Yale and University of Connecticut Researchers May Have Found Mechanism to Mimic Lowering Caloric Intake as a Way of Increasing Lifespan

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 Thursday in the journal Science.

Using the fruit fly Drosophilia melanogaster, Stewart Frankel, senior author of the study and associate research scientist in pediatrics, said he and his colleagues have identified a drug target that could potentially achieve the results of calorie reduction without actually eating less. This target is the Rpd3 histone deacetylase, an enzyme. 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 said. “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 percent to 40 percent 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 said. “Even gray hair is delayed.”

He said, 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 said.

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 said. “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 said. “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.

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