Chronic Senolytic Treatment and/or Aerobic Exercise Reduce Senescence and Improve Myocardial Function During Aging in the Heart

Aging is the predominant risk factor for cardiac dysfunction, driven primarily through a decline in cardiomyocyte and overall myocardial performance. Cellular senescence is becoming increasingly linked to its development, as senescent cardiomyocytes and interstitial cells accumulate with age and exhibit persistent DNA damage, mitochondrial dysfunction, and inflammation that collectively impair ventricular relaxation and contractility. Senolytics, which selectively eliminate senescent cells, effectively clear cardiac senescence and its burden, while aerobic exercise has shown promise as a non‐pharmacological intervention capable of modulating senescence. Despite this, neither approach has been evaluated as a long‐term preventive strategy or whether combining exercise with senolytics produces an additive effect. We hypothesized that when combined, chronic senolytics and aerobic exercise would produce a synergistic clearance of senescent myocardial cells leading to improved cardiac function. Male and female C57BL/6N mice (12‐months‐old) were randomly allocated to each group and received their intervention for 9‐months: naturally aged (VEH, n = 12), aerobic exercise (EX, n = 11), senolytics Dasatinib + Quercetin (D + Q) (SEN, n = 15) or both combined (SENEX, n = 16). Chronic D + Q, exercise, or both, significantly lowered the proportion of p16+, p21+, and γ‐H2AX+ cardiomyocytes and interstitial cells, while improving myocardial performance and diastolic function compared to naturally aged mice. At the whole‐heart level, protein expression of p16 and p21 increased with age, but was not altered alongside SASP by any intervention. Collectively, these findings demonstrate that long‐term exercise or senolytics limit senescence at the cellular level within the myocardium, and improve ventricular function, positioning exercise or senolytics as promising strategies to mitigate age‐related cardiac dysfunction.