Ketone ester effects on metabolism and transcription

Veech, Richard L.

doi:10.1194/jlr.r046292

Cited by 55 publications

(47 citation statements)

References 27 publications

(26 reference statements)

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“…Further work might determine if BHB itself is a segmental mimetic of DR, and could provide candidates for translational therapies of syndromes of aging through either administration of ketone esters (Veech, 2014) or, with a thorough understanding of its downstream signaling mechanisms, activation of BHB’s specific signaling effects. Future work to understand the nature of the persistent effect on memory in particular may lead to therapies to promote cognitive resilience to dementia or illness-associated delirium.…”

Section: Discussionmentioning

confidence: 99%

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

Newman

Covarrubias

Zhao³

et al. 2017

Cell Metabolism

378

299

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Summary A ketogenic diet (KD) recapitulates certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether KD might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that an isoprotein KD, fed on alternate weeks to prevent obesity (Cyclic KD), reduces mid-life mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies down-regulation of insulin, TOR, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, up-regulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice.

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Section: Discussionmentioning

confidence: 99%

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

Newman

Covarrubias

Zhao³

et al. 2017

Cell Metabolism

378

299

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“…The possible benefits of mild ketosis for the improvement of performance and cognition during endurance exercise as a result of the thermodynamic advantage afforded by ketone body oxidation over the oxidation of alternative substrates have been hypothesized (3, 6). Here, we found that a diet that contained a novel ketone ester [30% kcal from ( R )‐3‐hydroxybutyl ( R )‐3‐hydroxybutyrate] elevated circulating β‐hydroxybutyrate concentrations in rats and lowered plasma cholesterol, triglyceride, and glucose levels compared with pair‐fed, isocaloric diets in which the ketone ester was replaced by fat or carbohydrate.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, ketosis can occur in the pathologic setting of type 1 diabetes, where insulin deficiency results in a release of free fatty acids from adipose tissue that exceeds the capacity of other tissues to metabolize them, driving ketone body synthesis by hepatic mitochondria (3). In this situation, elevation of blood ketone levels to $20 μM (35) depletes blood bicarbonate and acidifies the blood to pH 6.9 (3). Physiologic ketosis, which contrasts with diabetic ketoacidosis, is a normal physiologic state with no known adverse medical consequences (3).…”

Section: Discussionmentioning

confidence: 99%

“…Elevation of ketone body levels increases the energy of ATPhydrolysis byreducingthe mitochondrialNAD couple and oxidizing the coenzyme Q couple, which thereby increases the redox span between complex I and complex II of the mitochondrial electron transport chain (3). Combustion of the end‐glycolytic substrate, pyruvate, produces 10 ATP, whereas combustion of the ketone body, D‐β‐hydroxybutyrate, produces 13 ATP (4), which thereby increases the efficiency of hydraulic work in the working, perfused rat heart by ∼30% compared with oxidation of pyruvate (5).…”

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confidence: 99%

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Novel ketone diet enhances physical and cognitive performance

Murray¹,

et al. 2016

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Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson’s disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.—Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.

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“…This suggests that the ketone bodies themselves possess antitumor effects, and that perhaps the effects of the KD are mediated, at least in part, by the ketone bodies. Additional evidence for this comes from data showing that the use of ketone supplementation can enhance the effects of the KD and may even be effective in some diseases when used alone (Veech, 2004, 2014; Kashiwaya et al, 2013; Poff et al, 2014; Shukla et al, 2014; Newport et al, 2015; Youm et al, 2015). Though the mechanisms are still under investigation, it is known that βHB is an endogenous Class I and IIa histone deacetylase (HDAC) inhibitor (Shimazu et al, 2013).…”

Section: β-Hydroxybutyrate As An Anti-cancer Agentmentioning

confidence: 99%

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

Woolf

Syed

Scheck

2016

Front. Mol. Neurosci.

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Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months. It is clear that increased survival of brain tumor patients requires the design of new therapeutic modalities, especially those that enhance currently available treatments and/or limit tumor growth. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacological means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). The KD, as the name implies, also provides increased blood ketones to support the energy needs of normal tissues. Preclinical work from a number of laboratories has shown that the KD does indeed reduce tumor growth in vivo. In addition, the KD has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. Furthermore, this diet can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones such as β-hydroxybutyrate (βHB) in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of chemotherapy and radiation. Thus, while we are only beginning to understand the pluripotent mechanisms through which the KD affects tumor growth and response to conventional therapies, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas. This has led to a limited number of clinical trials investigating the use of a KD in patients with primary and recurrent glioma.

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Ketone ester effects on metabolism and transcription

Cited by 55 publications

References 27 publications

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

Novel ketone diet enhances physical and cognitive performance

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

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