Intermittent metabolic switching, neuroplasticity and brain health

Key Points

  • Brain evolution, including higher cortical functions of humans (imagination, creativity and language), was driven by the necessity of sustaining high levels of performance in a food-deprived (fasted) state

  • Intermittent metabolic switching (IMS) occurs when eating and exercise patterns result in periodic depletion of liver glycogen stores and the associated production of ketones from fatty acids. IMS occurs rarely or not at all in individuals who eat three or more meals per day and who are fairly sedentary

  • The ketone β-hydroxybutyrate (BHB) is transported into the brain and into neuronal mitochondria, where it is used to generate acetyl CoA and ATP. BHB also acts as a signalling molecule in neurons that can induce the expression of brain-derived neurotrophic factor and thereby promote synaptic plasticity and cellular stress resistance

  • During fasting and extended exercise, adaptive cellular stress-response signalling pathways are activated and autophagy is stimulated, whereas overall protein synthesis is reduced. Upon refeeding, rest and sleep, protein synthesis is upregulated and mitochondrial biogenesis occurs, enabling neurogenesis and synaptogenesis

  • IMS can enhance cognition and motor performance and protects neurons against dysfunction and degeneration in animal models of stroke, epilepsy, traumatic brain and spinal cord injury, Alzheimer disease and Parkinson disease

  • Intermittent fasting can improve indicators of metabolic and cardiovascular health in humans by mechanisms involving reductions in oxidative damage and inflammation. However, it remains to be determined whether and how intermittent fasting impacts the brains of healthy humans and those affected with a neurological disorder

Abstract

During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease.

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Figure 1: Biochemical pathways involved in the metabolic switch.
Figure 2: Signalling pathways by which neurons respond to the metabolic switch during fasting and exercise.
Figure 3: Model for how intermittent metabolic switching may optimize brain performance and increase resistance to injury and disease.

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Acknowledgements

This work was supported by the Intramural Research Program of the US National Institute on Ageing.

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M.P.M., K.M., N.G., M.S. and A.C. researched data for the article, made a substantial contribution to the discussion of content and contributed to the writing, review and editing of the manuscript before submission'

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Correspondence to Mark P. Mattson.

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Glossary

β-Hydroxybutyrate

(BHB). A ketone, generated from fatty acids during fasting and extended exercise, that functions as a cellular energy source and as a signalling molecule that induces the expression of brain-derived neurotrophic factor.

Intermittent metabolic switching

(IMS). Repeating cycles of a metabolic challenge (fasting and/or exercise) sufficient to deplete liver glycogen stores and elevate circulating ketone levels, followed by a recovery period (eating, resting and sleeping).

Brain-derived neurotrophic factor

(BDNF). A protein produced and released from neurons in response to synaptic activity, exercise and fasting that acts to enhance synaptic plasticity and cellular stress resistance.

Mitochondrial biogenesis

The proliferation of mitochondria in neurons in response to metabolic challenges and neurotrophic factors to produce new mitochondria that promote synaptic plasticity and cellular stress resistance.

Deacetylase

An enzyme that removes an acetyl group from lysine residues of substrate proteins; the sirtuins SIRT1 and SIRT3 are deacetylases that play particularly important roles in adaptive responses of neurons to metabolic challenges.

Mechanistic target of rapamycin

(mTOR; also known as serine/threonine-protein kinase mTOR (MTOR) and mammalian target of rapamycin). A kinase that plays a pivotal role in stimulating cellular protein synthesis and suppressing autophagy when nutrients (glucose and amino acids) are plentiful.

Autophagy

A complex process by which cells recognize damaged dysfunctional proteins and organelles, engulf them in a membrane and target them for enzymatic degradation in lysosomes to generate recyclable undamaged components (for example, amino acids and lipids).

Ketogenesis

The process by which spillover of acetyl CoA results from β-oxidation of fatty acids in the liver during fasting and extended exercise.

Myokines

Proteins and peptides released from muscle cells during exercise that can enter the brain and affect neuroplasticity; examples include interleukin-6, cathepsin B and irisin.

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Mattson, M., Moehl, K., Ghena, N. et al. Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci 19, 81–94 (2018). https://doi.org/10.1038/nrn.2017.156

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