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This episode is Part 2 of an interview with features Dr. Dominic D'Agostino. Click here to view part 1. Dr. D'Agostino is a world-class researcher on nutritional ketosis and specifically ketogenic diets. He also has the practical long-term use of ketogenic diets which sets him up as the authority on ketogenic diets and ketogenesis. This episode covers a lot of ground including practical tips on eating a ketogenic diet and differences between exogenous ketone supplements and their role in the ketosis world.
In this 2.5-hour episode you will learn:
(For more, check the Timeline tab.)
"A ketogenic diet is unique from a dietary therapy point of view, because it's the only diet defined by an objective biomarker." - Dr. Dominic DʼAgostino Click To Tweet
Fasting – an ancient strategy to treat seizures – induces ketogenesis, a metabolic pathway that drives the production of ketones. A ketogenic diet, which is high in fat, moderate in protein, and low in carbohydrates, mimics fasting by inducing metabolic switching – the capacity to shift from metabolizing glucose to metabolizing fatty acids. Ketogenic diets are now a widely accepted therapy for people with epilepsy or other seizure disorders. And a growing body of clinical evidence suggests that ketosis also improves other aspects of neurological health, including general cognitive performance, brain trauma, and neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.
Scientists don't fully understand all the mechanisms that drive the benefits of ketogenic diets, but some evidence suggests that they involve changing the brain's neuropharmacology – its chemistry – starting with a chemical called gamma aminobutyric acid, or GABA, for short. GABA has a calming effect on the brain, quieting overactive neurons and exerting anti-seizure and anti-anxiety effects. Studies in rodents have shown that ketones markedly increases GABA synthesis.
Other evidence suggests that shifting the availability of fuels in the brain from glucose to ketones alters gene-linked metabolic networks that drive seizures, which are metabolically demanding. Ketones provide benefits that extend beyond the brain, however. For example, beta-hydroxybutyrate, an endogenous ketone, may reduce inflammation, increase lifespan, and suppress tumor formation. Learn more about beta-hydroxybutyrate in our overview article.
Implementing a ketogenic diet at home is challenging, at best. Close monitoring of dietary intake, measuring of biomarkers, and a clear understanding of who might (and might not) benefit from the diet are crucial for success.
But it's also important to realize that ketogenic diets aren't "one-size-fits-all." Rather, they fall on a spectrum, ranging from a five-to-one ratio of fats to protein and carbs (typically used in clinical settings) to a more liberalized one-to-one ratio, a type of low glycemic index therapy (commonly referred to as "modified Atkins") that might meet the needs of most healthy people. Each of the diet's versions elicits ketosis, to varying degrees, but circulating levels of ketones probably don't tell the whole story – good reason to employ a graduated approach when starting the diet, whether in a clinical setting or at home.
Overall composition of the diet matters, too. For example, Dr. D'Agostino gets most of his carbohydrates from fiber-rich vegetables. Fiber slows the rate of gastric emptying and improves gut health. And eating these carbs near the end of his meal helps reduce glycemic variability and insulin response. He also includes polyunsaturated and monounsaturated fats – like those found in salmon and avocados – to reduce his risk of having abnormally high blood lipids.
Dr. D'Agostino explains the ins and outs of ketogenic diets, including his personal protocol and tips for success – even a recipe or two – based on his own experiences. He also describes strategies that may help people starting out on their first foray into ketogenic diets.
Want extra resources?
Check out my earlier interview with Dr. D'Agostino and be sure to read our overview article on beta-hydroxybutyrate, a type of ketone produced in the body during periods of nutrient scarcity.
Furthermore, ketogenesis is a perennial favorite topic of the FoundMyFitness podcast. Aspects have been covered in many episodes, including:
What is "keto"?
What is "keto" (and what it is not).
What the differences are between a lifestyle ketogenic diet and a therapeutic clinical ketogenic diet.
Types of ketogenic diets
What are the types of ketogenic diets, and how the differ and what they have in common.
The clinical process of designing a ketogenic diet to manage epilepsy.
