And now she's transitioning both to athletic performance and health span. So it's really interesting to sort of get her perspective on where ketones fit into the whole picture of performance for an elite athlete and for an everyday athlete and then how that also may translate to health and longevity.
Now in the beginning part, probably the first half of this interview, we spent a lot of time talking about sports and athletics and athletic performance. So if that doesn't apply to you, if you're not interested, fast-forward halfway through and you'll pick up on some of more of the health aspects. But it's great to get a perspective. She thinks from a scientific mind of evaluating the evidence before making big claims and I think that's a good take-home message for all of us.
But I think you will get some takeaways here about where ketones fit into this picture and whether they're right for you. So enjoy this interview with Dr. Brianna Stubbs and make sure you go to DietDoctor.com; you can see the full episode and a transcript of it if you are a Diet Doctor member and also subscribe to our YouTube channel so get all our regular updates. All right, thanks, here's our interview with Dr. Brianna Stubbs.
Dr. Brianna Stubbs, thank you so much for joining me on the Diet Doctor podcast.
And so I was studying all the basic systems of the human biology in my undergraduate course and also at the University I was starting to take rowing more and more seriously and I'd been on the junior international team and the under 23 international team, so that was getting more and more serious as well.
And it was almost like this very random perfect storm of random events. So I was rowing on the team and all of a sudden I see this advert for a study looking at ketone esters in rowers and they were offering to pay people come into row machine test which I was doing for free otherwise. And I was in my freshman year, I was like this sounds like a great way to make a little bit of beer money, you know, go and do that.
But yes, I went and took part in this study and it was so relevant to my personal interest, but also was really building on what I was studying in the classroom; all of this biochemistry which kind of seemed bit dry to me quite frankly, as you study all this big metabolic pathway, the Krebs Cycle and study all the different pathways of fat burning and carbohydrate burning. We didn't really go into that much detail about ketosis.
I do remember we were taught about it, but it wasn't something that stuck in my mind. So doing this study and meeting the research team really started to trigger a lot of questions in me about how metabolism and sport interacted and also how ketones and supplementing with ketones could fit into this.
And so on as part of my medical training I was able to do a summer research project which I did in a lab group and I got more and more involved with the research there and so when it came time, my rowing was actually really taking off and I needed to step back a little bit from my studies to focus on that. The research lab offered me a position as an assistant, helping to run a number of these studies.
So it was good because it was flexible work and they were really understanding of the fact that my training was really demanding. And that assistant position kind of somehow converted into a PhD position that you know I was interested in doing good work. And so they brought me on. And really the good thing is while I was at the medical school were happy that I was doing a PhD and they could turn a blind eye to the fact that I was rowing all the time.
And they actually held the place open for me in medical school that I could have come back to at any point, which was a really nice safety net. So I was just really free to go after the research and pursue my own athletic ambitions as well. The two fitted alongside one another really nicely, because actually, especially as I progressed into the senior team, I moved into the lightweight category, so I had to think I spent a lot of time in caloric restriction and in more of a ketogenic state.
So actually understanding starvation metabolism and ketone metabolism, especially as it pertained to exercise, it was not hard work at all for me to really get into the literature and understand the implications of the physiological effects were having on my performance and therefore the implications for other athletes as well.
I think it's that personal experience that makes us driven even more and that much more interested in studying it and subsequently you've turned into an amazing researcher doing all the studies and sort of being on the forefront of ketones and ketogenic diets for athletic performance. Now, as we get into this, I think we need to differentiate a couple of different things.
I mean there's a ketogenic diet and then there's exogenous ketones and then for athletic performance, there's elite athletic performance, there's sort of everyday athlete performance and then there are the different sports with different demands. So there is really a lot of specifics. You can't just say it's good for sports, it's not good for sports. you sort of have to get into the specifics. So walk us through a little bit, you know, how do ketones in general help with sports and then kind of help us differentiate the specifics.
So, some of the values that he published in his study was showing that it was- I think it was 50% higher fat oxidation than it had ever been published before, like 1.5 g per minute plays a normal sort of 0.6 to 0.8 g per minute. So when you become keto adapted, you're really, really good at burning fat. Now, if we take a step back and look at it from a theory based perspective, we have a lot more energy on board our body stored as fat compared with glycogen.
