Courtesy of Blanka Rogina.

Methuselah, according to the Book of Genesis, lived for a remarkable 969 years. By comparison, a lifespan of 70 days isn't much to write home about, unless you're a fruitfly that is — in which case it's nearly twice as long you'd expect to live. Rogina and colleagues recently noticed that some of their mutagenized flies were doing just that — living for double the average of a normal fly. But these researchers did more than just give their mutant a catchy name — the I'm not dead yet (Indy) fly — they identified a single gene that when disrupted doubles lifespan and encodes a protein that is directly involved in energy metabolism. Altering energy metabolism can mimic a well-known cause of longevity in many species — restricting calorie intake.

The five independent P-element insertions that doubled the average lifespan of flies were at a single locus, from which Rogina et al. cloned a gene with homology to two mammalian dicarboxylate cotransporters. These membrane proteins function in the uptake and recycling of Krebs cycle intermediates. When two P-elements that disrupted the first intron of this gene were excised in two separate fly lines, Indy flies reverted to a normal lifespan. Furthermore, unlike other long-living mutant flies, their longevity was not due to delayed or altered fertility, and Indy flies showed no developmental delays, as seen in some long-lived C. elegans mutants.

Further clues as to how the Indy mutations might cause longevity come from the gene's expression at sites associated with fat and glycogen storage and energy metabolism. INDY's homology to dicarboxylate cotransporters indicates that it functions directly in intermediary metabolism — an important finding as other longevity-inducing genes have been found to have indirect effects on metabolism. The authors suggest that a mild reduction in Indy expression might create a metabolic state similar to that induced by longevity-promoting calorie restriction. Too great a disturbance of this process, however, is not beneficial to the fly — lifespan extension is most dramatic in Indy heterozygotes, and flies that carry an Indy mutation over an Indy-deleted chromosome die earlier than normal. The Indy gene provides the first direct genetic link between ageing and metabolism and a way into unravelling why reduced calorie intake extends lifespan. Research into Indy may even lead to life-extending drugs, but the prospect of another Methuselah is still some way off.