The body's metabolic physiology undergoes profound changes when consuming a ketogenic diet. Ketoadaptation occurs when the body shifts from burning glucose as a primary fuel source to principally using fatty acids and ketones. Over time, the body's capacity to transport and utilize ketones upregulates, resulting in enhanced fat oxidation. At the same time, mitochondrial biogenesis increases, and reactive oxygen species and inflammatory cytokines decrease. In this clip, Dr. Dominic D'Agostino discusses how the body adapts to a ketogenic diet and the possible impacts on age-related chronic diseases.
Rhonda: There's this conflict in my head with eating a lot of fat and its effects on the gut because I know a lot of my gut researchers, a lot of my friends are, kind of, looking at gut health and one of the main things that you do induce endotoxin, which is released from bacterial cell membranes. I remember it's one of main things needed to induce gut permeability is if you have a high-fat diet. You feed mice, you feed...this is all done in animals, of course, which is... There's lots of problems with that, but...
Dom: What's the typical fat source for that? Is it lard or is it...?
Rhonda: A variety of different fat sources. There's lard, there's corn oil. I mean, so there's there's a variety of different fat sources, but fat itself in order to be digested, you have make these bile acids like deoxycholic acid, which which causes endotoxin release. It also acts as a surfactant. I mean, it's like a detergent. So, I'm not convinced that it's not not healthy, but I'm not...I'm, sort of, trying to get to the...there's a disconnect in the literature because there's so much information out there showing the benefits of a ketogenic diet, nutritional ketosis.
Dom: Let me ask this question real quick. So when endotoxin is released from these bile acids, so there would be a predictable, a characteristic cytokine profile that would reflect that, right?
Rhonda: Yes, so there's a cytokine profile and you also measure endotoxin in the blood, which is a very tricky thing to do because there's a lot of false positives and I know someone who's trying to develop an assay to make it actual-, because he's very OCD about it. It's not out there for clinical use yet because of that reason, and even doing it in animal studies, there's a lot of researchers that don't really do it right, measuring endotoxin.
Dom: Is there any benefit to endotoxin? So when I go exercise right, and you measure my blood and we look at reactive oxygen species or inflammatory mediators, you could look at the blood and say, "Don't do that, this is not a good thing to do." Whereas if you have periodic spikes maybe and endotoxin, is it stimulating a hormetic effect where it's enhancing my resilience or resistance to toxins, do we know that?
Rhonda: So endotoxin, I would say based on everything that I have known and researched and from my interactions with people that have been doing this research. It's not like reactive oxygen species where there's it's a potent signaling molecule that has this hormetic effect, increases mitochondria biogenesis, it increases all these genes involved in dealing with stress there's lot of benefits. You know, endotoxin release from the gut, one, it causes more VLDL production because VLDL sucks soaks it up. So that's part of the reason why inflammation is also correlated with an increase in LDL number. It also binds to ApoB, it binds to the part, it binds to where the LDL receptors bind so that LDL can't be recycled as well. So it, kind of, prevents. There's a lot of bad things about endotoxin being released. Now I don't know, maybe there is some, sort of, slight benefit from endotoxin being released. You know, I don't want to get too into the endotoxin world. I'm just saying there is, in my...I'm trying to, like, understand in my mind how....
Dom: So you might be a little biased because some of the high-fat diet work has endotoxin. I'm a little bit, I need to get educated, I mean, I understand endotoxin from, kind of, like a basic science point of view.
Rhonda: Right, like, "sepsis, bad."
Dom: Yeah, from "sepsis, bad," but I do know when your body is challenged, even things like radiation. I mean, there are some things...you know, I don't know of any case where an auto antibody is a good thing, but I know most of the things that are bad out there do have some benefits, it's the level it's the level.
Rhonda: Absolutely, dose is very important.
Dom: And the phenotype's ability to adapt to that chemical, that stimulus is really important. Like, old people don't adapt to older phenotypes don't adapt to an oxidative stress stimulus as robust. So I would be interested, and there's ways to simulate endotoxin, right? Experimental models and that's something we can do, challenge, perhaps run an experiment where we have animals on different diets where we can challenge them and look at inflammatory cytokines. We're doing a lot of that work now.
