Dominic D'Agostino, Ph.D. on Modified Atkins Diet, Ketosis, Supplemental Ketones and More
Posted on April 10th 2016 (about 2 years)
This podcast is with Dr. Dominic D'Agostino, an assistant professor at the University of South Florida in Tampa and all around expert on ketosis.
In this episode we discuss...
- Dom's efforts at teasing out the differences between induced nutritional ketosis (through a low carbohydrate, high fat diet) and ketosis from the dietary introduction of exogenous ketones, like beta-hydroxybutyrate, especially in the context of therapeutic and performance enhancing effects.
- His work on formulating ketone esters.
- The differences in tolerability between MCT (medium chain triglycerides) powders versus liquids, as well as the amount of supplemental MCT a person would need to consume to achieve mild ketosis without carbohydrate restriction.
- The differences between different types of ketogenic diets.
- The modified atkins diet which has been demonstrated to have similar efficacy to the classical ketogenic diet in the treatment of drug-resistant epilepsy and how it may be a slightly more practical option for achieving therapeutic nutritional ketosis.
- The importance of making the correct carbohydrate choices, even and maybe especially in the context of a ketogenic diet, with a diverse variety of raw vegetables being the most favorable.
- What keto-adaptation is and what it means, at a physiological level, to be keto-adapted and how this is distinguished from short periods of ketosis we experience in our day-to-day lives.
- Some of Dom's ideas around cycling various dietary strategies as a way of promoting metabolic flexibility.
- How ketones, when used as a source of energy, may result in a net reduction in the number of damaging reactive byproducts known as reactive oxygen species than what may be produced by other forms of energy metabolism while also producing more ATP from, proportionately, the same amount of oxygen.
... and much more!
- Tim Ferriss on Ketosis, Microbiome, Lyme Disease, and Biomarkers
- Peter Attia, M.D. on Macronutrient Thresholds for Longevity and Performance, Cancer and More
Learn more about Dr. Dominic D'Agostino
A purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule. Plays a role in regulating blood flow to various organs as a vasodilator, and, in its role as a neuromodulator, adenosine is believed to promote sleep and suppress arousal. Adenosine is also involved in energy transfer as ATP and ADP, and signal transduction when in the form of cAMP.
Adenosine Triphosphate (ATP)
ATP is used in cells as a coenzyme often called the "molecular unit of currency" of intracellular energy transfer. It is one of the end products of photophosphorylation, cellular respiration, and fermentation and used by enzymes and structural proteins in many cellular processes, including biosynthetic reactions, motility, and cell division.
An enzyme that plays a role in cellular energy homeostasis. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, and modulation of insulin secretion by pancreatic beta-cells.
Amyotrophic Lateral Sclerosis (ALS)
A progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord.
Apolipoprotein B (ApoB)
The primary apolipoprotein of chylomicrons, VLDL, IDL, and LDL particle, which is responsible for carrying fat molecules (lipids), including cholesterol, around the body to all cells within all tissues. High levels of ApoB, especially associated with higher LDL particle concentrations, are the primary driver of plaques that cause vascular disease.
Apolipoprotein E (ApoE)
A lipoprotein produced in the liver and the brain. In the brain, ApoE transports fatty acids and cholesterol to neurons. In the bloodstream, it binds and transports cholesterol, bringing it to tissues, and recycling it back to the liver. Approximately 25% of the population have at least one copy of the ApoE4 variant, which is associated with higher circulating levels of LDL cholesterol and a 2 to 3 fold increased risk for Alzheimer's disease.
Cellular program that causes a cell to kill itself after damage has occurred. This is one of the ways that multicellular organisms protect themselves from cancer.
Star-shaped supporting cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells that form the blood–brain barrier, provides nutrients to neurons, maintenance of extracellular ion balance, and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries.
The tendency for something to promote the formation of fatty plaques in the arteries.
An intracellular degradation system that involves the self-destruction of a cell by degrading its cellular components. This process is used to generate energy and is one reason why fasting increases cellular autophagy to provide energy for surviving cells. Damaged cells are often cleared away via autophagy, and this mechanism is thought to help protect against cancer and even aging by reducing the burden of abnormal cells. **However, the relationship between autophagy and cancer is complex**: autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing it a useful means to scavenge resources needed for further growth.
