Do the Potential Benefits of Ketone Supplements Go Beyond Performance?

We talk with one of the top researchers in the world on ketone supplementation, Dr. Brendan Egan. We get into the types of supplements, their impact on our health, and possibly the least interesting question – do they help performance?

FT EP 285 with Brendan Egan

Six or seven years ago, ketone supplementation among professional athletes became all the news. Rumors had it that many of the riders in the Tour de France were taking ketones to help their performance. So, the question then became “Do ketones help performance?” It’s a question that’s been addressed on multiple podcasts and in countless articles.  

The truth is that might be the least interesting question about ketone supplements. At least the answer isn’t going to be very exciting. What is more exciting are all the other questions about ketones – how are these supplements different from the ketones produced in our bodies? What impact do ketones have on our health including conditions like cancer and neurological diseases? And finally, does taking ketones help our recovery and prevent overtraining?  

Joining us today to answer these questions is Professor Brendan Egan from Dublin City University in Ireland. Dr. Egan is one of the top researchers in the world on ketones and has explored both their potential performance benefits, but just as importantly, their health impacts. He recently published a 40-page review summarizing all the current research on the performance effects of ketones and the results were one-sided.  

Joining Dr. Egan, we’ll hear from ex-pros Alex Howes and Kiel Reijnen who were there when ketones were all the rage among the pros. We’ll also hear from Dr. Paul Laursen who has done some ketone research himself, and finally we’ll hear from Starla Teddergreen, an ultra-distance gravel rider who has been using ketones in her own training.  

So, get ready for this supplementation deep dive, and let’s make you fast! 

Episode Transcript

Rob Pickels  00:04

Hello, and welcome to Fast Talk your source for the science of endurance performance. I’m your host Rob Pickels here with Coach Connor. Six or seven years ago, ketone use among professional athletes was a poorly kept secret. As rumors were that teams are using them to fuel some impressive victories.

Rob Pickels  00:22

Rightfully, everyone has been asking, “Do ketones help performance?” The truth is the answer is a bit boring. It’s the word maybe. What’s more exciting are all the other questions about ketones: Does taking ketones help our recovery and prevent overtraining? Or, how about what impacts to ketones have on conditions like cancer and neurological diseases?

Rob Pickels  00:45

Joining us today to answer these questions is Professor Brendan Egan from the Dublin City University in Ireland. Dr. Egan is a top researcher and recently published a 40 page review summarizing the current research on the performance effects of ketones. Beyond that, he’s interested in the health impacts ketones may have. Joining Dr. Egan will hear from pros Alex Howes and Kiel Reijnen, who have seen ketone use in the pro peloton, as well as Starla Teddergreen, who has been using ketones in her own training. We’ll also hear from Dr. Paul Laursen who has investigated this question on his own. So let’s learn the difference between endogenous and exogenous ketones and let’s make you fast.

Trevor Connor  01:29

While the basic principles are the same, there’s a big difference between coaching professional and age group athletes. Professional athletes are the elite, the 1% of the sport the best of the best. These athletes vote everyday to train and demand the most from themselves and for their coaches. In our newest release for the craft of coaching with Joe Friel, we explore the art and science behind coaching professional athletes. Check out the craft of coaching module 13 at fast talk today. Well welcome Dr. Egan. It’s a pleasure to meet you. We’re really excited to have you on the show.

Dr. Brendan Egan  02:04

Thanks for the invite. It’s something I like talking about. So I’m delighted to be here.

Trevor Connor  02:07

Yeah. And I got to say I mean, quick step back, you know, we were going through the research on ketones, we are trying to find, you know, what’s, we don’t want to just do the standard episode here of do they help performance? Are they not help performance? We’re looking for a bit of a twist on this. So we were going through the research and I was really impressed how often your name came up. This is really an area that you seem to know a lot about.

Dr. Brendan Egan  02:33

Well, hopefully I convinced you that Oh, no, we we’ve been we’ve been active in this area for six or seven years now. And some of our work has been obviously focused on the performance side. But through a couple of reviews and different bits and pieces. We’ve also been interested in the more therapeutic application. So hopefully, we can get time to cover both of those angles today.

Rob Pickels  02:54

And it seems like you mentioned six or seven years, it seems like that’s the bulk of the research that’s occurred is in the past six or seven years, which is really interesting on this topic, because you can go back to 2019, read some reviews, some meta analysis. And then fast forward to today, there has been almost a tripling of research and understanding in that time. So this is a conversation that kind of needs to continue to happen in real time. Because you know, if anybody publishes a review in 2022, there’s already a dozen more studies that came out in 2023. It is

Dr. Brendan Egan  03:29

very fast moving at the moment, and you’re right, like 2016 was when the first big paper, let’s say came out in terms of exercise performance. And this ketone mono Ester, as I’m sure we will define as we go along here, we wrote a fairly large review that was published in late 2016. Online and then obviously, the 2017 citation. But at that point, those are kind of the two main articles, I think that would have stimulated people’s interest in the area. And I suppose the other big change that’s happened over the last number of years, I mean, it was the precedent was set with the 2016 cocktail, pepper and cell metabolism. That’s when the ketone mono Ester became commercially available shortly thereafter. And that’s really been, it’s the kind of the greater commercial availability in the last five years, let’s say that’s really amplified the amount of research that’s been done in this space, and it’s a lot of people find it quite an interesting topic. And there’s a good bit of hype around and there’s a lot of press, and so you know, that gets people’s interested as well.

Trevor Connor  04:25

So that kind of leads to a good starting point for this whole conversation. So we’re gonna be focusing on exogenous ketones. So there’s endogenous and exogenous endogenous ketones that are produced by your body. Our focus, as I said, is the exogenous which are ketones that you consume. So let’s talk a little bit about the different types first, can you tell us a little bit about what type of ketones are found in the body and I know that probably the primary one is BHB.

Dr. Brendan Egan  04:55

Yeah, exactly. So when we talk about ketone bodies, we’re referring to three more molecules in this case, which are acetyl acetate be dilute actually butyrate, which we refer to as bhp, I’m sure throughout this conversation, and the other one is acetone. So as you mentioned there, these are produced naturally within the body through a process known as keto Genesis. And that’s a metabolic pathway that takes place in the liver almost exclusively. And the the end product is a C two or three ketone bodies. But it turns out that Peter hydroxybutyrate is the one that circulates at the greatest concentration within the within the blood. And that’s the one that tends to be the focus of a lot of the measurement and a lot of the research that’s been done in this space. So we have these naturally produced ketone bodies. And they’re, as I said, they’re being produced all the time, they tend to be amplified them they’re the rate of mutagenesis is amplified in scenarios where there’s low glucose availability in the body. So these are scenarios like a low carbohydrate or ketogenic diet, as the name suggests, extending that out to something like a fast would be a little bit more severe, let’s say, and then a starvation type response. And I suppose to just take a step back, that’s where a lot of the initial interest in the in ketone bodies in the in the 60s, was the fact that they are clearly amplified as a survival mechanism in scenarios where you have this low glucose availability that was demonstrated in these starvation studies. So that’s kind of the big picture from the endogenous production point of view. But then we have exogenous sources of ketone bodies, and the so called exogenous ketone supplement class. And these are kind of broadly speaking, there’s two ways that you can consume these exogenous ketone supplements. One is as a as a as a ketone body itself. And that effectively goes into the bloodstream and elevates ketone bodies. The other way is to ingest the ketogenic precursor, and that will then be metabolized by the liver to produce beta hydroxybutyrate within the body and therefore elevate ketone body concentrations, and then the so called ketone Ester scenarios where you do both, you effectively ingest a molecule that has a ketogenic precursor molecule and a ketone body, and they’re bound together or esterified. And that’s the so called mono Ester or the digesters that people talk about. So that again, there’s a underneath that broad category of exogenous ketone supplements, we can probably talk about those different ketone precursors, ketone, salts, ketone esters, they all have slightly different properties. But that’s essentially what we’re talking about when we say exogenous ketone supplements.