Rhonda: And gut health in general, gut permeability. I would love to see some ketogenic research go in that direction because there's so many unanswered questions in my mind. And there's a lot of bad data out there, like so from the high-fat diet and the effects on the gut because when you look at controlled diets and the high-fat diet, well, the controlled diets have, like, 50% more fiber, and it's like, "Well, that's not really the same thing if you're just changing fat." So there's, you have sift through all sorts of crap, and it's, like, there's lots of data you just have to throw out, but still at the end of the day, I'm uncertain and I'm weary about me, eating a high-fat diet. Not not mention the fact that I have certain gene polymorphisms that may not be as compatible, but because of that, because of gut health, that's my major, the limiting factor for me is gut health and I like to see more research on ketogenic diets and gut health, like, that's something that I think is important.
Dom: How to optimize it.
Rhonda: Yeah, or just what the effects are, like maybe they're for one, we're starving out probably a lot of the pathogenic sugar-eating bacteria. So there's probably some good things going on. And then there's, well, what effect does medium-chain triglycerides has? Is it the same as long-chain fats? Maybe not. So maybe...so there is different types of fat there's studies that had been coming out very recently showing the effects of polyunsaturated fat on the gut biome, and how it has a positive effect. So maybe if you eat certain types of fat, more of these types of fat versus the others. There's lot of things out there to be explored.
Dom: Undoubtedly shifts it, yeah. It shifts it. I mean, your gut microbiome has an appetite for whatever you're feeding it and that probably influences profoundly your own appetite. So I think if you have sugar-eating gut microbes, you're probably going to be craving sugar if you go a few hours without having sugar. And I think I would be very interested in not only, like, shifting someone from a high-carb diet to two or three different types of ketogenic diets, I think, would be important with specific fatty acid compositions and fiber compositions. And I think it's the diversity of the fiber that's incorporated.
Rhonda: Diversity, yes, it is very important. There have been there's lots of different types of bacteria and they're eating different precursors to generate a lot of these other signaling molecules, short chain fatty acids and things like that that are regulating your immune system, that are regulating literally hematopoiesis, Tregs, natural killer cells lots of...and this is a whole blooming field of research. That's also another reason I've been a little hesitant to experiment with this because I'm so, fiber is so important for me, fiber from vegetables. You know, I'm not adverse to fiber from fruits, so fiber from fruits, legumes, beans, like, I like to get a lot of fiber in my diet, and so I don't know if that, is that compatible with it?
Dom: I get more fiber on a ketogenic diet. You know, and we're talking about a well-formulated ketogenic diet, as Jeff Volek likes to... And because that is really important because you talk to people that you eat ketogenic diets and it's all over the board. But I think a well-formulated ketogenic diet would have an abundance of fiber sources, everything from green vegetables, of course, but would include a salad, and I think it's really important from a gut microbiome perspective to get in raw vegetables, I think, from what I've known and a half-dozen individuals that I talk to that are, kind of experts in this field. They think that that has a pretty profound effect, and I have always done that and I would say my gut health has not... It may be due to what I eliminated in my diet. I grew up in an Italian family eating a lot of pasta, bread, so they were the staple foods, and I gravitated toward a Paleo diet mid-90s, early 2000s and then the ketogenic diet, and I have never had better gut health than when on a ketogenic diet, but my diet is, like I said, more of a modified Atkins and has a pretty liberal amount of vegetables in it. And I think the benefit to including the vegetables, they're just carriers for the fat and they also slow protein digestion, which helps minimize the insulin spike that you can get from protein and helps keep me in ketosis.
But, I mean, getting back to your question about the ketogenic diet or high-fat diet influencing endotoxin or factors, I would think that would show up in the literature that if some, and maybe it does, but it usually, a high-fat diet is in the context of a high-carbohydrate diet, too. So that's what we don't know when we talk about LDL particles being elevated, like, even skyrocketed, LDL, little peak. That is only understood in the context of a high-fat diet, which also includes also sugar like a western diet. So we don't yet understand lipidomics and the shifts in lipid profile of the ketogenic diet, LDL(p), specifically, we don't understand it in the context of ketoadaptation.
Rhonda: Okay, what's that?
Dom: Ketoadaptation, I would, it's, kind of, a term that Jeff Volek and Stephen Phinney coined, but I think it's very descriptive in my mind as a physiological process when your body has adapted to using fatty acids and ketones for fuel where you've biochemically and physiologically shifted your metabolism from burning glucose as the primary fuel to burning glucose and also equal or maybe more, in some cases, ketone bodies primarily from your central nervous system. So when that happens, that's acutely, you get an elevation of blood ketones and over time, what you do is get an upregulation of the transport mechanism so your ability to make ketones, utilize ketones, and metabolize ketones in the cell is dramatically increased as is the oxidative capacity of your cells.
