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  December 9, 2002

Enzyme Research Could Help
Extend Human Life Span
By Pat Keefe

A Connecticut research team has identified a genetic interaction with significant implications for diet and longevity.

The team, composed of faculty from the UConn Health Center and Yale School of Medicine, have shown in an article reported November 28 in the journal Science, that decreasing the activity of the enzyme, Rpd3 histone deacetylase, found in both humans and fruit flies, extends the life span of fruit flies through a pathway involving caloric restriction.

The research suggests that chemical manipulation of the enzyme may bring about beneficial life-span effects, without the severe dietary constraints of caloric restriction.

The team includes Dr. Stephen Helfand, associate professor, and Blanka Rogina, assistant professor, both of the Health Center's Department of Genetics and Developmental Biology, and Stewart Frankel, associate research scientist, pediatrics, section on developmental biology and biophysics at Yale Medical School.

"The universality and commonalities of biochemical and genetic pathways between diverse organisms is amazing," says Dr. Helfand, adding that the work may have practical effects in the future.

Scientists have long known that severely reducing caloric intake can extend the life span of mammals. Caloric restriction in rodents can increase their life span by more than 50 percent. Studies of primates have shown that caloric restriction delays age-related diseases. Because the diet is so restrictive, however, it is impractical for most people to follow.

Frankel says there may be a historical explanation for the connection between caloric restriction and improved life span: "We think this is an evolutionary adaptation for starvation conditions. It puts the body into a long-term maintenance state, so that whether you are a fruit fly, a mouse or, we think, a human, you can hang on long enough without food to reproduce."

In previous studies, Rogina and Helfand suggested that the life span-extending properties of a gene they discovered may be similar to caloric restriction. The gene, named "INDY" for "I'm Not Dead Yet" in a reference to the film Monty Python & The Holy Grail, prompted a search for drugs that affect the protein in order to extend healthy life span without dietary restriction in humans.

The new finding, that decreasing the activity of a single enzyme, Rpd3, extends life span in fruit flies through pathways associated with caloric restriction provides another specific focus for discovering drugs that could help maintain body weight and extend life span without the need to severely restrict caloric intake.

"We knew from our previous work - the INDY work in particular - that genes governing caloric intake or life span, can be manipulated to improve outcomes," says Rogina. "The Rpd3 work resembles the INDY findings, except at a whole other level."

"INDY is a gene mutation that induces a state of caloric restriction. Rpd3 is part of the pathway through which caloric restriction works," says Dr. Helfand. "The data suggest and our hypothesis is that INDY induces caloric restriction. With INDY, you put food in your mouth but it doesn't all get where it's supposed to go. Rpd3 is a more fundamental part of the pathway. Once caloric restriction is induced, Rpd3 appears to act as a regulator of life span extension."

The researchers say drugs already exist that affect the same pathway as Rpd3 histone deacetylase, and may affect Rpd3 itself. These drugs are used to treat other conditions and they or other drugs that are more specific for the Rpd3 pathway could be tested for their effects on body weight and maintaining healthy life longer in humans.

"This is very interesting and the implications are exciting," says Rogina. "But it's also only a small step. It will take years of research before we have a therapeutic intervention."

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