Trevor Connor  07:29

For our audience, when you hear precursors, probably the most common one out there that you’re gonna see in all the supermarket’s is the medium chain triglycerides, as your MCT is, you might see coconut oil all over the shelves.

Dr. Brendan Egan  07:43

But there’s an interesting point to make there, which is that even medium chain triglycerides or medium chain fatty acids, there are a number of fatty acids within that category. And they have slightly different channelings. And those channelings will have slightly different ketogenic properties. So in the case of coconut oil, you have a lot of lauric acid there, which is a C 10, or C two, it depends on the composition of the coconut oil. But that is not as good a ketogenic precursor as C six or ch. And so again, there’s small nuances there that that certain companies are taking advantage of. And then the other point maybe to make about the ketogenic precursors are this molecule butane dial, and so butane dial is a kind of molecule related to an alcohol and it’s processed through the liver, and produces, as I said, ketone bodies. But the reason that’s of interest is because butane dial tends to be the molecule that is associated with the ketone body when making these ketone esters. And more recently than some companies have begun to sell beauty and dialyze, its own individual molecule as a as a sort of exogenous ketone that again has generated quite a bit of interest, because it’s a lot cheaper than the ketone esters, which we know are quite expensive. And

Rob Pickels  08:53

something that I want to point out as we’re discussing the formation of these ketone bodies is that regardless of whether or not it’s an endogenous, and again, a reminder that something that’s produced by the body, or an exogenous, which is something that’s consumed, both of them are going to continue into metabolism, right, by being converted, essentially into acetyl. Co. A, and then going into the TCA cycle, and continuing almost as if we were going through glucose oxidation or fatty acid oxidation.

Dr. Brendan Egan  09:24

Yeah, it’s a great point I should have mentioned, you know, why are these been produced and the reason is because they in the case of starvation, the main thinking there is that the survival mechanism is that the brain is experiencing a certain amount of low glucose availability, we need an alternative substrate to support brain metabolism. free fatty acids can’t cross the blood brain barrier. So there’s a need then for another molecule, and it’s the elevation of free fatty acids, dry ketogenesis within the liver, which then allows the substrate to or fuel for want of a better word to get to the brand. So it turns out that Many tissues within the body can use ketone bodies as a fuel, the extent to which they do so varies considerably. So again, in a brain and starvation, it can contribute 50 60% of energy metabolism coming from ketone bodies. And skeletal muscle, it could be five or 10%. On average, depending on the study that you look at. In the failing heart, it seems for some reason that the failing heart begins to rely very heavily on prefers to use ketone bodies as well. So there are, you know, again, across many different tissues and many different metabolic states, there are specific considerations. And I think that’s where in this field, there becomes a kind of a need to dig into the weeds a little bit because it does vary in terms of what organ you’re talking about what metabolic state you’re talking about, when we talk about preferred or dominant or whatever the word that gets used for for ketone bodies and their uses a few.

Trevor Connor  10:49

Something that I found really interesting. There’s almost a parallel here. So we did an episode not that long ago, where we talked about lactate metabolism, we’re talking about a lot of the research of Dr. George Brooks, and pointed out that lactate is in a lot of ways a transport mechanism for glucose. So it allows you to take tissues that are producing a lot of lactate is transported out of the cell, send it to other tissues that can take it up and use it then take it into the TCA cycle. There seems to be almost a parallel here with ketones because ketones in the body are produced from acetyl CoA, which is essential for the using fat for fuel. And it seems fairly easy to transport ketones. As a matter of fact, what really caught my attention is the same MCT transporters that transport lactate around the body are also what transport ketones and once the ketones get to the tissue that can use it, particularly the brain that is converted back to acetyl CoA. So there does seem to be a parallel that ketones are a transport mechanism for the Krebs cycle to keep this oxidative metabolism going.

Rob Pickels  11:59

Well, and to further that a little bit, the primary source, Dr. Egan, as you pointed out, creation of ketone bodies is in the liver, but the liver itself doesn’t necessarily metabolize or use them. So it’s creating them for other tissues to benefit not for its own benefit.

Dr. Brendan Egan  12:14

And it’s in response to a change in, you know, substrate availability. So it’s, it’s a point well made, I don’t have much more to add there. Just a point that comes back to mind though, when I when we talked about it being a fuel for other organs, it’s also worth pointing out that it’s, it can also act as a signaling molecule. And I think that’s probably where we think more about ketone bodies as the so called pleiotropic compounds, you know, the fact that they can do many, many different things in different tissues. It’s not just that they act as a substrate, it’s that they can actually affect metabolism in different ways within within cells, by virtue of the fact that they can activate different signaling pathways. And there are activities around say things like protein synthesis, anti inflammatory effects, there’s likely to be effects within the brain, on that inflammation side of things as well. And so the point to make is that even things like epigenetic signaling or you know, epigenetic marks can be impacted by an elevation of BHB concentration. So it is, it’s much more than a substrate as I think there’s a nice review article that points that out.

Trevor Connor  13:16

Yeah, I think we’re actually going to dive pretty deeply into that today, the whole role as a signaling molecule and how it can it can help health. It’s about that. I think Rob, and I talked about this ahead of the show that that’s actually what’s more interesting than is their performance benefits to ketone bodies.

Dr. Brendan Egan  13:34

I would wholeheartedly agree. I mean, in some ways, it’s, it’s interesting, because we have our backgrounds that we’re interested in sport and performance, and he loves to hear about new or novel things being tried and so on. But that hype and and in some ways, in some ways, you know, there’s a controversy there. Because, you know, as we’ll probably talk about the evidence for performance benefits isn’t great. But in terms of the preclinical work and some of the mechanistic work that’s been done around therapeutic applications, there’s a huge amount of positive findings coming out from there. So if if someone said to me, you know, what’s the most interesting thing about ketone bodies, it is more or less than the therapeutic application players, not necessarily in sports performance.

Rob Pickels  14:11

And so because people are finding potential benefits, like we said, We’ll and we’ll talk about this on the performance side, there’s potential therapeutic benefits, more and more companies, because they’re becoming readily available, more and more companies are putting products on the market. I would love to talk before we dive much deeper about different types of exogenous ketones. You mentioned previously, ketone esters. Maybe we can talk more about that. But I’d love to also discuss ketone salts, and then raspberry ketones. And you chuckle

Trevor Connor  14:47

I saw that in the outline, and I was wondering who added that?

Rob Pickels  14:50

No, I added that I added that because I think that it’s important, right? Because and here’s the thing, I’ll just get it out of the way Raspberry Ketones are not ketones at all. And so So people will mark it raspberry ketones for things like weight loss. And I’m not even going to discuss whether there’s, you know, benefit or efficacy there. But I don’t necessarily want people to walk into their local supermarket see raspberry ketones and say, Oh, this is what all those guys are talking about. I’m gonna go ahead and take a lot of raspberry ketones here. Totally different. So we got to dive into this because I need to know what these are. You’ve never seen raspberry ketones never seen raspberry need to shop more. The Google algorithm hasn’t hasn’t tried to sell you raspberry ketones from all your research yet. Oh, boy.

