Ketone esters aid protein clearance in Alzheimer’s models

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A new mechanism links ketone metabolism with improved protein quality control, offering hope for neurodegenerative disease research.

Researchers at the Buck Institute for Research on Aging have uncovered a novel role for ketone esters in regulating brain proteostasis, the process of maintaining protein balance. The study, published in Cell Chemical Biology, identifies β-hydroxybutyrate (BHB), a ketone body, as a mediator that interacts with misfolded proteins. This interaction, demonstrated in mouse models of Alzheimer’s disease and aging, and in the nematode C elegans, alters the proteins’ solubility, facilitating their clearance through autophagy [1].

Previous research has demonstrated that increasing ketone bodies through diet, exercise, or supplementation can benefit brain health and cognition in both humans and our rodent friends. According to John Newman, MD, PhD, an assistant professor at the Buck Institute and senior author on the paper, there has been a good amount of speculating that these ketone-related improvements result from enhanced brain energy or reduced inflammation. In mouse models, reductions in amyloid plaques have been observed as a potential indirect outcome of these effects.

Dr John Newman of the Buck Institute is a senior author on the paper

However, Dr John Newman, senior author and assistant professor at the Buck Institute, said: “Now we know that’s 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.”

Longevity.Technology: Ketone esters, synthesized derivatives of ketone bodies, are playing an interesting role in neurodegenerative research. These compounds mimic the metabolic state of fasting, where ketones serve as an alternative energy source during glucose scarcity. Beyond their role as cellular fuel, ketone esters have emerged as influential metabolic regulators capable of interacting with misfolded proteins – a hallmark of Alzheimer’s disease and other neurodegenerative conditions. This misfolding contributes to the toxic aggregation of proteins like amyloid-beta, a key driver of Alzheimer’s pathology.

Despite significant advancements in understanding these mechanisms, drug development for Alzheimer’s has faced considerable hurdles. The disease affects over 6 million Americans [2], a figure expected to rise as populations age, exerting an immense burden on families, caregivers and healthcare systems globally. Current treatment options remain limited, often offering symptomatic relief rather than addressing underlying causes. This highlights the urgent need for novel approaches, such as exploring metabolic pathways to target proteostasis – a cellular process that maintains protein homeostasis. With ketone esters showing promise in clearing toxic protein aggregates via autophagy, innovative therapeutic avenues may soon be within reach, potentially alleviating the substantial global impact of Alzheimer’s disease.

Experimental validation

The Buck Institute’s interdisciplinary team used mouse models of aging and Alzheimer’s, alongside experiments in the nematode C elegans, to demonstrate these effects. Feeding a ketone ester to mice resulted in the clearance of insoluble proteins without pathological aggregation. In C elegans, genetically engineered to express human amyloid-beta – a hallmark of Alzheimer’s – ketone treatment restored movement, reversing amyloid-induced paralysis [1].

Lead author Sidharth Madhavan, a PhD candidate and lead author on the study, highlighted the significance. “The amyloid beta affects muscles and paralyzes the worms,” he said.

PhD candidate Sidharth Madhavan is the 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.” These findings suggest a conserved mechanism applicable across species, emphasizing its therapeutic potential.

Beyond energy metabolism

Ketone bodies are known for their role during fasting or ketogenic diets, where they provide energy in the absence of glucose; however, this study positions BHB as a signaling metabolite with implications beyond energy production, something Newman describes as 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.” Pointing out that ketone bodies are easy to manipulate experimentally and therapeutically, Newman suggested: “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.”

Interestingly, related metabolites also demonstrated similar effects in preliminary experiments, sometimes outperforming BHB. “It’s beautiful to imagine that changing metabolism results in this symphony of molecules cooperating together to improve brain function,” Newman said.

Implications for therapeutic development

This research provides a mechanistic basis for the observed benefits of ketogenic interventions in aging and neurodegenerative diseases. Previous studies have linked ketogenic diets and exogenous ketones to cognitive improvements in both rodents and humans, but the direct role of BHB in protein quality control represents a breakthrough [1].

The next steps involve exploring whether this mechanism extends to other tissues, such as the gut, and evaluating its therapeutic potential in human trials.

Collaborative insights and future directions

The study also shines a light on the Buck Institute’s collaborative environment, with contributions spanning proteomics, neuroscience and metabolic research. Detailed protein solubility maps, generated by the Schilling lab, and nematode experiments led by the Lithgow lab, reinforced the findings.

Newman emphasized the broader significance: “This is not just about ketone bodies. Understanding these mechanisms opens doors to new metabolic therapies that could revolutionize how we treat aging and neurodegeneration.”

This discovery not only advances our understanding of metabolism and proteostasis but also offers a promising avenue for addressing the enormous burden of neurodegenerative diseases; with continued research, ketone-based strategies might hold the key to enhancing healthspan and mitigating age-related conditions.