A ketone body that is synthesized in the liver from acetyl-CoA when fasting or in ketosis. It can be used to produce energy inside the mitochondria and has also been shown to act as a signaling molecule that alters gene expression by inhibiting class 1 histone deacetylases.
A highly selective permeability barrier made up of brain endothelial cells which are connected by tight junctions and separate the circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS). It allows the passage of water, some gases, and lipid-soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function, but prevents the entry of lipophilic, potential neurotoxins by way of an active transport mechanism.
Branched-Chain Amino Acids (BCAAs)
An amino acid having aliphatic side-chains with a branch (a central carbon atom bound to three or more carbon atoms). Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine and valine.
Restricting caloric intake by 30% has been shown to extend lifespan in some animals.
The process by which cancer is initiated and normal cells are transformed into abnormal cells. In order for a normal cell to transform into a cancer cell, genes that regulate cell growth and differentiation must be altered. DNA damage is a well-known initiator of cancer because it can lead to cancer-causing mutations.
The set of metabolic pathways that breaks down molecules (such as polysaccharides, lipids, nucleic acids and proteins) into smaller units that are either oxidized to release energy or used in other anabolic reactions.
A broad and loose category of small proteins (~5-20 kDa) that are important in cell signaling. They are released by cells and affect the behavior of other cells. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, and mast cells as well as endothelial cells, fibroblasts, and various stromal cells.
A secondary bile acid that is produced in order to aid in the digestion of fats and oils. It causes DNA damage and can cause tumorigenesis, particularly in the colon.
A drug that inhibits the enzyme pyruvate dehydrogenase kinase, thus increasing oxidative phosphorylation. Preliminary studies have shown DCA can slow the growth of certain tumors in animal and in vitro studies.
Presence in the blood of endotoxin, which, if derived from gram-negative rod-shaped bacteria may cause shock.
The study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself.
The most common movement disorder involving a tremor of the arms, hangs or fingers particularly during voluntary movement such as eating or writing.
A gene for which increases in activity have been associated with longevity. FOXO3 is a master regulator of many genes involved in dealing with stress, including DNA repair genes, protein misfolding genes, antioxidant genes, anti-inflammatory genes, etc. Humans with a more active version of this gene have a 2.7-fold increased chance of living to be a centenarian.
y-aminobutyric acid. An amino acid that is the major inhibitory neurotransmitter in gray matter.
Refers to how active a gene is. Genes that are highly expressed are active and producing protein and genes that are not expressed are not active.
The "hunger hormone", also known as lenomorelin, a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract, which then acts on hypothalamic brain cells both to increase hunger, and to increase gastric acid secretion and gastrointestinal motility to prepare the body for food intake. Studies have shown that fasting plasma ghrelin levels are negatively correlated with insulin resistance.
Imatinib, marketed under the name "Gleevec," is an inhibitor of tyrosine-kinases and is successfully used in the treatment of multiple leukemias including Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
Glioblastoma Multiforme (GBM)
A fast-growing, aggressive cancer that develops from star-shaped glial cells (astrocytes and oligodendrocytes) within the brain.
A metabolic pathway in which the liver produces glucose from non-carbohydrate substrates including glycogenic amino acids (from protein) and glycerol (from lipids).
When glucose is relieved of its ordinary role in the production of energy, it can, instead be utilized in the pentose-phosphate pathway to produce NADPH. NADPH is a reducing equivalent that is used to produce glutathione, one of the major antioxidants used in the body and brain, as well as fatty acids.
Facilitates the transport of glucose across the cell membrane of skeletal muscles and adipose tissue cells, thereby removing glucose from the bloodstream.
An amino acid found in high concentration in every part of the body. In the nervous system, glutamate is by a wide margin the most abundant neurotransmitter in humans. It is used by every major excitatory information-transmitting pathway in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain.
Glutamic Acid Decarboxylase
An enzyme that catalyzes the decarboxylation of glutamate into GABA, using vitamin B6 as a cofactor.
One of the most abundant non-essential amino acids in the human body. It plays a role in wound healing including at the level of the gut. It can be used as a nitrogen source to build proteins, and a carbon source for macromolecular synthesis, and as a substrate for the citric acid cycle.