Dr. Brendan Egan  15:36

So this question of I guess it’s already ingestible exogenous ketone supplements that that that orally ingested was a key element here because you know, the research on ketone, ketone metabolism and ketone bodies, I mean, it goes back a century and even the study of metabolic effects of ketone esters, for example, has been studied as as early as the 1970s. At that time, though, they weren’t really available for oral ingestion, so that it was only in the since the turn of the 21st century that that there’s been this availability of exogenous ketone supplements, and really only as I said, in the last six or seven years, have they been commercially available? And again, the whole backstory as to how they were developed and so on is interesting, but probably beyond the scope of what we talked about today. Yeah, so the the kinds of categories that I mentioned, there are the, you know, the ketogenic precursors, like I said, and medium chain triglycerides were being studied in the 90s for effects on on performance. And they at that time, aren’t really being studied as ketogenic precursors, they were just being studied as an alternative to carbohydrate or support for carbohydrate based fueling, fast forward that into, as I said, into the 2015 1617 range. And now there seems to be available ketone salts, and ketone esters, and more recently, then some developments on beauty and diet and so on. So if we just take if we just explain what they are, so the reason why it was, you know, people knew that ketone bodies were, as I said, having many many effects across multiple organ systems. Why weren’t they a supplement before? Now, the reason was, because it wasn’t possible to get them that oral orally ingested, perform. ketone bodies themselves are very acidic. So it’s very difficult to ingest them as a free acid without causing GI upset and having negative pH effects as well. So initially, some of you already work with ketone salts. So now we’ll define what ketone salts are, it’s where you take a ketone body and essentially buffer them by combining them with with salts, usually calcium, magnesium, sodium, and so on. So the challenge from the with the ketone salt is that when you ingest a ketone salt in a quantity, that would produce a meaningful increase in beta hydroxybutyrate concentrations within the blood, you’re also ingesting large salt ion load. And some of the early work that we did and others did was finding that when you were trying to push the doors that you would use for ketone salt in order to increase BHB concentrations, you end up getting a lot of diarrhea, you know, and so it’s kind of a bit like the old sodium bicarbonate story, you know, it’s much too much salt, you know, hyper osmotic load within the intestinal, you know, diarrhea, seals, and the ketone salts are still out there. And again, we could drill into more detail there, if you want. The reason I started hesitate is that we have to then start talking about receive economic CMYK, mixes and so on, which kind of gets a bit complicated, but let’s just say that there are, let’s say, more pure versions of ketone salts are now coming out that have less of a salt load and perform a little bit better. And it’ll be interesting to see over time whether those become more widely available, because they will be cheaper than the ketone ester. And that would that would be an important consideration, I think, as we’ll talk about, right, the next one.

Trevor Connor  18:47

Let’s move on. Yeah.

Dr. Brendan Egan  18:49

So that’s the ketone salts. And again, much of the performance research that we end up talking about is going to be the ketone esters, because like I said, it’s not that they’re totally ineffective as ketone salts are, aren’t totally ineffective for elevating ketone body concentrations, but they’re kind of prevailing thinking at the moment is that there’s probably a threshold or a sweet spot that ketone body concentrations need to get to, in order for there to be a performance benefit. On the other hand, for a therapeutic dose, it might be a little less than what we think there. And so, you know, I’m not ruling out the fact that ketone salts couldn’t be used in other scenarios. But from a performance point of view, the vast majority of research is focused on the so called ketone esters.

Rob Pickels  19:27

So to touch on that really quick, if I remember correctly, and I’m hoping you correct me because I’m going to be wrong. ketone salts, we can see an increase to about one millimole within the body and then when we talk about ketone esters, it’s in what the three to five millimolar range.

Dr. Brendan Egan  19:44

So a lot of it depends on the dose. Let’s define actually because I should have done that at the start when just in the in the resting stage, having eaten a meal, ketone body condiment, let’s say BHB concentrations will be around point one millimolar and after an overnight fast and I get up to point Two Point 3.4 After 16 to 24 hour fast, maybe they get up towards point 6.7 minimum per liter. And as you rightly say there are ketone salts at the doors that are generally used in the studies that have been published are getting around about the one millimolar range. So it’s a it’s a significant increase over arresting and over staying overnight fast, but still less than would typically be seen on a ketogenic diet, which is typically in the kind of one to three millimolar type of range for people who are strictly adhering to a ketogenic diet. The

Trevor Connor  20:30

number to throw out here is kind of the official definition of being in nutritional ketosis is over 0.5.

Dr. Brendan Egan  20:36

Yeah, correct. Yep, yep. And like that. So ketone salts can, relatively easily get someone into, you know, acute nutritional ketosis as it’s called. But whether that would have a performance benefit, I think is the is the point that we might be debating here. But then again, you could argue, well, maybe even as we’ve seen the ketone Ester work, even when the concentrations get up above the one or two millimolar range, it’s probably not having much of an effect on performance anyway. So it could all be a moot point. But in relation to your question, Rob, about the ketone esters, you’re right, it’s obviously dose dependent, but the ketone esters, you know, the kind of concentration is typically used in the research studies, which is usually around about 500 milligrams per kg of body mass. So basically, like, you know, 30 grams 40 gram type doors for the average size individual, they’re typically producing ketone body concentrations of around about three to four millimolar at rest, because we utilize a little bit during exercise tends to be around to minimum order during exercise. So they’re the types of ranges that we’re that we’re getting into. So I think the the point to make there is that ketone salts generally don’t get up to that level, whereas the ketone esters do and they’re kind of very predictable and far amadores dependent bases, you can really nicely tighter the concentration of bhp, if that’s your goal.

Trevor Connor  21:56

So Dr. Egan, I got a bit over the weekend, I had read several studies leading up to this recording but decided let’s let’s read one more. So I pulled out a review that you had written in 2022 going oh, quickly get through this opened it up. It was 43 pages along over 400 references, it would I would say it was a slightly thorough coverage of ketones and their impact. It was actually a really good read. But actually made a note here because this is what I found most interesting. You talk about the the pleura tropic effects and you say ketones have these benefits by modulating substrate utilization, inflammation, oxidative stress, catabolic processes and gene expression. So I would love to dive into that because as Rob said, at the very beginning of the show, everybody wants to talk about well, do they help performance? But I’m not sure that’s the interesting side of ketones. I think it’s the health impacts. That’s probably the more interesting side of these. So let me throw that to you. I know there’s there’s been shown to be benefits and Alzheimer’s has been shown to be benefits with cancer with oxidative stress with inflammation. Let’s kind of dive down that road and talk a bit about that.

Dr. Brendan Egan  23:16

So it echoes the point that we spoke about earlier, which is just as you said, these, these prior tropic effects and the ability to act both as a substrate but then also act as a signaling molecule. So in the case of you Let’s take something like TBI, for example, traumatic brain injury. So one of the hypothesized mechanisms there is that in the case of a TBI, there’s an bioenergetic crisis within the cell where effectively glucose utilization is not proceeding the manner that would normally do and that deficit that’s created might contribute to the severity of symptoms that follow a TBI. And in the again, this is now a preclinical research that’s been done. But in that work that’s been done providing or producing exogenous ketosis through these ketogenic precursors or through the ingestion of exogenous ketone supplements that can offset the ran energetic deficit by providing substrate to the brand. So that’s an example where you have a model the molecule or the or the metabolic state of potentially acting as just as a substrate providing that additional fuel in a scenario where or there is a deficit. You take it down to another level where we we published a piece of work summarizing the so called anti catabolic effects of exogenous ketones. And in that case, what we were talking we were summing up some of the literature around work that have been done with the infusion of ketone bodies, during either arrest and ability to stimulate muscle protein synthesis that process that leads to tissue growth is generally the way people focus on rest repair, recovering that kind of thing. But then also on the on the flip side of that by virtue of the fact that ketone bodies can act as anti inflammatory signaling Marlet rules that that can almost blunt the negative effects of an inflammatory insult on the body. And in the case of the work that we were referring to, it was showing that acute exogenous ketosis is blunting the inflammatory effect and therefore reducing signaling markers that are catabolic in nature. So they’re just they’re two very, you know, two very different examples. One is as as a substrate and the brand. The other is as as a signaling molecule or an anti inflammatory signaling molecule in muscle tissue. So again, just to illustrate the the broad range, and in terms of organs, mechanisms, and potential effects there. So I think that sort of sums up why there’s just this interest in the in the potential health benefits,

Trevor Connor  25:42

right. And suddenly, I found really address it is looking at the impacts on cancer. So again, anybody who’s interested, go back a few episodes and listen to that one we did on the work of Dr. Brooks, where we talked about the fact that something that’s very necessary for cancer formation is to have your your cells in a state of proliferation. And there’s a lot of recent research showing that carbohydrates, high glucose levels really promote that and is necessary, actually for the growth of the cancer cell. And we talked a lot about the Warburg effect there. So one of the things that’s really interesting about ketones is, as you point out, they can replace glucose as a substrate for fuel, particularly in the brain and heart and some of the other tissues. So here’s a potential way to continue to fuel important tissues without having that elevated glucose that can, unfortunately do some of these negative effects.

