Many gene mutations can extend life--at least in fruit flies. Although most of these life-extending mutations cause crippling side effects, researchers now report that the most potent longevity mutation known leaves flies relatively vigorous.
In 2000, molecular geneticist Stephen Helfand of the University of Connecticut in Farmington and colleagues discovered that a mutated "Indy" gene (the name is an acronym for the line "I'm not dead yet" from the movie Monty Python and the Holy Grail) nearly doubled the average lifetime of flies to roughly 70 days. That was a promising improvement--previously discovered mutations extended life by only 35% to 80% and most drastically curtailed metabolic rates, physical activity, or fecundity.
Not so for the Indy mutants, Helfand and colleagues report online 24 February in the Proceedings of the National Academy of Sciences. The mutant flies exhaled just as much carbon dioxide as normal flies, they found, indicating a comparable metabolic rate. And digital movies revealed that they flew at least as fast as normal flies. In addition, the mutants had 10% to 20% higher egg-laying rates than normal flies when fed high-calorie diets. However, on lower calorie diets that approximate what flies eat in the wild, egg laying was cut in half. "This could be why this mutation does not dominate in the wild," Helfand says.
The Indy gene's protein probably helps shuffle metabolites from the gut into nutrient storage sites and metabolic tissues such as the fly's fat body, the equivalent of a mammalian liver. Helfand speculates that Indy mutations might alter metabolism in a manner similar to caloric restriction, which extends life-span in mammals and other animals. He hopes future drugs might target Indy or other genes for similar, relatively consequence-free life extension. "That would be the Holy Grail," he says.
"Given the very large effect on life-span, it was particularly surprising not to see any effects on metabolic rate," says molecular geneticist Bill Orr of Southern Methodist University in Dallas. But while no serious tradeoffs were seen in this study, the Indy flies may turn out to have unforeseen weaknesses, such as unusual sensitivity to cold snaps, cautions biochemist Raj Sohal of the University of Southern California in Los Angeles.