A compound produced inside the cell that functions as an antioxidant and helps prevent damage from oxidative stress caused by the production of reactive oxygen species.
A sugar-alcohol compound that is the backbone of the triglycerides.
The metabolic pathway that converts glucose into pyruvate by enzymes, releasing energy. The free energy released in this process is used to form ATP and NADH. This pathway is differentiated from oxidative phosphorylation in its ability to function in the absence of oxygen and without the need for mitochondria.
The term for generally-favorable biological responses to low exposures to toxins or other stressors such as exercise, heat stress, fasting, and **xenohormetics**, which are molecules, including plant polyphenols, which are produced in response to stress experienced by plants and some evidence suggests may have longevity-conferring effects. Compounds like polyphenols themselves similarly are beneficial, in part, because they trigger mild cellular stress that induces beneficial stress response pathways.
In a hyperbaric oxygen therapy chamber, the air pressure is increased to three times higher than normal air pressure. Under these conditions, your lungs can gather more oxygen than would be possible breathing 100% oxygen and normal air pressure.
Condition in which the body or a region of the body is deprived of adequate oxygen supply. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.
Part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, blood vessels, and molecular mediators. Chronic inflammation is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
Insulin-like growth factor 1 (IGF-1)
One of the most potent natural activators of the AKT signaling pathway, stimulator of cell growth and proliferation, potent inhibitor of programmed cell death, primary mediator of the effects of growth hormone, and has been implicated in contributing to aging and enhancing the growth of cancer after it has been initiated. Similar in molecular structure to insulin, IGF-1 plays a role during childhood for growth and continues later in life to have anabolic, as well as neurotrophic effects. Protein intake increases IGF-1 levels in humans, independent of total caloric consumption.
A period of fasting between meals that can last several hours to days that increases the production of ketones due to the use of stored fat as an energy source. Intermittent fasting also activates some of the same genetic pathways as caloric restriction.
Experiments that are performed using cells or microorganisms outside of their normal biological context and are often done in a test tube or petri dish.
A restriction in blood flow to tissues which causes a shortage of oxygen and glucose needed to keep tissue alive. Ischemia usually occurs when blood vessels become clogged and dysfunctional.
The end results of a physiological process in which your body has biochemically, physiologically, and metabolically shifted from using primarily glucose to using glucose and equal, or in some cases more, fatty acids and ketones for fuel. Being adapted represents an increase in production, utilization and metabolism, general oxidative capacity of cells, as well as actual ability to transport ketones.
Molecules that are produced by the liver from fatty acids during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. Examples include acetoacetate, beta-hydroxybutyrate, and acetone. These ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
Production from glucose via an oxygen independent metabolic pathway called glycolysis in red blood cells, white blood cells and muscle cells during anaerobic exercise. Lactate is then able to be "shuttled" to other tissues including muscle, heart, and brain where it is used as an energetically favorable substrate for oxygen-dependent energy production.
Lactate Shuttle Theory
Lactate that is produced from an oxygen independent metabolic pathway (glycolysis) is shuttled to other tissues including muscle, heart, and brain where it is used as energetically favorable substrate for oxygen-dependent energy production.
A medical condition characterized by the buildup of lactate in the body and can occur as the result of an underlying acute or chronic medical condition, medication or poisoning.
A medium chain fatty acid that is composed of 12 hydrocarbons that has very potent antiviral activity, particularly against viruses that contain a viral envelope. It also has antibacterial activity and it plays a role in appetite suppression. Coconut oil is a good source of lauric acid.
LDL particle number is thought to be a better predictor of heart attack risk than total LDL cholesterol. Apolipoprotein B (ApoB) is used as a marker for LDL (p) since there is one ApoB molecule per LDL particle.
A hormone produced mainly by adipocytes (fat cells) that decreases your appetite and is involved in the regulation of body fat. Leptin interacts with areas of the brain that control hunger and behavior and signals that the body has had enough to eat. Leptin levels vary exponentially, not linearly, with fat mass.
Large molecules consisting of a lipid and a polysaccharide with an O-antigen outer core. These molecules are found in the outer membrane of Gram-negative bacteria, and elicit strong immune responses in animals. Also known as bacterial endotoxin.
A class of chemical compounds which humans consume in the largest quantities and provide them with the bulk of energy. Examples include carbohydrates, protein, and fat.