Rob Pickels  26:37

And not only that, Trevor, as far as I know, the ingestion of ketone esters and ketone salts will actually lower glucose within the bloodstream. Some of the early research that’s put out there was on glucose tolerance tests and blunted response in glucose within the blood.

Dr. Brendan Egan  26:54

Yeah, I got very interesting lines of work there. So if I just started with a comment on the on the cancer side of things, it’s actually probably an example of where there is some conflation of ketogenic diet and exogenous ketones, like in the cancer domain, there’s a huge amount of interest at the moment in ketogenic diets as adjunct therapies in you probably come across this work. And again, quite controversial, because there are some people who are obviously strong proponents of it. Others say that, you know, the evidence is weak and so on. And because I don’t work in the field, I don’t have a strong view as to who’s right or wrong there. But the premises as you talk where they’re traveling is this idea of potentially starving the cells of the Warburg effect can have a you know, can have a beneficial effect when combined with other therapies. On the other side, and Andrew coot, Nick has done some work with as well. He’s published some interesting work with exogenous ketones now that the ketogenic diet exogenous ketones in the cancer model, and in that regard, well, he’s not really talking about the exogenous ketones impacting on the cancer itself, but rather on the catabolic, the ataxia that occurs with with cancer. And so because there’s such a, there’s an inflammatory milieu that comes with cancer, that the in his mouse model that he worked with that you do see a blunting of that effect and an anti catabolic effect of these ketone products. So it’s a very interesting area, again, coming out from a couple of different angles there on the glucose lowering effect. Rather, that to me, again, is a very interesting area with one major caveat, which I’ll get to in a second. But there’s kind of two ways of thinking about the the effects that have been seen in those studies. One is that the ketone bodies, if they’re just taken in the in the fast and arrested stage, they will tend to lower blood glucose concentrations. The other is that if you if they’re ingested with carbohydrate ballers, they were blind to the rise in glucose that occurs. So from the point of view of say, for example, of a type two diabetic or someone with impaired glucose tolerance, they’re potentially lowering, you know, the concentration of glucose in the fasted state, or that’s technically not fast. But you know what I mean, in the resting state, let’s call it, but they’re also that mitigating the rise that occurs. And there are several, there are several other therapies that are used in diabetes that tried to just block the rise in glucose or, you know, the use of fiber, for example, or the use of protein congestion with carbohydrate containing meals. So this idea of trying to like blind the rise in glucose or hyperglycemia, that’s a quite an interesting area. So what would i What’s the one kind of caveat that I would give? The honest thing is that ketone esters in particular, are really expensive. So like, you know, a single dose is effectively $30, let’s just say, and in terms of a terribIe, of, you know, comparing this ketone shot, that’s a compared to adding more fiber to a meal, or, for example, a scoop of whey protein, which is also can have this modest lowering effect on on glucose. That’s where I think the application of exogenous ketone supplements in certain therapeutic situations is really going to be a problem because it’s just way too expensive compared to other therapies that are already established. So there’s quite a bit of work to do I think in that regard. Yeah. Remember

Trevor Connor  29:55

678 years ago was it when this all kind of hit The sports endurance world and everybody wanted to try ketone esters. I knew cyclists that were trying to get involved in studies because they’re so expensive. They’re like, Oh, here’s a way to get him somebody else’s cover

Dr. Brendan Egan  30:13

down, they realize, like, and they were they were sorry, they volunteered. But no, it’s true. Like, I mean, if you look as if we say, you know, some of the studies that have been done, where they’ve been an hour or two, let’s say an inauguration, and it’s a couple of doses of ketone Ester that’s about a $50, you know, let’s say, fueling strategy. In the case of some of the recovery studies that have been done, where it’s been, you know, two or three servings of ketone esters in the post exercise recovery period. And let’s say you’re doing that as, as, as an athlete several times a week, now you’re talking about, you know, hundreds of dollars a week as a recovery aid. And again, that may be relevant to elite athletes who are seeking that 1% and can afford it. But then for the average member of the population, you know, the question is there, is there enough benefit to be sure to be needing to spend that amount of money? And then equally, are there other less expensive forms of ketone exogenous ketone supplements, they could have the benefit. But again, as I said, at the moment, the benefits aren’t really, you know, often seen and that that that that’s certainly a major caveat.

Trevor Connor  31:17

Let’s hear from a couple ex pros Alex Howes and Kyle Rogen and who are racing in the Grand Tours, when ketones became popular, they have some thoughts on whether the expense was worth it even at the highest levels.

Alex Howes  31:28

Ketones are interesting, because I think there’s there’s some potential there. And you know, there’s a lot of talk and a lot of hype, but for 99.9% of people, there’s so much low hanging fruit out there. In terms of diet and nutrition and timing of food consumption. I think most people are better off just ignored it.

Kiel Reijnen  31:49

Yeah, these diet technologies that require hyper specificity in terms of usage are meaningless for the majority of population, right? Like if you’re not weighing out your food, and setting the timer between eating intervals, and you know, like recovery shake to carb consumption to intake of food or whatever other substance like when it relies on the timing, forget it. Most people can’t be that accurate.

Alex Howes  32:13

Yeah, I’d say just figure out the basics first before you start throwing something like ketones in there. Are you guys

Rob Pickels  32:19

seeing ketone? Like esters being used in the pro peloton?

Alex Howes  32:24

Yeah, but even then it’s highly variable, different rider rider, different teams a team, and honestly, there was a big to do about ketones there for a bit and everyone’s talking about how ketones are making racist faster and everything. And in my eyes, the reality was, was everybody just started eating more in general. I mean, it was only three years ago or so that everybody realizes like, oh, wait, we can if we do, you know, a proper glucose fructose blend, we could just suck down gels all damn day, you know, and we can eat 80 to 120 grams of carbohydrate, every single stage of the Tour at 20 grams per hour of every stage. Whereas when Kyla and I first tried to pro peloton, it wasn’t uncommon for people, you know, laugh at riders who had more than like five rice cakes, or you know, five paninis in a race. It’s like, what do you do? You just eating Frangie bands and like, I would take gels like early in a race if the pace was super high, right? You know, we’d be nuking it for the first hour and I you know, pull down to three gels in the first hour. And I had a director come up to me and he’s like, look, this isn’t sustainable. Like you can’t do that. Like you’re gonna you’re gonna bonk in the middle of the race, you know, you got to burn the fat. It’s like, Yeah, but we’re doing 111 100 kilojoules per hour for the first two hours like, like, I can’t eat a sandwich. I’m sorry, man. So that big shift in nutrition? Well, I think a lot of people attributed you know, the faster racing to the ketones I think it was 98% of that was people just consuming in my eyes a proper amount of carbohydrate. The ketones were just sort of the headline.

