains Caleb E. Finch, an aging expert at the University of Southern California.

"You can modify a process by removing one of its controlling parts," says Finch. "It's like if you started pulling computer chips out of a radio."

Next, the researchers put the parts back in, but only in certain areas. In separate experiments, they turned insulin receptor genes back on in different worm tissues: first in the intestine but not the brain, then the brain but not the muscle, and so on.

The results were striking: While putting insulin receptors back in muscle and intestinal cells had only a small effect on longevity, replacing the receptors in the nervous system restored the worms' normal life span.

This result was surprising, according to Ruvkun, because when worms get old they start to show decay all across their body, just as people do.

"For 50 years we've known about insulin signaling and we've always though that it works by engaging receptors on muscles and fat," he said. "It was always assumed that the tissue where you see the aging is where it would be functioning."

But instead, in the worm--and, Ruvkun suggests, perhaps in people as well--aging seems to be regulated by the brain. Ruvkun says this makes sense, as the entire body ages at the same rate, which might not be possible if aging were not regulated centrally.

The idea that the brain may control aging is attractive from an evolutionary perspective too. Closely related species sometimes age at very different rates. Perhaps small changes in brain insulin systems allow for these changes.

Ruvkun believes that the interaction between insulin and "free radicals" may explain its powerful effect on aging. Too many of these dangerous by-products of cellular metabolism can be lethal for an animal, but insulin can cause cells to stop producing enzymes which scavenge free radicals. If this process is turned off, he speculates, animals may live longer because they continue to eliminate free radicals.

But some scientists caution about reading too much about mammalian aging into results from the worm.

"One has to be careful about generalizing extensively from observations in the roundworm," said Dr. Richard Weindruch, who studies aging in mice at the University of Wisconsin. "It's not clear to what extent these findings represent the situation in mammals."

The role insulin plays in aging in mice is not yet known, but when mice are placed on a restricted diet, which lowers their insulin levels, they live longer.

It may be years before scientists fully understand how relevant the worm model is to human aging.

"Time will tell," says Finch. At the very least, "there will be a lot of exciting findings in animals that are closer to us than roundworms."