Dr Richard L Veech

Ketones

Ketones were discovered in Germany in the 1880's. They were used in medicine extensively in the 1920's to treat both epilepsy and diabetes. Medical doctors, not having an education in biochemistry, have always been afraid of ketones because of the problem of ketoacidosis that occurs when diabetes is out of control.

Ketones are part of our normal metabolism when we are starving. That's why they exist. If there is little food, so long as you have water you can live for at least 76 days, for much of that time with increased mental ability and physical energy. If you had to rely on glucose for energy you would be dead in six days.

In conditions of low blood insulin (Yalow and Berson) the liver produces ketones. A precondition for low blood insulin is low blood glucose, normally achieved by starvation, fasting, or by eating a very-low-carbohydrate diet. Ketones are small molecules, water soluble acids that pass easily through the blood brain barrier, and also into cells and into the mitochondria within cells.

There are three kinds of ketones:
Acetone - which is very small - you can ignore it as an energy source. Acetone, is formed by spontaneous decarboxylation of Acetoacetate (AcAc) and is found on the breath. This is the ketone measured by the Ketonix Breath Analyzer.
Beta-hydroxybutyrate (ß–OHB) - Is a powerful source of energy. When you are in ketosis this is the key energy source. D-3-beta-hydroxybutyrate - Is synthesized in the liver in approximately 1:1 ratio to (AcAc).
Acetoacetate (AcAc) - Is also metabolized, but it's not as powerful as BHP. You can buy Acetoacetate as an ester but Dr Veech doesn't recommend that you do.

BHP in the Mitochondria

When Beta-hydroxybutyrate is the fuel, in the mitochondria the NAD couple gets reduced. The next step up Q is then oxidized. That increases the redox span between NADH and Q. That span determines the energy potential of ATP.

This is why the heart gets 28% more energy metabolizing beta-hydroxybutyrate than it does metabolizing glucose. Measuring that energy gain was one of my early tasks in Hans Krebs laboratory. There's just the pressure generated by the heart and the volume of blood moved, measured in Joules.

Ketones

The problem is to get energy into the cell. Ketones are acids. When fasting your body will make 150gm of ß–OHB every day. There are many reasons why we want to create a product we can give people that will produce that effect. The market for that product would be huge and the health benefits immense. The problem is that it can't be a salt, because that would require giving people far more salt than they could tolerate. We can't give it to them as alcohol, because they would then become intoxicated. So the alternative is to develop an ester. In our laboratory we've developed an ester of 1, 3-butane diol which is a pre-cursor to D-3-beta-hydroxybutyrate. Our problem now it to create the ability to produce thousands of tonne's of this substrate cheaply, probably from corn as a source of carbon bonds.

Small quantities are currently being made in laboratories both at Harvard and Oxford Universities, and being tested on top class athletes and some military personnel. However they are not the target market. When this product is approved for general distribution I want to see priority given to people who need the product, those with Alzheimer's and Parkinson's disease. It should be given to people who suffer traumatic brain injuries and anyone who's been exposed to nuclear radiation.

One day there will be a nuclear terrorist event. All the emergency people who go into that area, firemen, police, medical staff, or the military deserve protection from the radiation, and good levels of beta-hydroxybutyrate will achieve that. Every city needs to have an emergency supply, for that purpose.

Mitochondria

There are mitochondria in every cell, but the cells of the heart and the brain are the most energy hungry and have more mitochondria. Mitochondria are a redox engine, or a fuel cell if you like. NAD is reduced by combing with water, to yield energy.

Delta G and TΔS®

Delta G is the Gibbs free energy change for a reaction within the mitochondria. Normally Delta G = Zero. Usually written as ΔG = Zero. ΔG is measured in Joules, or electrical energy across a membrane. If ΔG is positive the reaction is absorbing energy. If ΔG is negative the reaction is releasing energy.

ATP is the energy power of the cell. A common reaction that produces a lot of energy is the hydrolysis of ATP. ATP combines with water and produces ADP + P which has a strong negative value. (It releases energy.)

New directions in nutraceuticals TΔS® is a fast-growing, ambitious biotech company in the exciting field of nutraceuticals.

Established in 2005 and headquartered in the UK, the company is committed to generate sustained, multiple revenue streams from a family of sports and performance drinks for high-performance, endurance sports.

TΔS® is the front-runner in an entirely new strand of nutritional science. Its commercial activities build on the pioneering work of Professor Kieran Clarke at the University of Oxford and Dr. Richard Veech at the National Institutes of Health, Washington.

