57: Exogenous Ketones with Dr. Ben Bikman

Hello and welcome to the Metabolic Classroom. I am Professor Ben Bickman, a professor of cell biology and metabolic scientist. Thanks for joining me today. And we are going to be learning about the history and the use and the science behind ketones in general, but with a particular focus on exogenous ketones. Now, let's dive right in. First of all, what are ketones? Now, technically, ketones are an organic molecule that has a particular type of chemical bond. Bond. If this particular type of chemical bond is present, then the molecule will be considered a ketone. Now, within that pretty large family of molecules, there are things that are commonly referred to as the ketone. Bodies to me is a little cumbersome. So over the course of this lesson, I'm just going to call it just. I'm going to call them ketones. Now, you'll notice earlier I said the word exogenous. You've likely heard that term before as a term of physiology or as a term of medicine. But exogenous could be compared with the term endogenous, where one refers to something that is coming from outside the body. That's the exo part, the prefix exo or exogenous. The other endogenous, endo is coming from within the body itself. So the very fact that we have something called exogenous ketones, of course implies that there is something called endogenous ketones. Let's talk about those first. What are the ketones that we make? Now, first of all, there are three relevant ketones that fall within the ketone body family. But generally these are just ketones as we think of them. The main one, the mother ketone, is a ketone called acetoacetate. And then it will get split into two different types of ketones, one called acetone, which is a ketone that just gets excreted. It is irreversible. Once it is turned into acetone, it is gone. It must be eliminated from the body, either in the breath or in the urine. The other molecule that acetoacetate can turn into and indeed does so more readily or more more commonly, is one called beta hydroxybutyrate. And beta hydroxybutyrate being the most common. That's the one that is typically measured when you're getting your doing a finger stick and you're measuring your glucose or your or your ketones with a ketone meter, that is what you're measuring, beta hydroxybutyrate. However, when you are urinating out ketones and measuring your ketone levels on a urine stick, you're measuring the acetone because the acetone has to be excreted, there's no place for it in the body. But in contrast, beta hydroxybutyrate can be metabolized and this is why it is, is, is valuable. And we'll get on to later. We'll get into why you would want ketones in just a moment. But before we do do so, I wanted to highlight just some of the biochemistry within the body that puts the body in a position to be making ketones, which would be into a position that is generally going to be ketosis. Now ketones have the ability to have a hydrogen molecule that can come off of it, hydrogen ion that can come off of the ketone and that makes the ketone capable of making the blood more acidic. Now, at a normal level that most people could get to, it is impossible to make so much ketone that it actually affects your ph. I really need to emphasize this. It is practically impossible for a non diabetic person to do this. Now in contrast, if you have a person who is an untreated type 1 diabetic, they can get ketone levels that are so high that it gets into the realm of what's called ketoacidosis. But that's a substantially elevated ketone level that's like a house that is burning, whereas ketosis is a fireplace. Whereas then you compare that to the average individual and their ketone levels are so low, it's like a match. Now why is the average person having experiencing such low levels of ketones to the point that it often can't be even detected on a ketone meter? That's because their insulin levels are chronically elevated. So back to the biochemistry somewhat. When you are breaking down nutrients, whether it is through glucose or whether it is through fats, the common molecule will those where these pathways will converge, glucose burning or fat burning, they'll get to a molecule called acetyl coa and then acetyl COA will go into something called the citrate cycle. That's what I call it. It's the TCA cycle, the citric acid cycle, the Krebs cycle, all of those are the same thing. I call it the citrate cycle and in so doing is capable of generating much more energy for the cell. However, when you have a lot of acetyl CoA being, being, being made, you have a lot of molecules getting into the citrate cycle and it essentially starts to get too full. All of the enzymes that are busy creating energy from acetyl COA are, are overloaded. And so the acetyl COA starts to accumulate. And at that point, acetyl CoA has two options. It can either turn into lipid, so the acetyl COA molecules can start to join together. This is a process called lipogenesis. Or the acetyl COA can take the other pathway, the one less traveled, if you will, which is ketogenesis. It becomes ketones. Now, how does the cell, how does acetyl COA know which path it should go down? Well, it is entirely a function of the humble hormone insulin. If insulin is elevated, then acetyl COA will take the path of lipogenesis because insulin has activated that whole process and at the same time has inhibited the ketogenic pathway. It has closed that door. Every single enzyme of ketogenesis is going to be inhibited by elevated insulin. So insulin forecloses