Suppressing a gene in mice prevents heart from aging, preserves its function

Scientists prevented age-related changes in the hearts of mice and preserved heart function by suppressing a form of the PI3K gene, in a study reported in Circulation: Journal of the American Heart Association.

“The study provides evidence that delaying or preventing heart failure in humans may be possible,” said Tetsuo Shioi, M.D., Ph.D., senior author of the study and assistant professor of medicine at Kyoto University Graduate School of Medicine in Kyoto, Japan.

“Advanced age is a major risk factor for heart failure. One reason is that aging increases the chance of exposure to cardiovascular risk factors. However, natural changes due to aging may also compromise the cardiovascular system.”

According to the American Heart Association, 5.7 million Americans have heart failure, and nearly 10 out of every 1,000 people over age 65 suffer heart failure every year.

Shioi and his colleagues studied elderly mice genetically engineered to suppress the activity of one form of the PI3K gene, which is a part of the insulin/IGF-1signaling system that helps regulate the lifespan of cells.

A variation of PI3K, known as the p110á isoform, plays an important role in tissue aging. Suppressing the isoform’s activity in the roundworm C. elegans extends its life. And in fruit flies, suppression prevents the age-dependent decline of heart function.

The Japanese researchers compared aged mice with a functional p110á to aged mice with suppressed p110á and found that mice with the suppressed gene had:

• improved cardiac function;
• less fibrosis (fibrosis causes the heart to lose flexibility);
• fewer biological markers of aging; and
• a pattern of cardiac gene expression like that of younger mice.
“This 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,” Shioi said.

The researchers concluded that PI3K’s role in cardiac aging involved regulating other points further downstream in the insulin/IGF-1signaling pathway, which resulted in changes in how insulin acted in heart cells. The biological mechanism by which suppressing the gene’s activity improved the survival of the mice remains unclear.

“The heart failure epidemic in the United States and many other countries is due, in part, to our aging population,” said Mariell Jessup, M.D., an American Heart Association spokesperson and professor of medicine at the University of Pennsylvania School of Medicine in Philadelphia. “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. 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.”

Co-authors are: Yasutaka Inuzuka, M.D.; Junji Okuda, M.D.; Tsuneaki Kawashima, M.D.; Takao Kato, M.D.; Shinichiro Niizuma, M.D.; Yodo Tamaki, M.D.; Yoshitaka Iwanaga, M.D., Ph.D.; Yuki Yoshida, M.D., Ph.D.; Rie Kosugi, M.D., Ph.D.; Kayo Watanabe-Maeda, M.D., Ph.D.; Yoji Machida, M.D., Ph.D.; Shingo Tsuji, Ph.D.; Hiroyuki Aburatani, M.D., Ph.D.; Tohru Izumi, M.D., Ph.D.; and Toru Kita, M.D., Ph.D.

Author disclosures and funding sources are in the study.

Statements and conclusions of study authors published in American Heart Association scientific journals are solely those of the study authors and do not necessarily reflect the association’s policy or position. The association makes no representation or guarantee as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations are available at www.americanheart.org/corporatefunding.

NR09-1126 (Circ/Shioi-Inuzuka)