Published Online
on October 12, 2009

A more recent version of this article appeared on October 27, 2009

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Submitted on April 8, 2009
Accepted on August 20, 2009

Suppression of Phosphoinositide 3-Kinase Prevents Cardiac Aging in Mice

Yasutaka Inuzuka MD, Junji Okuda MD, Tsuneaki Kawashima MD, Takao Kato MD, Shinichiro Niizuma MD, Yodo Tamaki MD, Yoshitaka Iwanaga MD, PhD, Yuki Yoshida MD, PhD, Rie Kosugi MD, PhD, Kayo Watanabe-Maeda MD, PhD, Yoji Machida MD, PhD, Shingo Tsuji PhD, Hiroyuki Aburatani MD, PhD, Tohru Izumi MD, PhD, Toru Kita MD, PhD, and Tetsuo Shioi MD, PhD^*

From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto (Y. Inuzuka, J.O., T. Kawashima, T. Kato, S.N., Y.T., Y. Iwanaga, T. Kita, T.S.); Department of Cardioangiology, Kitasato University School of Medicine, Kanagawa (Y.Y., R.K., K.W.-M., Y.M., T.I.); and Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo (S.T., H.A.), Japan.

^* To whom correspondence should be addressed. E-mail: tshioi{at}kuhp.kyoto-u.ac.jp.

Background—Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging.

Methods and Results—We analyzed age-associated changes in murine heart and the manner in which suppression of the p110 isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart.

Conclusions—Suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.

Key words: aging • heart failure • insulin • phosphoinositide 3-kinase • rapamycin

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