Ketones – Potential to Achieve Brain Energy Rescue and Sustain Cognitive Health during Aging

Alzheimer’s disease (AD) is the most common major neurocognitive disorder of aging. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive ‘brain energy gap’. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition – mild cognitive impairment (MCI) - to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during aging. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimizing the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.

Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

Converging evidence made clear that declining brain energetics contribute to aging and are implicated in the initiation and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Indeed, both pathologies involve instances of hypometabolism of glucose and oxygen in the brain causing mitochondrial dysfunction, energetic failure and oxidative stress. Importantly, recent evidence suggests that astrocytes, which play a key role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. Therefore, exploring how the neuro-supportive role of astrocytes may be impaired in the context of these disorders has great therapeutic potential. In the following, we will discuss some of the so far identified features underlining the astrocyte-neuron metabolic crosstalk. Thereby, special focus will be given to the role of mitochondria. Furthermore, we will report on recent advancements concerning iPSC-derived models used to unravel the metabolic contribution of astrocytes to neuronal demise. Finally, we discuss how mitochondrial dysfunction in astrocytes could contribute to inflammatory signaling in neurodegenerative diseases.

Brain energetics, mitochondria, and traumatic brain injury

We review current thinking about, and draw connections between, brain energetics and metabolism, and between mitochondria and traumatic brain injury. Energy is fundamental to proper brain function. Its creation in a useful form for neurons and glia, and consistently in response to the brain’s high energy needs, is critical for physiological pathways. Dysfunction in the mechanisms of energy production is at the center of neurological and neuropsychiatric pathologies. We examine the connections between energetics and mitochondria – the organelle responsible for almost all the energy production in the cell – and how secondary pathologies in traumatic brain injury result from energetic dysfunction. This paper interweaves these topics, a necessity since they are closely coupled, and identifies where there exist a lack of understanding and of data. In addition to summarizing current thinking in these disciplines, our goal is to suggest a framework for the mathematical modeling of mechanisms and pathways based on optimal energetic decisions.

A hypothesis linking the energy demand of the brain to obesity risk

The causes of obesity are complex and multifactorial. We propose that one unconsidered but likely important factor is the energetic demand of brain development, which could constrain energy available for body growth and other functions, including fat deposition. Humans are leanest during early childhood and regain body fat in later childhood. Children reaching this adiposity rebound (AR) early are at risk for adult obesity. In aggregate data, the developing brain consumes a lifetime peak of 66% of resting energy expenditure in the years preceding the AR, and brain energy use is inversely related to body weight gain from infancy until puberty. Building on this finding, we hypothesize that individual variation in childhood brain energy expenditure will help explain variation in the timing of the AR and subsequent obesity risk. The idea that brain energetics constrain fat deposition is consistent with evidence that genes that elevate BMI are expressed in the brain and mediate a trade-off between the size of brain structures and BMI. Variability in energy expended on brain development and function could also help explain widely documented inverse relationships between the BMI and cognitive abilities. We estimate that variability in brain energetics could explain the weight differential separating children at the 50th and 70th BMI-for-age centiles immediately before the AR. Our model proposes a role for brain energetics as a driver of variation within a population’s BMI distribution and suggests that educational interventions that boost global brain energy use during childhood could help reduce the burden of obesity.