Ketone bodies have roles that extend beyond merely providing energy; they also function as potent signaling molecules that significantly influence the proteome and the maintenance of protein quality in the brain. Recent research conducted using mouse models of Alzheimer’s disease and aging, as well as the nematode C. elegans, demonstrates that the ketone body β-hydroxybutyrate has a direct interaction with misfolded proteins. This interaction alters their solubility and structure, facilitating their removal from the brain through autophagy. These findings suggest the exciting potential of ketone bodies as a comprehensive treatment option to help maintain the integrity of the proteome, thereby tackling critical aspects of aging.
Ketone bodies, generated by the body in response to fasting, impact cellular functions and aging processes beyond just energy supply. Research from the Buck Institute indicates that ketone bodies should be viewed as influential signaling metabolites that affect brain health in both aging and Alzheimer’s disease. A recent study has revealed that ketone bodies and similar metabolites significantly influence the proteome and protein quality management in the brain. The findings, published in Cell Chemical Biology, show that the ketone body β-hydroxybutyrate interacts directly with misfolded proteins, changing their solubility and structure, which allows them to be eliminated from the brain via autophagy.
Previous research indicated that increasing ketone levels through diet, exercise, and supplementation benefits brain health and cognition in both rodents and humans. According to Dr. John Newman, MD, PhD, an assistant professor at the Buck, there has been speculation that improvements linked to ketone bodies stemmed from enhanced energy supply to the brain or a decrease in inflammation. Observed benefits like the reduction of amyloid plaques in mouse models were thought to be a secondary effect. “Now we understand that this isn’t the full picture,” he stated. “Ketone bodies engage directly with damaged and misfolded proteins, rendering them insoluble, which aids their removal and recycling from cells.”
While acknowledging the significance of other factors like energy provision in promoting brain health, Newman describes this discovery as a breakthrough in biological understanding. “There is a new connection being established between overall metabolism, ketone bodies, and aging,” he commented. “The prospect of connecting shifts in a cell’s metabolic state to alterations in the proteome is tremendously exciting.” He also points out that ketone bodies are easy to manipulate for research and therapeutic purposes, suggesting, “This may open up powerful avenues for effectively clearing damaged proteins. We are only beginning to explore how these insights could impact brain aging and neurodegenerative diseases.”
As part of the research, the effects on the solubility and structure of proteins were confirmed through both in vitro experiments and in vivo studies involving mice treated with a ketone ester. The treatment in mice resulted in the elimination of insoluble proteins rather than their harmful accumulation.
This research also showcases the collaborative strength of the Buck. The Schilling lab created comprehensive proteome-wide solubility maps from both in vitro and mouse experiments. To verify whether the solubility changes induced by ketone bodies could counteract pathological aggregations, the Lithgow lab administered ketone bodies to genetically modified tiny nematodes that express the human version of amyloid beta, which leads to amyloid plaques. “The amyloid beta impacts muscle function and immobilizes the worms,” explained Sidharth Madhavan, PhD candidate and lead author of the study. “After treatment with ketone bodies, these worms regained their swimming abilities. Observing such significant changes in a living organism was thrilling.”
Madhavan is currently investigating whether ketone bodies and their related metabolites have similar effects in regions outside the brain, like the gut. The next critical step will be to explore this new mechanism for protein quality control in humans to determine how it can be applied in therapeutic contexts, he noted.
Newman emphasizes that this study introduces a new paradigm of how metabolism regulates protein quality control. “It’s not solely about ketone bodies,” he remarked. “We also examined related metabolites in our experiments, many of which displayed comparable effects. In fact, some outperformed β-hydroxybutyrate. It’s fascinating to think about how changes in metabolism can coordinate a variety of molecules working together to enhance brain function.”
