Episode 64 Navigating the Ketogenic Landscape with Dr. Dominic D'Agostino

Unlock the secrets of the ketogenic diet with Dr. Dominic D'Agostino as we navigate the nuances of ketogenic protocols, from their clinical roots in epilepsy treatment to their modern-day applications in enhancing athletic prowess and brain health. Whether you're a seasoned keto aficionado or simply curious about this high-fat lifestyle, you're in for a wealth of knowledge that could reshape your understanding of nutrition.

Timeline (Episode 64)

1:50 Dr. Dom has cows and gators in his backyard! His dogs have fought with gators. The mammals win! 

3:45 Definition of Ketogenic Diet (KD)

8:18 There are over 100 years of clinical use of the KD

9:04 Fasting was a “cure” for seizures

11:00 Effects on the brain – how does the KD affect normal healthy subjects

15:10 Dom has been a KD for 15 years

18:34 Dom used the old MET-Rx brand way back when!

21:00 Exogenous ketone ester supplementation studies – where do we stand on this?

21:58 Consume MCT oil (the poor man’s ketone ester)

26:30 Higher ketone levels is not better

27:00 Ketone esters > Ketone salts in extreme environments

28:00 Dosing of Ketone esters (higher is not better)

29:22 Don’t exceed 10 grams of Beta-hydroxybutyrate

34:07 Advantage of being in ketosis vis a vis performance – under conditions of glycogen depletion esp. in the cognitive domain

41:57 A good supplement to start with are MCT oils (since it will elevate your ketones)

45:20 Perhaps use these esters as a training aid; given acute may enhance PVT

49:30 Debunking the myth that high fat diets are always “bad.”

About our guest: Dominic D’Agostino

• Ph.D., Physiology, Neuroscience, University of Medicine and Dentistry of New Jersey, 2004
• B.S., Biological Sciences, Nutrition Science, Rutgers University, 1998

A researcher and professor with a diverse background in neuroscience, molecular pharmacology, nutrition, and physiology, Dominic D’Agostino, Ph.D., is a tenured Associate Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida (USF) Morsani College of Medicine. He is also a Research Scientist at the Institute for Human and Machine Cognition (IHMC). Dr. D’Agostino earned his Ph.D. in 2004 and subsequently entered into a postdoctoral fellowship in neuroscience at the Boonshoft School of Medicine at Wright State University in Ohio.

He has been awarded numerous grants that have resulted in national and international research collaborations and publications in such peer-reviewed journals as the Journal of Applied Physiology, Cell Metabolism, Neuroscience, Carcinogenesis, Nature Medicine, Journal of Neurophysiology, and the Journal of Microscopy.

About the Show

We cover all things related to sports science, nutrition, and performance. The Sports Science Dudes represent the opinions of the hosts and guests and are not the official opinions of the International Society of Sports Nutrition (ISSN), the Society for Sports Neuroscience, or Nova Southeastern University. The advice provided on this show should not be construed as medical advice and is purely an educational forum.

Hosted by Jose Antonio, PhD

Dr. Antonio is the co-founder and CEO of the International Society of Sports Nutrition and the co-founder of the Society for Sports Neuroscience, www.issn.net. Dr. Antonio has over 120 peer-reviewed publications and 16 books. He is a Professor at Nova Southeastern University, Davie, Florida in the Department of Health and Human Performance.

Twitter: @JoseAntonioPhD

Instagram: the_issn and supphd

Co-host Anthony Ricci EdD

Dr Ricci is an expert on Fight Sports and is currently an Assistant Professor at Nova Southeastern University in Davie Florida in the Department of Health and Human Performance.

Instagram: sportpsy_sci_d

Transcript

Speaker 1: 0:02

Welcome to the sports science dudes. I am your host, Dr Jose Antonio, with my co-host, Dr Tony Ricci. If you're a first-time listener, hit the subscribe button and like the show. You can find us on YouTube, Brumbles, Spotify and Apple Podcasts. Our special guest today is Dr Dominic DiAgostino. He got his PhD in I believe it's both physiology and neuroscience from the University of Medicine in Dentistry of New Jersey. That was back in 2004. Bs in biology and nutrition science at Rutgers that was back in 1998. He's currently a researcher and professor. He has quite a diverse background in neuroscience, molecular pharmacology, nutrition and physiology.

