Sci. Aging Knowl. Environ., 29 October 2003
Mutated, manipulated worms set nematode life-span record
Key Words: daf-2(e1370) daf-2(e1368) gonad ablation class 1 mutants class 2 mutants dauer
Living a long time means nothing without good health, and until now, the nematode worms with the greatest life spans have been sickly. Now, researchers have created extremely long-lived worms that are spry to boot. Neutering worms after slashing the amount of a particular protein makes them last six times longer than normal. The work suggests that animals don't have to give up good health to achieve remarkably long life.
Mutations in insulin/insulin-like growth factor 1 (IGF-1) signaling pathways extend life span in many species. In the tiny roundworm Caenorhabditis elegans, the daf-2 gene codes for the protein that initiates the signal upon binding a hormone. Researchers can double the life span of worms by blunting daf-2 activity; these animals seem robust. Some daf-2 mutations quadruple length of life, but these old animals barely wiggle and appear infirm, suggesting that extreme longevity can be bought only by sacrificing health. Arantes-Oliveira and colleagues wanted to test whether combinations of treatments would lead to healthy, very old animals, so they mucked around with worms carrying a life-extending daf-2 mutation that doesn't impair health.
The daf-2 mutation they studied hinders, rather than disables, the gene's activity and increases average life span by about 30%. To remove more DAF-2 protein, the team used a biochemical method called RNA interference (RNAi) to destroy messenger RNA made by the daf-2 gene. Like many daf-2 mutants, these animals lived about twice as long as normal. Previous work showed that removing the germ cells--which develop into sperm and eggs--from either normal worms or daf-2 mutants increases their life span, but removing the whole sperm- and egg-producing organs--the gonads--from normal animals doesn't. The team wondered whether eliminating the gonads from the RNAi-treated daf-2 mutants would have the same effect as in normal worms. To address the question, they laser-zapped the reproductive organs of treated mutants. To their surprise, the worms set a longevity record, living on average 124 days, compared to 24 days for unmolested, nonmutated crawlers. The animals also wriggled vigorously and ate voraciously, suggesting that they were hale. The scientists liken the elderly undulaters to healthy 500-year-old humans and conclude that very long life doesn't require a huge reduction in vitality.
Other researchers are intrigued by the superold worms. "It's such a big change" in longevity, says geneticist Marc Tatar of Brown University in Providence, Rhode Island. "It tells us that something magical is happening in the animal." Geneticist David Gems of University College London agrees. Finding such a long-lived and still healthy worm is "like pulling a rabbit out of a hat," he says. "It's nice to know the worms are not undergoing drastic metabolic shutdown." The team has yet to identify how the animals live so much longer than normal, but Gems is curious to know if extreme longevity requires another gene, daf-16, which the insulin/IGF-1-like signaling system deactivates and which is crucial for reproduction. Pinning down the details might help humans live long and still prosper.
October 29, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150