Cardiac aging is manifested as unfavorable geometric and functional alterations in heart. The current work was to test whether a ketogenic diet (KD) impacted aging-associated myocardial remodeling and dysfunction in mice and investigate the underlying mechanism. The young and aged male mice were fed with KD or standard chow for four months. Echocardiography results revealed that KD decreased left ventricular end systolic diameter (LVESD) and increased fractional shortening in aged mice. With KD feeding, aged mice exhibited reduced cardiomyocyte cross-sectional area, fibrosis, and mRNA expression of atrial natriuretic peptide (ANP), Col1A1 and alpha smooth muscle actin (α-SMA) in myocardium. KD enhanced activities of superoxide dismutase 2 (SOD2), glutathione peroxidase (GPx) and catalase, and reduced the levels of malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) in myocardium of aged mice. KD led to a downregulation of expression of C/EBP homologous protein (CHOP), glucose regulated protein 78 (GRP78), cleaved activated transcription factor 6 (ATF6), and spliced X box-binding protein 1 (XBP-1 s) in myocardium of aged mice. KD in aged mice reduced mitochondrial reactive oxygen species (ROS) formation, enhanced mitochondrial ATP production and mitochondrial membrane potential (MMP), and preserved activity of complex III and electron-coupling capacities between complexes I and III and between complexes II and III in myocardium. Importantly, KD in aged mice promoted autophagic flux, evidenced by reduced protein expression of p62 and enhanced protein expression of lysosome-associated membrane protein-2 (Lamp2) in myocardium. In conclusion, long-time KD intake delayed cardiac aging in male mice, possibly through abating oxidative stress, improving mitochondrial function, and promoting autophagic flux.

心脏衰老表现为心脏的不利几何和功能改变。当前的工作是测试生酮饮食（KD）是否会影响小鼠衰老相关的心肌重塑和功能障碍，并研究其潜在机制。用KD或标准饲料喂养年轻和老年雄性小鼠四个月。超声心动图结果显示，KD可降低老年小鼠的左心室收缩末期直径（LVESD）和缩短分数。使用KD喂养时，老年小鼠的心肌横截面积，纤维化和心钠素，Col1A1和α平滑肌肌动蛋白（α-SMA）的mRNA表达降低。KD增强了超氧化物歧化酶2（SOD2），谷胱甘肽过氧化物酶（GPx）和过氧化氢酶的活性，降低了老年小鼠心肌中丙二醛（MDA）和3-硝基酪氨酸（3-NT）的水平。KD导致心肌中C / EBP同源蛋白（CHOP），葡萄糖调节蛋白78（GRP78），裂解的活化转录因子6（ATF6）和剪接的X盒结合蛋白1（XBP-1 s）的表达下调。年小鼠。老年小鼠中的KD减少了线粒体活性氧（ROS）的形成，增加了线粒体ATP的产生和线粒体膜电位（MMP），并保留了复合物III的活性以及复合物I和III之间以及复合物II和III之间的心肌电子耦合能力。重要的是，老年小鼠的KD促进自噬通量，这通过心肌中p62的蛋白表达降低和溶酶体相关膜蛋白2（Lamp2）的蛋白表达增强来证明。