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Medium Chain Triglycerides
(MCT)s and the Ketogenic Diet



By Durk Pearson & Sandy Shaw

TABLE OF CONTENTS

  1. Medium chain triglycerides (MCTs) and the ketogenic diet
  2. The ketogenic diet may mimic calorie restriction
  3. Ketones and white matter: preserving brain connections
  4. The ketone beta-hydroxybutyrate improves cognition in memory-impaired human adults in just one dose
  5. A ketone extends lifespan of C. elegans
  6. What is a ketone?
  7. What is the difference between a ketogenic diet and ketone bodies?
  8. MCT supplements are converted to ketone bodies — not the same as the ketogenic diet
  9. How ketone supplementation may help maintain a healthy weight
  10. Ketones can overcome insulin resistance by mimicking insulin
  11. Beta-hydroxybutyrate can increase the production of superoxide dismutase
  12. The ketogenic diet in a pill: is this possible?
  13. Ketones derived from supplementary MCTs: possible treatment of neurodegenerative disorders
  14. How to benefit from a ketogenic diet without having to limit your carbohydrates: the C-8 solution
  15. References

MEDIUM CHAIN TRIGLYCERIDES
The Road (to Energy) Less Traveled

A form of dietary fat that has become of great interest, both to the public and to scientists, is known as MEDIUM CHAIN TRIGLYCERIDES (MCTs). MCTs, found in some foods (particularly tropical oils such as coconut and palm oils) have shorter chain lengths than the most common dietary fats— the long chain triglycerides such as palmitic and stearic acids. MCTs have myriad beneficial properties, some of which we discuss here, such as (importantly) the ability of MCTs to provide a RAPID SOURCE OF ENERGY for cells (including those of the brain). This is particularly important when the supply of glucose, the brain’s principal source of energy, is in short supply or unavailable due to insulin resistance. The particularly beneficial effects of the C-8 MCTs (MCTs with an 8-carbon fatty acid backbone) in relation to Alzheimer’s disease and weight loss are also discussed here. Caprylic acid is the common name for OCTANOIC ACID, the eight-carbon fatty acid found in some MCTs.

A 2016 study (Voller, 2016) reports that “[h]igh-dose OA [octanoic acid] (up to 710 mg/kg) was previously used in children with intractable epilepsy as part of a ketogenic diet treatment, with chronic administration for up to 2 years. Reported side effects were mild diarrhea and abdominal discomfort.” In a prior study, 4 mg/kg of oral OA was shown to be safe and potentially effective compared to placebo in a trial of OA against essential tremor. Essential tremor may be related to, but is not the same as, Parkinson’s disease. It involves a tremor associated with movement, as in eating or walking, rather than a resting tremor as in Parkinson’s.

THE KETOGENIC DIET
May Mimic Caloric Restriction

The KETOGENIC DIET, like caloric restriction, increases serum levels of ketones. Both of these dietary protocols “offer a robust protection against a multitude of acute and chronic neurological diseases.” (Maalouf, 2007) The oxidation of MCTs (medium chain triglycerides), mostly by the liver, is the source of ketones. “MCTs, the oxidation of which is not altered in obesity, could therefore be of interest in the dietary treatment of obesity.” (Binnert, 1998)

Unlike an ordinary diet, the ketogenic diet must contain a very restricted amount of carbohydrates (typically about 2% of total calories). This is necessary in order to provide the signal to the liver that causes it to produce ketones from fats. The great news is that nearly ANY diet can be converted to a ketogenic diet by the addition of modest amounts of MCTs.

KETONES AND WHITE MATTER: Preserving Brain Connections

White matter is a critical component of brain function. It provides the connections that allow different areas of the brain to communicate with each other. Without these connections, brain function resembles Alzheimer’s disease, where there is extensive damage to white matter and, among other things, a severe inability to access memories.

A major reason for this white matter degradation in Alzheimer’s (and also in aging, though to a less severe extent) is that with age, the brain gradually becomes unable to acquire the amount of glucose it needs to provide its energy needs. When that occurs, it turns to ketone bodies, which can be produced by the liver. Eventually, however, even the liver cannot supply enough ketone bodies, and the brain begins to make its own from certain fats contained in white matter. This is clearly a disaster, a process of cannibalization of vital connections leading to progressive cognitive decline.

KETONE BODIES AND MEMORY

The good news is that ketone bodies can provide the brain with energy and prevent the need to degrade white matter in order to get that energy. That brings us to a very recent paper (Guo, 2015) in which the researchers show that caloric restriction (CR) in mice causes a shift in energy use from glucose to ketone bodies that keep the brain supplied with energy. The old CR animals show a preservation of white matter integrity as well as long-term memory. The researchers used white matter structural connectivity in the corpus callosum as an indicator of structural integrity. The results revealed that calorie restriction caused a switch from cellular use of glucose as a fuel to ketone bodies (produced from fats), presumably (the authors suggest) due to the decreased glucose available in the restricted diet. These data support the notion that ketone bodies may mimic the effects of calorie restriction.

