Dr. Patrick: I want to talk about these cyclical ketogenic diets, but before I go there, since we're talking about muscle and the anti-catabolic effects of ketones on muscle, I'm also sort of interested in exercise performance as well like anaerobic exercise versus aerobic exercise if you are either on a ketogenic diet at that...you know, or doing some sort of modified or cyclical form of it, whatever it is, versus supplementation as well, you know, like how being in ketosis affects, you know, some aerobic versus anaerobic exercise.

Dr. D'Agostino: I get asked that question more than any other question, I think. So, in animal models, when you put them on a ketogenic diet...I think one of the first studies we did published at the Alzheimer's Institute at USF, the Byrd Alzheimer's, we didn't see a big robust effect on amyloid-β and tau. But we started the intervention after the pathology kicks in in these mouse models, so double and triple knockout. Although I think Dr. Veach and Dr. Mark Mattson, maybe they did ketone ester or started earlier in the ketogenic intervention. But in our study, we didn't see any like major changes in tau or amyloid, but the mice like ran faster. They ran like 30% longer and faster on the treadmill, and it was like remarkable. And I remember one of the PIs on the project, a very experienced Alzheimer's researcher was like, "Yeah, we've never seen anything like this." So that was an MCT supplemented ketogenic diet. We've done some research with ketone esters too.

So performance, you know, in animal models, we see it in humans, the data is messy and it's hard to make sense of it. So my general opinion...my speculation is that ketones probably have a small effect on exercise performance in the context of aerobic performance. And in regards to strength performance, my ideas about that have been changing over the last couple weeks because we're giving ketone supplements to some CrossFit athletes, and they're breaking PRs. But I think it could be potentially a placebo effect. Since everyone...excluding one person out of dozens of people, I think there's maybe something more. But I think ketones with caffeine, especially ketone salts with caffeine are a pretty powerful ergogenic aid. So I would loosely say that that's probably a performance-enhancing supplement, the combination of ketones caffeine and electrolytes.

But I think where ketone shine is using exogenous ketones as a means to preserve performance, resilience in extreme environments. So that's in the context of hyperoxia. So that's what I study. So, of course, when you're not having a seizure and your neurological function is maintained and preserved in the context of extreme hyperoxia like three or four or five atmospheres of high-pressure oxygen, that's going to be advantageous. But on the other end of the spectrum is hypoxia, right? So a lot of people who are mountain climbing, running, cycling at hypoxia. We know if we put athletes on a treadmill or bike in a hypoxic environment and give them glucose, that the performance-enhancing effects of glucose are not observed in hypoxia, which is kind of, you know, interesting. Whereas it's also shown that there may be an inhibition under hypoxic environments of pyruvate dehydrogenase. There might be some PDH deficiency or some snag or bottleneck in the metabolic pathway associated with glycolytic energy production under hypoxia.

And you would think that hypoxia...you know, chronically, it activates like HIF-1 alpha, and you have increase in glycolysis and transporters and things like that. But in the context of, you know, exercise performance under hypoxia, carbohydrate supplements don't seem to help. Whereas there seems to be...and it was brought to my attention in a couple of reviews and also serving on grant committees and stuff like that. There seems to be a good rationale for the use of ketones for fueling performance in a hypoxic environment, and that could be very strategic and beneficial in like a military setting or like a space, you know, setting or altitude, you know, setting.

My general feeling is that ketones have a small effect at increasing athletic performance. So there's only a few things that actually are powerful ergogenic aids. So we have caffeine. We have creatine monohydrate typically. There's other forms of creatine. You know, beta-alanine kind of works pretty good. And a few other odds and ends, but, you know, there's just a pretty short list of ergogenic, you know, supplements out there. I do think that with time as we understand dosing and the application of specific types of ketones in certain settings that ketones will be added to that list, but I'm not sure it'll be in the top tier list. But I do think it would be in the top tier list under extreme environments.

Dr. Patrick: What about swimmers or surfers?

Dr. D'Agostino: Yeah. I think being in a state of ketosis could be beneficial from the context of like brain injury, inflammation, and maybe just, you know, the stress of being out, you know, in certain extreme environments, or when we're exercising too, we're overproducing oxygen-free radicals. And these impart an adaptive response to the muscle too. So there could be a benefit to increase oxidative stress. I think the real benefit of ketones are not...I'm talking about this in their response, and I think your question is in the response to an acute setting like consume ketones, go exercise, what happens.

Dr. Patrick: Or be on a ketogenic diet. Yeah.

Dr. D'Agostino: Yeah. So, where I think exogenous ketones will help...and when I was talking that they would be added to the shortlist of ergogenic aids is used chronically as an adaptive response. So when we exercise, a lot of bad things happen, if we pull blood, you know, there's inflammation reactive oxygen species, things like that. If we use exogenous ketones chronically over time, I think it will help to facilitate the adaptive response to exercise over time, so suppressing inflammation or chronic inflammation, which would sort of enhance or augment adaptive responses to exercise over time. I think there's a good rationale for that, but the science is not there yet. But science is being done now. So like rodent studies are being done. I'm aware of a couple human clinical trials that are studying this. So, [crosstalk 01:23:16].

