We have previously shown that genefic overexpression of catalase targeted to mitochondria (mCAT) prolongs murine median lifespan by 17-21%. To better define the health impact of reducing mitochondrial reacfive oxygen species (ROS), we have now focused carefully on cardiac contribufions to aging. We have demonstrated that cardiac aging in the mouse closely recapitulates human aging, with cardiac hypertrophy and decline in diastolic and systolic functions in the absence of cardiac-extrinsic risk factors, and accompanied by the same molecular and biochemical changes that are seen in the aging human heart. Most significanfiy, mCAT substantially delays and attenuates both the functional and biochemical changes of cardiac aging. Furthermore, we have also found that mCAT protects from acute models of both cardiac hypertrophy and heart failure in the mouse, and that the hypertrophy model recapitulate much of the pathology of cardiac aging. Understanding the mechanisms by which reduced mitochondrial ROS and improved mitochondrial funcfion attenuates intrinsic cardiac aging and signaling pathways (Aim 1) is central to understanding this effect. Intrinsic cardiac aging is also believed to increase the susceptibility of the heart to failure. As heart failure associated with aging is likely to become the major cause of hospital admissions and mortality in North America, we will study the role of mitochondria in this cardiac aging-heart failure interaction (Aim 2). Finally, in order to better translate our findings to human health, we will determine the capacity of mitochondrially targeted antioxidant and protecfive daigs to recapitulate the MCAT benefits to cardiac aging and heart failure (Aim 3),

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Project 1: This project is studying a genefic mouse model of protecfion from mitochondrial oxidation and damage that appears to have significant protecfion from heart aging and failure. We wish to understand how these benefits are caused and then apply them using pharmacologic agents so that these same cardiac health benefits can be translated to the aging human populafion.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-6)
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University of Washington
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