AGING RESEARCH:
Old Flies May Hold Secrets of Aging
by
Elizabeth Pennisi

On p. 2137, a research team reports the discovery of a gene that, when altered, can double the life-span of fruit flies and may one day offer the promise of perpetual youth. Preliminary data suggest that the protein encoded by this gene transports and recycles metabolic byproducts. The researchers think that defects in the gene can lead to production of a protein that renders metabolism less efficient; as a result the body functions as if the fruit fly were dieting, even though its eating habits are unchanged. The work may lead to a better understanding of how metabolism plays into aging.

Blanka Rogina, Robert A. Reenan, Steven P. Nilsen, Stephen L. Helfand*, "Extended Lifespan Conferred by Cotransporter Gene Mutations in Drosophila," Science Vol. 290, pp. 2137-2140 (December 15, 2000).

ABSTRACT:

Aging is genetically determined and environmentally modulated. In a study of longevity in the adult fruit fly, Drosophila melanogaster, we found that five independent P-element insertional mutations in a single gene resulted in a near doubling of the average adult life-span without a decline in fertility or physical activity. Sequence analysis revealed that the product of this gene, named Indy (for I'm Not Dead Yet), is most closely related to a mammalian sodium dicarboxylate cotransporter -- a membrane protein that transports Krebs cycle intermediates. Indy was most abundantly expressed in the fat body, midgut, and oenocytes: the principal sites of intermediary metabolism in the fly. Excision of the P element resulted in a reversion to normal life-span. These mutations may create a metabolic state that mimics caloric restriction, which has been shown to extend lifespan.

Department of Genetics and Developmental Biology; School of Medicine; University of Connecticut Health Center; 263 Farmington Avenue, Farmington, CT 06030, USA.
* To whom correspondence should be addressed. E-mail: shelfand@neuron.uchc.edu .

Gene Mutation Doubles Lifespan
by
Paul Recer,
AP Science Writer

December 15, 2000; Washington, D.C. (AP) -- Mutation of a gene whimsically dubbed "I'm Not Dead Yet" (INDY) can double the life span of fruit flies, a laboratory discovery that researchers said may lead to drugs to help people live longer and, perhaps, even lose weight. Researchers at the University of Connecticut Health Center have found that the life span of fruit flies was extended from an average of 37 days to 70 days when a gene was modified on a single chromosome. Some flies in the study lived 110 days.

The same long-life gene exists in humans, said Dr. Stephen L.Helfand, senior author of the study, and "offers a target for future drug therapies aimed at extending life." In human terms, a doubled life span would be about 150 years. Helfand said the gene mutation appears to work by restricting calorie absorption on a cellular level -- in effect, putting the cells on a diet. This raises the possibility, he said, of one day developing a pill that would both extend life and control weight. "From what we know about this gene, that makes perfect sense," he said.

Helfand said a key finding of the study, which was appearing Friday in the journal Science, is that not only did the fruit flies live longer, but they also seemed to maintain a high quality of life. "It is not an empty or hollow increase in life span. It prolongs active adult life, and I think, delays the onset of aging," he said.

Some life-extension studies showed that animals tended to trade vigor and energy for a longer life, he said. But the mutant flies "do well throughout their longer life," Helfand said. "By the time that [80 - 90] percent of normal flies are dead, these mutants are still doing just fine."

Blanka Rogina, a co-author of the study, said female flies with the mutated genes were able to reproduce throughout life. They had the energy for the fruit flies complex courtship ritual and could lay up to 2,000 eggs in their lifetime, compared with about 1,300 eggs normally, she said.

The long-life gene was named for a comical line -- "I'm not dead yet'' -- from a Monty Python movie, Helfand said. The gene's name was suggested by co-author Robert A. Reenan and has been shortened to "INDY." "In academic circles," explained Helfand, "sophomoric humor, such as in Monty Python, is very common.''

There have been other studies that found long-life genes in fruit flies and nematodes. There also have been experiments in mice that show calorie restriction -- a severe diet -- can extend life by up to 50 percent.

But Huber Warner, Associate Director for Research into the Biology of Aging at the National Institute of Aging, said the Indy gene discovery is more significant because "it may be a different way to get the same effect that caloric restriction achieved in mice and other organisms." He said "it may be possible to develop a drug that inhibits metabolism in the same way as the mutated Indy gene." "Such a drug would have to be tested extensively in animals to assure that it is safe," Warner said. "If you wanted to slow metabolism in people, this research suggests that this could be a way to do it," he said. "It is strictly theoretical right now, but it is a possibility."

Helfand and his colleagues discovered the livelong gene by chance. He said they were screening a strain of fruit flies in another study and found that flies were living much longer than normal. They isolated the Indy gene and then tested it in a number of different laboratory fruit fly strains. In all cases, it extended life. But Helfand said the researchers discovered that if the gene is mutated too much, it actually shortens life.

The normal gene is on two chromosomes of the fruit fly. If one of these genes is altered, thus reducing the strength of the gene, then the flies enjoyed a long life. If both genes were knocked out altogether, said Helfand, the flies actually died sooner, perhaps starving to death. "If we restrict (the gene) a little bit there is a big advantage," said Helfand. "But if we make an animal that has only the mutated gene, we find that the animal lives a shorter than normal."

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On the Web:

1. National Institute on Aging: www.nih.gov/nia;

2. Science journal: www.eurekalaert.org.

Mutation Doubles the Lifespan of Fruit Flies

A change in a single gene nearly doubles the lifespan of fruit flies, from 37 days to around 70, according to a report in this week's edition of the journal Science. The researchers, led by Stephen L. Helfand of the Connecticut University Health Center in Farmington, CN, suspect that the mutation works by causing changes in the metabolism of food. Other studies have shown that research animals receiving full nutrition but lowered calorie intake tend to live longer, although how this might work is not well understood. Helfand suggests that it is likely to involve differences in the way that energy is used. "What is interesting about this line of research is the recurrence of the link between metabolism, caloric restriction and longevity. This study points to the possibility that if you genetically alter metabolism, you can alter lifespan," said Davi Finkelstein, research director for metabolic regulation research at the National Institute on Aging. "While there is an 80 percent homology between the fruitfly and human genomes, we are still many steps away from understanding how caloric restriction may affect human lifespan," Finkelstein said.