Lifestyle Ketogenic Diet
How adherence to a ketogenic lifestyle diet can be improved by titrating carbohydrates down slowly.
Whether the ketogenic diet has side effects and how they can be circumvented.
The Dom D'Agostino diet and protocol for optimal ketosis.
How dietary fiber can be beneficial when following a ketogenic diet.
Rhonda describes her experience with the ketogenic diet.
How Dom makes a ketogenic salad.
Dom explains the learning curve for the ketogenic diet and provides strategies for success.
What are the widely accepted clinical applications of the ketogenic diet.
What the contraindications are to a ketogenic diet.
Biomarkers and hyperlipidemia
How to start a ketogenic diet, and which biomarkers to measure to assess suitability.
Whether a person's APOE4 status determines if they can adopt a ketogenic diet.
How a very high-fat diet is probably not ideal for APOE4 carriers, and what modifications they might make.
Micronutrients and supplementation
The importance of micronutrients while on a ketogenic diet.
How a poorly formulated ketogenic diet can lead to selenium deficiency and possible cardiomyopathy.1
Whether someone with an APOE4 allele can follow a ketogenic diet.
Exogenous Ketones
How animal studies show that exogenous ketones can mimic the neuroprotective effects of a ketogenic diet.
How preclinical data has inspired numerous clinical trials on ketone supplements.1
How ketone esters and salts differ in their effects on ketosis.
How taking a ketone supplement with food (carbohydrates) or medium-chain triglycerides can alter ketosis.1
How ketone salts taken along with medium-chain triglycerides (MCTs) can slow gastric emptying resulting in delayed and sustained hyperketonemia.
How a large dose of exogenous ketones, consumed on an empty stomach, might precipitate a rapid insulin release, which can shut down endogenous ketone production.
Dom describes how to design an endogenous ketone formulation.
Why glucose can drop into hypoglycemic ranges with high-dose ketones.
How a reduction in glycolysis and insulin suppression are thought to be important for the anti-seizure effects of the ketogenic diet.
How the glycolytic inhibitor 2-deoxy-d-glucose has anti-seizure effects, but is cardiotoxic at higher doses.1
How insulin stimulates glycolysis, which may be detrimental in the context of cancer and seizure incidence.
How exogenous ketones can be used to augment a ketogenic diet.
How ketones have a satiating effect on the brain.
How ketones can stave off hunger associated with a low-calorie diet, increasing the likelihood of adherence.
How ketone mono- and di-esters differ in their efficacy.
Optimal blood concentration of ketones (Dom's pick)
Dom's experience with consuming 1,3 butanediol elevating his liver enzymes.
Which supplements Dom thinks pair well with a ketogenic diet.
How on a ketogenic diet so much fat is being oxidized that their is a risk of developing a carnitine deficiency.
Whether Dom thinks it's beneficial to consume exogenous ketones daily.
What Dom thinks is an ideal ketone range for a lifestyle ketogenic diet.
Dom describes how he resolved his surprisingly low vitamin D status
How two of the major ketones — acetoacetate and beta-hydroxybutyrate — have distinct physiological effects
How a ketogenic diet improves neurological features of Kabuki syndrome — a rare genetic disorder of the epigenetic machinery — in mouse model.1
How beta-hydroxybutyrate and possibly acetoacetate induce epigenetic effects.
Anti-catabolic effects of ketones
How ketogenic diets may not be optimal for adding muscle but are suitable options to preserving muscle and improving other metabolic parameters, particularly during weight loss.
How the ketones produced during fasting protect against muscle loss.
How ketones may be protective against the tissue wasting aspects of cancer cachexia and age-related sarcopenia.
How ketones work through anti-inflammatory pathways to protect against lipopolysaccharide-induced sarcopenia.
Exercise performance
How ketones affect human performance.
How the combination of ketone salts and caffeine can be a powerful ergogenic aid.
How ketones shine in performance in extreme environments.
How to harness the benefits of metabolic flexibility to maximize athletic performance.
