Combined Endurance and Resistance Exercise Mitigates Age‐Associated Cardiac Dysfunction

Abstract Aging is associated with a decline in cardiac function. Exercise has been shown to effectively reduce the risks of cardiovascular diseases. Here whether a combination of endurance and resistance exercises can improve cardiac function in aged mice during late life is investigated. Through transcriptome analysis, several signaling pathways activated in the hearts of 22‐month‐old mice after combined exercise, including cardiac muscle contraction, mitophagy, and longevity regulation are identified. Combined exercise training mitigated age‐associated pathological cardiac hypertrophy, reduced oxidative stress, cardiac senescence, and enhanced cardiac function. Upstream stimulatory factor 2 (Usf2) is upregulated in the aged mouse hearts with combined exercise compared to sedentary mice. In the human cardiomyocytes senescent model, overexpression of Usf2 led to anti‐senescence effects, while knockdown of Usf2 exacerbated cellular senescence. The results suggest that a combination of endurance and resistance exercises, such as swimming and resistance running, can mitigate age‐related pathological cardiac remodeling and cardiac dysfunction in late life. These cardioprotective effects are likely due to the activation of Usf2 and its anti‐senescence effect. Therefore, Usf2 can potentially be a novel therapeutic target for mitigating age‐related cardiac dysfunction.