Ketone Catabolism Is Essential for Maintaining Normal Heart Function During Aging

The heart uses various nutrient sources for energy production, primarily favoring fatty acid oxidation. Although ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging.

To investigate the functional significance of ketone use in the heart, we employed a mouse model with impaired ketolysis in the heart. In addition, we administered a ketogenic diet to evaluate the effects of exogenous ketone supplementation on cardiac ketone metabolism and function in this model.

The cardiac expression of SCOT (succinyl-CoA:3-ketoacid CoA transferase), a rate-limiting enzyme in ketolysis, decreases with age in mice. SCOT cardiomyocyte-specific knockout mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cardiomyocyte-specific knockout mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation.

These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.