Brain and memory
How mice fed a cyclic ketogenic diet at midlife showed improved healthspan and better cognition than younger mice.1
How a ketogenic diet reduced the formation of spontaneous tumors in mice.
Intermittent Fasting
How intermittent fasting or time-restricted eating may be a viable entry point to a ketogenic diet.
How there are interesting health overlaps between the ketogenic diet and intermittent fasting.
Neurodegenerative diseases
How the ketogenic diet may augment the treatment of some subtypes Alzheimer's and Parkinson's diseases.1
How the ketogenic diet shows promise in managing a variety of psychiatric disorders.1
Migraines
The strong scientific rationale for the ketogenic diet and exogenous ketones in managing migraine headaches.1
Autoimmune diseases
The preclinical evidence suggesting that a ketogenic diet may slow multiple sclerosis disease progression.
Cancer
The synergistic effect of the ketogenic diet and hyperbaric oxygen against tumor cells. (How a ketogenic diet might augment the immune system allowing it to better detect cancer cells.)
How some cancer cells can use ketones as fuel.
How to design a ketogenic diet that incorporates anti-carcinogenic phytonutrients and fiber.
Carnivore diet
Thoughts on eating an all-meat diet.
Whether it is optimal to eat a diet devoid of fiber.
The common misconception that calories do not matter when consuming a ketogenic diet.
Dom's lifestyle habits
How Dom incorporates the ketogenic diet, exogenous ketones, intermittent fasting, and exercise into his daily life.
The effects Dom experienced using heat stress and his blood pressure.1
How Dom uses continuous glucose and ketone monitors.
Measuring ketones
How the best measuring device for ketones depends on the application.
What the glucose:ketone index is and how it is used in the management of a ketogenic diet.1
How measured breath acetone levels while on a calorie-deficient ketogenic diet directly correlate with fat loss.1
How a continuous glucose monitor can be used to assess dietary adherence to a ketogenic diet.
How sleep deprivation impairs glucose metabolism.
The insights Rhonda got from using a continuous glucose monitor.
Concluding thoughts and where to find Dom D'Agostino.
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An intermediary compound in the biosynthesis of vitamin D. Also known as calcidiol, 25-hydroxyvitamin D forms in the liver from cholecalciferol (vitamin D3).
Acetyl coenzyme A is a molecule that was first discovered to transfer acetyl groups to the citric acid cycle (Krebs cycle) to be oxidized for energy production. Now it is known to be involved in many different pathways including fatty acid metabolism, steroid synthesis, acetylcholine synthesis, acetylation, and melatonin synthesis.
Latin for "at one's pleasure" or "as you desire." In biology, this term is used to describe "free feeding."
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
An enzyme that plays multiple roles in cellular energy homeostasis. AMP kinase activation stimulates hepatic fatty acid oxidation, ketogenesis, skeletal muscle fatty acid oxidation, and glucose uptake; inhibits cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, and lipogenesis; and modulates insulin secretion by pancreatic beta-cells.
A toxic 42 amino acid peptide that aggregates and forms plaques in the brain with age. Amyloid-beta is associated with Alzheimer's disease, a progressive neurodegenerative disease that can occur in middle or old age and is the most common cause of dementia. Heat shock proteins have been shown to inhibit the early aggregation of amyloid beta 42 and reduce amyloid beta plaque toxicity [1].
One of three common genetic variants of the APOE (apolipoprotein E) gene. The APOE4 allele, which is present in approximately 10-15% of people, increases the risk of developing Alzheimer's disease and lowers the age of onset. Having one copy of E4 increases risk 2- to 3-fold, while having two copies increases risk as much as 15-fold.
An immune disorder characterized by an immune response to and subsequent destruction of the body’s own tissue. The causes of autoimmune diseases are not known, but a growing body of evidence suggests they may be due to interactions between genetic and environmental factors. Autoimmune diseases affect approximately 7 percent of the population in the United States and are more common in women than in men. Examples include type 1 diabetes, Hashimoto’s thyroiditis, lupus, and multiple sclerosis.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
A chemical produced in the liver via the breakdown of fatty acids. Beta-hydroxybutyrate is a type of ketone body. It can be used to produce energy inside the mitochondria and acts as a signaling molecule that alters gene expression by inhibiting a class of enzymes known as histone deacetylases.
