Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac Ca_V1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca²⁺ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

心脏功能障碍是人类和小鼠衰老的标志。在此，我们报道了一项为期两周的治疗，以恢复 24 个月大小鼠心脏中年轻的桥接整合蛋白 1 (BIN1) 水平，从而使心脏功能恢复活力，并显着逆转衰老表型。我们的数据表明，与年龄相关的 BIN1 过度表达与内体循环失调以及心脏 Ca _V 1.2 和 2 型兰尼碱受体运输中断同时发生。这些缺陷会影响静息时的通道功能及其在急性应激期间的上调。体内超声心动图显示老年小鼠的收缩功能下降。使用腺相关病毒血清型 9 包装的 shRNA-mBIN1 敲除 BIN1 可恢复兰尼碱受体的纳米级分布和聚类可塑性，并将 Ca ²⁺瞬态振幅和心脏收缩功能恢复到年轻水平。收缩功能的增强与肌丝蛋白心肌肌球蛋白结合蛋白-C 磷酸化的增加相关。这些结果表明 BIN1 敲低是一种使老化心肌恢复活力的新型治疗策略。