What Ketone Supplements ACTUALLY Do to Your Body

[00:00:00]Let's bring in exogenous ketones, then.

[00:00:02]For the athlete who has the metabolic machinery to utilize those versus somebody that might bring those in along the journey of getting metabolically healthy.

[00:00:13]And what we know about the differences there, the machinery of the body and utilizing >> So, we're actually in the uh some ongoing studies to really uh tease apart the nuance of how age, sex, uh body composition, metabolic health status all seems to cause distinct effects in how people do metabolize ketone bodies. But, based on the precedents of literature that we have today, it appears that uh exogenous ketone bodies will, let's say from sports performance first. Let's start category by category.

[00:00:41]Exogenous ketone bodies number one, um are known Well, actually, let's back up for a second. Why would someone even consider exogenous ketones? Let's start there.

[00:00:52]Because many people may wonder, well, why would you even talk about exogenous ketones right now? They're just a byproduct of fat metabolism. I would just do a ketogenic diet. Well, someone may struggle with adhering to a ketogenic diet. Maybe they do really well with their high-carbohydrate diet, but they want to experience some of the benefits of ketones. So, the question is, what are those benefits? Well, there's been evidence that suggests just administering ketones even on themselves can cause shifts in lowering glucose levels, um causing kind of widespread shifts in metabolism. Uh they're also signaling molecules. We know that these these molecules signal uh various effects within the body. Uh we know that it also can block certain inflammatory processes like in a large 3 inflammasome, um which is a known uh inflammatory driver. We know that it can also change your epigenetics. So, the the the things that regulate how your genes actually express or turn your genes on and off. Um so, you have you have all this genetic machinery, but you only utilize some of it. Well, how does your body determine which part of the genes to utilize at any one moment? Well, um maybe it's the actual epigenetic regulation of those. And so, we know ketone bodies actually regulate how your genes are expressed.

[00:02:02]And one of those ways it does that is it increases antioxidant signaling through FoxO. And so, that antioxidant signaling also has been shown in a science paper to demonstrate that ketone bodies have antioxidant effects in and of themselves. There's multiple studies that show just adhering to a ketosis-based dietary pattern has anti-inflammatory effects in general. We There's There's a lot of signaling a lot of effects from energetic perspective neurologically speaking that that come along with ketone bodies.

[00:02:33]Obviously, we talked about the muscle effects, the anti-catabolic effects.

[00:02:37]And so, there's a lot a lot of things going on here with ketone bodies. So, there was this emergence of the utilization of exogenous ketone bodies. And this actually was once thought to emerge over the last 10 to 15 years, but actually goes back to the 1950s.

[00:02:54]So, in the 1950s and 1960s, medium-chain triglycerides, which is a form of fat that readily converts through exogenous consumption into ketone bodies. So, some people would define them as exogenous ketone bodies.

[00:03:06]MCTs are found in butter, they're found in coconuts, they're found in breast milk. And when consumed, they rapidly convert to ketone bodies in the liver.

[00:03:13]And they were actually used in the 1950s and '60s to help children who had malnutrition disorders. They weren't able to readily digest certain foods.

[00:03:21]And so, they applied ketone bodies as a alternative form of fuel substrate. And it actually helped these kids gain weight. So, that's actually the first medicinal administration of exogenous ketones that I've ever known to be discovered back in the 1950s and '60s in children.

[00:03:38]Now, fast forward to the 1960s, 1,3-butanediol, which is actual by chemical structural an alcohol, but actually when converted turns into ketone bodies in the liver.

[00:03:48]This was actually used in the 1960s by MIT to be looked at as an aerospace fuel substrate. One, it's extremely shelf stable. Number two, it readily converts to ketone bodies. And number three, it's nutrient dense. It's a form of fat, right? So, or it can be fur- converted to a ketone body, which is more nutrient dense than carbohydrates and other fuel substrates. So, that was actually the second form of looking at ketone bodies and actually been explored in many different models like uh dogs and other model systems as a potential tool. Fast forward to the last, let's say, 15 to 20 years, uh there was a project by the uh US Department of Defense called DARPA where they looked at uh something called the novel formulation from they funded the National Institutes of Health and also Oxford to develop a novel ketone formulation that could be used as a tool to optimize metabolism and potentially performance. And they developed 1,3-butanediol attached to beta-hydroxybutyrate.