the ketogenic pathway and opens the door to the lipogenic pathway, thereby converting the acetyl COA into fat, into new fat through lipogenesis. In contrast, if insulin is low, then the ketogenic pathways opened and encouraged. All those enzymes are very active. And now at that same time, the lipogenic pathway is closed because it requires insulin to be elevated for it to be fully active. So you can see that while acetyl COA is a nexus molecule standing at the crossroads of nutrient metabolism with two different fates ahead of it, two different paths, the lipogenic and the ketogenic, it is insulin that determines which path. Path it takes again, just to put a p, just to make it as succinct as possible. If insulin is elevated, the acetyl COA takes the lipogenic pathway. If insulin is low, acetyl COA will take the ketogenic pathway and giving rise to the endogenous ketones. Now, sometimes it can be difficult for someone to make ketones, or depending on their medical state, they may need their ketones to be elevated all the time. And thus we have a value to exogenous. Now, why would you even want ketones to be elevated? Before I get into a list of why ketones are even beneficial in the body, why it's a molecule that's beneficial, I just wanted to take one step back and just emphasize the fact. One of the reasons I look favorably at a ketogenic state is not necessarily because of the benefit of the ketones, although they are myriad as we'll get into, it's in large part because of what enabled the production of the ketones in the first place. And you can see probably where I'm going with this, which is having your insulin be low at a fasted state or at any given state, the longer you're spending where insulin is at a relatively lower level, the easier time it's going to be for you to be burning fat and, and keeping your weight down or getting your weight down. So and improving insulin sensitivity and a host of other benefits. So to me, much of the metabolic magic of a ketogenic state isn't so much the ketones. It's more a function of keeping your insulin under control, not to mention avoiding the rapid rises and drops in blood glucose levels, which can contribute to hunger. It contributes to brain disruption, which has been shown in diabetic populations. So it's a pretty good metabolic milieu as a result of just having the insulin down. Now, that's not the point of this lecture. The point is the ketones. So let's get back to that. So first, indeed, reflective of the earliest research highlighting the benefits of ketones, the brain thrives on ketones. Brain function appears to improve and cognition certainly improves. In fact, you have likely heard that the brain prefers glucose or that glucose is the preferred fuel. I don't know where that came from. I really don't know. There's certainly no study to say that of the two fuels that the brain uses, namely glucose and ketones, that it prefers glucose. In fact, I know of work that that suggests the exact opposite. And this is based on the work of Dr. Stephen Cunein and especially Dr. George Cahill. George Cahill is a legend. C A H I L L Look up any of his work. He's a legend in the realm of fasting and starvation and ketones and even insulin, because you can't really understand ketones without appreciating insulin. So in Dr. Cahill's work in particular, he found that within a fasted state, once the Gl with, with an absence of carbohydrate coming in, there are some cells of the body that have to metabolize glucose. Now, just to confirm or to make very clear, dietary carbohydrate is not the same as blood glucose. It is fair to say that the body needs glucose. There are some cells that must use it, like the red blood cells, because they don't have mitochondria, they don't. They can't get to acetyl CoA. They can only do something called non oxidative or anaerobic glycolysis. So some cells need glucose and the red blood cells are a perfect example. But that does not mean the body needs dietary carbohydrate because we can make abundant glucose. So as Glucose or carbohydrate consumption's gone down. The body overall is shifting the metabolic state to tell the brain that, hey, we're getting a little low on glucose, so we need you to eat a little less. And the brain immediately shifts over to, to ketones. Now, let me just really make it clear. In a fasted state, if a person's fasted for two or three days, which is kind of the work that Dr. Cahill did, blood glucose levels are going to be about 5 millimolar. Ketone levels may be about 2 or so millimolar substantially less than the glucose level. Even still, up to 70% of the energy that the brain is getting is now coming from the ketones. So the ketone, the brain is using more than twice the amount of ketone as it is glucose, even though in the blood glucose levels are more than twice as high as the ketones. So if the brain has any preferred fuel, it's not the glucose, it's clearly the ketone because again, to state it another and final way, even when ketone levels are half of at of what the glucose levels are, the brain is relying on the ketones for up to 70% of its energy needs. So if the brain has any preferred fuel, again, it's the ketones by far. Now, so what? There are myriad neurological disorders that appear to be a result of a brain glucose hypometabolism, where the common denominator between things like Alzheimer's disease, things like epilepsy, epileptic disorders, migraine headaches and many, many more. Despite all of the differences they have, the one thing they have in common is that they