Ketogenic diet, cardiometabolic diseases and aging

The ketogenic diet (KD), characterized by a high-fat, moderate-protein, and low-carbohydrate macronutrient composition, has gained growing interest as a potential nutritional approach to cardiometabolic diseases and aging. Emerging evidence suggests that ketone bodies, particularly β-hydroxybutyrate, act not only as alternative energy substrates but also as signaling molecules that influence vascular, metabolic, and epigenetic pathways. This review summarizes current knowledge on the cardiovascular and metabolic implications of KD, emphasizing endothelial function, cardiac energy metabolism, lipid profile, and blood pressure regulation. Experimental and clinical data indicate that KD enhances endothelial antioxidant capacity via Nrf2 activation and eNOS upregulation, reduces cellular senescence, and modulates epigenetic regulators such as histone β-hydroxybutyrylation and SIRT1. In heart failure, acute ketone supplementation improves cardiac output and energetics, while chronic adherence to KD may impair hepatic ketogenesis and lipid homeostasis, potentially offsetting its benefits. Evidence in hypertension and dyslipidemia remains controversial, with short-term improvements often contrasted by long-term elevations in LDL cholesterol and arterial stiffness. In patients with type 2 diabetes, KD promotes glycemic control and insulin sensitivity, yet the sustainability and cardiovascular safety of prolonged use are uncertain. Overall, KD represents a promising but complex therapeutic tool whose efficacy depends on individual metabolic context, diet composition, and duration. A balanced, intermittent, or cyclic ketogenic approach may offer a safer strategy to harness its cardiometabolic and anti-aging benefits.