Speaker 1: 0:48

You're also a tenured associate prof in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine. That is in Tampa, correct, that's Tampa, right? Yeah, I love Tampa. Tampa is a beautiful place. You've also been awarded many, many grants that have resulted in international research collaborations and publications In such peer-reviewed publications such as JAP. I love that journal Cell Metabolism, Neuroscience, Carson and Genesis that's a journal I'll ever be in Tony Nature Medicine, Journal of Neurophys and the Journal of Microscopy. So some heavy-hitting journals there Now what you're most known for is work on.

Speaker 1: 1:32

Certainly when you sort of leave the realm of just basic science. People know the ketogenic diet stuff that you've done. So first of all I want to welcome to you the sports science dudes. Thanks, tom, for taking time out of your day. I know you have cows in the background. You know moving and stuff, so you're the first guest that has like cows in your backyard.

Speaker 3: 1:54

Alligators too. I have a six-acre lake. We have a fish farm too and there's some alligators, but it's a little too cold for alligators today, but a lot of times I see them from my office and sometimes I do stand-up paddleboarding. I think you do that too, right, yeah, race, yeah, yeah, oh, really Race, oh, wow, yeah.

Speaker 1: 2:13

So you paddle where the alligators are.

Speaker 3: 2:16

I do, yeah, like one time. You know, a couple of times I'll have the little ones come up to me and I got to like push their head down, push them away with the paddle.

Speaker 1: 2:25

Yeah, yeah. Actually. I live right off the St Lucie River. I do quite a bit of paddling there. Alligators are the most right. When you approach them, they sort of just bugger off. They are not really aggressive, I mean, they're not like crocodiles.

Speaker 3: 2:38

No, yeah, we had a very big one that was aggressive, but we had him for dinner. Yeah, oh, okay.

Speaker 2: 2:49

And my dogs too.

Speaker 3: 2:50

So I got to protect. I got two big dogs. They got into a fight with an alligator two months ago, two or three months ago, and long story short, but the dogs had the alligator for breakfast.

Speaker 1: 3:01

Okay, so it wasn't a large one, at least it was sort of one of the smaller gators.

Speaker 3: 3:07

Well, when you hold it up, it measures just under five feet, but you know with a tail and everything. Yeah, but it was you pick them up. It was like 25 pounds, like the 10 footer that we had, which I needed my tractor, you know, to get that one.

Speaker 1: 3:22

Yeah, 10 footer, that'll take an adult human and do a little death roll and or you know what? You're swallowing water. So, yeah, absolutely. We could talk all day about alligators because I'm always looking for them, but anyways, I wanted to ask you, let's, let's. I want to talk the analogy of high protein and also the ketogenic diet and I'm going to ask 100 people who do work in nutrition what a high protein diet is. Oftentimes there's there's no agreement at all. In fact, I probably defined high protein higher than most people, but in the literature you'll see, high protein is anything higher than the RDA, anything more than 1.2 grams per kilo, even defined, as you know. If it's 35% of your diet which I don't like percentages because if you're eating a low calorie diet, I mean 35% of your diet is nothing Does that exist within the ketogenic, within ketogenic diets, in terms of definitions, that there's no agreement, or is there a universal agreement?

Speaker 3: 4:20

Yeah, I'm glad you bring that up because that's like one of the biggest areas of contention. You know the early ketogenic diets the medical ones, were like four to one ratio four parts fat in grams, not in like percentages four parts fat, one part protein. And if you work out the math it's like you know something like 0.6 to 0.8 grams per kilogram. It's pretty low protein protein.

Speaker 2: 4:47

Yeah.

Speaker 3: 4:47

So, and you know these early studies in pediatric epilepsy showed stunting of growth and that you know there's some side effects, I think, associated with a low protein. Protein is slightly insulinogenic so it could decrease your ketone levels, but over the years the levels of protein have been used higher in more clinical ketogenic diets.

Speaker 3: 5:13

We call that it goes like four to one, two to three to one, two to one, 1.5 to one, which is also called the modified Atkins diet, and that's the diet actually used in. If you go to clinical trialsgov, you'll find hundreds of clinical trials right now with the ketogenic diet and they're using a higher protein diet. It's still it's not like. I guess it would fit like 1.2 grams per kilogram. So it's right on the edge of that. You know, one to one. One study is like 1.6 grams per kilogram, which I think is more appropriate for, especially depending upon the population.

Speaker 1: 5:51

So is there a cutoff that you personally would say, hey, that's a little too much protein and it's the longer ketogenic.

Speaker 3: 6:00

And for athletes. I think 1.8 to even some athletes, two grams per kilogram is fine and I think that's good for medical as a medical therapy. I think 1.2 to 1.6, which is by all clinicians standpoint, is pretty, pretty high. I think if you talk to a neurologist who uses the diet for epilepsy is high, but I think that's most appropriate. I think what we don't want is a protein deficient diet, right, historically, even in the literature they point to it and there's various issues, you know, with kids, growth and things like that, and that's all attributed. It wasn't.