have all been shown to be at least partly affected by the brain not being able to get enough glucose very well, perhaps due to insulin resistance. But this is the earliest research from the early 1900s. You can find physicians publishing medical reports doct documenting the total stopping cessation of things like migraines or epilepsy. So pretty, pretty impactful. All just because the patients get into ketosis. So the brain clearly benefits with ketones and uses them very readily. In addition, Dr. Stephen Cun C u n N a n E he has found that the ketones help reduce oxidative stress and inflammation in the brain. And that could be one of the mechanisms whereby ketones have a neuroprotective effect in conditions like Alzheimer's, dise and Parkinson's. So the brain, the neurological system appears to thrive on ketones. Now, beyond the brain, we have improved physical performance and energy levels. It's been shown that ketones. I've even published some of this in my own lab. Look up work by. With the first author being a last name Parker, Parker et al from and I'll be the Bickman. I'll be the senior author, the corresponding author on that. We published a report in muscle finding that muscle cells per unit oxygen consumed are capable of producing more ATP, the main energy molecule of the cell. So the cell appears to be more efficient with its use of ketones, at least muscle cells and neurons and producing more energy. And at a, at a whole body level. This could be some of what we see at least in rodent studies and a human study finding that ketones can improve prolonged exercise. Now more of my own work, but I'm not the only one who's shown this, but I published a really good report in 2020 from my lab finding that ketones have a stimulating effect at fat tissue. Not only can ketones stimulate the brown adipose tissue, that's the adipose tissue that has a very high metabolic rate that typically only gets activated when you are shivering like you're in an ice bath, but ketones can do that too. Similarly, ketones are capable of turning white fat, the very low metabolic rate, lethargic miserly form of fat, and making it behave a little more like brown fat, increasing its metabolic rate by almost three times. This was a human paper. We, we were conducting studies in humans taking fat biopsies of human belly fat. And when people were not in ketosis, compared to people that were in ketosis, the metabolic rate of that fat tissue was about three times higher. So pretty substant all because the ketones were elevated. That was the only difference. So this is a benefit in this case. Appreciate for just a moment some of the paradox if you will, where in muscle the ketones are helping the muscle be more efficient with its energy. It's getting more ATP, so the muscle is being more miserly with its energy use. In contrast, adipose tissue appears to get a little more wasteful. It's less efficient. That's a, that's a very clever adaptation, very unique and, and one that ends up being favorable to our metabolic situation in today's world where we have people with too much fat and they need to burn it. Ketones, not only are ketones a product of the fat burning, but they actually then are feeding back obviously to enable more fat burning, creating a bit of a positive cycle here, a beneficial cycle. Also Newman and Verdin, in 2017 they published a paper finding that ketones could act to improve lifespan and Health span. There was a rodent study done that looked at these animals in the ketogenic diet or not. And the ketogenic diet animals lived longer, healthier lives. That's the closest study we have. Anyone who wants to talk about longevity studies can only ever rely on animal studies at best. Alternatively, they can look at insect studies, but there are no human studies that can really touch on longevity. It's purely in the realm of speculation, which is one of the reasons why I'm. I'm a little not hostile but indifferent or I don't appreciate some of the longevity focused sentiment that appears to pervade media, et cetera, because it's completely based on speculation, which I don't like as a basic scientist. Now I'm not done yet. There are still more benefits to ketones that I would not talk about if they didn't have substantial support. Another one, the fifth one is the in inhibition of inflammation. This is something I've discussed in previous metabolic classrooms. But there is a molecule that is kind of a master regulator of inflammation called the NLRP3 inflammasome. And those are all just letters N L R3P3. And inflammasome just refers to something that's controlling kind of the entire machinery of the inflammatory or immune response within a cell. But suffice it to say, when the NLRP3 inflammasome is turned on, the cell is very active with its immune activation. When ketones are elevated, it inhibits that process. So ketones have a direct anti inflammatory effect. This could be one of the reasons why ketogenic diets appear to be so beneficial for inflammatory dis, especially things like a joint disorder where the inflammation has such an obvious effect. Okay, now the last one that I want to mention is one that I've alluded to, which is that ketones can help with metabolic health and even weight loss. I've already described the effect where the ketones can stimulate metabolic rate in fat tissue by up to two to three times in humans. My own work, but also the very act of wasting ketones represents a kind of break to the traditional thermodynamic view of obesity. You've heard before the idea that you, the