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A gene mutation called "I'm not dead yet" may hold the secret of longer life

As the year 2000 draws to a close, it's difficult to avoid the pang of apprehension that comes with being another year older. Aging is the one aspect of life that none of us avoid, but most of us hate being reminded of. This month, however, there is an odd bit of news in the air, news that removes some of the sting from year's end. It seems that it just may be possible to live longer. Quite a bit longer.

The odd bit of news comes from the laboratory of a researcher named Stephen Helfand working at the University of Connecticut Health Center at Framington, Connecticut. Like many biologists interested in aging, Helfand studies the aging process in fruit flies, which have an easy-to-study life span of only 37 days.

Up till now, the only ways scientists have found to extend the lives of fruit flies involve costs few humans would contemplate: either flies had to be starved, or prevented from having offspring. One fruitfly mutation called grandchildless created females with no ovaries -- the mutant flies lived 50% longer than ordinary flies, but at the cost of not being able to bear children.

An unusual fruitfly mutation discovered by renowned geneticist Seymour Benzer at Cal Tech in 1998 offered a ray of hope. Dubbed methuselah, this mutation allowed healthy flies to live up to 50 days, extending the fruitfly life span 35%. Unfortunately, nobody has been able to figure out what the mutated methuselah gene does to prevent aging. Its everyday function remains a complete mystery.

Enter Stephen Helfand. His lab was working on a different problem, and stumbled across the anti-aging mutation by accident. Their work is reported this month in the journal Science. Hefland had been creating mutations in a gene by using a mobile bit of DNA called a P element. P elements jump from one spot to another on chromosomes more or less at random, creating mutations in whatever genes they intrude upon (Imagine adding a few lines of gibberish to a complex computer program at a random location, and you will get the picture.).

In his experiments Hefland maintained a control group of flies that also had an inserted P element, but at a chromosomal location far from the gene Hefland was attempting to study. Bizarrely, these control flies did not die when the other flies did, instead living on and on.

Looking more carefully at these flies, Helfand's team found they had a p element-induced mutation, a very interesting one: fruit flies carrying a mutated copy of this gene lived an average of 70 days vs. the usual 37 -- doubling the life span!

Screening their laboratory fruitfly stocks and those of other labs, the research team was able to find five different mutations of this mysterious anti-aging gene. Each of the mutations was cause by a P element that disrupted the anti-aging gene, each at a different place within the gene. Every one of the five mutations greatly extended the life

span of the flies. The Helfand research team named the gene Indy (I'm Not Dead Yet), based on a quip in the movie Monty Python and the Holy Grail.

The Indy mutation extends life without exacting any apparent cost. The Indy flies eat as much, lay as many eggs, and court vigorously, maintaining youthful vigor long after normal flies have aged and died.

What does Indy do? Now the story really gets interesting. The researchers isolated the DNA of the Indy gene, and compared its DNA sequence with the human genome project sequences: the Indy gene is 50% similar to a human gene called dicarboxylate cotransporter. Its very likely that Indy does the same thing in fruitflies that this awkwardly-named gene does in humans.

And that's the payoff. In humans, dicarboxylate cotransporter proteins act like tiny food pumps. The pumps move the preliminary products of food metabolism (dicarboxylic acids) into cells, where the rest of the food's processing takes place. In mutant Indy flies, poor dicarboxylic acid pumping means that less metabolic energy can be gleaned from the fly's food. In essence, the Indy mutation is the genetic equivalent of caloric restriction.

Starving is known to prolong life in flies and worms, but Indy's caloric restriction does not involve the unpleasantness of starving. The Indy mutation in effect puts flies on a severe diet, while the flies eat as much as normal and lead a normal vigorous life -- for far longer.

Is there a human gene that acts like Indy? No one knows, but there are strong indications that genes affect our own life spans. Tom Perls, head of Harvard Medical School's Centenarian Study, reports that siblings of those over 100 are four times as likely to live into their 90s as siblings of adults with average life spans.

Imagine a drug designed to inhibit a human Indy gene. It might allow you to live 50% longer -- to 120! No such drug exists yet, and we certainly don't know enough to be sure it would work if it did exist. But what a tantalizing prospect -- a suitable way, I think, to turn to the new year of On Science.

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