So glycogen is the storage form of carbohydrate and we have it in our liver, and we also have it in our muscles and then the energy in glycogen represents about 2000 cal. So, it's quite a lot more than most people would burn on an average 30 minute jog around the park, but for elite athletes with very high-energy rates and especially as the event starts to get longer, that might start to become a limiting factor for their ability to continue that exercise.
And so the theory behind the ketogenic diet therefore is that you... be able to up-regulate your body's ability to burn this fat stores where we have I think about 150,000 cal worth of fat store, many, many more times energy stored as fat. And so we can tap into that and in theory should push out the time in which you would get exhausted.
Now, I think this now brings us on to a point that you mentioned which is the difference between elite athletes and more recreational athletes. So, for early athletes actually there is very few events and the marathon is the longest event that is in the Olympics. And then now we're seeing marathons being completed in near two hours.
So, I mean it's not what I would class as an extreme endurance- obviously it's an endurance event, but it's maybe not something where the glycogen availability plus the ability to take on exogenous carbohydrate is really the limiting factor and what the limiting factor for performance for these athletes is the ability to produce energy as fast as possible.
Now fat has a more complex metabolic breakdown pathway, beta oxidation has many steps and glycolysis by comparison is quick and fast and in terms of oxygen efficiency also glucose is an efficient fuel source for exercising muscle. So at the moment the school of thought is that for elite athletes exercising at a very high intensity in order to complete their competition they probably still want to be able to burn carbohydrates.
But then if we look at the other part of people here and that's the people who are trying to run a marathon, maybe they're running three hours if they are quite good, but maybe more people completing marathons in more like five hours long and so actually people then on- so interested in that very, very high intensity performance is a completely different event.
And so for those people they actually might benefit from oxidizing more fat and also for those people things like body composition are going to also be more of an issue and being on a ketogenic diet might help them with that as well. So when people ask me, "Is the ketogenic diet good for sport?", you have to very clearly defined the type of sport you're interested in and also the level of the athlete you're talking about, because there have been some studies and it's not that well studied to date.
I would say that, well, a lot of people who hate the ketogenic diet saying that it doesn't work... but we haven't seen definitive performance decrements of the ketogenic diet-
Which is good, because I think some people are like, "You shouldn't do this. It's going to kill your performance." Well, no I think that some studies where it helps a little bit, some studies where it takes it a little bit off, and in some studies there is no effect. So when we look at the whole body of data I wouldn't feel I would say to an athlete, do what you feel makes you the best.
But in those two scenarios even if you are playing pick-up basketball casually or you are swimming a 50 m race in a master swim meet, a 0.5 of a percent less efficiencies through glycolysis is likely not to be a major limiting factor to your performance. And, you know, interestingly I've done a lot of work in with the military and this kind of gets a bit emotive, because people like- well, if the soldiers lost their ability to maximally sprint, what if they couldn't run away from an ambush or something like that.
And I actually had a number of conversations with some veterans who had done years of service and they were like, "We never sprint at 100%. "Because we are carrying ammunition, we are carrying our packs, "we are also trying to navigate where is the best way out of the situation. So there is never an occasion where I am running at 100%."
And so unless you need that 100% then actually maybe their potential for the ketogenic diet to take off that top-end glycolytic maybe it's less important for all but the very most elite people who sprint performance matters the most. So I mean, I would agree with something you said, which is that the other benefits in most cases could be said to outweigh the possible biochemical downsides.
The only thing, as well, to say in the spirit of fairness is that not everyone finds the ketogenic diet easy to adhere to. So I think, you know, as a community we can't say, "Thou shalt be on keto! And this is the only way."
I guess if you're enjoying it, if it's sustainable with your lifestyle, you are finding good health benefits, you are still able to go out and play your pick-up basketball and all of that and you feel better and you are losing weight and all of this, then of course this is like obviously what you should be doing, but if you're the type of person and it's just a struggle every time you walk past the bakery, then you know, probably don't go in the bakery. But still... right?