Other work has also shown that at least some of the beneficial effects of caloric restriction may be mimicked by supplementation with ketone bodies, which would moot the need for the brain to generate its own ketone bodies via the degradation of myelin. Myelin is the substance in white matter that makes it white and which lines the connecting tracts of the white matter and increases the speed of information flow via those connections. Myelin is the fatty insulation for your nerves.

Multiple sclerosis is a “classic” example of a demyelinating disease, with extensive damage to white matter. Cells in the MS brain, unable to derive enough energy from glucose (through oxidative phosphorylation), switch to the use of ketone bodies that it gets from the breakdown of myelin. The same switch for the same reason occurs in other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s, and Huntington’s. “...myelin loss not only causes a decrement in the nerve conduction velocity, but also determines axonal degeneration, the main causes of the disabling symptoms in demyelinating diseases.” (Ravera, 2015) Damage to the myelin sheath is termed the “primum movens” of MS; translated into English, the Latin phrase “primum movens” means (roughly) “first cause.” (Ravera, 2015)

BETA-HYDROXYBUTYRATE (BETA-OHB, A KETONE BODY) SUPPLIES AN ALTERNATIVE ENERGY SOURCE TO THE ALZHEIMER’S BRAIN

IMPROVES MEMORY IN ADULT HUMANS IN JUST ONE DOSE

“Glucose is the brain’s principal energy substrate.” (Reger, 2004)

A 2004 study in memory-impaired adult humans reported that a single dose of beta-hydroxybutyrate (a ketone body) resulted in a significant improvement as compared to placebo in the reading of a paragraph. (This worked only in those who did not have an apoE4 allele.) The researchers concluded that “[k]etone bodies may provide an alternative energy substrate in AD.”

KETONE EXTENDS LIFESPAN of C. elegans

A recent paper tells us that a ketone called D-beta-hydroxybutyrate (also called beta-hydroxybutyrate) increased the mean lifespan of the nematode C. elegans by about 20%. (Edwards, 2014) Although nematodes are not humans, it is good to recall the observation that we are still “partly worm” (referring to C. elegans), as we share a substantial portion of our genome with them.

What Is a Ketone?

“Three compounds are normally considered ketone bodies: beta-hydroxybutyrate (BHB), acetoacetate (ACA), and acetone.” Ketones are two- and four-carbon fragments of oxidized fat used as fuel when glucose is not available and are produced by the liver during an extended fast (Henderson, 2009) through the 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) pathway. (Balietti, 2010) To a lesser extent, astrocytes (a type of brain cell) also make beta-hydroxybutyrate). (Tieu, 2003)

What Is the Difference Between a Ketogenic Diet and Ketone Bodies?

The ketogenic diet is a high-fat diet with very low carbohydrate content, that induces a switch in cellular metabolism from glucose to ketones that are produced by the breakdown of fats—especially medium chain triglycerides—in the liver (mostly) and by astrocytes in the brain. The switch to the use of ketones for energy is because there is so little glucose available as a result of the restricted carbohydrate in the ketogenic diet.

MCT SUPPLEMENTS ARE CONVERTED TO KETONE BODIES — BUT IT IS NOT THE SAME AS THE KETOGENIC DIET

There is a vast difference, however, between supplementation with ketone bodies and being on a ketogenic diet. Though both increase blood-borne ketones, there are huge differences in other effects. “A high-fat diet can lead to significant elevation of blood ketones, but also to an elevation of blood free fatty acids.” “In addition, a ketogenic diet can lead to an elevation of blood cholesterol and triglycerides...” None of these things happen with ketone body supplementation. (Veech, 2013)

Ketone Feeding May Help Maintain a Healthy Weight by Replacing Glucose As the Major Source of Cellular Energy

As the author (Veech, 2013) explains: “...feeding a ketone ester diet may be of benefit in the treatment of obesity since it decreased brain malonyl CoA, an important metabolic determinant of appetite.” In a study of mice (Veech, 2013), feeding ketone esters elevated ketone levels in BAT (brown adipose tissue), which is a mechanism that, if it also takes place in humans (as is supported by the evidence), could be one way that ketone esters could help prevent weight gain. The fluorescent molecule that was used to detect ketones in the animals showed a different temporal pattern in the animals on the ketogenic diet compared to those receiving ketone bodies, reflecting separate processes.

