Pharmacological clearance of senescent cells improves cardiac remodeling and function after myocardial infarction in female aged mice

Cardiovascular diseases (CVD) are predominantly an aging disease. Important sex-specific differences exist and the mechanism(s) by which this sex-by-age interaction influences CVD development and progression remains elusive. Accordingly, it is still unknown whether cell senescence, a main feature of cardiac male aging, is a significant feature also of the female aged mouse heart and whether senolytics, senescence-clearing compounds, promote myocardial repair and regeneration after myocardial infarction (MI) in aged female mice. To this aim, the combination of two senolytics, dasatinib and quercetin (D+Q) or just their vehicle was administered to 22-24 months old C57BL/6 female mice after MI. D+Q improved global left ventricle function and myocardial performance after MI whereby female cardiac aging is characterized by accumulation of cardiac senescent cells that are further increased by MI. Despite their terminal differentiation nature, also cardiomyocytes acquire a senescent phenotype with age in females. D+Q removed senescent cardiac non-myocyte and myocyte cells ameliorating cardiac remodeling and regeneration. Senolytics removed aged dysfunctional cardiac stem/progenitor cells (CSCs), relieving healthy CSCs with normal proliferative and cardiomyogenic differentiation potential. In conclusions, cardiac senescent cells accumulate in the aged female hearts. Removing senescent cells is a key therapeutic target for efficient repair of the aged female heart.