Mechanistic Target of Rapamycin (mTOR)
A genetic pathway that senses amino acid concentrations and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, transcription and integrates other pathways including insulin, growth factors (such as IGF-1) and amino acids. mTOR plays a key role in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. **Rapamycin**, the drug for which this pathway is named (and the anti-aging properties of which are subject to much study), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
Medium Chain Triglycerides (MCTs)
A type of triglyceride containing between 6-12 carbon atoms that is metabolized differently than triglycerides containing more than 12 carbons. Examples of MCTs include: caprylic acid (C8), capric acid (C10), and lauric acid (C12).
Cancer that has spread from the part of the body where it started to other parts of the body. When cancer cells break away from a tumor, they can travel to other areas of the body through the bloodstream or the lymph system.
A drug commonly used for the treatment of type 2 diabetes that works by decreasing gluconeogenesis in the liver, reducing the amount of sugar absorbed in the gut, and increasing insulin sensitivity. Some animal research has been published indicating that metformin may lengthen lifespan.
The trillions of microorganisms that live on or in the body. Microbiomes exist all throughout the body including skin, mouth, intestines, gut, and hair. There is some evidence that certain population level gut signatures may have a strong correlative and even causative relationship with health status, including obesity.
Tiny organelles inside of cells that produce energy in the presence of oxygen. Often referred to as the "powerhouse of the cell" because of its role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as **mitophagy** in order to repair damage that occurs as a side effect of their energy generating activities.
The process by which new mitochondria are made inside of cells. Many factors can activate biogenesis including exercise, cold shock, heat shock, fasting, and ketones. PGC-1 is the transcription factor serving as the master regulator of this process.
The process by which damaged mitochondria are repaired by "fusing" together with normal mitochondria to exchange DNA and proteins and then once again "fissing" apart to give rise to two normal mitochondria.
Modified Atkins Diet
A change to the traditional "classic" ketogenic diet to make it less restrictive. One of the biggest differences is it doesn't have the same stringent restrictions on protein intake. It has been used to successfully treat drug-resistant epilepsy in adults.
An antioxidant that sequesters ROS, is used to make glutathione, and has been shown to break up pulmonary and bronchial mucus.
A protein that, in mammals, regulates the expression of hundreds of other antioxidant and stress response proteins that protect against oxidative damage triggered by injury and inflammation. One of the most well-known naturally-occurring inducers of Nrf2 is a compound known as sulforaphane.
A gene that has the potential to cause cancer. A proto-oncogene is a normal gene that regulates cell growth and proliferation but if it acquires a mutation that keeps it active all the time it can become an oncogene that allows cancer cells to survive when they otherwise would have died.
A type of movement disorder that causes fast low limb tremors resulting in unsteadiness while standing.
The process of generating energy that occurs when mitochondria couple oxygen with electrons that have been derived from different food sources including glucose, fatty acids, and amino acids.
A result of oxidative metabolism, which causes damage to DNA, lipids, proteins, mitochondria, and the cell. Mitochondria cause oxidative stress through the process of oxidative phosphorylation (the generation of energy), and it can also result from the generation of hypochlorite during immune activation.
Pentose Phosphate Pathway
A biochemical pathway that functions as a parallel to glycolysis, but, importantly, generates NADPH, which is necessary to create the cellular antioxidant glutathione.
Polyunsaturated Fats (PUFAs)
Include omega-3 and omega-6 fatty acids. Found in fish, nuts, and seeds. These fats are more prone to oxidation than other fatty acids. Additionally, PUFAs activate a master gene called PPAR which is involved in lipid metabolism.
Positron Emission Tomography (PET) Scan
A type of imaging test that uses a radioactive substance (tracer) to look for disease in the body. For cancer detection/metastasis the tracer used is fluorodeoxyglucose, an analogue of glucose. The concentrations of tracer imaged indicate tissue metabolic activity as it corresponds to regional glucose uptake.