Speaker 3: 6:41

It's almost like like there was not an understanding of protein metabolism, the knowledge of the. You know that they were not up on nutrition enough to understand that the side effects were associated with too much protein restriction. So super important, especially in growing child and especially in the age population, to age related sarcopenia is so important.

Speaker 1: 7:05

So, historically, when was the ketogenic diet first introduced? And I guess you know I'm always curious as to the first person to try it, like what's the thought process? Hey, let's give this child a super high fat diet. You know when did that happen and who was that person?

Speaker 3: 7:21

Yeah, the Mayo Clinic, there was a couple. Well, I guess you can go back a little bit farther with like banting and using a low they didn't call it at the time, but basically like a ketogenic diet to keep type one diabetes patients alive, because that was actually used, but prior to the, prior to insulin being, you know, developed. But you know, generally speaking, the ketogenic diet was developed at Mayo Clinic by a couple investigators working on it Wilder comes up as a name that he did a short clinical bulletin on this and just showed that it was highly efficacious for treating epilepsy, all different forms of epilepsy, even independent sort of the etiology of epilepsy, and they didn't really know, you know, what was causing different forms of epilepsy back then. So 1920, 1921, so we have over 100 years clinical use of a ketogenic diet in the literature.

Speaker 2: 8:24

If I can ask, in its origins, what would? What would those well, if not percentages, ratios or or even grams have been? Was it closer to some of the earlier you know, 85 percent fat and the crazy numbers that we heard? Well, I shouldn't say that we heard, but some people did apply, you know, 85 percent fat and a 10 percent protein max and 5 percent carbohydrate in its origins. Is that closer to where it was or yeah.

Speaker 3: 8:52

So what they tried to do, the idea was, at the time, to mimic the physiological state of fasting with they knew we knew millennia that fasting was a cure, you know for seizures. So you know this was written about by Hippocrates. It's, you know, in book of Matthew, it's in the Bible and it was all over throughout history that fasting was a way to manage seizures. So when subjects fasted they saw that it can control seizures. And when they drew blood they saw these ketone bodies forming in the blood and urine also in the breath.

Speaker 3: 9:28

So the idea then was to develop a diet that was eucaloric, that could sustain life and had the minimal amount of protein and that was about eight to 10 percent back then with a majority of basically just feed fat. This would and if you drew blood from someone who was eating this diet and you adjusted calories to be a calorie deficit or even eucaloric, their blood looked like they were fasting, meaning that glucose was low, insulin was low and the ketone bodies were elevated, similar to fasting. Wow, and the ketone bodies changing your metabolic physiology changes your brain energy. It also changes the neuropharmacology of your brain in many different ways that we study, actually, and this has an anti-seizure effect. They didn't know it back then, because they didn't even know that the brain could use ketones as a source of energy, but they just knew that this elevation of ketones in the blood produced this remarkable effect.

Speaker 1: 10:29

So if it has such a powerful effect on the central nervous system, if just any random person who's somewhat healthy embarks on a ketogenic diet? I know I've tried it, but I like rice too much, so there's no way. I can adhere to it, but what are the cognitive effects of it for someone who normally eats a mixed diet you know, carbs, fat, protein and switches over? What's the data show in terms of the effects on the brain?

Speaker 3: 10:59

Yeah, good question. So ketogenic diets and what we call therapeutic ketosis because there are many ways to achieve that tend to have a beneficial effect in the context of an energy deficit in the brain or a disrupted brain homeostasis or disrupted neurotransmitter systems in the brain. However, if you take normal healthy subjects and do a brain scan on them, like an FMRI, and then just look at cognitive function and look at brain neural circuitry, you'll see some changes that happen in regards to network connectivity. And this is you get more of a beneficial effect as the person ages, because there's age-related cognitive decline that may not be pathological, yet that you start to see some benefits as we age.

Speaker 3: 11:55

The brain's ability to use glucose as a fuel decreases with age and that's due to a number of different reasons. There are some vascular components. There's, you know, pyruvate dehydrogenase complex, the glut one transporter, the glut three transporter, which is on neurons. However, the brain's ability to use ketones as an energy source as we age is sustained and that does not decrease with age. So you have that. So the brain will use ketones if it's in the blood, meaning that if your blood ketone levels are elevated one millimolar which you'd get with like a, you know, a moderate ketogenic diet that would give the brain about a 10% boost in available energy. So that's from a millimolar perspective, so 10, 20 millimolar. For example, george Cahill at Harvard Medical School, with Oliver Owen, fasted subjects for 40 days. Believe it or not, this is research that's really caught my attention when I started doing, you know, research on.

