Ketogenic diet attenuates cardiac aging through inhibiting CD36/MAPK-mediated lipid accumulation: Comparable effects in aged male and female mice.

Aging is accompanied by a decline in circulating ketone bodies and progressive cardiac dysfunction, yet whether dietary ketone repletion counteracts cardiac aging in a sex-specific manner remains unclear. Here, we first investigated the associations between plasma ketone bodies and cardiac function in a human cohort, comprising 120 adults (44.78 ± 10.97 years; 66 male/54 female) and 121 aged individuals (69.59 ± 6.88 years; 75 male/46 female). And, we then evaluated the therapeutic potential of an 8-week ketogenic diet (KD) in physiologically aged mice (22 months, both sexes), which were daily supplemented with either chow diet (3.79 kcal/g, Aged group) or KD (7.24 kcal/g, Aged+KD group). In humans, circulating β-hydroxybutyrate (β-HB) levels were significantly lower in aged human individuals and positively correlated with key parameters of cardiac function, including ejection fraction (EF), fractional shortening (FS) and the ratio of early to late diastolic filling velocity (E/A ratio). In aged mice, 8-week KD supplementation elevated cardiac β-HB concentrations and attenuated cardiac remodeling in both sexes. Notably, KD improved systolic/diastolic function (e.g., EF, FS and E/A ratio), preserved mitochondrial function, reduced myocardial lipid accumulation, and ameliorated systemic dyslipidemia equivalently in both sexes. Mechanistically, KD suppressed CD36 membrane translocation and MAPK activation, whereas CD36 upregulation abolished these protective effects, establishing a causal role of the CD36/MAPK pathway in KD-mediated cardioprotection. Altogether, these findings identify β-HB as a biomarker of cardiac aging and show that KD rescues age-related cardiomyopathies through CD36-MAPK-mediated lipid metabolic regulation, with equivalent benefits in both sexes.