Novel ketone diet enhances physical and cognitive performance

Murray, Andrew J.; Knight, Nicholas; Cole, Mark A.; Cochlin, Lowri E; Carter, Emma; Tchabanenko, Kirill; Pichulik, Tica; Gulston, Melanie K.; Atherton, Helen; Schroeder, Marie A.; Deacon, Robert M. J.; Kashiwaya, Yoshiaki; King, Michael; Pawlosky, Robert J.; Rawlins, J. N. P.; Tyler, Damian J.; Griffin, Julian L.; Robertson, Jeremy; Veech, Richard L.; Clarke, Kieran

doi:10.1096/fj.201600773r

Cited by 146 publications

(117 citation statements)

References 65 publications

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“…Such findings suggest that BHB is not only a biomarker of the metabolic switch and an energy source for neurons but is also a peripheral signal that activates neuronal signalling pathways that enhance synaptic plasticity, cognition and neuronal stress resistance. Indeed, it was reported that oral administration of a BHB ester to rats for 5 days improves their spatial learning and memory and enhances their endurance in a treadmill test 108 . In addition to their roles as energy substrates and signalling molecules, BHB and AcAc are also precursors to membrane lipids in brain cells, including neurons and, notably, the oligodendrocytes 109 , suggesting a benefit of IMS for axonal myelination.…”

Section: Ims-associated Peripheral Signalsmentioning

confidence: 99%

Intermittent metabolic switching, neuroplasticity and brain health

et al. 2018

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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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Section: Ims-associated Peripheral Signalsmentioning

confidence: 99%

Intermittent metabolic switching, neuroplasticity and brain health

et al. 2018

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“…The unique ability of ketone bodies to supply energy to brain during periods of impairment of glucose metabolism make ketosis an effective treatment for a number of neurological conditions which are currently without effective therapies. Impairment of cognitive function has also been shown to be improved by the metabolism of ketone bodies . Additionally, Alzheimer's disease, the major cause of which is aging can be improved clinically by the induction of mild ketosis in a mouse model of the disease and in humans .…”

Section: Resultsmentioning

confidence: 99%

Ketone bodies mimic the life span extending properties of caloric restriction

Veech

Bradshaw

Clarke³

et al. 2017

IUBMB Life

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The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP 3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, D-b-hydroxybutyrate (D-bHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of D-bHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. V C 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5): [305][306][307][308][309][310][311][312][313][314] 2017 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Abbreviations: D-bHB, D-b-hydroxybutyrate; HIF-1a, hypoxia-inducible factor 1-alpha; IGF, insulin/insulin-like growth factor; FOXO, forkhead box transcription factor; HDAC, histone deacetylase; IIS, insulin/insulin-like growth factor receptor signaling pathway; ILP, insulin l...

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“…The inescapable fact that the brain eventually ceases to function in the complete absence of either glucose or oxygen has focussed the theories of neuroenergetics toward the oxidation of glucose as being the prime mechanism for energy acquisition of the mammalian brain. However, the ability of the brain to adapt to low glucose in insulin-injecting diabetes patients (Maran et al, 2000), to low oxygen in people at high altitude (Hochachka et al, 1996) and increased ketone body in diet (Roy et al, 2015; Murray et al, 2016) suggests that the brain makes use of more than one mechanism to acquire energy. These alternate mechanisms can compensate for decreased glucose and oxygen but can never completely replace oxygen- and glucose-dependent metabolic activities.…”

Section: Resultsmentioning

confidence: 99%

Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse

et al. 2017

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Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved.

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Novel ketone diet enhances physical and cognitive performance

Cited by 146 publications

References 65 publications

Intermittent metabolic switching, neuroplasticity and brain health

Intermittent metabolic switching, neuroplasticity and brain health

Ketone bodies mimic the life span extending properties of caloric restriction

Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse

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