Rhonda: After you start making more ketones.
Dom: After, yeah. It's, sort of, driven by being in a state of ketosis enhances fat oxidation over time. So when we say ketoadaptation, we should probably say keto and fat adaptation. So there's studies out there that show our metabolic physiology changes pretty profoundly from eating this. We basically, we burn what we eat, right? So with a high-carbohydrate diet, we are pretty much burning that as fuel and our bodies can adapt remarkably well to burning a macronutrient profile that's reflective of the ketogenic diet. And when we do that, a lot of really remarkable, beneficial metabolic processes happen including mitochondrial biogenesis, reduction of ROS, reduction of inflammation, a reduction of specific inflammatory cytokines that may be associated with with age-related chronic diseases are reduced
A test used in laboratory medicine, pharmacology, environmental biology, and molecular biology to determine the content or quality of specific components.
Proteins that provide favorable conditions for the correct folding of other proteins. Newly made proteins usually must fold from a linear chain of amino acids into a three-dimensional form. Group II chaperonins, the variety found in eukaryotic cytosol, are also referred to as CCT, which stands for "chaperonin containing TCP-1."
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.
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 type of toxin released when bacteria die. Endotoxins can leak through the intestinal wall and pass directly into the bloodstream. The most common endotoxin is lipopolysaccharide (LPS), a major component of the cell membrane of gram-negative bacteria. If LPS leaks into the bloodstream, it can trigger an acute inflammatory reaction. LPS has been linked with a number of chronic diseases, including Alzheimer’s disease, inflammatory bowel disease (Crohn’s disease or ulcerative colitis), cardiovascular disease, diabetes, obesity, autoimmune disorders (celiac disease, multiple sclerosis, and type 1 diabetes), and psychiatric disorders (anxiety and depression).
A molecule composed of carboxylic acid with a long hydrocarbon chain that is either saturated or unsaturated. Fatty acids are important components of cell membranes and are key sources of fuel because they yield large quantities of ATP when metabolized. Most cells can use either glucose or fatty acids for this purpose.
The production of red bloods cells, white blood cells, and platelets from hematopoietic stem cells, which occurs in the bone marrow. Also called hematogenesis, or hematopoiesis.
Biological responses to low-dose exposures to toxins or other stressors such as exercise, heat, cold, fasting, and xenohormetics. Hormetic responses are generally favorable and elicit a wide array of protective mechanisms. Examples of xenohormetic substances include plant polyphenols – molecules that plants produce in response to stress. Some evidence suggests plant polyphenols may have longevity-conferring effects when consumed in the diet.
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.
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.
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.
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
A cell-surface receptor that mediates the endocytosis of cholesterol-rich LDL by recognizing ApoB, which is embedded in the outer phospholipid layer of LDL particles. The LDL receptor is found in almost all cells; however, LDL receptors are especially abundant in the liver, because this is where ~70% of LDL recycling occurs. This receptor also recognizes the ApoE 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. Examples of MCTs include caprylic acid (C8), capric acid (C10), and lauric acid (C12).
The thousands of biochemical processes that run all of the various cellular processes that produce energy. Since energy generation is so fundamental to all other processes, in some cases the word metabolism may refer more broadly to the sum of all chemical reactions in the cell.
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.
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.
The process by which new mitochondria are made inside cells. Many factors can activate mitochondrial biogenesis including exercise, cold shock, heat shock, fasting, and ketones. Mitochondrial biogenesis is regulated by the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha, or PGC-1α.
A chemical reaction in which an atom, molecule, or ion loses one or more electrons. Oxidation of biological molecules is associated with oxidative stress, a key driver of many chronic diseases.
A result of oxidative metabolism, which causes damage to DNA, lipids, proteins, mitochondria, and the cell. Oxidative stress occurs through the process of oxidative phosphorylation (the generation of energy) in mitochondria. It can also result from the generation of hypochlorite during immune activation.
A diet based mainly on foods presumed to be available to paleolithic humans. It includes vegetables, fruits, nuts, roots, meat, and organ meats while excluding foods such as dairy products, grains, refined sugar, legumes, and other processed foods.
In general, anything that can produce disease. Typically, the term is used to describe an infectious agent such as a virus, bacterium, prion, fungus, or other microorganism.
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.
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 body's overwhelming and life-threatening response to an infection which can lead to tissue damage, organ failure, and death.
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 cAMP, nitric oxide, estrogen, norepinephrine, and even reactive oxygen species (ROS).
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.
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