Speaker 3: 13:02

Wait, when you say fasted, they just consume water, yeah, water, and I think they took maybe small amounts of electrolytes too. So, yeah, so yeah, you can't. No IRB would approve this nowadays, but I always reference it in my talk. And after seven to 10 days the ketone levels in the blood were elevated to about five millimolar. Glucose went down. The homeostatic mechanisms that maintain blood glucose are very powerful, so your glucose is never going to go to zero. So it'll drop down to like maybe two to three millimolar and then stay there, but the ketones will be like double that. That'll be like five to six millimolar. So the brain will basically can freely use those energy sources.

Speaker 3: 13:48

As for fuel, so after about a week of fasting, two thirds of brain energy metabolism is derived from ketone bodies. So that's really important in the context of. If we did not make ketone bodies, we would rapidly succumb to muscle wasting during a fasting state, because we would break down body fat and we would liberate fatty acids for fuel. And your heart and your skeletal muscles use fatty acids for fuel. But these long chain fats do not cross the blood brain barrier, so they go to the liver and through beta oxidation of fatty acids creates acetyl-CoA and then acetyl-acetate and then beta hydroxybutyrate, which is the main ketone in circulation. So these ketone bodies restore and maintain brain energy metabolism in the face of fasting and also in the face of carbohydrate restriction or zero carbohydrates.

Speaker 3: 14:46

We technically don't need them because you could follow a ketogenic diet and then the ketones largely replace glucose as the primary fuel for the brain. So this is a long-winded answer to your question. So in the context of a normal healthy person, the benefits from that would be like. I've been on a mild, moderate ketogenic diet for 15 years and for me, like I started it when I transitioned to a tenure-track position and I noticed that I did not get hungry and I had sustained energy and my fluctuations in energy were reduced. It was in some way kind of liberating because I followed like the low-fat, high-protein diet, eating rice and tuna, fish and things like that, and I would get hungry two or three hours later. On a ketogenic diet I could eat breakfast and not get hungry until dinner and then I could be working all day and not get hungry.

Speaker 1: 15:40

So there's a logistical advantage to that.

Speaker 1: 15:43

Now, this is interesting because you're doing what you do research on, I mean personally. It's part of your diet. Describe what you're eating, though, because I'm always curious that I have met very few people who have adhered to a ketogenic diet for any length of period of time. They've done it maybe for four weeks or eight weeks or whatnot. So describe your typical day. If there is such a typical day of what you eat, because I've always been I'm not surprised, but there's a limitation on the foods you can eat, and I think a lot of the foods I eat are carbohydrates like rice, pasta, fruits and vegetables. I would imagine you're somewhat limited, so tell us what you typically eat in a day.

Speaker 3: 16:27

Yeah, I always like to like tell me what you buy at the grocery store. So I have a chest freezer that has like about 300 pounds of meat in it. It's hooked up to my solar so if power goes out I still have it hooked up. So beef, pork, chicken. I eat a lot of turkey, a lot of eggs, a lot of fish that could be from shrimp, salmon. I eat a ton of mackerel and sardines I eat as far as like vegetables. I eat wild blueberries every day. We have avocado trees on the farm here, so a lot of avocados I eat, usually like one small apple per day. So apple, blueberries and broccoli I eat every single day and that makes up about maybe 50 grams of carbs, with about a third of that being fiber.

Speaker 2: 17:23

And.

Speaker 3: 17:23

I do. I'm of the opinion, unlike a lot of people, on keto or low carb, that fiber. I think fiber is important, not only for the microbiome, but you know it helps. There's many different aspects of eating plants the phytonutrients, the polyphenols, the fiber all these things are beneficial in my opinion. So, like for breakfast today I had steak and eggs, which I frequently have, and for lunch I had sardines or mackerel canned sardines or mackerel and some turkey that I had like a turkey leg, and for dinner I think we're going to cook up fish and I usually have my carbohydrates later in the day, like I'll have either a salad or broccoli, asparagus, and then at nighttime I make this like chocolate keto mousse that I put like blueberries in and some collagen powder with MCT kind of combined chocolate powder that I mixed together and it almost sounds like-.

Speaker 2: 18:29

I've always done this.

Speaker 3: 18:31

Even when I was in college, I would take metrics. I don't know if you remember metrics.