And then Dr. Volek has a more recent study with military cadets and that was a more intermediate duration and those athletes had I think it was maybe like 10% decrease in muscle glycogen, and then his study, the FASTER study, which is quite well known with athletes that have been on a ketogenic diet for a couple of years even, those athletes had no difference in resting muscle glycogen.
And muscle glycogen is a really important determinant of athletic performance. So we actually don't know how long it takes the body to adapt to be able to keep muscle glycogen stores optimal when you're on the ketogenic diet. But Dr. Volek's long-term data from those athletes who were on the diet for a long time suggest that you can-
So there's big things like muscle glycogen storage, smaller things like on a cellular level about levels of enzyme expression that may even be remodeling of adipose tissue, switching from white fat to brown fat, for example, changes in the amount of lipids in the muscles, so keto adaptation is a hugely dynamic process and there are so many different things that are changing.
Yeah, I think it's very hard to say that we have a good handle on exactly what the timeline of that processes is and maybe to fully keto-adapt is as Dr. Volek suggests a couple of years even-
I would say that I think it's kind of interesting to me how exogenous ketones might help with bridging that adaptation gap, whether it's in terms of the keto flu or whether it's in terms of athletic performance, so, you know, you want to fuel your workout but not completely- with a rapid energy source but not completely derail your progress with the ketogenic diet.
So the first thing that I always find really interesting is that athletes themselves, regardless of diet, are quite well poised to metabolize ketones because ketones get taken up into the muscle through the monocarboxylate transporters as we all know, but that transport is also used for lactate.
And so if you're athletically trained, you've already up-regulated that through exposure to lactate. So athletes can get ketones into the muscles quite efficiently compared with someone who is sedentary. So when we are thinking about how ketones might be useful for athletic performance, it's kind of interesting to think about why ketones even evolve for starvation.
They evolved as a fuel and they evolved to alter our carbohydrates burning and turn that down, stop us from breaking down our protein into glucose to complement lipid metabolism and preserve cognitive function. And all those things could be useful for an athlete.
So at Oxford we were trying to unpack this state of being in like fed state but also having ketones present as well, because before the discovery and availability of exogenous ketones, you either were in ketosis and you had low carbohydrate availability or you were- I wanted to say you were either in ketosis and had low carbohydrate availability or you carbohydrates, but no ketones. It was one or the other, it was pretty binary.
So first we had to see whether the athletes on a non-ketogenic diet could even burn ketones during exercise and so we ran some studies looking at levels of ketones after identical ketone drinks taking a rest or during exercise and we could see the exercise brought down the levels of ketones when you were even taking the same drinks.
So it was like, huh, ketones going down... that probably means they're being burned. I mean there are other possibilities there as well, but we strongly suspected that this decrease in levels of BHB represented ketones oxidation. And then we were looking at other- so ketones are burned. What's happening to the metabolism of other fuels?
So we did some muscle biopsy work and looked at muscle glycogen before and after exercise as normally at an intensity that's very glycolytic, so 75%, which is normally the most non-fat-adapted athletes that are pretty much completely relying on carbs for that.
And we could see that when we gave the athletes ketones and carbs rather than just carbs, they were hardly touching their muscle glycogen stores at all, which was kind of bizarre and very useful when you stop thinking about wanting to push out and extend the ability to keep exercising because we know that when your glycogen stores run out, that's kind of when you have to stop or take on extra fuel.
Another sign that carb metabolism was being modulated was blood levels of lactic acid. So lactate is produced as a byproduct from glycolysis, carb burning again and we could see the steady-state lactate levels were around about 2 mmol low and you took ketones prior to exercise- when you took ketones with- lactate levels were around about 2 mmol low when you took ketones and carbs before exercise rather than just carbs alone.
So that's like- and lactate is very easy to measure with just a fingerprint test when you're testing athletes as well, so is quite an easy test that people could see that their metabolism was shifting.