[00:04:40]This combination, when ingested, cleaves off beta-hydroxybutyrate and then the 1,3-butanediol readily converts to ketone bodies after liver processing.

[00:04:49]As a result, it elevates ketone bodies to levels of that you'd only achieve with uh days and days, maybe even weeks, of fasting within 15 to 30 minutes.

[00:04:58]And so, what they found is that administration dramatically shifted almost uh almost all of metabolism um through various tissues. It's quite remarkable how powerful the exogenous administration of these these substrates were. What was most interesting in that study is that they actually showed at the end of it, in the Cell Metabolism paper, that it actually improved high-level athletic performance in a cyclist trial uh by 2%. Now, someone may say, "Oh, 2%? Who cares?" Okay. Well, I would agree for most people 2% is probably not that relevant. But for a high-level athlete, 2% may be first or second place, and then it all becomes highly relevant, right? Especially when you control it for athletes where margins um are often uh hard to grab.

[00:05:37]So, that really caused this explosion of interest of exogenous ketones in the sports performance space. We've done a lot of studies in various ketone formulations on their ability to regulate performance, sports performance. And we published a uh really kind of systematic review in 2022 in sports medicine by Brennan Egan, actually looking at the evidence on sports performance. And you see that some and some exogenous ketones in certain context improve sports performance, some other context maybe not so much. It really depends on the type. And when they seem to be maybe most applicable is based on the type of ketone and also when they are administered over prolonged strenuous forms of exercise.

[00:06:15]And that seems to hearken back to a recent review we published looking at what's the key determinants of exercise performance. And it appears to that the sustainment of brain energy metabolism is a particularly important way to maintain performance. And so this really emerged this this field of sports performance, but there's a lot of nuance there and we're in early days in understanding when and where to apply them. In fact, we just completed the largest ever dose of exogenous ketone administered over the longest period of time in a randomized control trial. Just got published two days ago. Actually not two days ago, but some period of time recently.

[00:06:50]And what people will see is that over 31 days consuming 90 g of ketones per day.

[00:06:55]Okay, and this is the highest dose ever administered over any period of time.

[00:06:59]We found that it was safe and tolerable, which is encouraging. It shows that people can tolerate these molecules at high doses. And this is a 1,3-butanediol component attached to a BHB molecule.

[00:07:10]And we also showed that it improved cognition. So individuals who were already runners who were healthy and young, so they already are pretty much at what you'd expect to be peak level performance physically and mentally, they actually saw a performance boost.

[00:07:24]They had better executive function.

[00:07:26]They were able to engage in better cognitive switching task when two different tasks were presented to them in incongruent manners, meaning they were challenged with kind of inconsistent information. They were able to to look through that and actually choose the correct response. It's a very mentally engaging and difficult task that they were asked to endure and they were seeing performance improvements or they had resilience against performance decline.

[00:07:52]And so, this is very consistent effect.

[00:07:54]We see that exogenous ketones appear to improve, sometimes even the well person's cognitive performance.

[00:08:00]Some other things that we found quite interesting is because it it again, in this particular study, we only did a 5K time trial and we didn't see any performance differences, you know, no improvement or decline.

[00:08:09]What we did see that we found very very interesting is that the application of exogenous ketones over 31 days is what happened after we stopped administering exogenous ketones. So, even when sustaining ketones over 31-day period at these dosages, we saw that after you stop taking them all together, that you during a graded exercise task, which is this incremental increase in exercise intensity over a period of time, we saw that the placebo group saw a reduction in oxygen either uptake and or utilization. Whereas the ketone group sustained a higher level of oxygen uptake or utilization in VO2, absolute VO2, which is the volume of oxygen consumed. This is an indication that ketone bodies are causing permanent or semi-permanent changes in the way the body is either uptaking oxygen, utilizing oxygen, or how the muscle is actually delivering it. There was an analysis around five five or six years ago looking at just utilizing one dose of ketone bodies after exercise. And what they found is just over three weeks period of time that the administration of exogenous ketones allowed for athletes to have resilience against overtraining. So, they were able to do higher volumes over extended periods of time and they increased the amount of vascularization and capillarization in the muscle.

[00:09:29]Which means that they were actually to able to increase blood flow and vascular changes within the muscle that would in theory improve their performance. Again, they did improve their performance consistent with the study outcome.