Dr. Patrick: And what about like doing a maximum effort like you're doing some kind of sprint? You know, because you do need... If you're going into a state where your mitochondria can't work hard enough to produce energy, you need glucose, right? If you take one of those big boluses of ketone ester, you drop your glucose, what's that going to do for your sprinting?

Dr. D'Agostino: That's a good point. So, one of the criticisms of the ketogenic diet was that it inhibits the pyruvate dehydrogenase complex. So, whenever we're doing carbohydrate restriction, we're limiting glucose availability but also lowering insulin. And by lowering insulin especially, that inhibits glycolytic enzymes like hexokinase. The transporter for glucose gets internalized into the cell if...you know, the glycolytic flux is essentially decreased. But I think if you follow a ketogenic diet where you intermittently add small amounts of carbohydrates in, you can keep that PDH from being reduced. I've seen data to indicate that severe carbohydrate restriction could decrease the production and the activity of PDH. This is actually what happens with Alzheimer's disease too. So, with Alzheimer's disease, it's pathophysiologically linked to impaired glucose metabolism. So if you do an FDG PET scan, the PET scan shows glucose hypometabolism in the brain scan. Ketones as an alternative energy substrate makes sense.

In the context of, you know, athletes, you're kind of doing that with chronic ketosis. It decreases the glycolytic pathway, but your muscles and your heart and other tissues actually use fatty acids for a source of energy, the brain, not so much, right? And also, when you're on a ketogenic diet, then you're feeding ketones to the brain. So the brain's kind of like a different story. But I do think that it gets overblown. I think, you know, very severe carbohydrate restriction will decrease PDH, and then that will impair exercise performance with maximum exertion anaerobic. It's really important that if you do a low carbohydrate, that you have to train under those conditions. Do you know what I mean? You can't implement a ketogenic diet or low carb and then train and expect to maintain the same performance. You have to put your body into that state of ketosis and then train very hard to induce those adaptations to make it possible for your body to perform and maintain your performance in the context of insulin suppression and low glucose availability. So those adaptive processes will then come to benefit you come game time or performance time where you can then titrate the carbohydrates back in in small amounts. So this is just called metabolic flexibility, right?

So, train low when your glucose is low and your insulin is low in a semi-fasted state, and that will induce metabolic adaptations, i.e., metabolic flexibility that will then benefit you in the context of the actual event where you can add and titrate carbohydrates back in or mix fuels. Really, you want to be able to optimally use glucose, you know, fatty acids, beta-hydroxybutyrate, ketone bodies, lactate too, which is an important fuel.

One of the things that I used to take when I was mountain biking was Cytomax, which is alpha-L-polylactate, which is like lactate as an energy zone. My original interest in academia as a postdoctoral fellow was actually using lactate for brain injury like stroke and hypoxia. And I was tinkering around with that in a hippocampal brain slice preparation doing different measurements on that, and somehow I just got steered towards ketones. But I always wanted to revisit the lactate thing because, yeah, I think there's a lot that can be done in formulating more of a comprehensive multi-fuel delivery system for the brain. And lactate's been a bit under-appreciated and kind of stigmatized and criticized, but I think it's got a lot of potential.

Dr. Patrick: Yeah. Really, good info, Dom. You know, I've been reading some meta-analyses over the years about training in a fasted state versus fed state and how, you know, if you eat before, you know, you go for a run or something, that, you know, a lot of the mitochondrial adaptations can be blunted somewhat. And, of course, a lot of those studies are using high refined carbohydrate like some toast with jam, you know, where... And I've always wondered like, you know, what... And there is like sort of a cut-off where if you're training in a fasted state for longer than an hour, you're going to have performance drop off, right? I've often wondered like if these studies were done using a more modified Atkins diet or some form of a ketogenic diet, those mitochondrial adaptations that are being blunted somewhat with, you know, a high refined carbohydrate fuel intake prior to exercise, I'd wondered, maybe that wouldn't happen.

Dr. D'Agostino: Yeah. I think it comes down to like nutrient sensing, right? I mean, it's the whole thing going back to autophagy and like, you know...and just entering a state of ketosis, that if we're in a state where like AMP kinase is high, like M2 is low, you know, insulin is low, that whole pathway is low, when you exercise in that state, it may not optimize performance, but it will optimize the adaptations that could serve you later on for performance. And then when it comes time to... You might want to train sort of in a fasted state to induce adaptations and then tinker around with different fuel sources periodically to see if you could further augment your performance, you know. That's why we need to really periodize our training under certain... There's, you know, training to force adaptations and then there's sort of game day nutrition, which is going to be a little bit different than training nutrition if we want to force that...you know, if we want to maximize our performance.

But one thing you don't want to do is actually radically switch your dietary approach or supplement approach just prior to...you know, you don't want to train for an event and be like, "Oh, I want to start slamming, you know, MCTs and ketone esters and stuff on game day." No, you want to experiment with it very methodically, you know, before you do that. I do believe that the health benefits are really important when it comes to exercise, you know, and then...not only the health benefits, but I think you're going to get more adaptation in regard to...maybe not so much for powerlifting and strength training and things like that, but I think for aerobic performance and just cardiovascular benefits and just actually benefiting at the level of the skeletal muscle and the nervous system too benefits.