But typically again, as I said, when you get overset in intensity you don't burn that intramuscular lipid because you are reliant on carbohydrates and we saw that at this quite high intensity ketones turn the muscle back on to using fat even more. Which was... it was it was very stuck how different the metabolism was in the presence of ketones versus conventional carb fuel metabolism in these non-keto-adapted athletes.
And so what we saw in those athletes and this is, you know, heavily caveat where there's a small study and you know, a high-level athletes. But we did see a pretty consistent improvement in performance that was on average at about 400 m over 30 minutes which is about 2%. And to put in perspective 2% would be like separating the first and fourth place at the Olympic marathon. So for high-level athletes an improvement like that is meaningful.
So there's just more room for error in your performance. And then also as I was saying the training of the muscle actually better equips it to take up and metabolize ketones, so maybe there's less benefit when you're less well-trained. But that's a state we don't know, we still need to run the research study.
And so that's for the people who I feel like would respond and then on the other hand you could argue that actually when you take a ketones drink one of the key things that happens is ketones dampen lipolysis, which is the process of fat release from our adipose tissue. And so if you take a ketone drink and you dampen lipolysis and then you decrease your plasma free fatty acids, in a fat-adapted athletes... those people are really quite heavily reliant on those plasma free fatty acids.
Bret: 6:40 miles for 100 miles! Unbelievable.
So for anyone who's on a ketogenic diet and would like energy for their workout, so maybe they are training for some kind of race or event, I'd encourage you to try it because at the moment there's very little like risk cost- You know, the cost benefit analysis is try and see how it works for you. And I know is a way for us to do the science session to be able to give you the definitive recommendation.
But let's talk about the salts versus esters in terms of tolerability, efficacy and sort of what you would recommend to people if they just wanted to see if they had a little boost in their athletic performance.
So, I mean, let's maybe start with ketones salts. They are the most widely available in consumer products right now so is the easiest to find ketone salt and they tend to be the most price economical.
These molecules consist of typically the ketone beta hydroxybutyrate and that's because acetoacetate and acetone are not very stable and it's difficult to formulate them into a product. So take beta hydroxybutyrate and you bind it with an ionic bond to a mineral, that's typically something like sodium or calcium or potassium. Interestingly enough, but it's also possible to bind ketones to charge amino acids, but the amino acids have quite a big molecular weight, so you end up having to take like mountains and mountains of powder to get a decent amount of a ketones if you do that.
So mostly these minerals like we'd think of like table salt kind of thing, but it's ketones instead. One consideration that people should look out for and it's not always obvious, is that typically the salts mixtures of two optical isoforms of beta hydroxybutyrate- so when you do chemical synthesis outside the body, you end up with- well, I should have explained optical isomerism. Optical isomerism kind of refers to this property of molecules where it's always like handedness.
So if we think about our left and right hands, we have four fingers and a thumb and they are mirror images of one another, but they don't overlay on one another. And beta hydroxybutyrate has this property and the enzymes in our body that make ketones and also that break ketones down, specific to one-handed form- so if we give this other handed form that our body isn't really used to seeing, it certainly won't be making it, but it also is very slow to be breaking it down or using it for anything.
Bret:So people may hear those reference as an L and a D form of the ketone bodies. Brianna: Yeah, it's kind of confusing because people either call them R and S, or D and L. And I couldn't tell you exactly in which setting you should be using either one of them, but you use them in pairs, RS or DL.
And I am looking forward to finding out more about that. So especially for athletic performance but also in conditions, for example, Alzheimer's disease, where energy provision is like one of the really key things that the ketones are doing in this kind of situation, you'd always want to be prioritizing D or R beta hydroxybutyrate over the S or L form of beta hydroxybutyrate. So that's just something to be aware of with the salts.
And also you could have monoesters, so one ester bond, diesters, two ester bonds, triesters, three ester bonds. So actually there are tens maybe even hundreds of different possible ketone esters and the chemical structures of those molecules where they did a level of BHB versus acetoacetate, for example, those are all going to impact on what they are useful for, there is going to be big difference in like physical properties of those molecules, like how they taste, which is a really important one, how easy they are-
And I think a really neat example actually is... there is the acetoacetate diester that Dr. D'Agostino has been working on and they've actually seen that giving acetoacetate in certain use cases like the CNS oxygen toxicity and in some of the cancer models, actually it's better to give acetoacetate than beta hydroxybutyrate.