Speaker 2: 18:34

Yeah, I remember metrics.

Speaker 3: 18:35

Metrics with HMB. I bought it, the whole lot of it or whatever, and then I would put like two packets of metrics with HMB in a bowl, then I would put water in it and then I would stir it so it was like a pudding and I would eat that like every night. Sometimes I'd cut a banana in it and, like every day I'd come home from the lab working like doing my rat studies at like midnight, eating watching like Conan O'Brien or something, or Leno, like every night. That was my routine, leno.

Speaker 1: 19:04

We're going way back. Yeah, yeah, way back you know it's funny, the reason I moved to Florida is actually to work at Metrics. They had an office in oh really, yeah, they had an office in Boca Raton. It was actually Jeff Stout who got me the job. He was working down here as well. So I'm quite familiar with the Metrics white box and their protein powder and whatnot, but I think it's a dead brand now. I don't know anyone who even knows Metrics.

Speaker 2: 19:28

I used it in football.

Speaker 3: 19:31

Yeah, they have a few bars. When I played high school football I forgot how I got, but it really came in base and plus and I would mix it together. And I would mix it together and I would put a scoop of another product called Cytomax that had Alpha L polylactate in it.

Speaker 3: 19:50

I did it because I was into mountain bike racing and that was like my football fuel and at the time, I don't know, they don't still sell it. I took a Fedrin caffeine aspirin stack Basically what I just described there. There's no. Oh, creatin too. I was one of the first people to use creatin. This goes back to 1992. So I was using creatin monohydrate and fast forward like 30, some years later, 40 years later, and there's no innovation. There's nothing better than caffeine, creatin, maybe beta alanine or something like that. But ketones I mean, I study ketones so we can talk about that. So I think there's some beneficial effects of ketones too.

Speaker 1: 20:34

Well, yeah, talk about, at least in the exercise space. I'm starting to see and you would know this a lot better than me a lot of studies on exogenous ketone supplementation. The data is mixed, so explain because I'm not super familiar with the data. I read some of the ones that talk about whether performance goes up, performance goes down. Performance doesn't change. Tell the audience a little bit about the exogenous ketone ester supplementation studies.

Speaker 3: 21:01

Yeah. And then there's ketone salts too. Actually, that's kind of what I'm drinking here. I'm real electrolyte, so people think of salt, they think of sodium chloride. But well, I'll kind of take a step back.

Speaker 3: 21:15

So you add the ketogenic diet that can achieve ketosis. And the ketogenic diet is very unique in that it's defined by an objective biomarker, that's the elevation of blood, urine or breath ketones. You can also achieve that through fasting. So there's dietary ketosis. And then there's some drugs that can induce ketosis, but I won't go there. And then there's different forms of the ketogenic diet that can produce therapeutic ketosis. And then there are calorie-containing substances that can increase ketone bodies in the blood. So this is in the form of one would actually be MCT medium chain triglyceride, so that's. And then independent carbohydrate intake you can consume MCT. Perillo was selling this back in like 1980s, 1990s, john Perillo. Well, I remember. So cap-tree, and it's like maybe I used that too back in the day. But so you have MCT that's like the poor man's ketone ester, I guess, and then so ketogenic fat.

Speaker 3: 22:22

And then you have one-three butane dial, which is being sold as a ketone ester. So that's a dye, alcohol or glycol molecule. When you consume it, one-three butane dial is broken down, it does produce a slightly toxic aldehyde and then it also liberates beta hydroxybutyrate. Low levels, maybe you know low to like one millimolar, maybe two, but then it gives you a buzz because it's an alcohol. So basically, the stuff that's on the market now is they're selling cheap one-three butane dial and they're selling it as a ketone ester. But it's actually not. There are a couple ketone esters on the market Delta G, ketone aid, and I think, however, the backbone of a ketone ester is one-three butane dial and then you do a trans esterification reaction. Then you can add beta hydroxybutyrate to one-three butane dial. So when you consume it the beta hydroxybutyrate quickly goes up into circulation and if you do a pharmacokinetic profile, you see a first like initial spike and then the one-three butane dial gets broken down in the liver and then that releases beta hydroxybutyrate a little bit slower, but the whole like on an empty stomach. Your ketones go up and they come down and they're kind of out of your circulation within like two or three hours depending upon the dose. So now you can have a one-three butane dial, beta hydroxybutyrate monolester. You could have a diester of acetoacetate which will elevate both ketones, beta hydroxybutyrate and acetoacetate. We've done a lot of work with that molecule. It's very effective. And then you could have glycerol, and then you can make a triester of glycerol, a triester beta hydroxybutyrate or acetoacetate.

