(A) In young hearts, myocardium homeostasis, normal tissue function, and excess cardiac reserve are maintained through de novo formation of cardiomyocytes from resident cardiomyocyte stem cells (CMSCs) or division of incompletely differentiated, small cardiomyocytes. New cardiomyocyte formation matches a relatively low rate of cardiomyocyte apoptosis (purple cells). Appropriate CMSC function, including return to quiescence and suppression of cardiomyocyte death, may be maintained by homeostatic signals arising from the pericardium. (B) In disease-free, aging hearts, a declining ability to replace apoptotic cardiomyocytes due to progenitor dysfunction/senescence conspires with an increasing rate of cardiomyocyte death to produce compensatory hypertrophy. In the resting state and in the absence of further CVD, this adaptive change partially preserves heart function but predisposes to heart failure upon further stress. Interestingly, the INK-ATTAC SNC-killing transgenic strategy efficiently removes SA β-gal–positive pericardial SNCs from aged mice and prevents both cardiomyocyte hypertrophy and declining β-adrenergic stress tolerance. Based on this, we propose the existence of pericardium-derived prohomeostatic signaling that is disrupted during aging by pericardial SASP factors, although similar disruptive signaling may arise from senescent cardiomyocytes, CMSCs, or other cell types in the myocardium. (C) When challenged with cardiovascular stressors, such as ischemia in coronary artery disease, diabetes, or hypertension, the aged myocardium exceeds its functional reserve and decompensates. Apoptotic cardiomyocytes are not replaced, hypertrophy no longer preserves function, and excessive fibrosis leads to conduction defects, arrhythmia, and HF. To some extent, fibroblast senescence restricts fibrosis, but the long-term presence of these and other SNC types in the failing heart is suspected to be deleterious. It is currently unclear whether SNC removal can improve established heart failure or merely blunts development.