): The global proportion of individuals 65 and older is growing and is expected to reach nearly 17% by 2050. Aging is associated with a progressive decline in organ and tissue function resulting in alterations in cognition and physical function. In particular, brain aging is manifested as impairments in executive function, working memory, and episodic memory, and age-related sarcopenia leads to muscle weakness and impaired mobility. Both of these can have a profound impact on the quality of life, particularly for those suffering from Alzheimer?s disease. Ketone bodies, 3-hydroxybutyrate and acetoacetate, are important molecules providing energy to the brain during development, fasting, and exercise. Our work has shown that levels of ketone bodies decrease with aging. This is significant as glucose transport into the brain is impaired with aging. Interestingly, while the abundance of GLUT1 (which transports glucose into the brain) declines, MCT1 (which transport ketone bodies into the brain) has been shown to increase in the hippocampus of aged rats, the brain region essential for learning and formation of new long-term memories. Recent studies have shown that a ketogenic diet results in beneficial effects on age-related memory, which suggest ketones serve as an alternate fuel source when glucose uptake and catabolism is impaired. Additionally, 3-hydroxybuyrate has been shown to inhibit the NLRP3 inflammasome, activation of which has been linked with age-related sarcopenia. A major issue with the ketogenic diet is the low long-term adherence, and its restrictive nature with respect to fiber and essential nutrient intake. Increasing ketone concentrations in the blood through a supplement would therefore be of benefit for an aging population.
In aim 1, we propose to determine the effect of supplementation of a ketone monoester ((R)-3-hydroxybutyl-(R)- 3-hydroxybutyrate (3-HBHB)), which has been shown to increase circulating 3-hydroxybutyrate concentrations, on long-term memory in aged mice through a series of cognitive tests at baseline and after 7 weeks on the diet. We will then determine how hippocampal transporters, metabolic enzymes, and metabolites change in response to increased levels of ketones in the blood to provide a mechanistic understanding of how ketone esters impact hippocampal function. In our second aim, we will compare the muscle mass, strength, and voluntary physical activity of mice provided 3-HBHB with mice on a control diet, and then determine mechanistically how skeletal muscle mass and metabolism is affected by the ketone ester diet. The knowledge gained from this study could have important implications for the aging population, and could represent a foundation on which to develop robust therapeutic treatments to prevent age-related memory decline and sarcopenia.

Public Health Relevance

Aging is accompanied by changes in metabolism that may contribute to decline in cognition and physical health. The proposed research will investigate the therapeutic potential of a ketone monoester of 3-hydroxybutyrate for improving age-related memory loss and sarcopenia, as well as explore the potential mechanisms through which these changes may occur. We hypothesize that 3-hydroxybutyrate, an energy substrate and signaling molecule, will improve memory through increasing energy availability in the brain, at at the same time promote protein synthesis in muscle, slowing decline in muscle loss and physical function.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Williams, John
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University of California Davis
Earth Sciences/Resources
United States
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