Through this work, Richard has collaborated over many years, since 1993, with Prof. Kieran Clarke at the Oxford University in the UK.

Cheap Alternatives to TΔS®

At the moment people can adopt a very-low-carbohydrate diet, they can drink bullet-proof coffee, they can take C8 MCT oil, and achieve protective ketosis. That might mean beta-hydroxybutyrate at a level of 0.5 mmol/l to 3 mmol/l, seldom higher, and it takes about a week to achieve that. With TΔS®, you can be at higher levels than that in minutes.

There are some alternative efforts to make ketones available to people as a salt or ester. Beta-hydroxybutyrate is produced as D-beta-hydroxybutyrate by the body. When we try to manufacture it synthetically we produce two forms, some D-beta-hydroxybutyrate but an equal amount L-beta-hydroxybutyrate. This is critical; beta-hydroxybutyrate has both a left-handed and a right-handed form, it's racemic. In the body the D-beta-hydroxybutyrate is the one we need. The L-beta-hydroxybutyrate is ineffective. A product that mixes left-handed and right-handed forms is much cheaper to produce, but isn't what the body needs.

Some Recent Scientific Papers - R. L. Veech

Novel ketone diet enhances physical and cognitive performance (2016) 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.

Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. (2016) In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise.

An Ester of ß-Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans. (2015) Elevated plasma ßHB which correlated with decreased mevalonate, a liver cholesterol synthesis biomarker. Partial replacement of dietary carbohydrate with KE induced ketosis and altered cholesterol homeostasis in rats.

The Population Pharmacokinetics of D-ß-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate. Healthy volunteers (n?=?37) were given a single drink of the ketone monoester, following which, 833 blood BHB concentrations were measured. Further work is needed to quantify mechanisms of absorption and elimination of ketones for therapeutic use in the form of ketone monoester.

A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. (2013) Alzheimer's disease (AD) involves progressive accumulation of amyloid ß-peptide (Aß) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory. The 3xTgAD mouse model was used to test the hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis.

The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury. (2013) The pathological consequences of traumatic head injury result largely from the opening of the mitochondrial permeability transition pore, mPTP. The mPTP opens due to a decrease in brain phosphorylation energy resulting in a further decrease in brain ATP production and a measurable increase in brain heat generation and temperature. The increase in brain temperature can be measured transcranially by near infrared spectroscopy which can be used to diagnoses TBI and to monitor treatment. Effective therapy of TBI can be achieved by closure of the mPTP by administration of cyclosporine A or by oral administration of ketone body esters.

Ketoacids? Good medicine? (2004)
George F. Cahill, Jr and Richard L. Veech
D-beta-hydroxybutyrate, the principal "ketone" body in starving man, displaces glucose as the predominating fuel for brain, decreasing the need for glucose synthesis in liver (and kidney) and accordingly spares its precursor, muscle-derived amino acids. Thus normal 70 kg. man survives 2-3 months of starvation instead of several weeks, and obese man many months to over a year. Without this metabolic adaptation, H. sapiens could not have evolved such a large brain. Recent studies have shown that D-beta-hydroxybutyrate, the principal "ketone", is not just a fuel, but a "superfuel" more efficiently producing ATP energy than glucose or fatty acid.

The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. (2003)
Richard L. Veech
The effects of ketone body metabolism suggests that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. These inferences follow directly from the metabolic effects of ketosis and the higher inherent energy present in d-beta-hydroxybutyrate relative to pyruvate, the normal mitochondrial fuel produced by glycolysis leading to an increase in the DeltaG' of ATP hydrolysis. The large categories of disease for which ketones may have therapeutic effects are:(1)diseases of substrate insufficiency or insulin resistance,(2)diseases resulting from free radical damage,(3)disease resulting from hypoxia.

The energetics of ion distribution: the origin of the resting electric potential of cells. (2002) We conclude that the energy of ATP was expressed in Na+/K+ ATPase and its linked inorganic ion transporters to create a Gibbs-Donnan near-equilibrium system, an inherent part of which was the electric potential.

D-beta-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. (2000) Our previous work in heart showed that ketone bodies, normal metabolites, can correct defects in mitochondrial energy generation. The ability of ketone bodies to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases. These findings further suggest that ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.

The ß/a peak height ratio of ATP. A measure of free [Mg2+] using 31P NMR (1996) This is about the energy released in the mitochondria. I don't understand the mathematical nature of the abstract.