sentiment in some words that you eat it or you, you store it or you burn it. So that gives rise to the sentiment like eat less, exercise more. This. There's this idea that when you consume calories, you either are going to store them or you're going to burn them. However, ketones represent a new way out which is just Wasting them, excreting them. Now, ketones have a caloric value. We sometimes forget that we only think of calories as coming from things like fats and glucose. Yes, they certainly have an energetic value, but so too do ketones. Ketones are used by cells for energy. So appreciate the fact that when someone's in ketosis, every breath out, they are excreting acetone, which is an end product of. Of the ketone metabolism. Well, that was a molecule that had an energy to it. It was a caloric. A caloric molecule. Or every time they're urinating and they're urinating out ketones, that. Those are calories that are just being directly dumped from the body or wasted out of the body that did not have to be stored or burned. They didn't have to exercise those off to get them out. They were breathing them off. This is just another reflection of the. When insulin is low, which it must be when you are making ketones, the body cannot hold on to energy. It will mobilize every possible outlet. Every possible process will be turned on in order to waste energy, including increasing metabolic rate and making ketones that can then be just excreted from the body. All right, now, at this point, you're thinking surely 20 minutes in. Dr. Bickman, I thought we were talking about exogenous ketones. Well, let's get into it. And I thought it would be kind of fun at this point in the lecture to discuss some of the evolution or the history of it. First and foremost, there are some things that a scientist would want to get and we would want as consumers that would make an exogenous ketone ideal. One of these things would be the metabolism of it and how the body is able to absorb it. Can we actually get it from the guts into the blood getting absorbed through the stomach or lower in the small intestine? Clearly that is a metric that would have to be met. We also want to know what some of the precursors are involved. Is this a molecule that, once absorbed, is capable of being turned into a functional ketone? And then we'd also want to know what is the purity of it. Is this something. Are we getting what we want to get? And that's been sometimes a problem in the past, or if not a problem, then at least a consideration. Okay, so these are some of the things that would make. That would need to be considered when we are. When we are looking at exogenous ketones. So through a brief history lesson, the first used exogenous ketones were the ketone salts having Been born a number of decades ago, about 60 years ago or so. These were. Came in two different forms, what's called a D form and an L form. The body uses the D form of these molecules. There's kind of a mirror version, and we don't really use the L form much. But these ketone salts didn't distinguish between them, at least originally. Another consideration is that is the salt part of it, which for every ketone you're getting, you're getting a mineral like sodium or calcium or magnesium that enabled the ketone to be more stable and consumable. But it also means that you may be getting an enormous amount of mineral that needs to be excreted. You can't hold on to that much. Now, that's not necessarily a problem in most people, but it's. It's pretty common that a person, at a minimum, may find that they get much more mineral deposits on their teeth, that they really are starting to get a lot of stuff, a lot of like, kind of plaquey mineral deposits, especially on the lower part of the jaw where you have more saliva. So very commonly along those bottom teeth, a person can start to really get a lot of mineral deposits. That's kind of the best place to excrete it. Alternatively, it could give rise to greater kidney stone formation, which nobody wants. Another consideration is that the actual degree to which you can increase your ketones is fairly limited. Fairly limited. But this is a cheap option, and it is one that can increase your ketones. Rarely would you be able to get them higher than one millimolar. It just. You're getting so much mineral that it starts to limit how much you can take in. Then in the early 2000s, through the work of some early ketone research pioneers, rich doctors Richard Veach and Kieran Clark, they created a D only. So a highly absorbable getting the ketone we want that was bound in what's called an ester bond. And an ester bond is a type of bond that is binding lipids together, like when you're eating triglycerides. So we have a digestive system with an esterase enzyme that is capable of snipping those apart. The nice thing about that ester bond is that it stabilized the molecules, enabling us to consume them, and then we would split them apart and then it would be able to be absorbed. Some of the challenges, however, first and foremost being a fairly strong and. And pretty unpleasant smell and taste. The taste was kind of prohibitively bad. Anyone who's taken them knows exactly what I'm talking about. But yeah, anyway, it's a, a pretty strong taste that limited how much people wanted to take and often it was fairly expensive. Now with this idea in mind, when we would consume these metabol, the, these ketones, generally they were quite usable with the ester. The ketone ester included one form of direct beta hydroxybutyrate which is