Astragaloside IV Attenuates Cardiac Aging Through Restoring Mitochondrial Dynamics Homeostasis by Promoting SIRT3 ‐Mediated DRP1 Deacetylation

ABSTRACT Cardiac aging is a major risk factor for cardiovascular diseases, with an imbalance in mitochondrial dynamics homeostasis being a pivotal aspect. Although Astragaloside IV (AS‐IV) has been shown to delay aging, its specific effects on cardiac aging and the link to mitochondrial dynamics remain unclear. This study aimed to elucidate the role and regulatory mechanism of AS‐IV in delaying cardiac aging by using naturally aged mouse models and D‐galactose (D‐gal)‐induced H9c2 cell senescence models. The results demonstrated that AS‐IV reduced the expression of senescence markers (p16 INK4a , p21, and p53), β‐galactosidase (SA‐β‐gal), and senescence‐associated secretory phenotype (SASP) factors ( Il6 , Il1b , and Tnfa ) while also significantly ameliorating aging‐induced cardiac dysfunction and myocardial fibrosis. Furthermore, AS‐IV significantly enhanced mitochondrial morphology and function in cardiomyocytes. This improvement was demonstrated by increased mitochondrial membrane potential, elevated ATP production, and reduced ROS levels. Mechanistically, AS‐IV upregulated SIRT3 and promoted its interaction with DRP1, leading to the inhibition of DRP1 acetylation. This action suppressed excessive mitochondrial fission and thereby improved mitochondrial dynamics. Transfection with SIRT3‐siRNA attenuated the beneficial effects of AS‐IV. In conclusion, this study demonstrates that AS‐IV mitigates cardiac aging by activating SIRT3 to mediate DRP1 deacetylation, which in turn improves mitochondrial dynamics. These findings provide a strong theoretical and experimental foundation for the potential application of AS‐IV in preventing and treating age‐related cardiovascular diseases.