Feed a Cell, Deprive an Organism?
Authors: Seydel Caroline 
Published: August 2003

Throwing a wrench into the pathway that turns food into energy sounds like a bad idea, but it might lengthen life. Flies survive nearly twice as long as normal when they don't make enough of a protein called INDY, and new work shows that INDY shuttles organic molecules required for metabolism across the cell membrane. The protein's apparent role in energy production suggests a connection with a well-known life-extension method--calorie restriction--and the findings might help reveal how the long-lived flies persevere.

Two years ago, Stephen Helfand of the University of Connecticut Health Center in Farmington and colleagues found a gene in fruit flies that nearly doubles the insects' life-span. The gene, called
I'm not dead yet
(
Indy
), encodes a protein similar to members of a mammalian protein family that carry negatively charged organic molecules across the cell membrane.

To find out whether the INDY protein performs a similar function in flies, the team members engineered frog eggs--a common testing ground for protein function--to manufacture INDY, then they surrounded the eggs with radioactively tagged succinate, a molecule that's necessary to convert food into useable cellular energy. The INDY-producing eggs took up more than 50 times as much succinate as did normal eggs. Similar experiments revealed that INDY also moves other negatively charged molecules needed for metabolism, as do similar mammalian transporter proteins. Unlike the mammalian transporters, however, INDY does not piggyback its cargo with sodium ions.
Most cells maintain a low internal concentration of sodium ions. Some transporters rely on the preponderance of sodium outside the cell to propel their substrate across the membrane; the ions naturally flow into the low-sodium interior of the cells, carrying the organic molecule along with them. INDY, which apparently doesn't work this way, defines a new class of transporter.

In additional experiments, the researchers used antibodies that bind INDY to determine where in the fly the protein conducts business. They found it where it should be if it carries metabolic products: in the cell membranes of nutrient-absorbing tissues, such as the digestive tract and the fat body--the fly's version of a liver. Flies with life-extending mutations in the
Indy
gene had abnormally small amounts of the protein in these organs, indicating that the mutations don't generate an abnormal version of INDY but make less of it.

Discovering that INDY transports the products of metabolism "bolsters the notion that energy regulation is related to aging ... in the fly," says geneticist Marc Tatar of Brown University in Providence, Rhode Island. If INDY helps the cell turn nutrients into energy, reducing INDY quantities might lengthen life in a way similar to calorie restriction, Helfand conjectures. The work "suggests that somehow reducing energy or just nutrient flow has something to do with aging," Tatar says, "but it doesn't yet clarify how, or what the mechanism is." Understanding how
Indy
mutations tamper with metabolism could give researchers a tool to turn the screws on aging in mammals.

--Caroline Seydel

F. Knauf, B. Rogina, Z. Jiang, P. S. Aronson, S. L. Helfand, Functional characterization and immunolocalization of the transporter encoded by the life-extending gene
Indy
.
Proc. Natl. Acad. Sci. U.S.A.
99
, 14315-14319 (2002).
[Abstract]
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