The process by which fatty acid molecules are broken down. Beta-oxidation occurs in the mitochondria and produces acetyl-CoA, FADH2, NADH, and H+. Under conditions where glucose is limited, beta-oxidation is an important preceding step for producing the acetyl-CoA needed for ketogenesis.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
A highly selective semi-permeable barrier in the brain made up of endothelial cells connected by tight junctions. The blood-brain barrier separates the circulating blood from the brain's extracellular fluid in the central nervous system. Whereas water, lipid-soluble molecules, and some gases can pass through the blood-brain barrier via passive diffusion, molecules such as glucose and amino acids that are crucial to neural function enter via selective transport. The barrier prevents the entry of lipophilic substances that may be neurotoxic via an active transport mechanism.
A type of protein that acts on neurons in the central and peripheral nervous systems. BDNF is a type of neurotrophin – or growth factor – that controls and promotes the growth of new neurons. It is active in the hippocampus, cortex, cerebellum, and basal forebrain – areas involved in learning, long term memory, and executive function. Rodent studies suggest that lactate, one of many so-called exerkines, mediates some of the benefits of exercise on learning and memory via inducing neuronal BDNF expression.[1] Exercise in combination with heat stress increases BDNF more effectively than exercise alone.[2] BDNF is a profoundly universal point of convergence for mechanistically explaining essentially all known activities that promote brain health.
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.
A short-chain fatty acid produced by microbes in the gut. Microbial production of butyrate occurs in the colon during the fermentation of indigestible fibers, principally those from legumes, fruits, nuts, cereals, and whole grains. Butyrate exerts potent anticancer properties via its epigenetic actions on genes involved in colon cancer.[1]
The practice of long-term restriction of dietary intake, typically characterized by a 20 to 50 percent reduction in energy intake below habitual levels. Caloric restriction has been shown to extend lifespan and delay the onset of age-related chronic diseases in a variety of species, including rats, mice, fish, flies, worms, and yeast.
A highly restrictive diet that includes only animal-based foods, including meat, fish, eggs, and some dairy products. Carnivore diets typically produce a ketogenic effect but may lack certain essential nutrients.[1]
A wearable health-monitoring device that measures blood glucose levels in "real-time." Originally designed for people who have diabetes, CGMs demonstrate tremendous value as diagnostic tools, providing a more accurate reflection of glycemic state by directly measuring the postprandial glycemic response to every meal and thereby highlighting individual differences in those responses.
A ring-shaped protein found in blood plasma. CRP levels rise in response to inflammation and infection or following a heart attack, surgery, or trauma. CRP is one of several proteins often referred to as acute phase reactants. Binding to phosphocholine expressed on the surface of dead or dying cells and some bacteria, CRP activates the complement system and promotes phagocytosis by macrophages, resulting in the clearance of apoptotic cells and bacteria. The high-sensitivity CRP test (hsCRP) measures very precise levels in the blood to identify low levels of inflammation associated with the risk of developing cardiovascular disease.
A naturally occurring amino acid present in the muscles and brains of humans and other animals. Creatine plays central roles in skeletal muscle metabolism. It is widely used as an ergogenic aid (as creatine monohydrate) to promote performance in endurance and resistance exercise.
An antioxidant compound produced by the plant Curcuma longa, a member of the ginger family. Curcumin exhibits a wide array of beneficial health effects, including anti-inflammatory, anti-cancer, and anti-diabetes properties. It is responsible for the bright yellow pigment of turmeric, a type of spice commonly used in Indian food.
A broad category of small proteins (~5-20 kDa) that are important in cell signaling. Cytokines are short-lived proteins that are released by cells to regulate the function of other cells. Sources of cytokines include macrophages, B lymphocytes, mast cells, endothelial cells, fibroblasts, and various stromal cells. Types of cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.
