How the ketogenic diet improves health and memory in aging mice

The ketogenic diet has its fanatics and detractors among dieters, but regardless, the diet has a scientifically documented impact on memory in mice. While discovering how a high-fat, low-carb diet boosts memory in aged mice, Buck scientists and a team from the University of Chile identified a new molecular signaling pathway that improves synapse function and helps to explain the benefits of the diet on brain health and aging.

Published in the June 5, 2024 issue of Cell Reports Medicine, the results open new avenues for targeting memory effects at the molecular level, without requiring a ketogenic diet or even its by-products. The paper is titled “Administration of a ketogenic diet later in life improves memory by altering the synaptic cortical proteome via the PKA signaling pathway in aging mice.” »

“Our work indicates that the effects of the ketogenic diet largely benefit brain function and we propose a mechanism of action that provides a strategy for maintaining and improving this function during aging,” said the lead author of the study, Christian González-Billault. Ph.D., professor at the University of Chile and director of their Geroscience Center for Brain Health and Metabolism, and assistant professor at the Buck Institute.

“Building on our previous work showing that a ketogenic diet improves health and memory in aging mice, this new work indicates that we can start with older animals while improving the health of the aging brain, and that “Changes start to occur relatively quickly,” said John Newman, MD, Ph.D., whose Buck lab collaborated with Dr. González-Billault on the study.

Newman is both an assistant professor at the Buck Institute and a geriatrician at the University of California, San Francisco. “This is the most detailed study to date on the ketogenic diet and brain aging in mice.”

More than a century ago, researchers observed that rats who consumed less food lived longer. “We now know that being able to manipulate lifespan is not specifically about eating less,” Newman said, but is actually linked to signals inside cells that turn specific pathways on and off in response to available nutrients. . Many of these pathways are linked to aging, such as the control of protein turnover and metabolism.

Some of these signals are ketone bodies, consisting of acetoacetate (AcAc), β-hydroxybutyrate (BHB), and, to a much lesser extent, acetone. These molecules are usually produced in the liver. They increase when glucose is scarce, whether due to calorie restriction, strenuous exercise, or low carbohydrate intake, such as on a ketogenic diet.

Seven years ago, Newman led a team that published the first proof of concept that if a ketogenic diet exposes mice to increased levels of ketone bodies for much of their adult lives, it helps them live longer. long and age healthier. “The most striking effect on their health as they aged was that their memory was preserved; it was perhaps even better than when they were younger,” he said.

The current study, designed to determine what part of the ketogenic diet had an effect and how it affected the brain on a molecular level to improve memory, was led by González-Billault in collaboration with Buck scientists. Mice on a ketogenic diet received a ratio of 90% calories from fat and 10% from protein, while mice on a control diet received the same amount of protein but only 13% from fat.

The tested mice, of an “advanced age” of more than two years, were given a week of a ketogenic diet, alternated with a week of a control diet, to prevent the mice from overeating and becoming obese.

The benefits of the ketogenic diet, González-Billault said, have been demonstrated through neurophysiological and behavioral experiments with mice that test the effectiveness of mechanisms involved in memory generation, storage and retrieval in aged animals.

When they showed that the ketogenic diet seemed to benefit the proper functioning of the synapses responsible for memory, they dove deep into the protein composition of these synapses in the hippocampus, in collaboration with Buck Professor Birgit Schilling, Ph. D., who directs the Center for Proteomics and Mass Spectrometry.

“Surprisingly, we found that the ketogenic diet caused dramatic changes in synapse proteins,” Schilling said. What’s even more surprising, she said, is that the changes began after relatively brief exposure to the diet (tested after just one week of dieting) and only became more pronounced over time ( tested again after six weeks and one year).

Further testing indicated that within the synapses, a particular signaling pathway (protein kinase A, essential for synapse activity) was activated by the ketogenic diet. In isolated cells, the team then showed that BHB, the main ketone body produced in a ketogenic diet, appears to activate this pathway.

This leads to the idea, González-Billault said, that ketone bodies (especially BHB) play a crucial role not only as an energy source, but also as a signaling molecule.

“BHB is certainly not the only molecule at play, but we think it is an important part of understanding how the ketogenic diet and ketone bodies work,” Newman said. “This is the first study that truly links the deep molecular mechanisms of all ketone bodies to the path forward to improve brain aging.

Looking ahead, he said, the next step would be to see if the same memory protection could be achieved using BHB alone, or possibly being even more targeted by directly manipulating the BHB signaling pathway. protein kinase A.

“If we could recreate some of the general effects on synapse function and memory just by manipulating this signaling pathway in the right cells,” he said, “we wouldn’t even need to follow a ketogenic diet at all. the end.”