UC Davis

There has been increasing interest in the use of ketogenic diets (KD) to manage age-related diseases, and KDs started in early middle age have been shown to improve longevity and healthspan in mice. One of the potential mechanisms underlying the health-promoting effect of KDs is the promotion of mitochondrial biogenesis and prevention of age-related decreases in mitochondrial mass, a hallmark of mammalian aging. This dissertation investigates the impact of an isocaloric KD initiated in 12-month old mice on a panel of markers of mitochondrial mass in whole hindlimb skeletal muscle, brain, liver, and kidney. The dissertation work demonstrates that a KD increased activities of key mitochondrial enzymes in skeletal muscle and brain at an advanced age, but there were no patterns indicative of a widespread increase in mitochondrial content in these tissues or liver and kidneys. Morphological quantification of mitochondria was performed to look into specific regions within tissues, and the results of the study showed an increase in mitochondrial mass in red gastrocnemius muscle, but not prefrontal cortex, hippocampus, or liver left lobe following 1 month of a KD. These results highlight the tissue-specific alterations in mitochondrial content with a KD. This dissertation also investigated the effects on the healthspan of a KD started late in life and determined if an intermittent KD (IKD) could produce similar results to a full KD. At 18 months of age, mice were assigned to a control diet (CD), KD, or IKD (3 consecutive days of KD each week). The KD and IKD improved some measures of cognition, including working memory and spatial learning memory, promoted motor endurance, and prevented a significant decrease in composite healthspan score with aging as observed in control mice. The circulating level of cytokines were also reduced with KD and IKD, and this may contribute to the phenotypic effects observed with these diets. In conclusion, this dissertation work shows that a KD induces tissue-specific changes in mitochondrial content, and a KD and IKD initiated at late middle age improves measures of healthspan at an advanced age.