Open Future HealthProfessor Kieran Clarke - Physiological Biochemistry

Main web page for: Professor Kieran Clarke, Department of Physiology, Anatomy & Genetics, University of Oxford

Main web page: https://www.merton.ox.ac.uk/people/professor-kieran-clarke

Professor Kieran Clarke

Kieran Clarke, Oxford University professor of physiology and biochemistry.

Time Line

Prof. Clarke writes:

Kieran ClarkeMy own research is focussed on the effect on physical performance and cognitive function of mild ketosis. During periods of stress, elevated catecholamines, steroids and cytokines increase the metabolism of stored fat in the body. The increase in circulating free fatty acids causes insulin resistance, decreases skeletal and cardiac muscular efficiency and may decrease metabolic fuel for the brain, which cannot metabolize fat, but can metabolize ketones.

Ketone bodies contain more recoverable metabolic energy than fatty acids and yield 28% more energy on combustion than glucose. We are testing whether the negative effects of elevated free fatty acids can be overcome by mild ketosis using a diet containing ketone bodies.

Through this work, Kieran has collaborated over many years, since 1993, with Dr. Richard Veech at the NIH in the USA. On both sides of the Atlantic, efforts to commercialise the technology of which produces non-racemic ketone esters, is being developed. Testing by elite athletes is well underway. Dr Clarke's spin-off company, TΔS is here.

We are also testing the metabolic mechanism underlying the effects of the ketone body diet on exercise, endurance and cognitive function. We tested in rats using treadmill exercise and a maze test. Each of these characteristics were increased by the ketosis. We have further tested the ketone diet during endurance exercise, in a blinded placebo-controlled cross-over studies of rowing and cycling in elite athletes. Exercise, cognitive function and skeletal and cardiac muscle energetics were followed using non-invasive MRI of brain and muscle during exercise.

The ketogenic diet can also be used to treat metabolic diseases, such as obesity, Alzheimer’s and Parkinson’s diseases. Such studies have started recently.

More recently, basic science from our department has helped to change therapy for patients with neonatal diabetes and to improve the performance of endurance athletes. Today, our studies remain directed at understanding basic physiological mechanisms, how these are impaired in disease, with the ultimate goal of creating new therapeutic approaches to disease.

Researchers
Students and staff of the Cardiac Metabolism Research Group, Oxford University, 2016

A Very Important Research Paper:

Acute nutritional ketosis: implications for exercise performance and metabolism. Ketone bodies acetoacetate (AcAc) and D-ß-hydroxybutyrate (ßHB) may provide an alternative carbon source to fuel exercise when delivered acutely in nutritional form.

A few more Research Papers: (All but one include Dr Veech as a co-author.)

A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Alzheimer's disease (AD) involves progressive accumulation of amyloid ß-peptide (Aß) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory.   Ketone-ester-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the same regions of the hippocampus, amygdala, and cortex. Thus, a ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model. © 2013

Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin. High-fat feeding in combination with a low dose of STZ induced cardiac metabolic changes that mirror the decrease in glucose metabolism and increase in fat metabolism in diabetic patients, demonstrating that the severity of diabetes can be modified.

Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. 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. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease.

Novel ketone diet enhances physical and cognitive performance. 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 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.


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