Further, the author (Veech, 2013) reports that “...the addition of either 4 mM ketone bodies or insulin increased the efficiency of work output by about 30% — similar to the heats of combustion of the substrate molecules (ketones versus glucose).

Ketones Can Overcome Insulin Resistance By Mimicking Insulin

“The ability of ketones to mimic the metabolic and energetic effects of insulin demonstrates that ketones can overcome the effects of insulin resistance.” The author (Veech, 2013) suggests that, because “injury of any sort to the cell results in insulin resistance...” that “resuscitation or fluids used in the treatment of, for example, a hemorrhage or burns would be more effective if they contained ketone bodies which could overcome the insulin resistance associated with injury.”

Beta-Hydroxybutyrate Can Increase the Production of Superoxide Dismutase

“More recently, it has been shown that D-betahydroxybutyrate induces a transcription factor that increases the production of superoxide dismutase and metalothionine, both important in the destruction of free radicals.” The superoxide radical is involved in many destructive processes (when produced in excess), such as its conversion to peroxynitrite when it chemically reacts with nitric oxide. Peroxynitrite is a major factor in inflammatory diseases and in painful conditions as well. It is also a major damaging agent in heart failure.

The Ketogenic Diet in a Pill: Is This Possible?

The above question was the actual title of a 2008 paper (Rho, 2008). The authors, two MDs, answered in the negative. “At present, the answer is likely ‘no.’ We now know that ketone bodies themselves can mimic the ketogenic diet, though the exact comparison would depend, among other things, on the dose of the ketone bodies. (See next paragraph.) So, the answer now may be “YES it is, at least to a significant extent.”

“The ketone body beta-hydroxybutyrate (betaHB) has been described as a DR [dietary restriction] mimetic compound, in part because it increases in the plasma during DR and WHEN ADMINISTERED EXOGENOUSLY leads to decreased levels of oxidative stress.” (emphasis added) (Edwards, 2014) In the experiments performed by the authors (Edwards, 2014), C. elegans were fed on heat-killed E. Coli with the addition of 2, 10, or 20 mM DL-beta-hydroxybutyrate (betaHB), their lifespan was increased by 26% from 17.2 to 21.7 days, with 20 mM of the ketone having the greatest effect. When fed at concentrations of 50 mM or 100 mM, the organisms had reduced lifespans.

KETONES DERIVED FROM SUPPLEMENTARY MEDIUM CHAIN TRIGLYCERIDES: POSSIBLE TREATMENT OF NEURODEGENERATIVE DISORDERS

There is also evidence for the clinical use of ketone bodies (obtained by ingesting MCTs) to treat neurodegenerative disorders. In one study (Edwards, 2014), MCTs were catabolized to ketone bodies, increased plasma levels of betaHB (beta-hydroxybutyrate) and improved cognitive function in human patients with AD (Alzheimer’s disease).”

How to Benefit from a Ketogenic Diet
Without Limiting Your Carbohydrates

THE C-8 SOLUTION

It is possible to enter a state of mild ketosis, attain a level of ketones adequate to give the beneficial effects of a ketogenic diet, without having to dramatically cut one’s carbohydrate intake, if adequate quantities of the C8:0 medium chain triglyceride (1,2,3-propanetriol trioctanoate), are ingested. C8:0 MCT is a common food ingredient made from glycerin and one of the fatty acids from coconut oil. (Henderson, 2009)

In a 90 day study of Alzheimer’s patients with mild to moderate symptomology (Henderson, 2009), those who did not have an apoE4 allele who took C8:0 MCT described in the previous paragraph (which the authors called AC-1202) had a significantly improved cognition score compared to placebo. There was no difference detected for those who had that allele. However, see next paragraph.

A recent case history of a single patient who had an apoE4 allele developed severe Alzheimer’s disease (he had difficulty finding his way around his own house, for example).The patient was treated with beta-hydroxybutyrate, which resulted in significantly improved cognitive abilities (Newport, 2015). The author suggested that a previous study (Henderson, 2009) that found no improvement in cognition in patients with mild to moderate cognitive dysfunction who also had an apoE4 allele, might have been because of a lack of statistical power to detect changes in those with the allele, or that improvement might have been seen if the patients were studied for a longer period of time and/or a higher dose of ketone treatment had been used.

“In patients with Alzheimer’s disease, administration of medium-chain triglycerides [MCT] improved memory, and the degree of improvement correlated with blood levels of BETA-HYDROXYBUTYRATE. (emphasis added).