The aqueous component of the cytoplasm of a cell, within which various organelles and particles are suspended.
An omega-3 fatty acid found in the human brain and the meat of fatty fish. DHA plays a key role in the development of eye and nerve tissues, and is essential for normal brain function in humans. DHA may also reduce the risk of Alzheimer’s disease1 and cardiovascular disease, and may be useful in treating certain inflammatory conditions, such as rheumatoid arthritis. Dietary sources of DHA include krill oil and the meat and roe of salmon, flying fish, and pollock. [1] Patrick, Rhonda P. "Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease." The FASEB Journal (2018): fj-201801412R.
An omega-3 fatty acid found in the meat of fatty fish. EPA reduces inflammation in the body and helps counter oxidative stress in cells. It is crucial for modulating behavior and mood and has demonstrated beneficial effects in managing anxiety and depression. EPA may reduce risk of developing certain chronic diseases such as cancer or cardiovascular disease. Dietary sources of EPA include herring, salmon, eel, shrimp and sturgeon.
A bioactive compound found in green tea. EGCG is a type of catechin. It is a potent scavenger of reactive oxygen species and has demonstrated antioxidant, anti-inflammatory, and anticarcinogenic properties in both clinical and in vitro studies.
Genetic control elicited by factors other than modification of the genetic code found in the sequence of DNA. Epigenetic changes determine which genes are being expressed, which in turn may influence disease risk. Some epigenetic changes are heritable.
A group of neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures are caused by abnormal or excessive electrical activity in the cortex of the brain.
The most common movement disorder involving a tremor of the arms, hands, or fingers, particularly during voluntary movement such as eating or writing.
A diet that mimics the effects of fasting on markers associated with the stress resistance induced by prolonged fasting, including low levels of glucose and IGF-1, and high levels of ketone bodies and IGFBP-1. More importantly, evidence suggests these changes in the cellular milieu are associated with a sensitization of cancer cells to chemotherapeutic drugs while simultaneously also conferring greater stress resistance to healthy cells.[1] Evidence also continues to emerge that properties of the fasting-mimicking diet, particularly its ability to cause immune cell turnover, may also make it useful in the amelioration of auto-immune diseases like multiple sclerosis.[2]
[1] Cheng, Chia-Wei, et al. "Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression." Cell Stem Cell 14.6 (2014): 810-823. [2] Choi, In Young, et al. "A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms." Cell Reports 15.10 (2016): 2136-2146.
A neurotransmitter produced in the brain that blocks impulses between nerve cells. GABA is the major inhibitory neurotransmitter in gray matter.
A type of tumor that forms in the brain and spinal cord in neurons called glial cells. Roughly one-third of all brain tumors are gliomas. Malignant gliomas are highly aggressive, and survival rates for patients are poor, at roughly 10 percent after three years.[1] A protein associated with human cytomegalovirus, a common beta-herpes virus, is expressed in more than 90 percent of gliomas.[2]
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.
One of the most abundant non-essential amino acids in the human body. Glutamine plays key roles in several metabolic functions, including protein and glutathione synthesis, energy production, antioxidant status, and immune function. In addition, it regulates the expression of several genes. Although the body can typically produce all the glutamine it needs, during periods of metabolic stress it must rely on dietary sources of glutamine such as meats, fish, legumes, fruits, and vegetables.
A value (between 0 and 100) assigned to a defined amount of a carbohydrate-containing food based on how much the food increases a person’s blood glucose level within two hours of eating, compared to eating an equivalent amount of pure glucose. Glucose has a glycemic index value of 100. Whereas eating high glycemic index foods induces a sharp increase in blood glucose levels that declines rapidly, eating low glycemic index foods generally results in a lower blood glucose concentration that declines gradually.
