Genetic models of lifespan extension in mammals have not been previously known, and caloric restriction has been the only experimental manipulation shown to retard aging of mammals. We have now demonstrated that overexpression of catalase targeted to mitochondria (MCAT) leads to lifespan extension in mice. Also, we have shown that while overexpression of wild type catalase (targeted to peroxisomes) and Cu-Zn superoxide dismutase (SOD1) have little effect on murine lifespan by themselves, the combination of overexpression of these two produces a significant extension of mean lifespan. These are the first demonstrations that genetically augmented antioxidant defenses can appreciably extend lifespan in mammals. This proposal seeks to extend and better understand these findings.
In Aim 1, we will study the physiologic, pathologic and molecular alterations that are responsible for the extended lifespan of MCAT mice. We will compare these changes to those associated with the extended lifespan of calorically restricted mice to determine whether these two mechanisms act through similar or different pathways.
In Aim 2, we will build upon our initial observations by creating two improved models of augmented antioxidant protection. We will generate transgenic mice expressing both MCAT and SOD1 from the same promoter and with uniform tissue expression, and we will enhance the redox capacity of MCAT mice by expressing both MCAT and the glutamate-cysteine ligase modulatory subunit (the rate limiting step controlling glutathione synthesis) from the same promoter and with uniform tissue expression. Each model evaluates the benefit of protective mechanisms in different subcellular compartments and/or different antioxidant pathways, and complements the models studied elsewhere in this P01.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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University of Washington
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Basisty, Nathan B; Liu, Yuxin; Reynolds, Jason et al. (2018) Stable Isotope Labeling Reveals Novel Insights Into Ubiquitin-Mediated Protein Aggregation With Age, Calorie Restriction, and Rapamycin Treatment. J Gerontol A Biol Sci Med Sci 73:561-570
Kramer, Philip A; Duan, Jicheng; Gaffrey, Matthew J et al. (2018) Fatiguing contractions increase protein S-glutathionylation occupancy in mouse skeletal muscle. Redox Biol 17:367-376
Zhang, Huiliang; Gong, Guohua; Wang, Pei et al. (2018) Heart specific knockout of Ndufs4 ameliorates ischemia reperfusion injury. J Mol Cell Cardiol 123:38-45
Ge, Xuan; Ciol, Marcia A; Pettan-Brewer, Christina et al. (2017) Self-motivated and stress-response performance assays in mice are age-dependent. Exp Gerontol 91:1-4
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
Liu, Sophia Z; Marcinek, David J (2017) Skeletal muscle bioenergetics in aging and heart failure. Heart Fail Rev 22:167-178
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
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

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