The keto diet, arguably one of the most popular diets, has scientifically shown that it impacts memory in mice. However, new research from the University of Chile helps explain why and how the diet benefits brain health and ageing.
A keto diet follows the principles of eating high-fat, low-carbohydrate foods. It is widely debated and has a keen following. Previously research has shown its impact on memory in mice. Still, during further investigations, a team of scientists identified a molecular signalling pathway that improves synapse function and explains the diet’s benefit on brain health and ageing.
“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 ageing,” said the study’s senior author, Christian González-Billault, PhD, who is a professor at the Universidad de Chile and director of their Geroscience Center for Brain Health and Metabolism, and adjunct professor at the Buck Institute.
The link between lifespan and the keto diet
“Building off our previous work showing that a ketogenic diet improves health span and memory in ageing mice, this new work indicates that we can start with older animals and still improve the health of the ageing brain and that the changes begin to happen relatively quickly,” said John Newman, MD, PhD, whose laboratory at Buck collaborated with Dr González-Billault on the study. Newman is an assistant professor at the Buck Institute, and a geriatrician at the University of California, San Francisco. “It is the most detailed study to date of the ketogenic diet and ageing brain in mice.”
Over ten years ago, researchers showed that rats that consumed less food lived longer. “We now know that being able to manipulate lifespan is not about specifically eating less,” said John Newman, MD, PhD, but actually is related to signals inside cells that turn on and off specific pathways in response to available nutrients. Many of those pathways are related to ageing, such as controlling protein turnover and metabolism.
Some of those signals are the ketone bodies, which consist of acetoacetate (AcAc), β-hydroxybutyrate (BHB) and to a much lesser extent, acetone. These molecules are routinely produced in the liver. They increase when glucose is in short supply, whether this is due to calorie restriction, intense exercise or low carbohydrate intake, such as with a keto diet.
Improved memory in mice following a high-fat, low-carbohydrate diet
The study aimed to answer what part of the keto diet affects memory and lifespan. The mice following this diet were fed 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% fat. The test mice, which were over two years old, cycled between the keto diet and control diet to control overeating.
The benefits of the ketogenic diet, said, González-Billault, were demonstrated through neurophysiological and behavioural experiments with the mice that tested how well the mechanisms involved in memory generation, storage, and retrieval function in aged animals. This showed how the keto diet appeared to benefit how well the memory synapses worked, leading to the researchers investigating the protein composition at these synapses in the hippocampus.
“Surprisingly, we saw that the ketogenic diet caused dramatic changes in the proteins of the synapse,” said Birgit Schilling, PhD. Even more surprising, she said, was that the changes started after a relatively brief exposure to the diet (tested after only one week on the diet) and only became more pronounced over time (tested again after six weeks and a year).
Further testing indicated that in synapses, a particular signalling pathway (protein kinase A, which is critical to synapse activity) was activated by the ketogenic diet. In isolated cells, the team showed that it appears that BHB, the main ketone produced, is activated by this pathway. This leads to the idea, said González-Billault, that ketone bodies (specifically BHB) play a crucial role not only as an energy source but also as a signalling 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,” said Newman “This is the first study to really connect deep molecular mechanisms of ketone bodies all the way through to improving the ageing brain.”
