The latest research from the Buck Institute for Research on Aging has found that ketone bodies, which are produced by the human body to provide fuel during fasting, play a role far beyond energy production in regulating cellular processes and aging mechanisms. This research shows that ketone bodies can be best understood as crucial signaling metabolites that affect brain function in aging and Alzheimer’s disease. A new study published in Cell Chemical Biology reveals that, in experiments using mouse models of Alzheimer’s disease, aging mice, and the nematode C. elegans, scientists at the Buck Institute have discovered that the ketone body β-hydroxybutyrate can directly interact with misfolded proteins, altering their solubility and structure so that they can be cleared from the brain through the process of autophagy.
Previous studies have demonstrated that increasing ketone body levels through diet, exercise, and supplementation is beneficial for brain health and cognition in both rodents and humans. John Newman, MD, PhD, an assistant professor at the Buck Institute and the senior author of the study, said that in the past, many people believed that the improvements based on ketone bodies were due to increased energy supply to the brain or a reduction in brain inflammation, and the improvement in amyloid plaques in mouse models was just an indirect by-product.
“Now we know that it’s not that simple. Ketone bodies directly interact with damaged and misfolded proteins, making them insoluble so that they can be removed from the cells and recycled,” Newman said.
While acknowledging that other mechanisms such as energy supply are also important for brain health, Newman calls this discovery “new biology.” He pointed out, “This is a new link between metabolism in general, ketone bodies, and aging. Directly linking changes in a cell’s metabolic state to changes in the proteome is really exciting.” Given that ketone bodies are easy to manipulate experimentally and therapeutically, Newman added, “This might be a powerful avenue to assist with the global clearance of damaged proteins. We’re just scratching the surface regarding how this can be applied to brain aging and neurodegenerative diseases.”
In addition to testing changes in the solubility and structure of proteins in test tubes, the project also involved feeding ketone esters to mice to confirm that the test tube results could be replicated in the brain. It was found that the treatment with ketone esters led to the clearance of insoluble proteins rather than their pathological aggregation.
This work also highlights the collaborative strength of the Buck Institute. The Schilling lab generated detailed proteome-wide solubility maps from both the test tube and mouse experiments. To test whether the solubility changes caused by ketone bodies could help improve models of pathological aggregation, the Lithgow lab fed ketone bodies to tiny nematode worms that had been genetically modified to express the human equivalent of amyloid beta, which causes amyloid plaques. Sidharth Madhavan, a PhD candidate and the lead author of the study, said, “The amyloid beta affects the muscles of the worms and paralyzes them. Once they were treated with ketone bodies, the animals recovered their ability to swim. It was really exciting to see such a dramatic impact on a whole animal.”
Madhavan is currently exploring whether ketone bodies and related metabolites have similar effects outside the brain, such as in the gut. He added that a key next step will be to test this new protein quality control mechanism in humans to help guide the best way to apply it in therapies.
Newman said that the study highlights a new form of metabolic regulation of protein quality control. He said, “This is not just about ketone bodies. We tested similar metabolites in test tubes and many of them had similar effects. In some cases, they performed better than β-hydroxybutyrate. It’s beautiful to imagine that changing metabolism results in this symphony of molecules cooperating together to improve brain function.”
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