Speaker 3: 24:06

So the other, the last form of ketones I'll talk about, is essentially taking a monovalent or a divalent cation. That's a fancy word for sodium, potassium, calcium, magnesium. You could theoretically take certain amino acids that are alkaline, like arginine or citrulline or histidine or things like that. Lithium you could also use as a cation. So the ones that are on the market are basically taking these balanced electrolyte preparation like sodium and calcium especially, and magnesium and potassium too, and then you spread out the beta hydroxybutyrate across different electrolytes. So when you consume the product it's like consuming an electrolyte product but it's giving your body ketones.

Speaker 3: 24:54

So there's a product on the market I love. It's called Element LMNT and that's like a Rob Wolfhouse. It's a supplement. They use it big in CrossFit, I think the military uses it. The product that I'm drinking now, ketostar, has the same electrolytes as Element, but instead of like sodium chloride it's sodium, beta hydroxybutyrate and then it's like potassium, magnesium, calcium. So you consume it gives your body electrolytes which tend to be depleted on ketogenic diets.

Speaker 3: 25:26

And I could go into why has a naturetic and a diuretic effect, but it's also giving your body a source of energy, basically the two or three forms of energy that your brain can use, right, glucose being the primary ketones. Your brain can also use lactate, so that's the ketone salt, and I think there are many benefits. The salts will get you into that one to two millimolar range. Now a ketone ester can get you to three, four and five millimolar and everybody thinks more is better. But it's almost like blood glucose, like higher blood glucose is not better, right. So you actually can create a situation where there's an energy toxicity.

Speaker 3: 26:06

By consuming a large dose of a ketone ester, your ketones get really high. That can actually change your blood pH, which we have shown in the lab, I mean in rodent models. When we first started using these compounds, we started, you know, taking out rodents because the dosage was too hot that it would succumb to ketoacidosis. So the ketone asters are really pretty potent and you have to consume a lot of them. But I think the message that I try to get across experimentally we see this too is higher is not better.

Speaker 3: 26:41

Higher ketones can actually impair performance. It's like your body's trying to get rid of that metabolic acidosis and you have energy toxicity. However, with that said, we study very extreme environments and we study, like, very high pressure oxygen toxicity. You know hypoxia and these extreme environments where a ketone ester could be favorable over a ketone salt. But I think for 90 plus percent of the applications where you'll get a benefit of a ketone product, I think a ketone salt, a ketone electrolyte would work. But dosage, timing, I mean there's so many unanswered questions and it's a very nascent field.

Speaker 1: 27:23

Yeah, so actually I was going to ask you about the dosing issue. I mean, for pretty much any type of supplement caffeine creates in beta-alene. We know the dosing, so what would it be? In fact, before you know, we had you on the podcast. I just looked up random ketone ester products online and there's like a bazillion of them. It's its own category. So if you could tell the audience if you were to look at this category, how would you determine whether one is dosed correctly?

Speaker 3: 27:56

Yeah.

Speaker 3: 27:56

So good question. So higher is not better. So I'll say that. You know, even in the context of like stuff that we study, like cancer, I mean, we could get cancer cells to grow faster if your ketones get higher.

Speaker 3: 28:12

There are, ketones are very interesting in that they're metabolite, but they have epigenetic effects, they have signaling effects so, and they can also have, when your ketone levels acutely get above 2 millimolar. That stimulates a release of insulin. And a very prominent feature of exogenous ketones is that it lowers blood glucose, and that is due to a number of different reasons Enhancement of insulin sensitivity, that's what some of the marketers will tell you. But if you take a large dose, acutely, of ketones, that's how our body regulates ketosis right. So we get onto a ketogenic diet, our ketones get elevated, there's ketoneuria, we excrete some ketones, but then the ketones will stimulate the pancreas to release a little bit of insulin and that will decrease beta oxidation of fatty acids in the liver and that's the counter regulation. That's how we, in a very elegant way, that's how we get our endogenous ketone production optimized. I guess you could say so.

Speaker 3: 29:16

When it comes to dosing of ketones, I would say I wouldn't go any higher than 10 grams of beta hydroxybutyrate. So most of the ketone salt products have two grant, like it's very dusted, I think that's one they have low. And then the one three butane diol is not technically beta hydroxybutyrate, but I think if you take about maybe 20 grams of one three butane diol, that might be equivalent to like 10 grams. Now maybe 20 to 30 grams of one three butane diol, which is what you'll see advertised, would be about 10 grams of beta hydroxybutyrate.

