OVERALL: MITOCHONDRIAL PROTECTIVE INTERVENTIONS, AGING AND HEALTHSPAN P01 - SUMMARY/ABSTRACT We propose a highly focused, integrated and interactive effort to examine the hypothesis that mitochondrial targeted therapeutics are capable of resisting age-related disease and improving health and function in multiple organ systems in aging mammals. We are focused on heart, skeletal muscle and retina (vision) in aging; the vital function of each of these organs is highly reliant on mitochondrial energetics; each declines reproducibly with age and each contributes to frailty in the elderly human population. Most importantly, we show evidence that each of these age related healthspan limitations can be not just attenuated, but substantially reversed in old animals treated with a mitochondrial therapeutic agent, the tetrapeptide drug SS- 31. Thus, we have developed a strong translational goal of applying mitochondrial protective agents to achieve substantial health benefits in the aging mammalian models of mice and rats. The potential translational impact of this approach is high, as SS-31 is already in multiple phase II clinical trials, including three inspired by the prior animal studies performed by our P01 investigators. We propose three Projects: 1) Mitochondrial ROS and Cardiac Aging (Rabinovitch); 2) Mitochondrial Function and Skeletal Muscle Aging (Marcinek) and 3) Mitochondrial Function and Vision Aging (Prusky/Szeto). While each of these thee projects has their specific organ focus, each also shares a common third Aim of working jointly to establish the healthspan and lifespan benefits of SS-31 when it is continuously delivered to mice beginning at middle age, with and without the added stress of a high fat diet. We propose 5 Cores to provide vital support and services that are used by all three projects to accomplish their aims: A: Administration (Rabinovitch); B: Murine Healthspan and Lifespan, (Ladiges); C: Proteomics (MacCoss); D: Mitochondrial Protective Chemistry (Szeto) and E: Magnetic Resonance & Optics Spectroscopy (Conley).

Public Health Relevance

OVERALL: MITOCHONDRIAL PROTECTIVE INTERVENTIONS, AGING AND HEALTHSPAN P01 ? PROJECT NARRATIVE This Program Project tests the hypothesis that mitochondrial targeted therapeutics are capable of resisting age-related disease and improving health and function in aging mammals. We are focused on heart, skeletal muscle and vision aging; the vital function of each of these organs is highly reliant on mitochondrial energetics; each declines reproducibly with age and each contributes to human frailty. Attenuating or reversing aging of these organs would have a high impact on the quality of life of the elderly human population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG001751-33A1
Application #
9209215
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (O2))
Program Officer
Fridell, Yih-Woei
Project Start
1997-08-15
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
33
Fiscal Year
2017
Total Cost
$2,023,566
Indirect Cost
$534,376
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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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
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
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
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

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