Ketogenic diets: An historical antiepileptic therapy with promising potentialities for the aging brain

Balietti, Marta; Casoli, Tiziana; Stefano, Giuseppina Di; Giorgetti, Belinda; Aicardi, Giorgio; Fattoretti, Patrizia

doi:10.1016/j.arr.2010.02.003

Cited by 43 publications

(39 citation statements)

References 116 publications

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“…Ketone bodies are an energy source for metabolically active tissues under conditions of glucose deficiency [74]. Whereas ketogenic diets have shown therapeutic potential in some neurological diseases [75,76], ketone bodies are toxic at high concentrations and can stimulate insulin release, generate oxygen radicals, and cause lipid peroxidation, contributing to oxidative stress [77,78]. Increased ketone bodies have been reported in metabolic disorders (i.e.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment

Cassol

Misra

Dutta

et al. 2014

Aids

109

107

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Objective(s):HIV-associated neurocognitive disorders (HAND) remain prevalent in HIV-infected patients on antiretroviral therapy (ART), but the underlying mechanisms are unclear. Some features of HAND resemble those of age-associated cognitive decline in the absence of HIV, suggesting that overlapping mechanisms may contribute to neurocognitive impairment.Design:Cross-sectional analysis of cerebrospinal fluid (CSF) from 100 individuals (46 HIV-positive patients and 54 HIV-negative controls).Methods:Untargeted CSF metabolite profiling was performed using liquid/gas chromatography followed by mass spectrometry. Cytokine profiling was performed by Bioplex. Bioinformatic analyses were performed in Metaboanalyst and R.Results:Alterations in the CSF metabolome of HIV patients on ART mapped to pathways associated with neurotransmitter production, mitochondrial function, oxidative stress, and metabolic waste. Many CSF metabolites altered in HIV overlapped with those altered with advanced age in HIV-negative controls, suggesting a pattern indicative of accelerated aging. Machine learning models identified neurotransmitters (glutamate, N-acetylaspartate), markers of glial activation (myo-inositol), and ketone bodies (beta-hydroxybutyric acid, 1,2-propanediol) as top-ranked classifiers of HAND. These CSF metabolites correlated with worse neurocognitive test scores, plasma inflammatory biomarkers [interferon (IFN)-α, IFN-γ, interleukin (IL)-8, IL-1β, IL-6, IL-2Ra], and intrathecal IFN responses (IFN-γ and kynurenine : tryptophan ratio), suggesting inter-relationships between systemic and intrathecal inflammation and metabolic alterations in CSF.Conclusions:Alterations in the CSF metabolome of HIV patients on ART suggest that persistent inflammation, glial responses, glutamate neurotoxicity, and altered brain waste disposal systems contribute to mechanisms involved in HAND that may be augmented with aging.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment

Cassol

Misra

Dutta

et al. 2014

Aids

109

107

View full text Add to dashboard Cite

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“…Several monocarboxylic acid transporters, including MCT1 and MCT2, carry it across the blood-brain barrier [37]. Of interest, up-regulation of MCT1 in particular is associated with high utilization of ketone bodies in the neonatal period and on a ketogenic diet [38]. Recently, the monocarboxylate transporter SLC16A6 was identified as the key transporter for exporting βOHB from the liver, in model organisms; zebrafish lacking Slc16a6a develop fatty liver during fasting mainly due to the diversion of acetyl-CoA to lipid synthesis rather than ketone bodies [39].…”

Section: Metabolism Regulation and Function Of Ketone Bodiesmentioning

confidence: 99%

Ketone bodies as signaling metabolites

Newman

Verdin

2014

Trends in Endocrinology & Metabolism

747

670

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Traditionally, the ketone body β-hydroxybutyrate (βOHB) has been looked upon as a carrier of energy from liver to peripheral tissues during fasting or exercise. However, βOHB also signals via extracellular receptors and acts as an endogenous inhibitor of histone deacetylases (HDACs). These recent findings support a model in which βOHB functions to link the environment, in this case the diet, and gene expression via chromatin modifications. Here, we review the regulation and functions of ketone bodies, the relationship between ketone bodies and calorie restriction, and the implications of HDAC inhibition by the ketone body βOHB in the modulation of metabolism, and diseases of aging.

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“…Early studies on polyols such as 1,2-, 1,4-, and 2,3-butanediols revealed that they and monounsaturated FAs ( 61 ). Also, incorporation of MCTG into the KD may be helpful in formulating more tolerable ketogenic regimens for the long-term treatment of drug-resistant epilepsy (62)(63)(64)(65).…”

Section: Kesmentioning

confidence: 99%

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Hashim

VanItallie

2014

Journal of Lipid Research

120

108

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This article is available online at http://www.jlr.org family, its importance for purposes of this review is minimal.). KBs have been dubbed "metabolism's ugly duckling" because, in the mid-19th century, they were fi rst discovered in large quantities in the urine of patients succumbing to diabetic ketoacidosis. Thus, it is not surprising that physicians of the era considered KBs to be toxic byproducts of impaired carbohydrate metabolism. It took almost half a century for medical scientists to understand that KBs are normal metabolites manufactured by the liver in increasing amounts when dietary sources of carbohydrate and glucogenic amino acids are in short supply ( 1 ). Unfortunately, some physicians still fail to distinguish between the safe "physiological" hyperketonemia that occurs in healthy individuals during fasting or adherence to a ketogenic diet (KD), and the pathological, out-of-control hyperketonemia associated with insulin-defi cient diabetes.When Owen et al. ( 2 ) reported that during a prolonged fast KBs can provide 60% or more of the brain's daily energy requirement (thereby sparing ‫ف‬ 80 g/day of glucose that otherwise would have been derived largely from breakdown of the body's limited protein stores), it was finally acknowledged that, as in Hans Christian Andersen's 1843 fairy tale, the creature fi rst thought to be an ugly duckling was turning out to be an emerging swan. It became evident that the ketogenic response to starvation is an indispensable metabolic adaptation designed by nature to preserve strength and prolong life during times when food is unavailable ( 3 ) .It is now known that (in nondiabetic individuals), owing to the blood's effi cient buffering capacity, plasma KB Abstract Ketone bodies (KBs ), acetoacetate and ␤ -hydroxybutyrate ( ␤ HB), were considered harmful metabolic by-products when discovered in the mid-19th century in the urine of patients with diabetic ketoacidosis. It took physicians many years to realize that KBs are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KBs as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer's disease (AD), there is preliminary evidence that these same areas remain capable of metabolizing KBs. Because the ketogenic diet (KD) is diffi cult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB levels to у 2 mM, KB esters, such as 1,3-butanediol monoester of ␤ HB and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, ...

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Ketogenic diets: An historical antiepileptic therapy with promising potentialities for the aging brain

Cited by 43 publications

References 116 publications

Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment

Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment

Ketone bodies as signaling metabolites

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

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