PPAR-alpha (Peroxisome proliferator-activated receptor alpha)
One of the three isotypes of a subfamily of nuclear receptor proteins (the PPARs) that **functions as a transcription factor**. PPAR-alpha is a major regulator of lipid metabolism in the liver and is activated under conditions of energy deprivation. It is necessary for the process of ketogenesis, a process that is a key adaptive response to prolonged fasting and is inducible by strict carbohydrate restriction. Activation of PPAR-alpha promotes uptake, utilization, and catabolism of fatty acids by upregulation of genes involved in fatty acid transport, fatty acid binding and activation, and peroxisomal and mitochondrial fatty acid β-oxidation. Expression of PPAR-alpha is highest in tissues that oxidize fatty acids at a rapid rate, especially the liver, but also brown adipose tissue (BAT), the heart, and kidney.
One of the enzymes involved in the process of converting pyruvate, which is derived from glucose, into energy in the form of ATP inside of the mitochondria.
Reactive Oxygen Species (ROS)
Chemically reactive molecules containing oxygen, which are generated by oxidative phosphorylation, as well as immune activation and can damage cells (including lipids, proteins, mitochondria and DNA). **Reactive Nitrogen Species** are another type of damaging byproduct that is produced naturally by the immune system. The two species are often referred to collectively as **ROS/RNS**. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen. RNS are produced in animals starting with the reaction of nitric oxide with superoxide to form peroxynitrite. Preventing and efficiently repairing damage from ROS (**oxidative stress**) and RNS (**nitrosative stress**) is one of the key challenges our cells face in their fight against diseases of aging, including cancer.
Cellular respiration is the process by which oxygen is utilized to generate energy inside of the mitochondria.
The body's overwhelming and life-threatening response to an infection which can lead to tissue damage, organ failure, and death.
Short-Chain Fatty Acids
Also referred to as volatile fatty acids (VFAs) and possess an aliphatic tail of less than six carbon atoms. Produced when dietary fiber is fermented in the colon, and primarily absorbed through the portal vein during lipid digestion. The SCFA butyrate is particularly important for colon health because it is the primary energy source for colonic cells and has anti-carcinogenic as well as anti-inflammatory properties.
A molecule that allows cells to perceive and correctly respond to their microenvironment, which enables normal cellular function, tissue repair, immunity, cognition, and more. Hormones and neurotransmitters are examples of signaling molecules. There are many types of signaling molecules, however, including thinkgs like: cAMP, nitric oxide, estrogen, norepinephrine, and even reactive oxygen species (ROS).
Single Nucleotide Gene Polymorphism (SNP)
A change in one nucleotide DNA sequence in a gene that may or may not alter the function of the gene. SNPs can affect phenotype such as hair and eye color, but they can also affect our disease risk, the way we absorb and metabolize micronutrients, macronutrients, and much more.
The Warburg effect
The observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.
Type II Diabetes
A long term metabolic disorder that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. COmmon symptoms include increased thirst, frequent urination, unexplained weight loss, increased hunger, feeling tired, and sores that do not heal. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations.
A fat-soluble compound that is present inside the inner-mitochondrial membrane of cells. It plays a role in aerobic cellular respiration which produces energy in the presence of oxygen. The heart, liver, and kidney have the highest CoQ10 concentrations.
A progressive worsening of memory and other cognitive functions that is thought to be due to chronic reduced blood flow to the brain which is commonly due to the accumulation of cholesterol and other substances in the blood vessel walls that obstruct the flow of blood to the brain.
Vascular Endothelial Growth Factor (VEGF)
Originally known as vascular permeability factor (VPF). VEGF's normal function is to create new blood vessels during embryonic development, after injury, in muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply, and cancers that can express VEGF are able to grow and metastasize.
Very-Low-Density LDL (VLDL)
Enables fats and cholesterol to move within the water-based solution of the bloodstream. VLDL is assembled in the liver from triglycerides, cholesterol, and apolipoproteins, and converted in the bloodstream to low-density lipoprotein (LDL), VLDL transports endogenous products, whereas chylomicrons transport exogenous (dietary) products.
The maximum rate of oxygen consumption as measured during incremental exercise and indicates the aerobic fitness of an individual, and plays a role in endurance capacity during prolonged, submaximal exercise.
Sometimes called the protein immunoblot. Used to detect specific proteins in a sample of tissue homogenate or extract. It uses gel electrophoresis to separate native proteins by 3-D structure or denatured proteins by the length of the polypeptide. The proteins are then transferred to a membrane (typically nitrocellulose or PVDF), where they are stained with antibodies specific to the target protein.
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