A Ketogenic Diet Increases Markers of Mitochondrial Content in a Tissue Specific Manner in Adult Mice

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Dysregulation of mitochondrial energy metabolism is a major hallmark of mammalian aging. Calorie restriction (CR) has been shown to effectively increase lifespan and is associated with a metabolic shift toward a decrease in glycolysis and an increase in fatty acid oxidation. This shift in fuel utilization that occurs with CR relies heavily on mitochondrial energy metabolism. Thus, a diet that can mimic the metabolic reprogramming that occurs with CR may reduce age‐related decline in mitochondrial function and energy metabolism, and contribute to healthy aging and longevity. A ketogenic diet, which is depleted in carbohydrates, would drive the utilization of fat as a fuel and increase mitochondrial fatty acid oxidation. By chronically stimulating pathways in mitochondrial oxidative metabolism, the ketogenic diet could influence mitochondrial function and biogenesis, and may prevent age‐related decreases in mitochondrial content. In this study, mice were fed an isocaloric control (CLT), low carbohydrate (low‐CHO), or ketogenic diet (KD) from the age of 12 months. Tissues were collected after 1 month and 14 months of dietary treatment for evaluation of mitochondrial content. The results showed that the low‐CHO and KD increase markers of mitochondrial content in skeletal muscle in old mice (age of 26 months). The activities of both Complex I and IV were increased (p<0.05) in the low CHO and KD diet compared to the CTL diet. Old mice fed a KD also maintained activity of Complex I compared to the young mice, while mice fed the CLT and low‐CHO diets showed a decline (p<0.05) in Complex I activity with aging. Mice fed a KD also showed increased muscle citrate synthase activity with age. However, these changes are tissue specific with liver showing only an increase in Complex IV activity with aging in the KD group. In summary, the study demonstrates that long‐term ketogenic diet may prevent age related decline in mitochondrial content in some tissues in adult mice.Support or Funding InformationNIH Grant PO1AGO25532