Chris Case  34:12

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Trevor Connor  35:19

So I don’t know if this is in your area, but I am interested in all the research on ketones and Alzheimer’s, because there’s a fair amount of research showing that Alzheimer’s, there’s a breakdown of glucose metabolism in the disease. And the problem that you have is lipids can’t cross the blood brain barrier. But ketones can and brain cells can use ketones as an alternate fuel source. So there does seem to be some demonstrated benefits to ketone bodies and Alzheimer’s.

Dr. Brendan Egan  35:48

Yeah, and, you know, again, mechanistically, as you described there, it does make sense that this would be a valuable therapeutic approach. It’s interesting to me that there hasn’t been a huge number of studies in this space using the the ketone exogenous ketone supplements. I mean, it’s funny that the best work that’s probably been done as Stephen Canadiens research out of the University of Sherbrooke, and he’s actually not using ketone esters. As far as I know, he may have done some imaging work that did use the ketone esters, but when it comes to is, let’s say intervention type work that’s generally been done with MCT type formulations. But, you know, the evidence is pretty good there and that he is seeing positive effects with relatively modest changes in ketone body concentration. So yeah, it does strike me that I mean, maybe it’s your right, it’s not an area that I’m active in. So I haven’t checked the clinical trial register, but it will be worth checking to see if there is anyone, at the moment performing these types of studies using something like a ketone Ester extended out over, say, weeks and months, because that, to me, is the obvious question, you know, if you have someone who’s, you know, early onset or showing mild cognitive impairment, whether an intervention such as this can mitigate the declines that are likely to occur again, I like to research around the study of older adults. And what you realize is that storing them for eight weeks or 12 weeks at a time, doesn’t tell you a huge amount that you don’t already know that certain interventions work. The question is like if can they stick to an intervention and do it over multiple years? And then can that mitigate the decline? Because you know, that’s ultimately what we’re doing. We got reverse things. At the moment, let’s say, an aging some people some biohackers, totally different. But in terms of the types of interventions that we use, at the moment, it’s more slowing the decline rather than reversing aging, that is the outcome we’re looking at.

Rob Pickels  37:37

I think that this is a great place to point out that nutritional ketosis through fasting specifically, has been used for hundreds and hundreds, if not 1000s of years for the treatment of things like epilepsy, right. And so as I’m tying this into the brain conversation, but I’m really doing this to point out something that I think is important, when we induce nutritional ketosis through fasting, there is a whole host of other things that occur within the body that may or may not put us into otherwise healthy or unhealthy states. And it becomes really difficult to suss out the difference between what is the effect of the ketone body, and what is the potentially beneficial or deleterious effects of glycogen depletion, other signaling, hormone changes, so on and so forth. And what I find really interesting as we talk about exogenous ketones is we’re much more able to understand the effect of this one particular substance, as opposed to the 100 different changes that happen when you starve yourself, and your body creates its own ketones.

Dr. Brendan Egan  38:41

Yeah, no, it’s great point. And due to that point, we published a paper which again, is it’s open access, if your listeners are interested, it’s talking about the points of divergence and convergence between exogenous ketone ingestion versus the ketogenic diet. And in which is kind of related to your point about about fasting. The point I would make there is that again, you have scenarios where you have some commonalities. So for example, it’s fairly well established that that appetite suppression is common to both situations there. So say a ketogenic diet and exogenous ketone ingestion, generally associated with a suppression of appetite. Whereas on the other hand, there’s something very, very different about them, which is free fatty acid concentration. So a ketogenic diet will lead to an elevation and free fatty acid concentrations in the blood. Exogenous ketone ingestion is actually highly likely lytic. You know, one of the best established actions of ketone bodies is an anti lipolytic effect. So when they’re ingested in an acute form, they tend to lower free fatty acids fairly dramatically, and that that might actually Rob to go back to your point about glucose and glycaemia. That might be a mechanism as well why they’re having an effect. They’re basically sensitizing the body to the effects of insulin by lowering free fatty acids. But so the the point there is you can run through a number of different metabolic effects, or metabolic responses to either the diet or to the ingestion of the exogenous ketone supplement. And it kind of brings us back to the question you opened with in terms of endogenous versus exogenous, you know, there, there is quite a difference between the two states. And it’s important to keep that in mind when when reading research in particular, and trying to interpret what could be performance benefits or therapeutic benefits between the two different approaches.

Rob Pickels  40:27

It’s something to point out really quick, and I don’t want us to go down this rabbit hole, we need to keep the episode going. But it makes sense that ketone is lipolytic, right? Because ketones often occur at the end of beta oxidation of fatty acids. And so if your body is sensing the amount of ketone concentration, and it’s gone up, essentially, this beta oxidation has done its job. And we can slow down that process. In which case, we would want to slow down the breakdown of adipocytes, or adipose tissue into a free fatty acid. Am I thinking about that correctly?

Dr. Brendan Egan  41:04

Yeah, there has to be some kind of self control was not the right word. But we usually talk about a negative feedback loop, in other words, the regulation or can’t just run out of control. So there’s a kind of thinking at the moment that there is a certain concentration where lipolysis is allowed to proceed, when you exceed that concentration, lipolysis will be slowing down. And that’s kind of that’s how you then strike this optimal balance between having enough free fatty acids around to drive you to Genesis, but not happy in a situation where it runs out of control for lunch. But

Trevor Connor  41:33

for anybody in our audience who’s new to these terms, who hasn’t heard lipolysis before, basically, what we’re saying is, when you consume these ketones, what we’re seeing is normally your your deposits, your fat cells supply a certain amount of fat for your muscles and other tissues to use for fuel. And that gets down regulated, it isn’t pushing out as much free fatty acids for the muscles to use. Likewise, you’re also seeing a bit of a slowdown in glycolysis, which is your body’s use of glucose for fuel. So it seems that it’s gonna rely a little more on these ketones for fuel. But I know in your study, there was questions about that could actually hurt performance because ketones aren’t used that much for fuel? I think it was only it only provided about 10 15% of the substrate for energy during exercise. And if you’re, you’re reducing lipolysis, if you’re looking at reducing glycolysis, back and fatigue, essentially,

Dr. Brendan Egan  42:32

yeah, so the idea, I guess is by having more of the ketone bodies around you are providing alternative substrate, but the question becomes is the body going to use that during exercise, and well, you know, what’s very well established is that it’s sort of low to moderate intensities, the body can easily switch back and forth between carbohydrate fat, they’re the fuels we tend to focus on. But when you get to higher intensities of exercise, as you well know, particularly, you know, above lactate threshold and close to two Max, the body who tends to rely very, very heavily on carbohydrate, unless there’s been a kind of a ketogenic diet, diet intervention, or whether the person is very well tuned to be able to utilize fat or to, you know, quite high intensities of exercise. So the same kind of logic applies there in terms of ketone bodies, you know, and again, in theory, if you look at some of the thermodynamic calculations, and so on, they would be an efficient fuel to use in a cell. But in terms of what we know about, again, those oxidation rates that you mentioned, are that percentage contribution, or there’s some cell work that shows that when pyruvate and ketone bodies are around at the same time that skeletal muscle cells do prefer pyruvate. So there’s this kind of idea that ketone bodies would be, you know, get them really high, the muscle will just use them as a fuel, it probably doesn’t work out like that, because again, at high intensities of exercise, there are probably good reasons why the body tends to rely more heavily on carbohydrate. But the flip side of that is, as you mentioned, there are again mechanistic basis as to why high levels of ketone bodies in the blood get into the muscle would perhaps inhibit glycolytic pathways. And if you’ve got inhibition of like little pathways, there’s a chance that you’re gonna, your top end performance is not going to reach were short. And I think that’s where the fear or the kind of the drawback that some people will point to in terms of ketone bodies is that and high intensity exercise, they’re not going to be beneficial. In fact, there’s a couple if not three studies now that show negative effects during very short duration, high intensity exercise, and again, the thinking is now much more evolving that if ketone bodies are going to be valuable as an ergogenic aid or as a performance aid, it’s more than likely going to be as moderate or lower intensities, much longer duration of exercise challenge.