[00:09:40]But, this is also consistent with emerging evidence that shows that a single dose of exogenous ketones increase erythropoietin or EPO, which is the drug that was abused by many Tour de France athletes to increase red blood cell count. Well, if you have increased red blood cell count and you have increased oxygen delivery to the muscle, this is all making sense, especially if they're administered over chronic periods of time. So, our data is just the first to ever show that even after you stop taking them, you have persistent uh and permanent or maybe semi-permanent changes to how your physiology works. But, we've done a number of other studies uh just in other environments including uh some work funded by Special Operations Command uh administering exogenous ketones. That was actually a project utilizing HVMN or KetoneIQ, which is a 1,3-butanediol-based product. And at that time, they had it at linked to BHB. And when we administered that, we actually saw that uh when exposing individuals to either 15 or 20,000 ft altitude almost instantly, not quite Everest but pretty close to it, that that reliably reduces cognition, executive function, and other key parameters, which obviously are highly relevant for individuals exposed to high altitude exposure and need to perform at optimal levels, athletes going into altitude, or special special operations forces who are going to be flown into environments of high altitude and have to perform immediately both physically and cognitively. What we saw is that ketone bodies actually not only increase SPO2 levels, so the amount of oxygen within the blood, again also showing that ketones regulate the amount of oxygen in the body is able to absorb, and increase cognition, again consistent with other literature even outside of extreme environmental settings, that ketones seem to support brain energy, function, and metabolism. So, exogenous ketones are quite a unique um field uh that is being now applied not just to the well person or a high-performing individuals, but now to disease populations who are experiencing cognitive decline um or mental health conditions where they're trying to understand can these improve, uh, conditions like anxiety, depression, or otherwise.

[00:11:39]>> Okay, so we know they're working. My question, do we know if there's any difference between somebody who is ketogenic versus somebody who's on a more standard type diet using them in the latter to hack ketosis?

[00:11:54]>> Yes, that's a great question that we really don't have any a low lot of research on. So, we can speculate here.

[00:11:59]I'm going to be very clear to the audience that this is what I'm talking about now is very much speculation with very little evidence to know which way is going to happen.

[00:12:06]There's only been one study by Jeff Volek's group, uh, at Ohio State University that actually looked at the co-administration, uh, ketone, uh, components. They used a ketone salt that also had caffeine in it intake on in top of a ketogenic diet, but it's really hard to tease apart from that study what the implications of ketone supplements will be on top of a ketogenic diet. But, one would suspect that the body is always going to work to balance itself.

[00:12:28]So, if you're on a ketogenic diet, you're pretty you have low insulin levels, you have low glucose levels, you're producing, uh, higher ketone levels from higher fat breakdown and and higher utilization of fat as the energy source, that if you now infuse higher levels of ketones on top of that, yes, you would have, in theory, the machinery to more readily utilize the utilize those, uh, fuel substrates, um, and maybe do so more efficiently, but you also might do it a partial degree jump in the amount of ketone production because we know that ketones, in and of themselves, are self-regulating. We know that ketones can also, uh, stimulate a very small, but non, uh, neglectable amount of insulin. And the reason it does that, it all it also stimulates and and attenuates fat breakdown. And why does that happen, Jess? You think, okay, a ketone body, why would it try to blunt fat breakdown? Well, when ketone bodies are extremely high, Jessi, the body needs a way to know to not cause them to just continuously be broken down, uh, un- in uncontrolled manners. So, the body has built-in mechanisms to to self-regulate. So, when ketones are extremely high, they actually stimulate GPR 109A receptors on the fat cells, which actually temporarily attenuates some of the fat breakdown. This is a way of when ketones are high, it's preventing ketone bodies from coming higher than are necessary.

[00:13:45]Additionally, when ketones are high enough, we also know there's evidence in cell culture models by Jim Johnson's group that ketone bodies can actually help attenuate stimulate just a little bit of an insulin response at certain levels.

[00:13:56]And again, that's another way of having self-regulation. It's a way of preventing ketone bodies from becoming completely unregulated. Why is that important? I'll use an example. My disease, type 1 diabetes, where in the complete absence of insulin, ketone bodies go so high, so rapidly that they It's not the ketone bodies that cause a problem. It's actually the acid load that comes from the production of ketone bodies that is so rapidly elevating that can't be controlled by the body's blood buffering capacity through bicarbonate.

[00:14:28]And as a result, acid levels get too high and they have something called diabetic ketoacidosis. So, the body, when it's functional and doesn't have a complete or a tissue system not working like in the context of type 1 diabetes, it's working to self-regulate.