But when you start to look at the biochemistry- so for example beta hydroxybutyrate may just be better for athletic performance, because if you give BHB then it's going to be converted into acetoacetate and that conversion generates one molecule in part of NADH, which is used for energy production, so you get this extra energy production step in the conversion of BHB to acetoacetate that you wouldn't get if you just gave acetoacetate, for example.
Then you have the esters, there's none of this mineral load, so they are kind of a little bit more potent in terms of BHB delivery or at least the BHB monoester is very potent in that you could take maybe like a 30 g or a 40 g dose and be at like 6 or 7 or 8 mmol of ketones within 30 minutes.
So, you know, people like... oh, esters make you sick... Well, it's like no, that one ester made people sick... It's going to be different for different compounds and it is now something that we're exploring at Buck, like how can we change up how ketone esters work and stick them together to get different clinical end points.
And the institute is set up in a very collaborative way. So everyone comes together very often and there's a lot of sharing of knowledge and expertise between labs. So I think it's a great way to accelerate knowledge and discoveries here. For example we are collaborating with the bioinformatics and AI core to do a very broad look at how different biomarkers are changed during ketogenic diets and compare that to exogenous ketones.
And they have this fantastic way of looking at all of the different markers and showing us like what are the most important differences. And then we also have a fantastic proteomics and mass spectrometry core and we are going to be looking at how beta hydroxybutyrate itself is added to proteins as a post-translational modification. And again if that's different between the diet and exogenous ketones as well.
So what I- bringing into the team a little bit is this knowledge about exogenous ketones so we're using it as a tool and alongside the ketogenic diet now we will always be comparing diet to esters or diet to exogenous ketones of any kind. And we also are interested in running alongside that arms where we give just targeted S or L beta hydroxybutyrate by itself so that we can isolate any energy effects of the ketones from any potential signaling effects of the ketones as well.
So the experimental designs that are being set up will hopefully allow us to start to tease apart things that are down to carbohydrate restriction, things that are down to BHB, potentially as an energy and then things that are down to BHB as a signal as well. And we can really tap into all of our colleagues and PIs over at Buck to be able to do that - so it's a fantastic environment.
When we talk to people about starting a ketogenic diet for their health, whether it's reversing type 2 diabetes, whether it's for weight loss, whether it's for treating insulin resistance or metabolic syndrome, lowering the blood pressure, all these different effects, generally it's the effect of lowering insulin and glucose that is the most important.
That's only going to happen with the nutritional carbohydrate restriction. Adding the ketones probably aren't going to help with that, but can the ketones have an additive effect or different effect? Sounds like that's what you're starting to research. Do we have any data, one way or the other now? Or is it something that we're going to have to wait and hold on for future studies?
Because this is actually more complicated than just insulin. There's so many different pathways that feed into longevity. And I think that some of these are going to be hit by just consuming ketones by themselves, obviously not all of it. And we say, when we have visitors up at Buck and they are like, "What do I need to do to live longer?" And we are like sleep enough, do some exercise and look at your diet.
And if you're not going to go full ketogenic diet, then do periods of fasting, or time restricted eating. You're always going to meet people where they're at and, you know, I think that we need to be reinstalling periods off ketosis back into our everyday life, because it's something that we've evolved with as a species; periods of plenty and periods of less.
So weather that's just getting up to 16 hours of fasting, 16/8 kind of eating window, whether it's doing one 36-hour fast a week or whether it's going on a ketogenic diet, all of these are going to be small changes that people can make that's going to promote health span and lifespan.
And I think it's always important to meet people where they are at, you know- It would be hard for me to sit down and tell people, "You need to do what I'm doing and train like 18 hours a week like part of my Ironman training."
Most people will never going to be able to, or want to do that. So it's just like anything that you're doing now, maybe add 5% more and that's always going to be a positive step in the right direction. And another study that I think exemplifies this really nice is John Little at the University of British Columbia looked at the difference that a low carbohydrate breakfast could make to total glucose exposure during the day.