the most usable, if you will, form of ketone in the body. And then it had a molecule, butanediol, which could be converted into bhb. So it would be kind of a precursor molecule. Now up to the present day, the latest evolution in this is what's called a bioidentical beta hydroxybutyrate. So a bit a bioidentical bhb. This is directly the form we would be making, is the form that now can be taken. Thankfully it has a pretty good pH, it's not very acidic, it has an acidity just roughly in the realm of lemon juice. So it's very palatable. And of course it is a bioidentical form, so which with itself a very minimal flavor impact, unlike the ketone esters, because it is bioidentical to what we make, it is immediately usable, immediately available for energy once you consume it. So it works very quick. And I can state that with some experience having used it. I literally just had some of these of bioidentical BHB earlier and looked at my ketone change with a breath ketone monitor. Now I, I just have sort of revealed a bit of a personal preference now and I have no problem stating this because I have no vested interest in doing so. Any if you're curious about it, the my favorite brand is one that you can get called American Ketone. It's called Original Ketone but the company is American Ketones. Just go to american ketone.com I have no vested interest. I've tried them. I've had samples of all of these types that I've just mentioned and this one is by far my favorite and appears to be the most effective. So it's one that if I'm recommending any, it's I'm recommending that. Now as you consider this, of course, remember why when should exogenous ketones be used? Well, it really would be anytime you want high ketones or anytime you want some of the benefits I mentioned earlier. Like you want a higher metabolic rate to facilitate weight loss. Ketones have been shown to help with satiety and appetite control. So you're trying to control your cravings. So you're sipping on the ketones in the evening. If you're anything like me, that's when I have my most cravings. You want to control inflammation or you are an you're exercising and you want an extra fuel source beyond just the glucose and the fats. You want that extra macronutrient to fuel your exercise. Those are all reasons why you would be interested in exogenous ketones. Now, I have had a bit of an evolution, getting more familiar with ketone biochemistry. Early on I was a little wary of exogenous ketones because I worried about someone drinking ketones while they're eating a cinnamon roll or something. Where you have high insulin and high ketones, that would be an unnatural state. You don't normally have that because typically if you have high insulin, you're inhibiting ketone production, you inhibit ketogenesis. But with the rise of exogenous ketones, particularly the bioidentical bhb, you can get a substantial increase in ketones very quickly. Could those ketones be reversed in their ketogenic pathway? What was once an acetyl COA molecule that was diverted to ketone? Can it go back and turn into acetyl COA and now take that other path, namely going down the path of lipogenesis? So is it possible for the ketone to be metabolized into fat? No, it is not, because this is a process that's happening in the liver. The liver is the cell that is making ketones that is then spilling into the blood. Now, other cells can make ketones, but they typically keep them. The liver is an exception because it is not able to overcome or to reverse one of those steps. When you take the acetyl COA and you're converting it over a few steps to the ketone, some cells can go from ketone back up to acetyl COA and then. But the liver is not one. So the liver is a cell that or its cells are capable of making the ketones, but then not capable of burning them. It just does not have the enzymatic pathways to do so. So that is not a well placed fear. And despite my speculation early on, that appears to not be justified. I know of no evidence that shows that the liver can take the ketone and turn it back into fat, or that any cell can do that. So you can use the ketones without that fear, at least. Now, I don't mean to sound like I am just a uniform advocate of them. I use exogenous ketones particularly for exercise and particularly in the evening. Just my personal use to, to help me that the tartness, especially of the my my favorite one, the American Ketone company one, has a tart, fruity flavor with ice and it's mixed with water and it really just helps me personally with cravings. I would be very curious to hear how you have used exogenous ketones. In fact, however, you're watching this and if you're on the YouTube insulin IQ channel, please share in the comments. I'll be curious to scroll through and see how you guys have been using them. But there are myriad benefits to ketones having been proven valuable for decades, having been once viewed as metabolic garbage, literally quoted metabolic garbage? Really? Dr. Cahill, that I, who I cited earlier, was the one to help establish the fact that ketones are a viable and beneficial nutrient or energy source in their own right, and even beyond energy signaling to the cell to do all kinds of things, and some of which I've mentioned, like controlling inflammation, increasing metabolic rate and fat cells, et cetera. I hope this information's been helpful. Nothing thrills a professor's heart more than having a student who feels like they've learned something new. And until next time, more knowledge, better health. I'll see you then.