Ketogenic diet attenuates aging-associated myocardial remodeling and dysfunction in mice.

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.