Trevor Connor  44:42

So before we finally dive into the big question of are they performance enhancing, which I think you’ve mostly answered, so it’s not going to be a giant surprise? Are there any other impacts of ketone bodies on muscle metabolism?

Dr. Brendan Egan  44:57

Well, it’s kind of I briefly touching on what I mentioned about the anti catabolic effects. So I think there’s, there’s some interest in the area of the ability of ketone bodies to stimulate muscle protein synthesis as part of the overall recovery from exercise. And that, to me is quite an interesting area. And I often say if someone would give me money to do whatever ketone research I wanted, it would be looking at recovery. And there, you know, there are a couple of lines of evidence, there’s some interesting work that was done around overtraining and the recovery from or the the adaptation that’s there the mitigation of overtraining symptoms. And that’s going back a couple of years now. But the model that was effective use, there was twice a day of training for three weeks and ketone bodies use during recovery for each training session. And that ultimately, allowing the ketone consuming group to, as I said, mitigate the the symptoms of overreaching. But there been a couple of other recovery type studies that have been done since then that kind of point to and again, I would say the science is not settled on this by any means we need a lot more studies. But there are just one or two markers that are pointing to something positive about the use of ketone bodies during recovery. And I think it could send around this idea that they may support, sort of growth and regeneration. Again, these are acute studies. In the case of some of that mechanistic work, they need to be extended out into longer term training studies. But I think that’s something where effects on muscle metabolism are of interest here.

Trevor Connor  46:23

Let’s hear from Dr. Paul Larsen and his thoughts on the effects of ketones on recovery.

Dr Paul Laursen  46:28

I do believe there’s a benefit for exogenous ketones, it will really depend on the context. But there’s, you know, there’s a bunch of work that I mean, for me, the big benefit that we’re seeing now is in the context of the recovery phase after the workout. That’s I think, you know, we’re still seeing the studies from Peter Hezbollah’s lab where we’re seeing increases in EPO increases and angiogenesis, and better recovery profiles, less overreaching symptoms. So to me, it’s the it’s still early days. But if the evidence is strong enough, and even the anecdotal evidence that I’m I’m seeing from athletes and colleagues that I’m working with is there’s a, there’s a great benefit there. For more of the recovery phase, versus the acute phase, there might be an individual response in the acute phase. But I think the big bang for buck is going to be in your recovery phase.

Rob Pickels  47:29

And I think that this is a great way to segue into the performance conversation because as we discuss the ketones potentially ability to improve training load to improve sleep, right, ketone ingestion prior to going to bed, seems to improve REM duration and other markers of sleep health, as well as increasing angiogenesis, right, the formation of new blood vessels, it almost feels like there’s more supporting the long term use of ketones as a supplement to improve training, adaptation over time, as opposed to the acute ingestion to improve performance right now, in this moment,

Dr. Brendan Egan  48:16

I think you’re I think, just summed up very nicely there. I mean, it sometimes I wonder is, it wasn’t the circumstances, you know, that the kind of the hype that came out around 2016, and 17, where there was obviously the landmark story that landed in 2016. And then there was all the talk of Tour de France, cyclists using them for performance, and it kind of snowballed from there. And like us, we got into, like, you know, if people are doing if athletes are using the supplements, let’s let’s try out these performance studies and see if there’s anything happening. And you know, then we do want someone else as well. And all of us, you know, on a PhD will generally follow a kind of a series of studies that are related. So all of a sudden, you know, it’s there’s a several groups that are doing performance related research. Yes, when you take a step back now and look at where’s the promise, it’s those mechanisms that you describe it, which are seem to be not actually in the performance space, but in the kind of recovery and adaptation space. So in the review that you mentioned, that we wrote, in end of last year, there’s about about 30 studies now that have been done with exogenous ketone supplements and performance. And you know, to sum it all up, there’s probably a couple that have shown a benefit. Maybe one or two that people would claim there’s a trend there or something like that. But like I said, for high intensity performance, there’s at least two or three that your negative effects on performance. So there’s been so many studies that are a little bit different and little tweaks here and there and the types of studies but there’s no strong signal for a benefit in the performance side, yet of the small handful of studies that have looked at, say recovery and adaptation. There’s, you know, I would say a lot more of a signal there in terms of positive direction. So I think if somebody while they’re rabbit studies where it looks to be a bit more promising,

Trevor Connor  49:57

yeah, I actually found it very interesting in your You exist said you reference over 400 studies here and use the word surprising at one point in the study, or you say it is surprising how much research has been done. And yet, we’re really not finding performance benefits. And your conclusion I’m just going to read this is despite the mechanistic basis for potential beneficial effects of eks. So that’s your supplement, the evidence of prep present is overwhelmingly against Eks being an ergogenic aid. And

Rob Pickels  50:27

one thing that I do want to point out, and I’d love to get the researcher opinion on this, as somebody and I have used ketones in multiple forms, and I’ve talked about it on the show, I don’t know that the current research is supportive of the benefit of acute ketone supplementation. And we can dive into that a little bit deeper. But, you know, unfortunately, one of the difficulties with research is that you have to design a research study that you’re actually able to carry out that you can control variables that you can see significant differences between conditions. And almost the benefit of ketone does not necessarily lend itself to designing a study that someone like yourself is actually able to conduct.

Dr. Brendan Egan  51:11

Now look at the great points. So let’s try to unpack that a bit. So if there is, you know, a couple of studies that show a benefit, or you look at the individual data points within a study, and you see there’s some people who seem to have derived a benefit, I think an unleashed athlete or coach who’s curious might think to themselves, well, could that could I be the one who’s going to respond here for want of a better word. And I think that could be where some of the anecdotal use of ketone bodies where there are, you know, there are prominent people who do say that they derive a benefit. And there are clear examples of companies or sorry, partnerships between say, prospecting teams and ketone software companies as well. And, you know, there’s athletes who talk about using them, and there’s at least a picture using them, and so on. Now, again, they could be doing nothing for all those people. But it does strike me as and I think we wrote this in the paper, you know, there’s a, there’s a kind of a discordance between what the published research is saying versus the apparent prevalence of use among pro athletes. So I’m one and the, the point that I was making is that any individual coach or athlete could take on a kind of an n of one type of experiment where they test their performance under a couple of different conditions, by manipulating variables around the provision are not of ketone supplements. And ultimately, if they’re, you know, happy that they’ve objectively demonstrated a benefit themselves, they may have gone take them and and, you know, that’ll be the anecdote that we hear. And, you know, the mean value in the study may not show a benefit, but for the, you know, athletes whose using it and driving the benefit. Great, you know, but the other piece, Rob, that you might have been kind of getting out there is that, to do a study that we do, you know, we’re limited, you know, the number one thing that we need to get as participants. If we set the bar as we want to recruit only people with a vo two Max above 70, you know, to mimic, say, a poor cyclist, for example, in Ireland, very simply put, we have very few people who fit that bill, who also want to volunteer for a research study to be poked and prodded and, you know, give blood and have their training disrupted, and all these other things that you need to do to standardized testing. So there is a chance, of course, that the researchers like myself and others are just not studying. And these athletes, were studying good athletes, and we’re studying acne to potentially derive benefit from, you know, various different interventions. But they may not be the athletes who who derive benefit from from ketones, because they’re not fit enough. And to sort of underscore that point, you’ve probably seen the letter and maybe you’ve covered on the podcast, the literature around nitrate supplementation, or performance. And in that literature, it’s kind of become accepted now that the people who benefit most from nitrate supplements and be reduced are the least fit. And the fitter you get, the less likely nitrate is to benefit performance. The opposite is kind of true. Here are our hypothesis. Now we’ve put it into a couple of papers now are about this is slightly different here. If you look at mechanisms of that sort of pathways in of ketone oxidation and skeletal muscle, they their capacity and enzyme activity increases with training and probably correlates. Again, this one study with a smile ensign is what looks like a correlates with type one fiber topology as well as type one fiber dominance. So there’s a chance again, it’s just a hypothesis that in the more elite and the more trained an individual is, there may be better able to utilize ketone bodies, and maybe that is where you would get your one or 2% improvement. But then again, that’s just a speculation, someone’s gonna have to do the research.