Speaker 3: 29:57

I have a product the product that I use, ketostar, has 10 grams of beta hydroxybutyrate salts, excluding the electrolytes, so, and I just take a half of it. So my threshold for feeling something is about five grams. So I will take half of a dose, half of a packet, especially in the morning. It's got the electrolytes in it, it's got sodium and I'll mix it with creatine monohydrate. So I mix that up and then I'll work for like two hours and then bam, like I'll feel it, you know, and it's not just a creatine, it's just.

Speaker 3: 30:30

And then the ketones tend to work very good with caffeine too. So I say the threshold dose would be about five grams, you know, and I think, in regards to performance, cognitive performance, once you get about 10 to 20 grams is probably about the sweet spot and that'll elevate your ketones about one to two millimolar. If you are using it for like extreme environments or sports or things like that, you could probably dose higher throughout an event. You know, 10, 20, 30, 40, 50 grams Throughout the course of like a race or something like that would be appropriate.

Speaker 1: 31:07

So let's talk about exercise performance, and you know I do a lot of standup paddling. It's an endurance event. Races are anywhere from three miles to six miles and there's a race around Key West that's a 12 mile race, so it takes me a while to do it. So let's take the endurance stuff and let's take the strength power stuff. What does the literature say in terms of the effects? Let's deal with just exogenous ketone ester supplementation.

Speaker 3: 31:35

Yeah, so of all the things to study. So if you look at PubMed and I guess if you go, if you look at PubMed, the rise of peer reviewed publications is something like in 2023, it was like 700 publications If you do ketogenic diet. But a lot of those are actually exogenous. Some of them are exogenous ketone studies. Okay, so right, if you look that up and then and there's a reason I'm going down this direction is just kind of put context into things. And then if you go to clinicaltrialsgov and you look at emerging like research or research that's being done now I think you have I'm giving a talk on this soon.

Speaker 3: 32:15

So I had some numbers 504 studies as of February 11th on ketogenic diet, if you search that term on clinicaltrialsgov registered trials and. But if you dig in to actually what's being studied, about a third of them to even like 40% of them are not ketogenic diet. They're actually ketone supplements. They're using different like MCTs. Some of them are combining and they're not mutually exclusive. You could do a diet and I think it works well if you combine it with a ketone supplement and there's, I think, in as far as exercise, maybe about out of like the 504 studies, like I mean I think there's like 40 studies on exercise.

Speaker 3: 33:03

So the data is very, very mixed on that as of right now, probably because the aversive taste, probably because of the dosing. You know studies, the tolerability of these things, the studies that have been done, the performance studies, are giving exogenous ketones and then looking for an effect. They're just giving an acute dose and they're kind of shooting in the dark as to what would be the ideal dose based upon some earlier pharmacokinetic work. And then they do treadmill exercise, biking exercise, rowing, various tasks and then they look for an effect. So I never thought when I got into studying the ketogenic diet I didn't even know if Jeff Bolik's work, so I just knew of the neuroscience, you know the basic. And then I discovered like a year or two later I was like, oh my God, someone's using studying the ketogenic diet or ketones for performance. So that was like odd to me that it would. Even people would go in that direction. So I think the advantage of being in ketosis during exercise is, if you believe in the central governor theory, are you familiar with that?

Speaker 3: 34:13

Like you know, like your brain, yeah, yeah, so, and this will tie into some of recent work that we did so basically preserving brain energy metabolism and fuel flow to the brain in the context of extreme exertion, right, you know, and I think, or glycogen depletion, hypoglycemia induced by exercise, that's where I think ketosis can have an advantage, in particular in the cognitive domain, reaction time, decision making, and you know we do a variety of different tests on that. So that's really where the benefits are gonna come in. When, given acutely, the studies that have not been done that actually there's some on clinical trials that go there doing is, I think, of ketones almost like a steroid, right? So there's like you give amphetamine or caffeine then you get an effect, whereas if you took like a dose of a steroid and then had them exercise, you're not gonna see an effect. So ketones are really, in my opinion, a training aid.

Speaker 3: 35:21

So therapeutic ketosis can enhance the adaptive response to exercise for a variety of different reasons that we can go into. You know lower inflammation, there's epigenetic effects, there's, you know, effects on muscle, anti-catabolic effects. So I think that no one has studied exogenous ketones yet in the context of a training aid, you know, over a period of even like a couple of weeks to months. So now, when given acutely, I would say about 50% of the studies show like a small but significant effect. A quarter of the studies show like a negative effect. This usually has to do with like tolerability issues. Like I said, if you get ketones too high, that can inhibit physiological processes. It puts a metabolic strain on the body like an energy toxicity, and there's about maybe a quarter of the studies that just show like no effect at all in regards to performance.

