Study reveals cognitive benefits of ketogenic diet in aged mice

In a recent study published in Cell Reports Medicine, researchers examined the impact of cyclic ketogenic diet treatments in improving the age-related decline in brain function using long-term potential recordings and behavioral testing in aged mice.

​​​​​​​Study: Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice. Image Credit: Egoreichenkov Evgenii/Shutterstock.com

Background

The progressive cognitive decline that occurs with age involves complex multifactorial changes in the neural networks and is characterized by brain aging hallmarks such as mitochondrial dysfunction, aberrant neuronal activity, and improper molecular waste disposal, especially in the cortex and hippocampus.

The defective neuronal activity that results from these changes includes regression of dendritic tree structure, neurochemical imbalance, changes in gene expression, glucose metabolism impairments, etc.

Dietary interventions have been explored extensively in recent times in murine model experiments to improve memory and learning.

Studies have shown that intermittent fasting, caloric restrictions, and ketogenic diets force a switch from glucose metabolism to fatty acid β-oxidation in the neurons, which consume ketone bodies for energy production.

Ketone bodies such as β-hydroxybutyrate are known to lower reactive oxygen species production and increase mitochondrial biogenesis, targeting the hallmarks of aging by lowering inflammation and senescence. Ketone bodies are also known to lower hyperexcitability in neurons and improve cognition.

About the study

In the present study, the researchers aimed to elucidate the molecular mechanisms regulated at the synaptic level by ketogenic diets and their impact on dendritic organization and the proteomic landscape in neurons.

They used aged mice models to examine the regulation of key synaptic proteins and study the reconfiguration of neuronal activity by ketogenic diets.

The researchers used mice aged between 20 and 23 months to model aging-associated decline in brain function. They fed one group with a control diet while the other group was on a cyclic ketogenic diet regimen for four months.

A cyclical regimen of a control diet and a ketogenic diet has been reported to be non-obesogenic by previous studies.

Blood samples were taken at the end of each diet cycle to measure metabolic parameters such as β -hydroxybutyrate and glycemic levels. All the metabolic parameters were measured before behavioral tests were administered to ensure that the animals were subjected to the least stress before measuring behavior.

Behavioral tests consisted of various physical and cognitive tasks, such as the elevated plus maze test, open field test, novel object recognition, Y maze, rotarod, and Barnes maze test to analyze the performance of the mice along motor function, spatial orientation, and memory parameters.

The elevated plus maze test was administered to determine if the carbohydrate restriction and the cycling of diets induced any anxiety in the mice.

The feeding regimen was also replicated in young, three-month-old mice, and the control and ketogenic diet groups of younger mice were also subjected to the same set of behavioral tests for comparison.

Transversal hippocampus slices from euthanized mice were also prepared for electrophysiological examinations such as long-term potential recordings and measuring field excitatory postsynaptic potentials and basal synaptic transmission.

The morphology of the neurons was also examined to determine whether changes in synaptic function correlated to altered synaptic organization.

Results

The study found that ketogenic diets improve long-term potential hippocampus and working memory recordings. Furthermore, mice fed a ketogenic diet for a longer term showed changes in the protein kinase A signaling pathway associated with the presynaptic compartment.

The researchers also found that the beneficial effects of the ketogenic diet in aged mice were connected to the activation of cyclic adenosine monophosphate (cAMP) dependent signaling.

The results indicated that the cyclic administration of a ketogenic diet for four months significantly improved long-term and working memory in aged mice.

Additionally, aged mice that were on the cyclic ketogenic diet regimen also showed motor coordination that was comparable to young mice that were on the control diet.

The in vivo Western blot analyses also revealed an increased abundance of brain-derived neurotrophic factor (BDNF) and protein kinase A substrate phosphorylation, supporting the findings. The morphological analyses showed an increase in dendritic arborization in aged mice that were on the ketogenic diet regimen.

Conclusions

The findings presented new insights into the biological processes and molecular mechanisms through which cyclic ketogenic diets improve brain function in aging mice.

These improvements in long-term and working memory were achieved even when the ketogenic diet was administered in later stages of life. The study revealed novel findings on the impact of ketogenic diets on the cortical synaptic proteome landscape and morphological changes in dendrites.