Yale Bulletin and Calendar

December 6, 2002|Volume 31, Number 13

Scientists aim to create drug
with impact of low-cal diet

Drastically lowering caloric intake is a proven way of extending life in mammals, and a Yale researcher working with colleagues from the University of Connecticut has shown how the body may translate lower calories into longer life, it was reported Nov. 28 in the journal Science.

Stewart Frankel, senior author of the study and associate research scientist in pediatrics, says that using the fruit fly Drosophilia melanogaster, he and his colleagues have identified a drug target -- the enzyme Rpd3 histone deacetylase -- that could potentially achieve the results of calorie reduction without actually eating less. Co-authors of the study were Blanka Rogina and Stephen Helfand, both of the Department of Genetics and Developmental Biology at the University of Connecticut Health Center in Farmington.

"We think we can mimic caloric restriction, which has been shown to decrease levels of this enzyme," Frankel says. "If you decrease the level of enzyme without eating less, you still get life span extension."

Researchers studying everything from yeast to monkeys have demonstrated that decreasing caloric intake by 20% to 40% has a dramatic effect on late-life diseases. In rodents and monkeys, significantly reducing caloric intake led to improved memory, reduced incidences of heart disease and cancer, and improved physical vitality.

"The calorie-restricted rodents look young," Frankel says. "Even gray hair is delayed."

He points out, however, that the diet is difficult to follow because the amount of food allowed is so restricted. "So, having a drug that could do the same thing would be very attractive," Frankel says.

Although researchers know that drastically reducing caloric intake changes the expression of hundreds of genes, it is still a mystery how this happens. By studying Drosophilia, a multi-cellular organism with many gene similarities to mammals, Frankel and his colleagues found that the key to regulating these genes may be the enzyme Rpd3 deacetylase. Lifespan extension occurs when the enzyme is inhibited.

"We think this is an evolutionary adaptation for starvation conditions," Frankel says. "It puts the body into a long-term maintenance state so that whether you are a fruitfly, a mouse or -- we think -- a human, you can hang on long enough without food to reproduce."

"The trick is to find specific drugs to target this enzyme," he says. "We already know it can be inhibited by small molecule drugs. A putative inhibitor, phenylbutyrate, has long been used for urea cycle disorders and is in clinical trials for diseases where there are problems with gene expression, such as sickle cell anemia and adrenoleukodystrophy." Adrenoleukodystrophy is a genetic abnormality that leads to progressive neurodegeneration and is caused by the buildup of certain fats in the brain.

-- By Jacqueline Weaver

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