Mutated gene doubles fruit fly's life span.

The lab-grown flies just kept on living, although the biologist needed them to die so he could study their tissues. "I was getting quite agitated," recalls Stephen L. Helfand of the University of Connecticut Health Center in Farmington.

All turned out for the best. Intrigued, Helfand and his colleagues began to investigate their strain of long-lived flies. As they report in the Dec. 15 SCIENCE, the researchers ultimately found a mutated gene that nearly doubles the average life span of Drosophila melanogaster, the common fruit fly.

Beyond offering further proof that single genes can have dramatic influences on longevity, an idea that drew skepticism just a decade ago, the new finding may help scientists explain how severely reducing calorie intake extends life span in a variety of animals (SN: 11/25/00, p. 341). The gene identified by Helfand's group encodes a cell-surface protein that may help a fly's gut absorb select nutrients.

Helfand and his collaborator Robert Reenan have dubbed the gene Indy, for "I'm not dead yet," from a line in the film Monty Python and the Holy Grail.

It was Reenan and his lab mate Blanka Rogina who discovered that Helfand's long-lived flies and another strain with similar longevity both had mutations in Indy. The mutations, a piece of DNA inserted into Indy, don't fully disable the gene but do reduce its activity, thereby slowing production of its protein.

Flies have two copies of Indy, and such a mutation in one of them extends the fly's average life span at 25 [degrees] C from 37 days to about 70 days. The single mutation also increases the flies' maximum life span by about 50 percent.

If the DNA insertion occurs in both copies of Indy, the flies enjoy only a 10 to 20 percent increase in the typical life span. If one copy has the DNA insertion and the other is totally disabled, the flies actually live shorter-than-normal lives.

The researchers contend that these data fit the theory that Indy's protein plays a role in calorie intake or metabolism. Somewhat reducing the protein's production creates a calorie-restricted diet that extends life span, they suggest. If Indy is even less active, however, the flies may essentially starve.

The scientists haven't observed any downside to their mutant flies' longevity. When other researchers developed long-lived fly strains by breeding the oldest flies in successive populations, those strains were often less fertile than normal.

The flies with Indy mutations may even be more fertile than normal flies. "There's no delay in the onset of fertility and, in fact, they lay eggs longer," says Helfand. The mutant flies also seem as active physically as normal flies are.

The insect protein encoded by Indy resembles several proteins in mammals that enable intestinal and kidney cells to take in metabolites, such as citrate, to produce energy. The new study has startled the few researchers who study these transport proteins. They've primarily probed the proteins' role in kidney stone formation, not aging.

"It's a total surprise," says Ana Pajor of the University of Texas Medical Branch in Galveston. "At meetings, there's usually only four or five of us ... really keen on the topic."

While linking these transport proteins to aging could support the connection between calorie restriction and longevity, Pajor cautions that researchers must still identify what metabolite the Indy protein transports.

Once that occurs, says Helfand, it should be possible to make an altered metabolite that blocks the transporter. Such a compound might serve as a drug that mimics calorie restriction and increases longevity, he speculates.

Knowing a possible function for Indy's protein should accelerate research on its relevance to aging, notes John Tower of the University of Southern California in Los Angeles. There's another gene, methuselah, that when mutated extends the fly life span 35 percent, but its protein's role remains murky, he says.