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 #
5P01AG001751-31
Application #
8643181
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
31
Fiscal Year
2014
Total Cost
$171,775
Indirect Cost
$60,594
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Sweetwyne, Mariya T; Pippin, Jeffrey W; Eng, Diana G et al. (2017) The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age. Kidney Int 91:1126-1145
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
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
Basisty, Nathan; Dai, Dao-Fu; Gagnidze, Arni et al. (2016) Mitochondrial-targeted catalase is good for the old mouse proteome, but not for the young: 'reverse' antagonistic pleiotropy? Aging Cell 15:634-45
Campbell, Matthew D; Marcinek, David J (2016) Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods. Biochim Biophys Acta 1862:716-724
Loeb, Lawrence A (2016) Human Cancers Express a Mutator Phenotype: Hypothesis, Origin, and Consequences. Cancer Res 76:2057-9
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

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