Two-month ketogenic diet alters systemic and brain metabolism in middle-aged female mice

The ketogenic diet (KD) is a very low-carbohydrate, high-fat diet that reduces glucose catabolism and enhances β-oxidation and ketogenesis. While research in female rodents is limited, research in male rodents suggests that ketogenic interventions initiated at midlife may slow age-related cognitive decline, as well as preserve muscle mass and physical function later in life. This study aimed to investigate the effects of a KD on global metabolic changes in middle-aged females to inform potential mechanisms behind the anti-aging effects of this diet in an understudied sex. Targeted ¹H-NMR metabolomics was conducted on serum, the liver, the kidney, and the gastrocnemius muscle, as well as the cortex and the hippocampal brain regions in 16-month-old female mice after a 2-month KD. Analysis of the serum and liver metabolome revealed that the 2-month KD resulted in increased concentrations of fatty acid catabolism metabolites, as well as system-wide elevations in ketones, consistent with the ketogenic phenotype. Metabolites involved in the glucose-alanine cycle were altered in the gastrocnemius muscle, serum and the liver. Other tissue-specific alterations were detected, including distinct effects on hepatic and renal one-carbon metabolism, as well as region specific differences in metabolism across hippocampal and cortical parts of the brain. Alterations to hippocampal metabolites involved in myelinogenesis could relate to the potential beneficial effects of a KD on memory.