And he found that even just taking out the carbohydrate as a breakfast had an impact on overall exposure during the day that could likely be clinically meaningful. So it's even if you change out like one of your meals a day and make it very, very low carbohydrate, this is going to start to help you metabolic health and then also help how you age as well, so I think it can be kind of extreme for people, some people, to contemplate making that big shift to the ketogenic diet.
But it's like take the first step, start somewhere, whether it's with a little bit of fasting, whether it's with one low carbohydrate meal a day. I know that once you start really committing to that lifestyle, you actually have to really commit to end up with that keto adaptation. But there are sort of like intermediate steps that you can do just to get your body ready for it and understand the process a little better.
And actually for some of these people feeling like that they are making progress and they are not alone that's really, really powerful. And helps them to reach their goals.
So the way that I like to frame up these whole things is like you're either at a point in your life where you are prioritizing performance and in that case you're often trading off the factors that would help you with longevity. I think it's like you kind of have to prioritize one or the other. And when I was an elite athlete, it was performance.
But for many people and especially as you age you need to- You aren't going to be pounding like goo shots and all of that. You're going to be taking metformin and it doesn't matter so much how much you lift in the gym, but maybe the metformin and the health span that you'll get from taking that, then that's more worthwhile.
So yeah, it seems to me that when you look at the metabolic pathways, like I'm told, for example, athletes are always wanting to boost that for muscle growth and then when we think about longevity- oh no, turn it down. You've got to pick one of the two things that you're going after there.
So, we still don't want to completely turn off mTOR. So how do you balance, how you see mTOR in terms of having adequate protein intake for lean muscle mass, or in the setting of a low-carb ketogenic diet? How do you balance that?
For example if you look at John Newman study on mice on the ketogenic diet and at the study that came out of UC Davis at the same time, mice on a ketogenic diet, they were actually seeing different levels of gene expression related to mTOR in the liver place in the muscle place, in other tissues - the brain for example. And so I think we're really only just starting to unpack the tissue specific effects of ketogenic dieting or protein ingestion. Just because we say, protein does this to mTOR, we don't actually know whether this is the same in all of the tissues.
And so there's really probably very few people that actually get what an academic paper actually means when it comes out. So, nowadays we take our interpretations from the popular media or from we read on social media or other people's takes as well. And it sometimes misses some important nuances, but I do think that there's a desire to oversimplify everything.
So like protein restriction does this to mTOR, which does this to lifespan or, you know, ketone esters do this to performance. And as we've already discussed, there's a lot of nuance in terms of the ester in terms of the performance, in terms of the athletes level. So you just can't capture all of the necessary nuance in a headline that's click bait.
I'm enjoying the change of sport and so there's a certain amount of that in there as well, but yeah I mean I don't think- and you know, even on joints and bone health and all that, I don't think that it's necessary going to be the ideal thing for me to do forever.
I mean, I have some like short-term goals that I want to hit and then after that I think I probably would like readdress my- I don't know that I'll be an Ironman triathlete forever or doing it at the level which I'm currently trying to push for forever and ever. No and I totally agree that there's probably like a bell curve in terms of health benefits to especially endurance exercise, -because it's hard on your body.
And so yeah, I mean more exercise is certainly not always better. You have to be able to support it with sleep and nutrition and recovery, which is hard when you got a full-time job. I think the people who coach triathletes the best are the people who are like- There's no point in getting up at 3 AM just so that you can hit the hours of training that you want to hit to try and do Ironman... like that's not productive for health.
And so it comes back to kind of why are you competing in sports... is it your life, is it going to be a professional for most people? The answer is no. And even for me now, I want to compete at a high level, but I don't think I want to be a professional triathlete. That's a small amount of people and most people do it for a relatively short amount of time. So, you know, the average person who is competing in Ironman, you know, it shouldn't be coming at the expense of your health...
But it's been fun to turn my endurance background into this new sport and I've enjoyed traveling and the community there is really great as well. And so as long as you practice it in a healthy way and make sure it complements your lifestyle, then I think it's certainly better than being a couch potato.
