This application raises the possibility that the female heart is superior to the male heart and adapts better to aging and cardiac failure because the female heart inherits a larger and/or more efficient pool of cardiac progenitor cells (CPCs) that persists throughout life. The female heart acquires a richer CPC compartment than the male heart and local factors within the female myocardium protect the CPC pool size during the difficult journey of life. The fundamental premise of this research is that estrogen enhances telomerase function and IGF-1 signaling in CPCs promoting CPC division and lineage commitment. Similarly, IGF-1 synthesis is higher in the female than in the male heart, and IGF-1 protects CPC function and thereby the youth of the heart. Together, estrogen and IGF-1 potentiate the turnover of cardiomyocytes and vascular cells and concurrently preserve CPC number. The formation of reactive oxygen species (ROS) in the myocardium increases with age and the amount of ROS and the age of the cells determine whether death signals trigger apoptosis or necrosis. Low quantities of ROS induce apoptosis and high quantities induce cell necrosis. Apoptosis does not alter myocardial structure while cell necrosis stimulates inflammation, fibroblast proliferation, and myocardial scarring, which are typical of the heart senescent phenotype. Therefore, the male aging myopathy is a stem cell myopathy in which a defective stem cell compartment conditions aging and death of myocytes and coronary vessels, which are delayed in the female heart. IGF-1 and estrogen attenuate oxidative stress, interfere with death signals, and may convert cell death from necrosis to apoptosis. Based on this hypothesis, the IGF-1-IGF-1 receptor system opposes myocardial aging and the occurrence of heart failure with senescence, extending lifespan. Interventions with IGF-1 might attenuate the generation of ROS and its impact on cell death, and organ and organism aging, changing dramatically current understanding of IGF-1-signaling and lifespan in mammals. Consistent with this notion, targeted mutation of the p66shc gene decreases the formation of ROS, increases the resistance to oxidative challenge, and prolongs life in mice. This demonstrates that a gene modifies the generation and effects of ROS on lifespan. For this reason, the work above will be complemented with the study of the p66shc-/- mouse to test more distally whether oxidative stress, cellular aging, and mechanisms of cell death are critical determinants of the aging heart in males and females. If this were correct, the impact of ROS on the heart should be attenuated in p66shc-/- mice, delaying the onset of the male cardiomyopathy, eliminating gender differences with respect to aging and lifespan. Thus, the genetic-molecular status of the heart may condition the outcome of aging and genetic manipulations may interfere with the development of the cardiac senescent phenotype in both genders.
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