Ketogenesis Increases BDNF Expression to Improve Late Life Cognitive Function

Ketone bodies are a family of metabolites produced during the metabolic stress of fasting or calorie restriction. A ketogenic diet is intended to produce a similar degree of ketogenesis without a low calorie intake by reducing carbohydrate intake relative to fat intake. Too much ketogenesis is a bad thing, but modest increases appear generally beneficial, one part of the big puzzle that is the sweeping metabolic response to a low calorie diet.

The brain receives a sizable fraction of its energy supply in the form of ketone bodies, and ketogenic diets have been shown in animal studies to improve cognitive function, particularly memory, in late life. Other lines of evidence suggest that parts of the mammalian brain are operating right at the edge of their capacity even in youth. For example, exercise increases cerebral blood flow for a time, and during that short period of time, memory function is improved. Thus one might look at any approach that increases delivery of nutrients and oxygen to the brain as a possible way to improve cognitive functions.

In today's open access paper, researchers report on their study of the effects of a ketogenic diet in mice. The authors were searching for mechanisms to explain the established improvement in cognitive function observed as a result of this intervention. Interestingly, they find that a ketogenic diet upregulates BDNF expression in the brain. There is a sizable body of work showing that increased BDNF expression can improve function in the aging brain. For example, changes in metabolite levels influencing BDNF expression may be an important mechanism linking the composition and activity of the gut microbiome to cognitive aging. BDNF can also dampen neuroinflammation and boost neurogenesis, both very relevant to brain aging.

Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice

In this work, we provide cellular and molecular mechanistic evidence that an intermittent ketogenic diet (KD) in aged animals improves brain functions. We show that KD improves memory and potentiates synaptic function, remodels the synaptic proteome, and activates protein kinase A (PKA) signaling. The activation of the cAMP-dependent signaling connects the different layers here studied, providing a novel mechanism for the beneficial effects observed after KD administration in aged mice. KD consumption prompts cells to transition from using glucose to ketone bodies as a primary source of energy. To this end, the liver synthesizes acetoacetate and β-hydroxybutyrate (BHB) from fatty acids, with BHB being the most abundant one. Although dysregulated elevation of ketone body blood levels are associated with pathological conditions such as diabetes, physiological range concentrations are beneficial in experimental models of aging.

Studies in the field of aging have consistently demonstrated that a KD reduces midlife mortality and modifies brain function in mice after long-term administration. Recently, a study showed that ingesting a KD, starting at age 18 months, improves spatial memory and muscle endurance after 5 months of administration. Here, we report that 4 months of a cyclic KD administration (alternated weekly with a control diet to prevent obesity) starting at age 20-23 months significantly improves working memory and long-term memory in 26- to 27-month old mice.

This cyclic KD restores long-term potentiation (LTP) in the hippocampus of aged mice, as it was significantly improved compared with the control group, resulting in a performance closer to young mouse values. Interestingly, this was consistent with the reduced latency to find the escape hole in the Barnes maze, 12 days after the test was initiated, which supports a role of a KD in long-term memory. When PKA levels were compared between groups, no significant differences were registered, although an increasing trend was observed in the KD conditions. Thus, we postulate that changes in the cAMP-pathway induced by the KD modify the activity, rather than the amount, of PKA. Although PKA expression was not substantially upregulated by the KD, we confirmed the activation of the signaling pathway, as BDNF, a canonical target of this route, was overexpressed in the KD group. BDNF regulates synaptic plasticity and structural changes in dendritic spines, promoting learning and memory processes. In addition, it is well known that BDNF and neurotrophic factor signaling is impaired in the aging brain.

In summary, our data provide new insights into molecular mechanisms and biological processes that a cyclic KD regulates in brain function, an aspect that has been understudied in the field of aging. In addition, we reveal here that a KD has the potential to modify brain function and motor activity in aged mice, even when administered later in life. This study also proposes new mechanisms by which the administration of a cyclic KD improves memory and neuronal function in aging that had not been discovered previously. Specifically, a KD induces changes in the proteome landscape of cortical synapses that directly impact the structure and function of synaptic organization, proposing a scenario whereby ketone bodies (specifically BHB) play a crucial role not only as an energy metabolite, but also as a signaling metabolite.

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