Further, direct application of beta-hydroxybutyrate protected cultured hippocampal neurons against Abeta [amyloid beta] toxicity. Finally, exogenous administration of either beta-hydroxybutyrate or acetoacetate reduced neuronal loss and improved neuronal function in animal models of hypoxia, hypoglycemia, and focal ischemia.” (emphasis added) (Maalouf, 2009)

In 2015, Morrone noted that “[t]he ketogenic diet aims to create a state of fasting within the body. This reduces metabolic induced stresses, including damage from reactive oxidative species and pathogenic mitochondrial biogenesis. Ketogenic diets may also decrease the production of advanced glycation end products, which accumulate on Abeta [amyloid beta] plaques, potentially assisting in one of the aforementioned clearance cascades by decreasing reuptake of Abeta by RAGE [the advanced glycation end product receptor].”

COMING UP: In the second part of this report on MEDIUM CHAIN TRIGLYCERIDES and KETONES (scheduled for the next newsletter), we tell you more about how the brain can benefit from MCTs and/or ketones, about a diversity of diseases and conditions that can be ameliorated with a ketogenic diet or ketone supplements or C-8 MCTs (from which C-8 ketones are derived), nutrients that may enhance the effect of ketone supplementation, and much more.

References

  • Balietti et al. Ketogenic diets: an historical antiepileptic therapy with promising potentialities for the aging brain. Ageing Res Rev. 9:273-9 (2010).
  • Binnert et al. Influence of human obesity on the metabolic fate of dietary long- and medium-chain triacylglycerols. Am J Clin Nutr. 67:595-601 (1998).
  • Cota et al. Hypothalamic mTOR signaling regulates food intake. Science. 312:92 (2004).
  • Dashti et al. Long-term effects of a ketogenic diet in obese patients. Exp Clin Cardiol. 9(3):200-5 (2004).
  • Edwards et al. D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging. 6(8):621-43 (2014).
  • Findlay et al. BACE1 activity impairs neuronal glucose oxidation: rescue by beta-hydroxybutyrate and lipoic acid. Front Cell Neurosci. 9: 382 (2015).
  • Guo et al. Early shifts of brain metabolism by caloric restriction preserve white matter integrity and long-term memory in aging mice. Front Cell Neurosci. 7(213) (2015).
  • Henderson et al. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond). 6: 31. (2009).
  • Henderson and Poirier. Pharmacogenetic analysis of the effects of polymorphisms in APOE, IDE and IL1B on a ketone body based therapeutic on cognition in mind to moderate Alzheimer’s disease; a randomized, double-blind, placebo-controlled study. BMC Med Genet. 12:137 (2011).
  • Kashiwaya et al. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease. Neurobiol Aging. 34(6):1530-39 (2013).
  • Kashiwaya et al. D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci U S A. 97(10):5440-4 (2000).
  • Kashiwaya et al, Control of glucose utilization in working perfused rat heart. J Biol Chem. 269:25502-14 (1994).
  • Kimura et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A. 108(19):8030-35 (2011).
  • Klosinski et al. White matter lipids as a ketogenic fuel supply in aging female brain: implications for Alzheimer’s disease. EBioMedicine. 2:1888-904 (2015).
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  • Maalouf et al. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience. 145:256-64 (2007).
  • Maalouf et al. The neuroprotective properties of caloric restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 59(2):293-315 (2009).
  • Morris et al. Age related memory impairments due to reduced blood glucose responses to epinephrine [adrenaline]. Neurobiol Aging. 31:2136-2145 (2010).
  • Morrone et al. Interaction between therapeutic interventions for Alzheimer’s disease and physiological Abeta clearance mechanisms. Front Cell Neurosci. 7 (64) (2015).
  • Newport et al. A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer’s. Alzheimer’s Dement. 11(1):99-103 (2015).
  • Pan et al. Dietary supplementation with medium-chain TAG [MCT] has long-lasting cognition-enhancing effects in aged dogs. Br J Nutr. 103:1746-54 (2010).
  • Paoli et al. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 67:789-96 (2013).
  • Ravera and Panfoli. Role of myelin sheath energy metabolism in neurodegenerative diseases. Neural Regen Res. 10(10):1570-1571 (2015)
  • Reger et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. 25:311-4 (2004).
  • Rho and Sankar. The ketogenic diet in a pill: is this possible?” Epilepsia. 49(Suppl. 8):127-33 (2008).
  • Samuel et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain-fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A. 105(43):16767-72 (2008).
  • Sengupta et al. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature. 468:1100- (2010).
  • Taggart et al. (d)-beta-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem. 280:26649-52 (2005).
  • Tieu et al. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest. 112(6):892-901 (2003).
  • Tunaru et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its antilipolytic effect. Nat Med. 9(3):352-5 (2003).
  • Veech. Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat. Ann N Y Acad Sci. 1302(1) (Nov. 8, 2013).


© Durk Pearson & Sandy Shaw

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