Trevor Connor  54:39

And on that note, I gotta point out, you’ve just submitted a paper where you’ve shown under particular circumstances or conditions, you do see a bit of an improvement and running economy and runners using just a ketone supplement. Did you want to talk a little bit about that?

Dr. Brendan Egan  54:55

We were interested in this just as an intellectual question. You know, most of the studies have been and carbohydrates fed or carbohydrate feeding during exercise compared to carbohydrate plus ketones. And we were interested in the question of, well, what happens if it’s just Nagara hydrate, and ketones are used. So we designed a three condition study where it was carbohydrate alone, carbohydrate plus ketones versus ketone alone. And these were in relatively good runners. And we brought them in for like I said, the those those visits, and we did a graded exercise test with five by eight minute stages, took a run in economy. So these were running speeds of 1011 1213 and 14 kilometers per hour. So you know, not super fast. But you know, below a threshold and enough, you know, a nice graded steady state protocol at each stage in order to be able to look around economy. And what we saw was that there was a decrease in oxygen utilization is an improvement around the economy. And all of the submaximal running speeds indicate on only condition compared to carbohydrate only, and the ketones plus carbohydrate we’re somewhere in between. So, you know, we don’t make any claims about what this actually means from a follow up point of view, because you know, the running speeds are kind of slow. And, you know, they may not be practical to only consume ketones, but just as an as an example of kind of going back to basics and asking the question, you know, there’s not a performance measure. As such, it’s just, you know, this outcome measure, that’s a fairly good predictor of running performance, ie run an economy, that does seem to be impacted acutely, by consuming ketones as opposed to consuming carbohydrates. So what people end up doing with that data, whether people go into sort of longer duration performance type studies, like ultra endurance, for example, you know, it remains to be seen, but as from an observation point of view was interesting, because the effect was around about three or 4%, which again, is the kind of change and run an economy that people go crazy about when they see these carbon fiber shoes having that effect. So it’s, yeah, I’d be interesting how their fields TextView without research and whether it stimulates other people to do some of their work,

Trevor Connor  56:56

and Astec. So I think that paper leads to something really interesting, that was also in one of your reviews, talking about the three potential ways that ketone supplements can be ergogenic. So you just talked about one, which is better economy or efficiency. But what were the the other potential ergogenic benefits that you can see from ketone bodies?

Dr. Brendan Egan  57:19

Yeah, so we’ve touched on a couple of the mechanisms already here. But let’s, we’ll try and tie them all together here. So you know, in the in the first case, it’s a question of whether ketone bodies can be used as a substrate within the muscle. And as we mentioned earlier, when they’re provided as a source of as an exogenous ketone supplement, the evidence from a couple of studies now seems to say that that will ultimately produce around about a five to 10% contribution to energy provision during exercise. So it’s not huge. It’s still a small proportion relative to carbohydrate, and fat, but it does seem to be a contribution of sorts. So the question then becomes, how does that small contribution as an alternative substrate, how does that impact on overall fuel utilization, or in the case of the study that we did there, maybe it impacts on oxygen consumption. So one of the mechanisms again, we hinted at this earlier, when we talked about the fact that there are differences between the different substrates in terms of the so called delta G or the Gibbs free energy, for ATP that’s produced by the different substrates, there’s a difference in the amount of ATP that’s produced per carbon molecule, there’s a number of different, you know, very detailed biochemistry, ways of looking at these different substrates. But the bottom line, and all of that is that there is a suggestion that ketone bodies are a more efficient fuel than glucose or fat, when it comes to ATP provision. You know, these are things that are very difficult to measure. So we obviously didn’t measure them in the study that I just described. But the concept, you know, in terms of if running economy was improved, it reflects the fact that oxygen utilization was less, and maybe that that has been explained by a small amount of oxidation of ketone bodies by the muscle, ultimately improving efficiency by reducing the oxygen needs. That was the speculation within the paper, again, remains to be confirmed, you know, in terms of those detailed measurements. And then the the third mechanism that was that’s proposed is around the reduced reliance on carbohydrate utilization. So the idea here is that in many endurance sports, carbohydrates can become limiting because of the nature of the limited amount that we can store within the liver within the muscle. And that over especially over longer durations of exercise, some people do have trouble consuming enough carbohydrate in the form of a sports drink in order to be able to support carbohydrate utilization at certain intensities of exercise. So there’s been this idea again, put forward as far back as 2016, that in the presence of exogenous ketosis, that carbohydrate utilization is the rate or less in other words, so called carbohydrate sparing as well it’s been called. But to be honest, if you look at the At the evidence around that there’s only really two studies that have looked at carbohydrate, glycan muscle glycogen concentrations within the muscle. And one of them showed that there was so called carbohydrate sparing. The other showed that there was no difference between the ketone condition versus the carbohydrate condition. So the jury’s kind of out on that, like I described our reasons why Kavita utilization will be reduced because of the effect on glycolysis that I mentioned earlier. So it then becomes a question of whether you’re, you know, kind of reducing utilization to the extent that’s beneficial, or whether you’re reducing utilization to the extent that impairs performance. And that, again, is something that’s debated because we’ve got evidence on both sides of the of the aisle there in terms of in terms of those effects. So they’re the they’re the three potential oncogenic mechanisms, a little bit of evidence for all three levels of contradictory evidence after all three as well. So again, like many things in this field, at the moment, there, there’s quite a bit more work to do before we fully understand those.

Rob Pickels  1:01:01

So we have three potential acute mechanisms. We talked previously about maybe a fourth mechanism that’s a little bit more chronic or long term. And that’s improved recovery, improved adaptation, improved ability to handle training load, but I do want to bring in another potential acute mechanism for improving performance. And this is something that I experienced through my own exogenous ketone years, and is potentially backed up by a paper that came out in 2023, from coffee, so I love seeing the research after I’ve experienced something. And, you know, I think the title of the paper really sums it up exogenous ketosis increases circulating dopamine concentration, and maintains mental alertness in ultra endurance exercise. And I do want to bring out that performance is essentially multifactorial, right, we cannot describe who is going to win the race. With laboratory tests, we might have a good sense of we might be able to predict with some accuracy, but the fact of the matter is, people have to go out and they have to compete. And because of that, these things like mental alertness can become really important. And for me to describe my experiences, I’ve trained a lot for a multi day mountain bike stage racing or other ultra endurance level exercise. And I will say I’m a very carbohydrate centric individual. My background is as a sprinter as a hurdler, and I’ve made the switch to being in these longer endurance things. And something that I notice, I can crush and we’ve talked about this Trevor always like cries a tear when I tell him how much carbohydrate I take in during exercise. But something that I noticed oftentimes is this sort of mental fatigue, in addition to muscular fatigue, and that mental fatigue is, while I’m a mountain biker, my reaction time just a little bit slower, either not as fast or even closer to crashing, but also my mood can become a little bit more negative. To tell you the truth, I don’t want to be out there anymore. I’m starting to complain, Oh, God, it’s so hot out my saddle. so uncomfortable. All of these things. And what I have noticed when I have used an exogenous ketone supplement is that that mental alertness almost almost comes back and almost feels like you’re taking a little bit of a stimulant, the world looks a little bit brighter, my mood is a little bit happier. And I’m no longer saying, Oh, God, I can’t wait until I get home, I almost have this mental energy. My legs almost still feel exactly the same. But it almost flips kind of my outlook. And I do believe that things like that become very difficult to measure, but can ultimately really impact performance.

