Project Summary Ketogenic diet (KD), a high fat low carbohydrate diet is used to treat intractable epilepsy, is becoming increasingly popular for weight management, and it can potentially slow cognitive ageing and alleviate symptoms of neurological disorders such as stroke, Parkinsons disease, and Alzheimers. However, KD also causes bone loss and increases fracture risk in children. It is not known if KD causes bone loss in adults. Based on prior studies, it is also possible that KD may reduce the ability for exercise to increase bone strength. The mechanisms responsible for KD bone loss have not been identified. Determining if β-hydroxybutyrate (BHB), the most abundant ketone body is linked to bone loss is important, because this molecule is thought to lay a large role in the neurological benefits of KD. This project will use a mouse model to evaluate age differences in ketogenic diet induced bone loss, determine if KD decreases the ability of exercise to make bone stronger, and investigate if BHB causes bone loss. Aim 1 will determine how age and diet duration affect the magnitude of KD induced bone loss and decrease in bone strength. Aim 2 will evaluate if KD reduces the ability of exercise to increase bone strength and if this is mediated by muscle and tendon. Aim 3 will focus specifically on defining the role of BHB in bone loss. In the long term, this project will help clarify how KD affects bone, and it can contribute to the use of KD or BHB supplementation to deliver neurological benefits without increasing fracture risk. As a clinical researcher, I strive to develop therapies to improve skeletal health, and as a biological anthropologist, I use skeletal remains to reconstruct the behavior and health of past people. Through the K99/R00 career development award, I seek to combine the anthropological and biomedical strands of my research career by examining the combined effect of ketogenic diet and exercise on bone health throughout life. During the fellowship, I will receive training in molecular biology and laboratory skills essential for the study of cellular responses to diet and exercise. I will also expand my knowledge of muscle and tendon, gaining the ability to conduct innovative interdisciplinary research that achieves new perspectives on how exercise and diet affect bone strength. UC Davis is an unparalleled location for conducting the proposed project and training. I will have access to cutting edge facilities and equipment. Through numerous seminars, workshops, and training opportunities I will interact with faculty, students, and staff, broadening my understanding of skeletal health. Through the K99/ R00 I will develop an innovative interdisciplinary research career that explores the relationship between diet, behavior, and health in past human populations and contributes to the development of therapies that use diet and exercise to decrease fracture risk.

Project Narrative Ketogenic diet is popular for weight management and may help treat neurological disorders, but it may also cause severe bone loss that increases fracture risk. This project contributes to public health by characterizing the effect of ketogenic diet on bone strength throughout adulthood, if KD prevents exercise from increasing bone strength, and investigating if ketone bodies are a primary mechanism driving bone loss. In the long term, the findings can improve understanding of how ketogenic diet contributes to fracture risk and the development of therapies to prevent bone loss on a ketogenic diet.