New Frontier in Protein Quality Control and Brain Health

Beyond their use as fuel during fasting, the body's production of ketones controls cellular functions and aging processes. According to research from the Buck Institute, ketones are best understood as potent signaling metabolites that impact brain function in aging and Alzheimer's disease.

According to a recent study, ketone bodies and related metabolites significantly impact the proteome and protein quality control in the brain.

In a study published in the journal Cell Chemical Biology, Buck Institute researchers who study aging and Alzheimer's disease in mice as well as the nematode C. elegans, found that the ketone body β-hydroxybutyrate directly interacts with misfolded proteins, changing their structure and solubility to allow autophagy to remove them from the brain.

Prior research has demonstrated that increasing ketone bodies in humans and rodents through diet, exercise, and supplements can improve cognitive function and brain health.

Many hypothesized that the ketone body-based improvements were due to a decrease in brain inflammation or an increase in brain energy, with the reported improvements in amyloid plaques in mouse models being an indirect consequence, according to Senior Author John Newman, MD, PhD, Assistant Professor at the Buck Institute.

Now we know that is not the whole story. Ketone bodies interact with damaged and misfolded proteins directly, making them insoluble so they can be pulled from the cell and recycled.”

John Newman, Assistant Professor and Study Senior Author, Buck Institute for Research on Aging

Newman refers to the finding as “new biology,” even though he acknowledges that other processes, such as energy supply, are also crucial for brain health.

It 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. Noting that ketone bodies are easy to manipulate experimentally and therapeutically. This might be a powerful avenue to assist with global clearing of damaged proteins. We are just scratching the surface as to how this might be applied to brain aging and neurodegenerative disease.”

John Newman, Assistant Professor and Study Senior Author, Buck Institute for Research on Aging

To verify that the results in the test tubes were replicated in the brain, the project also involved feeding mice ketone ester and testing the shifting solubility and structure of proteins in test tubes. In mice, the ketone ester treatment caused insoluble proteins to be cleared rather than aggregated pathologically.

The piece also highlights the power of Buck's collaborative environment. The Schilling lab produced comprehensive proteome-wide solubility maps from the test tube and mouse experiments.

The Lithgow lab fed ketone bodies to tiny nematode worms genetically altered to express the human counterpart of amyloid beta, which causes amyloid plaques, to see if the solubility changes brought about by ketone bodies improved models of pathological aggregation.

The amyloid beta affects muscles and paralyzes the worms. 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.”

Sidharth Madhavan, PhD Candidate and Study Lead Author, Buck Institute for Research on Aging

Madhavan is investigating whether ketone bodies' effects and related metabolites are comparable in areas other than the brain, like the gut. He adds that testing this novel protein quality control mechanism in humans will be a crucial next step in determining how best to use it in treatments.

According to Newman, the study reveals a novel protein quality control metabolic regulation.

Newman added, “This is not just about ketone bodies. We tested similar metabolites in test tubes and a bunch of them had similar effects. In some cases, they performed better than β-hydroxybutyrate. It is beautiful to imagine that changing metabolism results in this symphony of molecules cooperating together to improve brain function.”