Tiny Worms Yield Genetic Clues to Longevity

The worm, in literature, traditionally has been a reminder of death and mortality, an ignominious symbol of the brevity of life. Edgar Allan Poe even constructed a poem around the idea and named it, ominously, “The Conqueror Worm.”

But in a UC Irvine laboratory, one species of worm recently has earned an entirely different reputation. Squirming in petri dishes, swimming in solutions, moving under the constant scrutiny of the microscope, thousands of tiny roundworms are providing researchers with clues that longevity may be controlled by a single gene.

Through complex chemical and electrical processes, Tom Johnson, an assistant professor of molecular biology and biochemistry, and a group of nine student and post-doctorate researchers, have been able to produce genetic mutations in a nematode known as Caenorhabditis elegans and identify one mutated gene that they believe extends the roundworm’s life span by 60 percent. If the mutated gene is producing longer-living worms, then it’s the first time genetic researchers have been able to identify a single gene responsible for longevity in an organism, according to geneticists interviewed by The Times.

Johnson presented his findings in June to a conference on aging at the Mount Sinai Medical Center in New York.

“People have been trying to do this for 60 years,” Johnson said. “It’s been talked about for a long time and it’s contrary to many theories. A few years ago, I didn’t think there could be a single gene that could lengthen life. This is such an unusual finding.”

The research team’s objective is as simple as the research itself is complex, Johnson said.

“Our approach,” he said, “has been to ask real fundamental questions. We’re looking for genetic stock that prolongs life, and we’d like to identify a whole battery of these genes.”

Although Johnson said that he believes “most of us in basic biology” assume that genetic research findings can be duplicated in other species, possibly humans, he emphasized that a mutant gene in a roundworm is not the Fountain of Youth.

“With these findings, we’ll eventually be able to clone the gene and, if there are similar genes in higher mammals, we’ll be able to identify them,” he said. “But any kind of gene research like this in humans probably is still at least 10 years off. It would be very difficult to do correctly and there are very severe ethical limitations.”

J. Edwin Seegmiller, a genetics researcher and the director of the Institute for Research on Aging at UC San Diego, said there is “considerable evidence that genes may be involved in the life span of a human being.”

“We certainly know that there are genetic factors that can cause diseases (in humans) that result in early death,” Seegmiller said. “We think there may be quite a number of genes that may contribute to longevity. There’s an old folk saying: The best way to live to a ripe old age is to choose the right grandparents.”

Seegmiller called Johnson’s finding “a very interesting development. It’s a good model system.” As to its applicability to human life, however, he said that “it’s entirely too early to tell.”

The mutant gene causing all the excitement resides in the cells of an earth-dwelling worm about a millimeter long that Johnson and his team of researchers have been tinkering with for 2 1/2 years. The nematode, Johnson said, is perfect for longevity research because of its simple genetic makeup, its low cost to obtain and the fact that its life span is usually less than a month. At any one time, in a climate-controlled case in the lab, Johnson can observe several hundred nematode cultures with about 50 of the worms in each culture. Similar research on mice, he said, would take 200 years.

Genetic ‘Maps’

Johnson received his original supply of nematodes from a researcher at the University of Houston, an associate professor of biology named Mike Klass, who had produced life-extending genetic mutations in the roundworms but had been unable to trace the effect to a single gene. Using Klass’ nematodes and their thousands of offspring, Johnson and his colleagues exposed the roundworms to chemicals and electricity, producing many mutant generations. These generations were watched, day by day, and when they died their life spans were recorded on genetic “maps,” not unlike a family tree, which helped the researchers to trace the longevity effect back to a single gene. Johnson called this gene Age One.

“It’s incredibly tedious, as you can imagine,” Johnson said.

Although genes responsible for longevity have existed in theory, genetic makeup has been identified as the culprit in more than one exotic disease that shortens life.

“Most of the genetic work in the last 30 years has been centered on genes that cause disease,” Seegmiller said. He named progeria--an aging disease that strikes children, causing them to suffer the physical signs and debilitations of old age--as a disease that “we believe is caused by a single gene mutation.” A similar disease, Werner’s syndrome, which strikes middle-age adults, also may be gene-related.

Rare Form of Cerebral Palsy

Seegmiller discovered that a form of cerebral palsy called Lesh-Nyhan Disease, which causes children to compulsively mutilate themselves by biting their lips and tongues, is caused by a gene that resides on the X chromosome. The culprit, known as the HPRT gene, is found in only 100 families in the United States, Seegmiller said.

Seegmiller said he would love to secure funding for human research into a longevity gene. For now, however, he said that research on non-human life, such as the nematode, can yield much data.

“The beauty of Johnson’s system,” he said, “is that the nematode has a limited number of cells and the genetic origin of every one of those cells has been worked out. There are 1,000 cells in the body of the worm, a much simpler system than a human being. It’s a good place to start.”

Aging research, Johnson said, is beginning to receive more attention and encouragement from institutions that provide research grants and funds. But the future of the funding and research is uncertain, he added.

‘So Little Known About It’

“I’ve been working on the subject of aging since 1980,” he said. “There’s so little known about it. There’s a real push on now by the National Institute on Aging (part of the U.S. Public Health Service) to encourage this sort of research. But people doing aging research are getting (the monetary equivalent of) about 1 1/2 MX missiles a year. That’s minuscule.

“Aging research is at a critical point now. It’s starting to move more from the theoretical to the experimental. And scientists traditionally overestimate how long technology takes to infiltrate into the field. I can’t say anything is impossible.”