Researchers Alter Genes to Extend Worm’s Life Span
Canadian researchers have discovered a set of genes that determine the life span of the common nematode, a finding that sheds new light on the aging process and that may eventually allow them to delay the inexorable processes of decay and death.
By manipulating the newly discovered genes, the team at McGill University in Montreal was able to increase the life span of the nematode worms fivefold.
They report in today’s issue of the journal Science that altering of the genes to prolong life span slowed the metabolism of the worms and reduced their entire lifestyle to a more leisurely pace. This relaxed rhythm of life, some experts speculate, may slow the accumulation of DNA defects that are thought to cause aging.
Although the causes of aging in humans are undoubtedly much more complex, researchers are confident the discoveries will provide invaluable clues about this hitherto mysterious process. “Historically, the genes that have been found in worms have played an important role in humans as well, “ said molecular biologist Pamela L. Larsen of USC, who recently obtained similar results with a different set of nematode genes.
The team’s ability to extend the life span of the worms is “absolutely amazing,” said molecular biologist Judith Campisi of the Lawrence Berkeley National Laboratory.
“What we have here is a very powerful animal model for studying how genes regulate lifestyle and possibly metabolism,” added USC gerontologist Caleb E. Finch. “This field is breaking wide open. In the next year, we will know precisely what these genes do.”
Experts took pains to distinguish the new findings from the discovery last month of the mutant gene involved in Werner’s syndrome, which causes premature aging. In that case, mutations in the gene shortened life span, whereas in the nematodes, intentional mutations increased it.
“It’s important that the mutations make life span longer,” Larsen said. “If you can increase life span, then you must have changed something that previously reduced life span.” The normal form of the gene probably produces a protein that in some way limits life span, she said.
Once that protein has been identified and its function defined, experts agreed, it may be possible to interfere with its normal activity and thereby increase life span or make old age healthier.
The organism being used in the new studies, Caenorhabditis elegans, is one of the most thoroughly studied of all species. A microscopic, transparent worm, it is composed of exactly 959 cells. Researchers have traced the lineage of each of these cells all the way back to the original fertilized egg and know precisely how the nematode develops.
Several teams are now working to decipher the order of the estimated 100 million chemicals, called bases, of the organism’s 3,000 to 8,000 genes.
Researchers have previously found ways to extend the life span of Caenorhabditis to a lesser degree. Molecular geneticist Thomas E. Johnson of the University of Colorado, for example, has found he can double its normal nine-day life span by mutating a gene called age-1.
Investigators also have found a family of nematode genes, called daf genes, that regulate how long the organism stays in a dormant state called diapause. Mutations in these extend life span by making the dormant state last longer.
The new genes discovered by biologists Siegfried Hekimi and Bernard Lakowski of McGill are quite different, however, because they seem to directly control the aging process. The genes, called clk-1, clk-2 and clk-3, appear to regulate what Hekimi calls “a central biological clock” that controls metabolism and life span.
Mutations in clk-1, for example, cause individual cells to divide more slowly. As a result, the worms spent more time in each phase of their life cycles, living about 50% longer.
But the most intriguing results came when Hekimi and Lakowski crossbred the worms to produce combinations of mutations. With one such combination, they reported, the mutants lived nearly two months, as opposed to the normal nine days. This is the greatest increase in life span ever achieved, albeit just slightly longer than that reported by Larsen in her earlier study.
Although the mutants looked and behaved normally, they ate less, defecated less often and wiggled their bodies more slowly when they swam, Hekimi said. He and Lakowski also believe that they use the energy contained in their food more efficiently, although that has not been proved.
If, in fact, the worm’s metabolism is operating more slowly, that is a key point, they said. The prevalent theory of aging is that it is caused by the accumulation of damage to DNA and other cellular components brought about by highly reactive byproducts of metabolism--the process by which food is converted into energy.
If that process proceeds more slowly, Hekimi speculated, less damage may occur, or the body’s natural repair process may be more effective. Support for this idea also comes from a recent study in monkeys, which demonstrated that reducing food intake--a strategy that has been shown to increase life span in a variety of species--causes a lowering of body temperature and a reduction in the metabolic rate.
But scientists still have a long way to go before the research can be converted to clinical application. “We’re just at the very early stage of [finding] these genes,” said molecular biologist Cynthia Kenyon of the Lawrence Berkeley National Laboratory. Environment, stress and a host of other factors probably play crucial roles in aging as well.
Nonetheless, researchers are scrambling to find other genes for aging and the human counterparts of those already discovered. The search “is really going to be hot,” Finch said.
