Ketogenic diet’s role in boosting healthspan and memory in mice

Buck scientists uncover new signaling pathway that could provide new targets for improving memory without embarking on ketogenic diet.

It may have spawned myriad dieting books, but the ketogenic diet has a solid science background. Previous research has documented its impact on memory in mice, and now a team from the Buck Institute and the University of Chile have investigated just how the ketogenic diet achieves its brain-boosting effects.

Longevity.Technology: While exploring how the high fat, low carbohydrate diet boosts memory in older mice, the researchers identified a new molecular signaling pathway that improves synapse function and helps explain the diet’s benefit on brain health and aging. Published in Cell Reports Medicine, the findings provide new directions for targeting the memory effects on a molecular level, without requiring a ketogenic diet or even the byproducts of it.

“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 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.

“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,” said John Newman, MD, PhD, whose laboratory at Buck collaborated with González-Billault on the study. “It is the most detailed study to date of the ketogenic diet and aging brain in mice.”

It was over a century ago that researchers first observed that rats that consumed less food lived longer. Newman explained that scientists now know that being able to manipulate lifespan is not about specifically eating less, but rather is all down to signals. Signals inside cells can turn specific pathways on and off in response to available nutrients, and many of those pathways are related to aging, such as controlling protein turnover and metabolism.

Key signals in the body, ketone bodies, include acetoacetate (AcAc), β-hydroxybutyrate (BHB), and, to a lesser extent, acetone. These liver-produced molecules surge when glucose is scarce, triggered by caloric restriction, intense exercise, or a low-carb ketogenic diet.

Seven years ago, Newman and his team presented pioneering evidence showing that a ketogenic diet, by elevating ketone body levels in mice throughout their adulthood, can extend their lifespan and promote healthier aging.

“The most striking effect on their health as they aged was that their memory was preserved; it was possibly even better than when they were younger,” he said.

Now, González-Billault and Buck scientists have collaborated on a study to pinpoint which aspect of the ketogenic diet enhances memory and its molecular effects on the brain. Mice on the keto diet consumed 90% of calories from fat and 10% from protein, while control mice had 13% fat but the same protein. Elderly test mice, over two years old, cycled between a week on the keto diet and a week on the control diet to avoid overeating and obesity [1].

Neurophysiological and behavioral tests revealed the ketogenic diet’s positive impact on memory mechanisms in aged mice, according to González-Billault. Following these findings, the team, with Buck professor Birgit Schilling, PhD, delved into the protein composition at hippocampal synapses, demonstrating enhanced synaptic function.

“Surprisingly, we saw that the ketogenic diet caused dramatic changes in the proteins of the synapse,” said Schilling.

What was even more surprising, González-Billault noted, was that these changes began after just one week on the diet and became more pronounced with continued exposure, observed at six weeks and one year [1].

Further testing revealed that the ketogenic diet activates a specific signaling pathway (protein kinase A) in synapses, essential for synaptic activity. The team demonstrated in isolated cells that BHB, the primary ketone body produced during the diet, appears to trigger this pathway. This suggests, González-Billault said, that ketone bodies, particularly BHB, are vital not only as an energy source but also as signaling molecules [1].

“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 aging brain.”

Newman indicated that future research will focus on whether BHB alone can provide the same memory benefits or if directly manipulating the protein kinase A signaling pathway might be even more effective.

“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,” he said, “we wouldn’t even need to eat a ketogenic diet in the end.”

[1] https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00285-4