[00:14:42]So, if you're on a ketogenic diet and you take exogenous ketones, you almost certainly would be able to utilize them potentially more efficiently because you've developed the machinery to rapidly metabolize exposure to ketone bodies. But, you're probably also going to dampen to a degree some of your own ketone production at least for a window of time simply because that's how the body is self-regulating to keep you in balance.

[00:15:02]>> Early in the conversation, we were talking to the newbie about adopting a keto diet, you mentioned salt and the benefit there for the new person.

[00:15:13]How do you look at things like MCT oil, exogenous ketones as a tool in that earlier phase?

[00:15:20]>> Sure. So, MCTs can be utilized uh as a form of fat in a diet. You need to be very careful with MCTs because if you're never exposed to them before, you have to slowly introduce them, otherwise they can cause GI discomfort. So, slowly introducing them over time is a very effective way to blunt some of the gastrointestinal issues that when someone consumes at very high levels for the first time may experience. So, just slowly incorporating that's important, but they do increase ketone bodies. And in my all intents and purposes, they're not going to do anything to attenuate your They're only going to be beneficial in my opinion uh unless they cause gastrointestinal issues on a ketogenic diet. Uh ketone salts is another form of ketones tell you it's ketone bodies. So, these can provide mineral loads along type of ketone uh levels as well. So, they're ketone bodies attached to a salt uh whether sodium, magnesium, potassium, calcium, one of these minerals. Uh but you you can consume those up to a certain level. You have to be cautious because again, if you're someone with hypertension or other issues like that, you can't consume you're not recommended to consume uh an overabundance of sodium. And for most individuals, uh it's very hard you have to be cautious of the amount of mineral load that you're consuming. So, to a degree, you can consume these, but they're somewhat self-limiting and that you can only consume so much without uh uh without uh maybe consuming too much sodium. So, that's always that's the limitation there. So, for MCTs, it's gastrointestinal issues that you can only have so much and you can't over consume MCTs and just get more high ketone levels because it's a fat. So, it's self-limiting in its digestion rate.

[00:16:49]Salts are rapidly digested into ketone bodies. They come with a mineral load.

[00:16:53]You have to be cautious about how much that mineral load you're consuming because you don't necessarily want to over consume a mineral. So, you want to keep that within balance, but they're very rapidly form of rapid form of uh ketone elevation. You have something like 1,3-butanediol, which has been used for 60 years. Readily converts over to 1,3-butanediol um and uh are actually commercially available in a reasonable cost. They don't come with a sodium load um and they're generally well tolerated within a reasonable dose.

[00:17:20]And like a product like Keto 1 That's a company that sells a product like that.

[00:17:25]We've done research on that before. Then you have other molecules where it's 1,3-butanediol attached to another molecule.

[00:17:30]Could be acetoacetate molecules. It could be 1,3-butanediol or sorry, beta-hydroxybutyrate. And these are just other tools of what they call the monoester or acetoacetate diester that have been used in various contexts.

[00:17:42]And this is just attempting to further elevate ketone bodies to some degree. And the question is, you know, for a lot of these things, it really comes down to what's the goal. If your goal is to seek cognitive benefits, many of these will do that. And we've seen that with many of these iterations.

[00:17:57]And then it comes down to what's practical and and cost-efficient. You know, can you can you consume that's reasonable and practical? Um And you know, for some individuals, they want to boost the highest levels possible. Okay, well, then they have to consume something that's going to allow for that. If you want to have a kind of a middle ground and have elevation of ketone bodies to therapeutic levels for whatever your goal is, but be cost reasonable, then it's a different one.

[00:18:19]So, there's a lot of different considerations here on what someone may or may not want to use.

[00:18:24]But a lot of times more may not always be better.

[00:18:29]Sometimes it's actually about hitting the minimal effective dose with these these strategies to maximize your benefit without over consuming them, which I think is a generally good principle for most scenarios. Typically, there's a point of diminishing returns with over consumption with anything.

[00:18:45]>> Since you made it to the end of this clip, I know you're going to love the full episode. Click here to watch. I'll see you over there.

[00:18:51]>> A very low-carbohydrate and very high-fat diet known as the ketogenic diet has been known to have powerful [music] metabolic changes. When people utilize these high-carbohydrate diets since the 1970s as the one optimal [music] form of diet, it is