This Program Project Grant application challenges the accepted but never proven paradigm that the adult heart is a post-mitotic organ composed of an irreplaceable number of parenchymal cells, which is established at birth. The common theme of this proposal is based on the premise that the heart is a self renewing organ in which a stem cell compartment controls the physiologic turnover of cardiac cells and conditions myocardial aging and tissue regeneration in pathologic states. The long-term goal is the understanding of the origin and developmental control of cardiac stem cells (CSCs), their distribution in the heart and mechanisms of aging, the etiology of their death and senescence, and their therapeutic potential for the aged and aged-infarcted heart. The recognition that CSCs are present in the heart imposes a reconsideration of the various theories of cardiac development, maturation and, most importantly, myocardial aging. The notion that cardiomyocytes age at the same pace, and the age of the cells, organ and organism coincides is no longer acceptable and will be proven wrong by the interrelated studies to be performed in the five projects included in this application. We will try to ascertain the origin of CSCs and, more specifically, whether they are remnants of the embryonic cardiogenic plates that remain in the myocardium or whether they derive from the bone marrow and colonize the heart through the circulation and continuously replenish the CSC pool. The time-dependent decrease in the number of functionally competent CSCs mediated by critical shortening of telomeres and alterations of chromosomal proteins may result in CSC aging with forced entry into an irreversible state of quiescence. The complex process of stem cell senescence is expected to involve loss of locomotion, growth and differentiation, limiting cell turnover and expanding the population of old poorly functioning myocytes. Thus, CSC senescence leads to the old heart phenotype. If this were the case, genetic manipulation increasing the CSC pool and their survival should delay aging and the impairment in cardiac performance with time. The ability to activate and mobilize CSCs from the site of storage to areas of damage and promote myocardial regeneration may postpone the remodeling of the aged and aged-infarcted heart and the onset of terminal failure in the elderly. If successful, this research will make the impossible dream of myocardial regeneration a feasible reality.