Alzheimer’s Study Shows Ketone Bodies Help Clear Misfolded Proteins

Ketone bodies are produced by the body to provide fuel during fasting, and are thought to have roles in regulating cellular processes and aging mechanisms beyond energy production. Research by Buck Institute scientists, including experiments in the nematode Caenorhabditis elegans, and in mouse models, provides what they suggest is a direct molecular mechanism for the regulation of misfolded proteins by ketone bodies and related metabolites. The results, they said, indicate that ketone bodies, including β-hydroxybutyrate (βHB), may be considered powerful signaling metabolites affecting brain function in aging and Alzheimer’s disease (AD). The findings also point to potential metabolism-related mechanistic targets for therapeutic development in aging and in AD.

Reporting on their work in Cell Chemical Biology (“β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain”), senior author John Newman, MD, PhD, a Buck Institute assistant professor, and colleagues stated, “Here, we provide a direct molecular mechanism for the regulation of misfolded proteins by ketone bodies and related metabolites … Together, these data provide foundational evidence for a novel mechanistic component of ketone body biology.”

Ketone bodies are a class of lipid-derived small molecule metabolites that include acetone, acetoacetate, and (R)-β-hydroxybutyrate (R-βHB), the authors noted. “The primary function of acetoacetate and R-βHB production is to provide cellular energy to extrahepatic tissues during periods of reduced glucose availability, such as fasting, starvation, high-intensity exercise, and ketogenic diet.”

Previous studies have shown that boosting ketone bodies through diet, exercise, and supplementation can be good for brain health and cognition, both in rodents and humans. “There is clear preclinical literature support, and early clinical data, for ketogenic therapies in aging and AD. … ketogenic diet and exogenous ketones have been shown to improve cognitive and motor behavior in several mouse models of AD,” the authors stated. “Early human studies of ketogenic compounds have improved cognitive scores in patients with mild to moderate AD.”

The researcher’s newly reported work demonstrated that ketone bodies and similar metabolites have profound effects on the proteome and protein quality control in the brain. Working in cells, in mouse models of AD and aging, and in the model organism C. elegans, the findings indicated that the ketone body β-hydroxybutyrate (βHB) interacts directly with misfolded proteins, altering their solubility and structure so they can be cleared from the brain through the process of autophagy.

In addition to testing the changing solubility and structure of proteins in test tubes, the researchers also studied the effects of ketone bodies in model organisms. To assess whether the solubility changes caused by ketone bodies helped improve models of pathological aggregation, the investigators fed ketone bodies to nematode worms that were genetically modified to express the human equivalent of amyloid beta, which causes amyloid plaques. “The amyloid beta affects muscles and paralyzes the worms,” said Sidharth Madhavan, a PhD candidate and lead author on the study. “Once they were treated with ketone bodies the animals recovered their ability to swim. It was really exciting to see such a dramatic impact in a whole animal.”

When the team fed a ketone ester to mice, they found that the ketone ester treatment resulted in clearance rather than pathological aggregation of insoluble proteins. The investigators in addition generated detailed proteome-wide solubility maps from their experiments in test tubes and from their mouse experiments.

Newman noted an existing theory that the ketone body-based improvements are caused by increased energy to the brain or a reduction in brain inflammation, with reported improvements in amyloid plaques in mouse models being an indirect by-product. “Now we know that’s not the whole story,” he said. “Ketone bodies interact with damaged and misfolded proteins directly, making them insoluble so they can be pulled from the cell and recycled.”

Newman said the study highlights a new form of metabolic regulation of protein quality control. “This is not just about ketone bodies,” he said. “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.”

While acknowledging that other mechanisms like energy supply are also important to brain health, Newman calls the discovery new biology. “It’s a new link between metabolism in general, ketone bodies, and aging,” he said. “Directly linking changes in a cell’s metabolic state to changes in the proteome is really exciting.”

Given that proteostatic mechanisms such as autophagy are known to be activated by nutrient deprivation, the authors noted, it’s not surprising that evolutionary pressures would encourage the clearance of pathogenic proteins during ketosis to promote cellular health in organisms needing additional substrate for ATP production. “In this situation, ketone bodies are janitors of damaged proteins, chaperoning away molecular waste so organisms can operate at peak molecular fitness,” they pointed out.

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

In their paper, the team further concluded, “We show that βHB-induced insolubility leads to clearance of highly insolubilized proteins in vivo, likely via βHB communication with cellular protein degradation pathways. This work identifies βHB as a global regulator of cytosolic protein solubility, and identifies new metabolism-related mechanistic targets for therapeutic development in aging and AD.”

Madhavan is now pursuing whether ketone bodies and related metabolites have similar effects outside the brain, such as in the gut, and suggests that the key next step will be to test this new protein quality control mechanism in people to help guide how best to apply it therapeutically.