How age creeps up on worms

They’re only about 1/25th of an inch long, and no wider than a thread. You need a microscope to see these squirmy roundworms. But some scientists will tell you they are almost half human, genetically speaking.

Called Caenorhabditis elegans, this little worm was the first creature to have all its genes sequenced, more than 19,000 of them. More recently, when the human genome was sequenced, researchers found that C. elegans shares about 40 percent of its genes with us.

Two such genes were recently discovered in the laboratory of Gary Ruvkun, a professor of genetics at Harvard Medical School and Massachusetts General Hospital in Boston. One of the genes regulates the development from an egg to an adult in a whole Noah’s ark of animals – jellyfish, fruit flies, zebra fish, mice, and, possibly, humans. The other regulates the life span of many animals.

When the aging gene is not working right, the worms live three times longer than normal, according to Ruvkun. The development gene keeps an animal forever youthful in the sense that it never develops into a reproducing adult.

Working with Catherine Wolkow, Kotaro Kimura, and Mingsum Kee, Ruvkun found that when a gene called daf-2 doesn’t function normally in C. elegans‘ brain, the worm’s life span increases threefold, from 10 to 30 days. Checking the human genome, they found a human gene that is related to daf-2.

“We didn’t know how the worm gene actually regulates aging until we compared it with the human copy,” Ruvkun says. The human gene is responsible for making a protein receptor in cells. This receptor is activated by insulin, and the activation converts blood sugar into energy. In C. elegans, signals from its brain activate the worm equivalent of insulin, fueling the animal’s metabolism. When the gene doesn’t work, the worm burns less fuel and lives longer.

Loss of the daf-2 gene leads to the increased activity of proteins (enzymes) that mop up highly reactive molecules, known as free radicals, which result from metabolism of blood sugar. Ruvkun believes that the rate at which free radicals damage our brains is a primary determinant of life span.

“This is the first indication that aging may be regulated from the brain,” Ruvkun notes. “And it fits nicely with recent findings that insulin in rats, and possibly humans, may also act in the brain to control metabolism.”

That theory goes well with experiments showing that the life of lab rats can be increased by feeding them a healthy diet containing 30 percent less calories than normal. The same strategy appears to be working with monkeys, who have many genes in common with humans. Some humans have begun reducing their foot intake to 1,000 or less calories a day in hopes of living longer. The scientific jury is still out on that case.

Living for 240 years

When damage from free radicals in the brain reaches a certain point, death occurs. Ruvkun thinks this final decay is programmed into the brain, causing different species to expire after different set life spans. Roundworms go in days, dogs in years, humans in about eight decades.

When the clock runs out, he says, “decrepitude kicks and everything begins to go in synchrony during the final 10 percent of life span, rather than various parts of the body failing from wear and tear at different rates.”

Is there any way to keep the clock ticking longer? Worms who have lost the function of their daf-2 gene live for the human equivalent of 240 years. Is it possible to tinker with the human daf-2 that way?

Ruvkun believes it might be “technically possible, but I wouldn’t predict it to happen anytime soon. We can do the experiment in C. elegans in 30 days; it would take 50 years in humans even if we got permission, which I doubt.” Instead, Ruvkun and his team are starting to do daf-2 experiments on mice. He wants to determine if designed changes in mouse daf-2 can increase life span.

In other experiments, Thomas Perls, an assistant professor of medicine at Harvard Medical School, is looking at the gene in people who live to be 100 years old. He wants to see if centenarians have variations of daf-2 that delay the inevitable.

The inevitable, of course, is not inflexible. “The huge variation in life spans between different animals, like mice and elephants, shows that it can change during evolution,” Ruvkun points out. Thousands of years ago, human life spans were much shorter. Thousands of years from now they may be much longer.

People, however, would like something quicker. What about eating foods and taking supplements known to be antioxidants, like vitamins E and C? “Our work suggests that the key free radical damage occurs in the brain only, not in other tissues,” Ruvkin answers. “We don’t know if antioxidant vitamins get into the brain.”

A universal regulator

In the meantime, Ruvkun and colleagues Amy Pasquinelli, Brenda Reinhart, and Frank Slack are studying the development gene, known as let-7. They found that animals missing this gene never develop from a youthful larva to a full-grown adult capable of reproducing itself.

The researchers note that let-7 is the smallest such gene yet to be discovered in any animal. Further work revealed a matching gene in fruit flies, those annoying winged specks that hover over overripe bananas. Using samples of genetic material sent by colleagues from Australia to New Haven, Conn., Ruvkun’s team also looked for let-7 in jellyfish, clams, zebra fish, mice, and humans. All these species have the gene.

This surprising discovery “implies that this way of keeping developmental time may be universal,” notes Andre Adoutte of the Center for Molecular Genetics in France.

“It’s amazing that such a small gene does so much,” Ruvkun adds. “We believe it evolved about a billion years ago, and most animal species have inherited this gene from a common ancestor.”

Let-7 may be necessary for caterpillars to turn into butterflies and tadpoles into frogs. Insects may need it for their metamorphosis from immature nymphs, grubs, and maggots to their drastically different adult forms.

Multiple copies of let-7 show up in the newly sequenced genetic blueprints of humans. But “we don’t have a larval stage, so we don’t know what purpose the gene serves,” Ruvkun admits. He speculates that the gene may be involved in regulating the “molting” of baby teeth, or the growth of certain tissues at puberty when humans become capable of reproduction. However, Ruvkins says, “It’s all a guess at this point.”

What’s not a guess is the potential value of comparative genetics. C. elegans gets along with 302 nerve cells; humans boast trillions of them in a single brain. The worm lives out its life cycle in 10 days; a lucky human takes 80 years or more. By worming their way up the genetic ladder from C. elegans to fruit flies, to zebra fish, to humans, it will now be easier for scientists to answer some tough fundamental questions about evolution and biology. Just as worms are, genetically speaking, half human, so we are half worm.