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Innovative Research Reveals Molecular Mechanism Behind Ketogenic Diet’s Memory Enhancement
The ketogenic diet, renowned for its high-fat, low-carbohydrate composition, continues to be a subject of fascination and debate among dieters and scientists alike. Recent groundbreaking research has uncovered a significant pathway that explains the diet’s positive impact on memory, particularly in older mice. This discovery opens up new potential for memory enhancement without the need for strict dietary adherence.
A collaborative effort between scientists at the Buck Institute for Research on Aging and the University of Chile has identified a novel molecular signaling pathway that enhances synapse function, thus benefiting brain health and aging. Published in the June 5, 2024, issue of Cell Reports Medicine, the study offers promising new avenues for targeting memory improvements at a molecular level.
The Mechanism Unveiled
“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,” said Dr. Christian González-Billault, the study’s senior author. González-Billault is a professor at the Universidad de Chile and director of their Geroscience Center for Brain Health and Metabolism, as well as an adjunct professor at the Buck Institute.
The research builds on previous findings that demonstrated the ketogenic diet’s ability to improve healthspan and memory in aging mice. Dr. John Newman, whose laboratory at Buck collaborated on the study, emphasized the significance of these results. “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,” said Newman, an assistant professor at the Buck Institute and a geriatrician at the University of California, San Francisco.
Historical Context and Recent Findings
The link between diet and longevity has been a topic of scientific inquiry for over a century. Early research showed that rats consuming less food lived longer, but modern studies have shifted focus to the cellular signals that regulate lifespan. These signals, including ketone bodies produced during a ketogenic diet, play a crucial role in aging-related pathways such as protein turnover and metabolism.
Seven years ago, Newman led a team that provided the first evidence that a ketogenic diet, sustained over much of an adult mouse’s life, could extend lifespan and improve health. Remarkably, the mice maintained or even improved their memory with age. The current study aimed to dissect the ketogenic diet’s specific effects on the brain at a molecular level.
Experimental Approach and Results
In this study, mice over two years old were alternated between a ketogenic diet and a control diet to avoid overeating and obesity. Neurophysiological and behavioral tests revealed that the ketogenic diet enhanced synaptic function crucial for memory. Further analysis identified significant changes in synaptic proteins in the hippocampus, particularly involving the protein kinase A (PKA) signaling pathway.
“Surprisingly, we saw that the ketogenic diet caused dramatic changes in the proteins of the synapse,” noted Dr. Birgit Schilling, who led the proteomics analysis. The changes were rapid, occurring after just one week on the diet, and became more pronounced over time.
The research highlighted that β-hydroxybutyrate (BHB), a primary ketone body, activates the PKA signaling pathway, underscoring its dual role as an energy source and signaling molecule.
Future Directions
The findings suggest potential for memory enhancement without a ketogenic diet by directly targeting the PKA signaling pathway. “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,” said Newman, “we wouldn’t even need to eat a ketogenic diet in the end.”
This pioneering research offers a promising outlook for new therapeutic strategies to combat age-related cognitive decline. 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,” represents a significant step forward in understanding and potentially manipulating brain health and memory through molecular mechanisms.
Funding and Acknowledgments
The study was supported by funds from the National Institutes of Health, the Chilean National Fund for Scientific and Technological Development (FONDECYT), the Center of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT) at Universidad de Los Andes, and the Chilean National Research and Development Agency (ANID).