Glycemic response: The change in blood glucose concentration following consumption of a carbohydrate-containing food or beverage. Glycemic response is highly individualized and is a critical component of metabolic health. Evidence suggests that the microbiome participates in the regulation of host glycemic responses, ultimately influencing multiple aspects of human health.[1]
A highly branched chain of glucose molecules that serves as a reserve energy form in mammals. Glycogen is stored primarily in the liver and muscles, with smaller amounts stored in the kidneys, brain, and white blood cells. The amount stored is influenced by factors such as physical training, basal metabolic rate (BMR), and eating habits.
A series of enzyme-dependent reactions that breaks down glucose. Glycolysis converts glucose into pyruvate, releasing energy and producing ATP and NADH. In humans, glycolysis occurs in the cytosol and does not require oxygen.
The chief protein components of chromatin found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes acting as spools around which DNA winds, and playing a role in gene regulation.
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.
Abnormally low blood glucose. Hypoglycemia can occur due to low glycogen stores, diabetes medications, or other drugs. Maternal alcohol consumption can cause hypoglycemia in breastfed infants. Symptoms of hypoglycemia include confusion, heart palpitations, shakiness, and anxiety.
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.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
One of the most potent natural activators of the AKT signaling pathway. IGF-1 stimulates cell growth and proliferation, inhibits programmed cell death, mediates the effects of growth hormone, and may contribute to aging and enhancing the growth of cancer after it has been initiated. Similar in molecular structure to insulin, IGF-1 plays a role in growth during childhood 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 proinflammatory cytokine produced by macrophages. IL-1 beta is an important mediator of the body’s inflammatory response. It is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.
A pro-inflammatory cytokine that plays an important role as a mediator of fever and the acute-phase response. IL-6 is rapidly induced in the context of infection, autoimmunity, or cancer and is produced by almost all stromal and immune cells. Many central homeostatic processes and immunological processes are influenced by IL-6, including the acute-phase response, glucose metabolism, hematopoiesis, regulation of the neuroendocrine system, hyperthermia, fatigue, and loss of appetite. IL-6 also plays a role as an anti-inflammatory cytokine through inhibition of TNF-alpha and IL-1 and activation of IL-1ra and IL-10.
A broad term that describes periods of voluntary abstention from food and (non-water) drinks, lasting several hours to days. Depending on the length of the fasting period and a variety of other factors, intermittent fasting may promote certain beneficial metabolic processes, such as the increased production of ketones due to the use of stored fat as an energy source. The phrase “intermittent fasting” may refer to any of the following:
Experimental evidence from animal models links gut flora, an increase in intestinal permeability and endotoxemia of intestinal origin to low-grade chronic inflammation and obesity in animals.
A metabolic pathway in which organisms produce ketones. Ketogenesis occurs primarily in the mitochondria of liver cells via the breakdown of fatty acids and ketogenic amino acids. Insulin is the major hormonal regulator of ketogenesis; however, glucagon, cortisol, thyroid hormones, and catecholamines can induce greater breakdown of free fatty acids, thereby increasing the substrates available for use in the ketogenic pathway. The primary ketones used by the body for energy are acetoacetate and beta-hydroxybutyrate.
A diet that causes the body to oxidize fat to produce ketones for energy. A ketogenic diet is low in carbohydrates and high in proteins and fats. For many years, the ketogenic diet has been used in the clinical setting to reduce seizures in children. It is currently being investigated for the treatment of traumatic brain injury, Alzheimer's disease, weight loss, and cancer.
Modified ketone bodies sold commercially as a dietary supplement. Ketone esters may be neuroprotective and useful in the treatment of neurodegenerative diseases such as Alzheimer’s disease.