Dr. Brendan Egan  1:03:53

Okay, very nice anecdote, and one that I’ve heard, repeated by many people who have used these, these supplements. And as you say they can it’s a tricky kind of thing to measure in a research setting. So we have done some work. And I’ll talk as well about the the paper that you mentioned shortly, as well. But we’ve done similar work because we were interested in whether there are cognitive effects of these ketone supplements in the context of exercise. So one of the studies that we published a few years ago was a simulated soccer match. And the that particular simulated soccer match involves having your participants run at various different speeds, it’s quite hard for them to be demanding because they’re constantly listening to beeps and being told what speed to run out, and it’s back and forth. And it’s up, you know, over this 20 meter track. And the reason I bring that up is because, you know, mentally or currently demand is important, because within that particular story, what we saw in the control condition, which is carbohydrate alone, was that there was a decline in cognitive performance over the course of the 90 Minute protocol. Whereas in the case of the ketone condition, current performance was meant And so we didn’t enhance performance, we just mitigated the decline that occurred within that. And that actually that pattern, again, there’s various different cognitive measures that can be used, you know, some of them are around attention, some of them around task switching, odds are around reaction time, there’s a lot of these kinds of different test batteries that tend to be used across the studies. But there does seem to be a signal there to be honest around commission, and it’s probably around mitigation or decline as opposed to enhancing cognition, you know, there’s a, if you can you look on online, you hear some of these claims, it’s, you know, ketones enhance mental clarity or the, you know, the improve whatever. Again, it’s hard to sometimes reconcile those claims with the evidence, but we don’t actually see an increase in cognitive performance, we just see a prevention of the of the decline. So in the case of, of the ultra endurance study that you mentioned, I mean, when I saw those results, I wasn’t too surprised, because like that ultra endurance is, you know, very, very demanding, from a cognitive point of view. Just as an aside, we did, we did another study where it was just at one hour on a treadmill, followed by a 10k time trial. And in that we didn’t actually see any decline in cognitive performance, even in the control condition. And it got us thinking around this idea that, you know, maybe in order for there to be a benefit, you have to offset a decline. And in that case, the exercise challenge, or it could be, it could be an exercise challenge, if it’s mentally fatiguing. That’s maybe where something like ketone bodies could come into effect, and again, through this use of exogenous ketone supplements. And then one other piece of color that allowed there is that we’ve done a couple of studies now they’re on published at the moment, but hopefully will soon see the light of day around the use of hypoxia to cause cognitive decline. And what we see in those particular stories is, again, a little signal there that suggest that using exogenous ketones, as a countermeasure to that decline in cognitive function does seem to be effective in acute hypoxia as well. So I think there’s, there’s a bunch of research coalescing around this idea. And I would, again, phrase it very carefully as mitigating declines in cognitive function, as opposed to enhancing cognitive performance or anything like that. And it’ll be interesting to see how this field develops over the next while because I agree if if you take the idea that performance is multifactorial, it’s not all about muscle metabolism, then there are potentially other mechanisms about how ketone bodies measure improve performance, again, in the kind of in the Ultra Space and those cognitive demanding domains.

Trevor Connor  1:07:26

Finally, let’s hear from Starla. Tedder green and the benefits she’s experienced from ketones on her alter endurance gravel events.

Starla Teddergreen  1:07:33

So I’ve used it experimentally, just to see Yeah, if it makes any kind of a difference. And I feel like when I’ve used it in training is it keeps my energy more stable. Like, I don’t feel like there’s any peaks and valleys like I feel, it’s more even, I guess, throughout the training. And so I’ve definitely found some benefit. But I can’t actually say if it’s just making it up, or if that’s actually how I felt, but I’ve always I mean, I’ve never felt anything negative from it. And whether it’s just a placebo effect or not, I think it is positive. I’ve taken it in the mornings before the workouts and then have the little liquid bottle that I take during the actual workout or during the race. So yeah, I’ve definitely used it in training and in racing and found positive effect from it.

Trevor Connor  1:08:30

Well, guys, it’s been a great conversation, but I think we need to start to wrap it up. Doctor, you get to you’re new to the show. So you haven’t had this experience before. But we like to always finish out with what we call our our one minutes, which is we each get one minute, to summarize what we think is the most important message or the most salient point that we’d like our listeners to leave the show with.

Dr. Brendan Egan  1:08:52

There are lots of mechanistic reasons as to why ketone bodies can be effective, both in the multifactorial performance domain as well as therapeutic applications. But the big challenge remains, I think, at the moment that the hype is often greater than the research evidence that’s to hand. And there’s a big question mark about the expense of supplements and whether they will ever be an agent that’s affordable, that makes them suitable as as as a use as opposed to other lower hanging fruit that don’t cost as much I think that’s that’s the big needle we’re trying to thread here with this with this domain is how to have benefits but also in cognizant of the costs. And let’s see where it goes over the last few years.

Rob Pickels  1:09:31

I think that that’s an amazing lead in to what I want to say is yeah, there are big questions. We don’t necessarily know even within studies, maybe they were responders and non responders. But something I do want to point out is that, as far as I know, the ketone esters available on the market are considered generally recognized as safe meaning it’s very unlikely that they will do deleterious harm to your body. They might do deleterious harm to your performance. Um, but from a health perspective, taking these is generally recognized as safe. And I encourage everyone, I think that there is a lot of naysayers who act like experts without ever actually trying it themselves. And I want to caution everyone away from that it is money, I get it, but at the same time, it is just money. If you’re interested, go ahead and try it. If it works for you, awesome. If it doesn’t work for you don’t keep wasting your money on you know, I’m

Rob Pickels  1:10:28

not, I’m not trying, I have no stock in any of the companies that are out there. I’m not going to push any one company over another. But it is okay. And we talk a lot about experimentation on here it is okay to do a little and have one anecdote in my opinion.

Trevor Connor  1:10:43

So my message is we often in the research really tried to simplify things down to, hey, you take this, then you do a time trial, running, cycling, whatever type of time trial and does it improve performance or not? And that’s kind of where we leave it. I would say by that metric. Yeah, you demonstrated pretty clearly that. Probably not the thing to invest money on if you’re looking to take it right before a race and see some improvements in your race performance. But what I found very interesting about all this research on ketones is all the other impacts it has on our bodies, particularly the health benefits. So yes, the supplements are expensive. So you might want to look at some of the precursors or periodically putting yourself in a state where you’re naturally producing ketones, but I think there are broader and longer term health benefits. I think there’s recovery benefits. I think the there is something to this it’s just don’t waste your time taking it right before race.

Rob Pickels  1:11:42

Yeah, and it’s early days. I think with time we’re going to understand that a little bit better right

Dr. Brendan Egan  1:11:46

now are starting to be continued. We’ll be back here a year or two time seeing what we got right or what we got wrong.

Trevor Connor  1:11:52

Oh, Dr. Egan. Thank you. It was a pleasure talking with you.

Dr. Brendan Egan  1:11:55

Thank you good conversation.

Rob Pickels  1:11:57

That was another episode of Fast Talk. Subscribe to Fast Talk where ever you prefer to find your favorite podcast. Be sure to leave us a rating and a review. The thoughts and opinions expressed on Fast Talk are those of the individual. As always, we love your feedback tweeted us @fasttalklabs or join the conversation at Learn from our experts at or help keep us independent by supporting us on Patreon. For Dr. Brendan Egan, Dr. Paul Larson, Alex Howes, Kiel Reijnen, Starla Teddergreen , nd Trevor Connor. I’m Rob Pickels. Thanks for listening.