We have previously shown that genetic over expression of catalase targeted to mitochondria (mCAT) prolongs murine median lifespan by 17-21%. To better define the health impact of reducing mitochondrial reactive oxygen species (ROS), we have now focused carefully on cardiac contributions 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 significantly, 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 function 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 protective daigs to recapitulate the MCAT benefits to cardiac aging and heart failure (Aim 3).

Public Health Relevance

We have previously shown that genetic over expression of catalase targeted to mitochondria (mCAT)prolongs murine median lifespan by 17-21%. To better define the health impact of reducing mitochondrial reactive oxygen species (ROS), we have now focused carefully on cardiac contributions 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 significantly, 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 function 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 protective daigs to recapitulate the MCAT benefits to cardiac aging and heart failure (Aim 3),

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG001751-30
Application #
8431793
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
30
Fiscal Year
2013
Total Cost
$163,176
Indirect Cost
$57,559
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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