A metabolic state that results in the body’s production and use of ketones. Ketosis occurs under conditions of fasting, starvation, and low carbohydrate intake. Evidence suggests that ketosis may be beneficial in Alzheimer's disease.[1]
A type of lipoprotein. LDL is formed in the liver and transports lipid molecules to the cells. Often referred to as the “bad cholesterol,” LDL can drive the progression of atherosclerosis if it becomes oxidized within the walls of arteries. LDL particles exist in different sizes, ranging from large, fluffy molecules to small, dense molecules. Some evidence suggests that LDL particles increase the risk of developing heart disease, whereas the large, fluffy type of LDL may be cardioprotective.[1]
Large molecules consisting of a lipid and a polysaccharide with an O-antigen outer core. Lipopolysaccharides are found in the outer membrane of Gram-negative bacteria and elicit strong immune responses in animals through pattern recognition conferred by a toll-like receptor known as TLR4. Even a low dose LPS challenge of 0.6 ng/kg body weight given intravenously can induce a profound, if transient, 25-fold and 100-fold increase in plasma IL-6 and TNF-alpha, respectively.[1] Also known as bacterial endotoxin.
The three basic components of the human diet. Macronutrients are consumed in large quantities and provide necessary energy for the body. They include carbohydrates, fats, and proteins.
An enzyme that participates in genetic pathways that sense amino acid concentrations and regulate cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. It plays key roles 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 dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin.
Rapamycin, the drug for which this pathway is named (and the anti-aging properties of which are the subject of many studies), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
A diet pattern thought to confer health benefits found traditionally in Mediterranean countries, characterized especially by a high consumption of vegetables, olive oil, and a moderate consumption of protein.
A class of saturated fats. Medium-chain triglycerides are composed of medium-length fatty acid chains (six to 12 carbons long) bound by a glycerol backbone. They occur naturally in coconut oil, palm oil, and butter, but they can also be synthesized in a laboratory or food processing setting. Evidence suggests that MCT therapy improves cognitive function in older adults with Alzheimer's disease.[1] Examples of MCTs include caprylic acid (C8), capric acid (C10), and lauric acid (C12).
A natural pigment produced by the body's melanocytes. Melanin imparts dark color to skin, hair, and other external features. It serves as a natural sunscreen; as such, it impairs vitamin D synthesis in the skin. Dark-skinned people are more likely to be vitamin D deficient due to the presence of melanin.
A type of skin cancer. Melanomas typically form in the melanocytes, the pigment-producing cells located in the basal layer of the epidermis (skin). Melanomas commonly metastasize (spread) to other parts of the body. They account for approximately 10,000 deaths in the US each year.
The collection of genomes of the microorganisms in a given niche. The human microbiome plays key roles in development, immunity, and nutrition. Microbiome dysfunction is associated with the pathology of several conditions, including obesity, depression, and autoimmune disorders such as type 1 diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, and fibromyalgia.
A collective term for the community of commensal, symbiotic, and pathogenic microorganisms that live in a particular environment. The human body has multiple microbiotas, including those of the gut, skin, and urogenital regions.
Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their 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 during their energy-generating activities.
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.
A type of dietary fat. Monounsaturated fats – often referred to as "healthy" fats – contain only one double bond in their chemical structure. They are typically liquid at room temperature but solidify upon chilling. Monounsaturated fats are found in nuts, avocados, and oils, such as those from olives, peanuts, or canola.
A dietary pattern that promotes excessive weight gain. Obesogenic diets are typically rich in saturated fats and added sugars. Obesogenic diets may change the gut microbiome prior to the development of obesity, altering microbial metabolite production and promoting a wide range of disease states.[1]
A type of polyunsaturated fat that is essential for human health. Omega-3 fatty acids influence cell membrane integrity and affect the function of membrane-bound cellular receptors. They participate in pathways involved in the biosynthesis of hormones that regulate blood clotting, contraction and relaxation of artery walls, and inflammation. They have been shown to help prevent heart disease and stroke, may help control lupus, eczema, and rheumatoid arthritis, and may play protective roles in cancer and other conditions. Omega-3 fatty acids include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is found mainly in plant oils such as flaxseed, soybean, and canola oils. DHA and EPA are found in fish and other seafood. The human body can convert some ALA into EPA and then to DHA, but the efficiency of the process varies between individuals.
A type of movement disorder that causes fast low limb tremors resulting in unsteadiness while standing.
A neurodegenerative disorder that affects the central nervous system. Parkinson’s disease is caused by destruction of nerve cells in the part of the brain called the substantia nigra. It typically manifests later in life and is characterized by tremors and a shuffling gait.
