God Fathers of Ketones
Richard Veech M.D. Ph.D.
Dr. Richard Veech is the premier researcher in metabolism and an associate of Dr. Hans Krebs of the Krebs Cycle and oxidative phosphorylation. His focus has been on Alzheimer’s disease and other neurological diseases and has pioneered the work and development of D Beta Hydroxybutyrate ketones. As we understand that Alzheimer’s disease may be a form of Diabetes Type 3, lacking the ability to utilize sugar metabolism, the ketone is an alternative fuel to nourish brain cells, heart cells, skeletal muscle and may have implications on longevity itself. His article has won the Best Research in 2016 in Cell, and the implications of this ketone derived from fatty acids may have huge implication not only in disease states of the brain but also cancer and all other chronic diseases. There has been research that suggests that the use of Beta Hydroxybutyrate ketone will replicate the animal and clinical results of calorie restriction on longevity. This is a major breakthrough in medicine, and Dr. Veech is kind enough to share his life’s work with all of us for prevention and treatment of chronic diseases.
Professor Kieran Clarke.
Having gained her PhD in Biochemistry from the University of Queensland and subsequently spending four years working at Harvard University Medical School NMR Laboratory in Massachusetts. Spent over 20 years’ experience in cardiovascular magnetic resonance (MR) imaging and spectroscopy.
Currently head the Cardiac Metabolism Research Group (CMRG) within the Department. Ours is a large group, split into a number of smaller groups. Our research is directed towards understanding the metabolic control of gene expression in heart failure and in the diabetic heart, as well as the use of stem cells to treat the infarcted heart. In recent years, my own research has focused on the effects of diet on energy metabolism in heart, brain and skeletal muscle, and thereby on physical performance and cognitive function.
A generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span.
Dominic D' Agostino, PH.D.
Summary of Research Program
The laboratory develops and tests metabolic-based therapies, including calorie restricted diets, ketogenic diets, exogenous ketogenic agents and metabolic-based drugs that target specific pathways linked pathophysiologically with seizure disorders, neurodegenerative diseases, metabolic dysregulation, cancer, muscle wasting and exercise performance. Our past and current projects, supported by the Department of Defense (DoD) and Office of Naval Research (ONR), have identified cellular and molecular correlates of CNS oxygen toxicity (CNS-OT) seizures, a phenomenon which limits the capability of Special Operations (SpecOps) diving. Our efforts have focused specifically on measuring neuronal excitability, reactive oxygen species (ROS) production, biomarkers of oxidative stress and global blood and tissue metabolomics.
In 2009 we became interested in understanding the anticonvulsant and neuroprotective mechanism of nutritional ketosis and developed exogenous ketones that produce therapeutic levels of blood ketone. Therapies developed and tested include naturally-derived and synthetic agents that induce hyperketonemia independent of calorie restriction or carbohydrate restriction. The ketogenic diet is the standard of care for drug-resistant and refractory seizures resulting from a variety of etiologies. The brain’s ability to use exogenous ketone bodies for fuel has not been exploited therapeutically, and evidence suggests that therapeutic ketosis confers protection against seizures, hypoglycemia and neurodegenerative disorders by numerous mechanisms, including supporting brain energy metabolism. In addition to neurological disorders, metabolic-based therapies can target cancer metabolism, which derives energy primarily from glycolysis and substrate level phosphorylation. Due to mitochondrial defects, most cancer cells lack the metabolic flexibility to generate ATP from ketones. Our goal is to develop and test therapies that exploit the metabolic defects of cancer by targeting cancer-specific glycolytic metabolism (e.g. Warburg effect) and develop “press pulse” protocols enhance the efficacy existing cancer therapies. Independent of energy metabolism, our more recent work has shown that the ketone β-hydroxybutyrate is an inhibitor of NOD-like receptor family pyrin domain-containing protein (NLRP3) inflammasome, which suppresses inflammation. An emerging area of interest for me is developing metabolic-based therapies that improve health biomarkers linked to obesity, insulin resistance, type-2 diabetes, wound healing and exercise performance and resilience. Our in vitro and in vivostudies continue to validate the efficacy, mechanism of action and safety of metabolic therapies (diet supplements, drugs), including exogenous ketones, with pharmacokinetic and toxicology studies. Our data has produced remarkable results in animal models of seizures and cancer, and current efforts have focused on moving these metabolic-based therapies into human clinical trials.