They were able to mimic the spontaneous genetic mutation Connecticut researchers found in the fruit fly by feeding C. elegans specially engineered bacteria that knock down the activity of Indy. Their model netted a 15-20 percent increase in lifespan in addition to the other benefits. Unlike true genetic knockouts, with scientists completely removing both copies of a gene so 100 percent of function is gone or taking out one copy so the gene functions at half capacity, the MCG scientists cannot determine the exact gene activity level in their animal model. "These worms reflect what happens with reduced activity in the transporter," Dr. Ganapathy says. "But we don't yet have a stable mutant line. That is one of the aims for the NIH grant."
Oddly, the maximum benefit, at least in the fruit fly, doesn't come from zero activity. Rather flies live the longest with about half the normal gene activity. Dr. Fei wants to find the optimal degree of activity. He and his co-investigator, Dr. Ganapathy, already are working on a knockout mouse that has half the normal Indy activity so they can look at the impact on longevity in mice that usually live two years instead of a few weeks.
To confirm that the gene functions similarly in worms and humans, they also plan to take the Indy gene out of the C. elegans and replace it with the human gene to see if that reverses the effect. "We call it humanizing the worm," Dr. Ganapathy says.
He noted an interesting difference between worm and human genes is that the human Indy gene is more adept at transporting tricarboxylates or citrates, a primary precursor for fat and cholesterol. "If you find a drug which can block the function of this transporter, it might interfere with the use of citrate for fat and cholesterol synthesis which should help people lose weight and reduce thei
Contact: Toni Baker
Medical College of Georgia