The ketogenic diet is both praised and criticised by many, yet its influence on memory in mice is supported by scientific evidence. While studying the impact of the high-fat, low-carbohydrate diet on memory enhancement in older mice, researchers from the Buck Institute, along with a team from the University of Chile, discovered a novel molecular signalling pathway. This pathway enhances synapse function, shedding light on how the diet supports brain health and combats ageing. The findings, published in the June 5, 2024, issue of Cell Reports Medicine, open new avenues for addressing memory improvements at a molecular level without necessarily adhering to a ketogenic diet or its by-products.
The study’s lead researcher, Christian González-Billault, PhD, a professor at the Universidad de Chile and director of their Geroscience Center for Brain Health and Metabolism, also an adjunct professor at the Buck Institute, highlighted the broad benefits of the ketogenic diet on brain function. He noted that the study provides a precise mechanism of action that could aid in maintaining and enhancing brain function during ageing. John Newman, MD, PhD, collaborating with Dr González-Billault and based at the Buck Institute while also serving as a geriatrician at the University of California, San Francisco, pointed out that their current research builds on earlier findings which demonstrated that the ketogenic diet boosts healthspan and memory in ageing mice. Dr Newman emphasised that this effect appears rapidly and can be initiated in older animals, enhancing brain health as they age, leaving no doubt about the significant and rapid effects of the ketogenic diet on brain health.
Historically, it has been observed that rats with reduced food intake tend to live longer. However, according to Dr Newman, the key to manipulating lifespan lies in reduced consumption and the cellular signals triggered by nutrient availability. These signals often involve pathways associated with ageing, such as those controlling protein turnover and metabolism. Key among these signals are the ketone bodies—acetoacetate (AcAc), β-hydroxybutyrate (BHB), and to a lesser extent, acetone—produced in the liver when glucose levels are low, which can be due to caloric restriction, intense exercise, or a low-carbohydrate diet like the ketogenic diet.
Seven years ago, Newman led a pioneering study which demonstrated that exposing mice to increased levels of ketone bodies throughout their adult life via a ketogenic diet not only helped them live longer but also maintained and possibly enhanced their memory as they aged. The present study, led by González-Billault, aimed to discern which aspects of the ketogenic diet were responsible for these effects and how they affected brain function at a molecular level. The study involved feeding mice of advanced age a diet consisting of 90% calories from fat and 10% from protein, alternated weekly with a control diet to prevent overeating and obesity.
The advantages of the ketogenic diet were confirmed through a series of neurophysiological and behavioural tests that evaluated memory processes in aged mice. These tests indicated significant benefits to the functionality of synapses responsible for memory. Buck professor Birgit Schilling, PhD, who heads the Proteomics and Mass Spectrometry Center, conducted a deeper analysis of the protein composition of these synapses in the hippocampus. The surprising results showed that even a brief exposure to the ketogenic diet led to dramatic changes in synaptic proteins, which became more pronounced over time.
Further tests revealed that the ketogenic diet activates a specific signalling pathway in the synapses—protein kinase A—known to be crucial for synaptic activity. This pathway seemed to be stimulated by BHB, the primary ketone body produced during a ketogenic diet, highlighting its role as an energy source and a crucial signalling molecule. Dr González-Billault believes that while BHB is critical, it is likely not the sole molecule involved, but understanding its role is a significant step towards comprehending the overall impact of the ketogenic diet and ketone bodies on ageing brains.
Looking ahead, Dr. Newman envisions a future where we can replicate the protective effects of the ketogenic diet on memory by directly targeting the protein kinase A signalling pathway. This approach could eliminate the need to adhere to the diet itself, offering a more targeted method of enhancing synaptic function and memory in ageing individuals. This promising direction underscores a profound leap forward in our understanding and capability to influence brain health as we age, instilling a sense of hope and optimism in the field of neuroscience and geriatrics.
More information: Diego Acuña-Catalá et al, Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice, Cell Reports Medicine. DOI: 10.1016/j.xcrm.2024.101593
Journal information: Cell Reports Medicine Provided by Buck Institute for Research on Aging