The movement of a drug or other xenobiotic substance into, through, and out of the body. Pharmacokinetics comprises absorption, distribution, metabolism, and excretion, often abbreviated "ADME." Many factors influence pharmacokinetics, including a person's age, gut health, and circadian rhythms, as well as the substance's bioavailability.
The observable physical characteristics of an organism. Phenotype traits include height, weight, metabolic profile, and disease state. An individual’s phenotype is determined by both genetic and environmental factors.
Dietary fats acids that have more than one unsaturated carbon bond in the molecule, such as omega-3 and omega-6 fatty acids. PUFAs are present in fish, nuts, and seeds and are more prone to oxidation than other fatty acids. PUFAs activate a master gene called PPAR, which is involved in lipid metabolism.
Relating to the period after eating. Postprandial biomarkers are indicators of metabolic function. For example, postprandial hyperglycemia is an early sign of abnormal glucose homeostasis associated with type 2 diabetes and is markedly high in people with poorly controlled diabetes.
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.
Oxygen-containing chemically-reactive molecules generated by oxidative phosphorylation and immune activation. ROS can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
A related byproduct, reactive nitrogen species, is also produced naturally by the immune system. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from ROS (oxidative stress) and RNS (nitrosative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
The loss of skeletal muscle tissue with age. Sarcopenia is one of the most important causes of functional decline and loss of independence in older adults.
An essential trace mineral. Selenium is incorporated into selenoproteins, a class of highly conserved proteins that exert potent antioxidant activity. Selenoproteins play critical roles in reproduction, thyroid hormone metabolism, DNA synthesis, and protection from oxidative damage and infection. One of the best-known selenoproteins is glutathione peroxidase. Selenium can be obtained from supplements and foods such as Brazil nuts, yellowfin tuna, beans, and some grains.
A microtubule-bound protein that forms the neurofibrillary "tau tangles" associated with Alzheimer's disease. Tau tangles disrupt transport of metabolites, lipids, and mitochondria across a neuron to the synapse where neurotransmission occurs. Diminished slow-wave sleep is associated with higher levels of tau in the brain. Elevated tau is a sign of Alzheimer's disease and has been linked to cognitive decline.
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.
A molecule composed of a glycerol molecule bound to three fatty acids. Triglycerides are the primary component of very-low-density lipoproteins (VLDL). They serve as a source of energy. Triglycerides are metabolized in the intestine, absorbed by intestinal cells, and combined with cholesterol and proteins to form chylomicrons, which are transported in lymph to the bloodstream.
A proinflammatory cytokine. TNF-alpha is produced by a wide range of cells, including macrophages, lymphocytes, glial cells, and others. TNF-alpha signaling inhibits tumorigenesis, prevents viral replication, and induces fever and apoptosis. Dysregulation of the TNF-alpha signaling pathway has been implicated in a variety of disorders including cancer, autoimmune diseases, Alzheimer’s disease, and depression.
A metabolic disorder characterized by high blood sugar and insulin resistance. Type 2 diabetes is a progressive condition and is typically associated with overweight and low physical activity. Common symptoms include increased thirst, frequent urination, unexplained weight loss, increased hunger, fatigue, and impaired healing. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, diabetic retinopathy (and subsequent blindness), kidney failure, and diminished peripheral blood flow which may lead to amputations.
A fat-soluble vitamin stored in the liver and fatty tissues. Vitamin D plays key roles in several physiological processes, such as the regulation of blood pressure, calcium homeostasis, immune function, and the regulation of cell growth. In the skin, vitamin D decreases proliferation and enhances differentiation. Vitamin D synthesis begins when 7-dehydrocholesterol, which is found primarily in the skin’s epidermal layer, reacts to ultraviolet light and converts to vitamin D. Subsequent processes convert D to calcitriol, the active form of the vitamin. Vitamin D can be obtained from dietary sources, too, such as salmon, mushrooms, and many fortified foods.
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