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Researchers from the Buck Institute and the University of Chile have discovered how the ketogenic diet enhances memory in aging mice through a novel molecular pathway.

Led by Dr. Christian González-Billault and collaborator Dr. John Newman, the new study, published in Cell Reports Medicine, showed that a high-fat, low-carbohydrate ketogenic diet not only boosts memory in older mice but also improves synapse function. This finding marks a significant step in understanding the diet's impact on brain health and aging.

The study titled "Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice" unveiled a promising strategy for maintaining and enhancing brain function during aging, independent of actually following a ketogenic diet.

"Our work indicates that the effects of the ketogenic diet benefit brain function broadly, and we provide a mechanism of action that offers a strategy for the maintenance and improvement of this function during aging," explained Dr. González-Billault, professor at Universidad de Chile and director of their Geroscience Center for Brain Health and Metabolism.

Newman, assistant professor at the Buck Institute, added, "Building off our previous work showing that a ketogenic diet improves healthspan and memory in aging mice, this new work indicates that we can start with older animals and still improve the health of the aging brain, and that the changes begin to happen relatively quickly."

 "It is the most detailed study to date of the ketogenic diet and aging brain in mice."

The ketogenic diet, characterized by high fat and low carbohydrate intake, triggers production of ketone bodies such as β-hydroxybutyrate (BHB). These molecules play a crucial role in enhancing synaptic function and potentially mitigating age-related memory decline.

Initial experiments involved older mice fed alternating weeks of ketogenic and control diets to prevent obesity. Neurophysiological and behavioral tests confirmed enhanced memory function linked to improved synaptic performance in the hippocampus.

Proteomic analysis by Buck Institute's Dr. Birgit Schilling revealed significant changes in synaptic proteins following brief exposure to the ketogenic diet, suggesting rapid molecular adaptations. Specifically, activation of the protein kinase A pathway in synapses was identified as a key mechanism, driven by BHB as a signaling molecule.

"BHB is almost certainly not the only molecule in play, but we think this is an important part of understanding how the ketogenic diet and ketone bodies work," Dr. Newman noted, according to Neuroscience News.

Future research aims to explore whether isolated administration of BHB or direct modulation of the protein kinase A pathway can replicate the memory benefits observed with the ketogenic diet.

"If we could recreate some of the big-picture effects on synapse function and memory just by manipulating that signaling pathway in the right cells," Dr. Newman emphasized. "We wouldn't even need to eat a ketogenic diet in the end."