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),

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG001751-29
Application #
8378136
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
29
Fiscal Year
2012
Total Cost
$173,405
Indirect Cost
$61,047
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Campbell, Matthew D; Marcinek, David J (2016) Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods. Biochim Biophys Acta 1862:716-24
Loeb, Lawrence A (2016) Human Cancers Express a Mutator Phenotype: Hypothesis, Origin, and Consequences. Cancer Res 76:2057-9
Treuting, P M; Snyder, J M; Ikeno, Y et al. (2016) The Vital Role of Pathology in Improving Reproducibility and Translational Relevance of Aging Studies in Rodents. Vet Pathol 53:244-9
Liu, Sophia Z; Marcinek, David J (2016) Skeletal muscle bioenergetics in aging and heart failure. Heart Fail Rev :
Ahn, Eun Hyun; Lee, Seung Hyuk; Kim, Joon Yup et al. (2016) Decreased Mitochondrial Mutagenesis during Transformation of Human Breast Stem Cells into Tumorigenic Cells. Cancer Res 76:4569-78
Kruse, Shane E; Karunadharma, Pabalu P; Basisty, Nathan et al. (2016) Age modifies respiratory complex I and protein homeostasis in a muscle type-specific manner. Aging Cell 15:89-99
Chiao, Ying Ann; Kolwicz, Stephen C; Basisty, Nathan et al. (2016) Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY) 8:314-27
Ahn, Eun Hyun; Hirohata, Kensen; Kohrn, Brendan F et al. (2015) Detection of Ultra-Rare Mitochondrial Mutations in Breast Stem Cells by Duplex Sequencing. PLoS One 10:e0136216
Birk, Alexander V; Chao, Wesley M; Liu, Shaoyi et al. (2015) Disruption of cytochrome c heme coordination is responsible for mitochondrial injury during ischemia. Biochim Biophys Acta 1847:1075-84
Quarles, Ellen K; Dai, Dao-Fu; Tocchi, Autumn et al. (2015) Quality control systems in cardiac aging. Ageing Res Rev 23:101-15

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