Studies of myocardial aging in humans are complex, dictated by the difficulty to separate the effects of time on the heart from concomitant morbidities, and a variety of ethnic, lifestyle, and environmental factors, which affect physiological aging. Because of the mystery of aging, the need to acquire information on a large animal model, maintained under controlled conditions during the organism lifespan, is of critical importance to define the etiology of the aging heart, and recognize novel targets for the management of the aging myopathy. Project 3 will characterize the mechanisms that determine the transition from adulthood to cardiac aging and senescence in male and female Beagle dogs raised and kept in a highly regulated environment at the Lovelace Biomedical and Environmental Research Institute (LBERI) in which a detailed record of the health history of the animals is maintained. The major hypothesis to be tested is that stem cells in the dog heart change their phenotypic characteristics with age so that the balance between myocytes and fibroblasts being formed is lost, resulting in an increase in collagen content and alterations in ventricular compliance. This hemodynamic abnormality, together with a smaller myocyte progeny, increases diastolic load per cell. Myocytes function as supporting cells in the myocardial niches, and myocyte stretch may activate a large pool of CSCs, and replicating CSCs undergo telomere attrition with loss of growth reserve. Aged CSCs generate myocytes that rapidly acquire the senescent phenotype and old myocytes typically show prolonged relengthening and decreased shortening, further impairing diastolic relaxation and, eventually, overall cardiac performance. Diastolic heart failure with normal or near normal ejection fraction comprises -50% of pafients affected by chronic heart failure, and the information to be obtained in this Project is fundamental for understanding whether myocardial aging is dictated by stem cell defects and whether preserved CSCs may be implemented as a novel strategy for the treatment of this devastating, obscure disease.

Public Health Relevance

The research discussed in this project is directed to the identification of the mechanisms responsible for the development of diastolic dysfunction in the aging heart of a large animal model. The information to be obtained may lead to the discovery of new therapeutic options for this epidemic disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-7)
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Brigham and Women's Hospital
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Borghetti, Giulia; Eisenberg, Carol A; Signore, Sergio et al. (2018) Notch signaling modulates the electrical behavior of cardiomyocytes. Am J Physiol Heart Circ Physiol 314:H68-H81
Wysoczynski, Marcin; Guo, Yiru; Moore 4th, Joseph B et al. (2017) Myocardial Reparative Properties of Cardiac Mesenchymal Cells Isolated on the Basis of Adherence. J Am Coll Cardiol 69:1824-1838
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