Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis

Poff, Angela M.; Moss, Sara; Soliven, Maricel; D’Agostino, Dominic P.

doi:10.3389/fnut.2021.783659

Cited by 27 publications

(23 citation statements)

References 106 publications

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“…TBI can occur in athletic contexts, with the severity ranging from small but repeated sub-concussive insults up to overt high impact insult resulting in loss of consciousness [311,312]. Ketosis achieved by ketogenic diet or ingestion of EKS has been widely hypothesised to present a promising prophylactic and/or post-injury therapeutic strategy for TBI through a mechanism whereby KBs serve as an alternative substrate for energy provision during the post-injury period of impaired glycolytic metabolism [40,95,255,[313][314][315][316]. In the post-injury period, several features of bioenergetic impairment are observed including increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase via depletion of the cytosolic NAD + pool.…”

Section: Utility Of Eks In Traumatic Brain Injury (Tbi)mentioning

confidence: 99%

“…In the post-injury period, several features of bioenergetic impairment are observed including increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase via depletion of the cytosolic NAD + pool. Ultimately, glucose becomes a less favourable energy substrate and ATP provision decreases, whereas KBs are an alternative substrate that can contribute significantly to cerebral metabolism [40,95,255,[313][314][315][316]. A recent pre-clinical study of TBI using controlled cortical impact in Sprague-Dawley rats demonstrated therapeutic promise for EKS as post-injury daily oral gavage of R-BD R-βHB KME protected against TBI-induced morphological and functional deficits [317].…”

Section: Utility Of Eks In Traumatic Brain Injury (Tbi)mentioning

confidence: 99%

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Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

Evans

McClure²,

Koutnik³

et al. 2022

Sports Med

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The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by serving as an alternative substrate for energy provision, and by modulating inflammation, oxidative stress, catabolic processes, and gene expression. Of particular relevance to athletes are the metabolic actions of ketone bodies to alter substrate utilisation through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. There has been long-standing interest in the development of ingestible forms of ketone bodies that has recently resulted in the commercial availability of exogenous ketone supplements (EKS). These supplements in the form of ketone salts and ketone esters, in addition to ketogenic compounds such as 1,3-butanediol and medium chain triglycerides, facilitate an acute transient increase in circulating AcAc and βHB concentrations, which has been termed ‘acute nutritional ketosis’ or ‘intermittent exogenous ketosis’. Some studies have suggested beneficial effects of EKS to endurance performance, recovery, and overreaching, although many studies have failed to observe benefits of acute nutritional ketosis on performance or recovery. The present review explores the rationale and historical development of EKS, the mechanistic basis for their proposed effects, both positive and negative, and evidence to date for their effects on exercise performance and recovery outcomes before concluding with a discussion of methodological considerations and future directions in this field.

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Section: Utility Of Eks In Traumatic Brain Injury (Tbi)mentioning

confidence: 99%

Section: Utility Of Eks In Traumatic Brain Injury (Tbi)mentioning

confidence: 99%

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

Evans

McClure²,

Koutnik³

et al. 2022

Sports Med

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show abstract

“…KD is a complex, pleiotropic intervention with many potential mechanisms for epileptiform spike suppression, including both energetic and signaling functions of BHB, reduced insulin levels, provision of substrates for fatty acid oxidation, and many others (Gavrilovici and Rho, 2021; Newman and Verdin, 2017; Poff et al, 2021; Puchalska and Crawford, 2021). Importantly for potential clinical applications, pleiotropic mechanisms that are not required for ED suppression may underly undesired side effects associated with KD.…”

Section: Resultsmentioning

confidence: 99%

Small-molecule ketone esters treat brain network abnormalities in an Alzheimer’s disease mouse model

Newman

Kroll

et al. 2022

Preprint

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Altered brain network activity and the resulting hypersynchrony are important for the pathogenesis of cognitive decline in Alzheimer's disease (AD) mouse models. Treatments that reduce epileptiform discharges (EDs) or network hyperactivity improve cognition in AD models and humans. We first show that ketogenic diet, but not fasting, rapidly and persistently reduced EDs in the hAPPJ20 Alzheimer's mouse model over timescales of hours to months. Then, to identify the specific mechanism of the pleiotropic ketogenic diet, we developed small molecule ketone esters to deliver ketone bodies pharmacologically. Two ketone esters recapitulate ED suppression without other dietary manipulation, over time scales of minutes to one week. This small molecule rescue was associated with reduced low-frequency oscillatory activity similar to the recently reported mechanism of an NMDA receptor modulator molecule in this model. Long-term KD resulted in cognitive improvement and in a sex-stratified analysis also improved survival in the more severely affected hAPPJ20 males. Agents that deliver ketone bodies via small molecules or act on downstream targets may hold therapeutic promise in AD through the mechanism of improved network function and reduced epileptiform activity.

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“…To prove the purported beneficial effects of fasting-induced KB production, the best way is to perform clinical trials with exogenous KB [97]. Although data are still scant, there is some preliminary evidence of the positive effects of KB administration in some physio-pathological conditions.…”

Section: Ketone Bodies As Potential Effectors Of Fastingmentioning

confidence: 99%

Traditional and Medical Applications of Fasting

et al. 2022

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Fasting has been practiced for millennia, for religious, ethical, or health reasons. It is also commonplace among different species, from humans, to animals, to lower eukaryotes. Research on fasting is gaining traction based on recent studies that show its role in many adaptive cellular responses such as the reduction of oxidative damage and inflammation, increase of energy metabolism, and in boosting cellular protection. In this expert review, we recount the historical evolution of fasting and we critically analyze its current medical applications, including benefits and caveats. Based on the available data, we conclude that the manipulation of dietary intake, in the form of calorie restriction, intermittent fasting, dietary restriction with the exclusion of some nutrients, prolonged fasting, and so forth, is anthropologically engraved in human culture possibly because of its positive health effects. Indeed, many studies show that fasting ameliorates many biochemical parameters related to cardiovascular and cancer risk, and neurodegeneration. Mechanistic studies are plentiful, but largely limited to cell cultures or laboratory animals. Understandably, there are no controlled trials of any form of fasting that gauge the effects on [any cause] mortality. Physicians should be aware that misinformation is pervasive and that their patients often adopt dietary regimens that are far from being clinically validated. Moreover, doctors are often unaware of their patients’ religious or traditional fasting and of its potential health effects. Based on current evidence, no long-term fasting should be undertaken without medical supervision until future research will hopefully help shed further light on fasting and its effects on human health.

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Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis

Cited by 27 publications

References 106 publications

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

Small-molecule ketone esters treat brain network abnormalities in an Alzheimer’s disease mouse model

Traditional and Medical Applications of Fasting

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