Our central hypothesis is that myocardial aging is dictated by time-dependent changes in the phenotypic properties of c-kit-positive human cardiac stem cells (hCSCs), which condition the structural and functional characteristics of the myocardium. The possibility is raised that hCSCs undergo telomere attrition with aging, and telomere shortening alters their growth behavior; hCSCs with shortened telomeres form a smaller progeny than hCSCs with long telomeres. Also, hCSCs with shortened telomeres generate different proportions of myocytes, endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts than hCSCs with long telomeres; fibroblasts predominate in the former, and myocytes, ECs, and SMCs in the latter. Thus, telomere length is viewed as a novel biomarker of biological cardiac aging. The progeny derived from hCSCs with shortened telomeres rapidly acquires the senescent phenotype and old myocytes show abnormalities in Ca2+ transients and diastolic relaxation, affecting myocardial compliance. Sarcomere stretching in myocytes operating as supporting cells within the hCSC niches may favor spontaneous Ca2+ oscillations in hCSCs and/or translocation of Ca2+ from myocytes to hCSCs via gap junction channels, promoting cell cycle reentry; and sustained cell division induces telomere attrition and the generation of an old cardiac progeny. Throughout life, the female heart possesses a larger pool of hCSCs with a young phenotype than the male heart, pointing to a gender difference in the aging process of the heart. A small pool of hCSCs with long telomeres may be preserved in the senescent female and male heart so that these cells can be harvested, expanded in vitro, and potentially delivered back to the same patient, reversing the aging myopathy and heart failure in the elderly.

RELEVANCE (See instructions): This research aims at the identification of the etiology of myocardial aging and the recognition of cardiac stem cells (CSCs) with intact growth reserve in the old human heart. If successful, CSC treatment may be proposed to reverse the aging myopathy and restore the youth of the organ.