A Gene Tweak Could Keep Heart Young

MONDAY Oct. 12, 2009 -- Japanese scientists have prevented age-related deterioration in the hearts of mice by suppressing the activity of a gene involved in the insulin-signaling system that helps regulate the life span of cells, and they say the finding is potentially applicable to the control of heart failure in humans.

"A lifelong genetic modification of the human heart is not possible," said Dr. Tetsuo Shioi, an assistant professor of medicine at Kyoto University Graduate School of Medicine, and lead author of the report in the Oct. 12 online edition of Circulation. "However, drugs that lower insulin are available and can prevent cardiac aging, increase exercise tolerance and reduce heart failure in middle-aged to aged members of the population."

Shioi and his colleagues have been working with the phosphoinositide-3-kinase (PI3K) gene, which is the subject of intense activity in many U.S. and foreign laboratories. The gene plays an important role in both the aging and proliferation of cells, and research is aimed at developing gene therapy not only for heart disease but also for some forms of cancer.

The Japanese study used elderly mice that were genetically engineered to suppress the activity of one form of the PI3K gene. That variant, called the p110alpha isoform, plays an important role in tissue aging. Previous studies have shown that suppressing the variant's activity extends the life of one species of roundworm and prevents the age-related decline of heart function in fruit flies.

In the study, the researchers found that older mice with suppressed p110alpha activity had better cardiac function, fewer biological markers of aging, less of the fibrosis that can reduce heart function and, in general, a pattern of heart gene activity seen in younger mice, compared to those with normal gene function.

"Our paper indicated that insulin signaling is a conserved and important mechanism that regulates cardiac aging," Shioi said. "Thus, it is highly likely that our result can be translated to the prevention of cardiac aging and heart failure in the aged human population."

The benefits indicated by the study results might be obtained by measures much simpler than genetic engineering, he said. "I plan to make the relation between insulin signaling and caloric intake, because caloric restriction is associated with low insulin in blood and is the most powerful intervention for life span extension," Shioi said. "Another plan is to test the effect of drugs that mimic caloric restriction, such as resveratrol, on cardiac aging."

Resveratrol, a molecule found in red wine, has aroused interest because it has been shown to extend life span in some animal studies, although those studies indicated that impossibly large wine intake might be needed to achieve an effect in people.

While he acknowledged that the exact molecular mechanism by which suppression of the gene's activity improved survival of the mice is not clear, Shioi said the study "showed that aging of the heart can be prevented by modifying the function of insulin and paves the way to preventing age-associated susceptibility to heart failure."

An estimated 5.7 million Americans, many of them elderly, have heart failure, with their hearts unable to pump enough blood to meet the body's needs.

"Aging humans experience a slow but gradual loss of heart cells and a host of other cellular and sub-cellular abnormalities, which make the remaining cells contract less efficiently," Dr. Mariell Jessup, an American Heart Association spokesperson and professor of medicine at the University of Pennsylvania, said in a news release from the AHA. "Thus, this early work in a mouse model, clarifying the role of PI3K in cardiac aging, could ultimately allow scientists to understand if human hearts are similarly influenced."

More information

Causes, symptoms and treatment of heart failure are described by the U.S. National Heart, Lung and Blood Institute.

Posted: October 2009


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