Beyond Ketones: Metabolites Team Up to Clear Brain Proteins

Buck Institute researchers have uncovered a metabolic symphony in the brain - ketone bodies and similar molecules team up to clear harmful misfolded proteins linked to Alzheimer's disease and aging.

The research team, led by Dr. John Newman, found that β-hydroxybutyrate (βHB) - a key ketone body - directly interacts with misfolded proteins. This interaction changes the proteins' structure and solubility, making them easier for cells to remove through autophagy.

Their experiments showed striking results across multiple models:

• In test tubes, ketone bodies changed protein structure and solubility
• In nematode worms engineered to produce human amyloid beta (an Alzheimer's-related protein), ketone treatment restored swimming ability
• In mice, ketone ester supplements led to clearance of insoluble proteins

The findings go beyond just ketone bodies.

Newman explains: "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's beautiful to imagine that changing metabolism results in this symphony of molecules cooperating together to improve brain function."

Previous research showed ketogenic diets and supplements might help brain health, but the mechanism wasn't clear. This study reveals metabolites act directly on problematic proteins rather than just reducing inflammation or providing energy.

The findings open new therapeutic possibilities. Since metabolite levels can be modified through diet, exercise, and supplements, this research suggests practical ways to support brain health and potentially slow neurodegeneration.

The team is now investigating whether these effects extend beyond the brain to other tissues. The next step is testing this protein quality control mechanism in humans to develop targeted therapies for aging and Alzheimer's disease.

The complete study appears in Cell Chemical Biology as "β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain" (DOI: https://doi.org/10.1016/j.chembiol.2024.11.012).