Speaker 1: 36:21

When you're talking about sorry, Tony, when you're talking about toxicity, how does that manifest clinically? What do you feel?

Speaker 3: 36:28

Yeah, so well, it depends on the agent that you're consuming. So you could have like GI toxicity, which would be the ability you know these agents have are pretty acidic. They can be pretty acidic when they're hydrolyzed in the gut, so that acidity can create what you've and I've probably consumed. Like you know, I'm pretty confident that I've consumed more ketone esters than anybody else on the planet. So we were testing these things like a long time ago when Patrick Arnold was making it like back in 2009 for me.

Speaker 3: 37:03

So actually that's he got me and he was able to synthesize some molecules that got me started academically, so I'm very thankful. Patrick is known for other things in the world of you know performance enhancement but he was actually the one that made the molecule that worked really well in our lab. So you have GI intolerability is part of the toxicity Plus. What happens is that the liver has to work pretty hard to break down the one-three-butane dial and then if your ketone spike up really high, especially with one-three-butane dial, one-three-butane dial by itself has a narcotic effect. So NASA looked for like the ideal space food and they looked at many different molecules. Mit did research looking at this and one-three-butane dial made the top of the list.

Speaker 3: 37:52

The only problem with it is that it had a mild narcotic effect. You got buzzed off of it. Some people like that, but it also has. It tastes like paint thinner, right so you have to mask the taste. It tastes really, really bad. Patrick and I found ways around that. Like you could make one-three-butane dial jello shots, like you could. There's different things that you could do. You could make jello out of it and just like slides down. So I don't think anyone's picked up on that, but I'm sure someone will listen to this and come out with jello shots of one-three-butane dial.

Speaker 1: 38:26

Don, you had a question.

Speaker 2: 38:28

Yeah, no, first essential governor goes way back to Angelo Mosso. Gosh, you're talking like 1890, la Fadeca. I actually read that, which was originally in Italian and I had the translation. So my question Dom, you mentioned something really cool, so it would make early sense initial sense, I should say to see the potential benefit in more endurance activities where motor responses are relatively systematic, they're proactive versus reactive. But Teton metabolism is a comparable rate then to glucose metabolism and neuronal activity and as a result of that, so let's look at a complex cognitive processing, it's actually higher. It's higher. Okay, great, it's a little bit higher. That's my question, dr Richard V. Great, he quicker.

Speaker 3: 39:17

It's quicker then. Yeah, that's actually where Delta G comes from. The Delta G of ATP hydrolysis is about 25% higher with ketones versus like glucose molecule. So I think that's actually how the late Dr Richard V Choo is a student of Hans Krebb, the Krebb site, so we're going way back. He was actually like a bit of a mentor to me. Getting me into this field Showed that the working heart preparation, the hydraulic efficiency of the heart energetically could be increased by 25% if it was essentially burning ketones as an energy source relative to glucose.

Speaker 3: 39:55

So, whether that happens in the brain, no one has definitively shown, but it makes sense that it could.

Speaker 2: 40:02

Okay, yeah, and I was asking for the best assertion based upon what we know. So, hence, a sport where rapid cognitive processing, and then you require that mode of response that has to be coordinated, such as boxing.

Speaker 3: 40:15

this ketones could benefit in that realm arena as well, then, potentially, yeah, a lot of MMA fighters, a lot of mixed martial arts guys, ufc guys are using it. Many of them have contacted me and they said these things are working. I would be a little bit suspicious of something like one three butane dial, because that has a narcotic effect that could actually slow you down, whereas you'd probably want to use a ketone electrolyte because these guys are sweating anyway and so you want to replenish the sodium, potassium, magnesium, things like that, and deliver beta hydroxybutyrate yeah, reaction time, psychomotor vigilance, decision making All these things are the things that are improved on ketosis, not so much physical performance, but yeah.

Speaker 2: 41:05

Yeah, so BHP with an electrolyte?

Speaker 3: 41:07

that could be very advantageous for the boxing for the MMA oh yeah yeah, mix in some creatine with it, so maybe AlphaGPC, a couple other things in it, but yeah, I mean that's kind of describing what I take, but yeah.

Speaker 2: 41:21

Awesome, thanks yeah.

Speaker 1: 41:22

Tony, this is I mean, we do a lot of this stuff with Jamie Tartar over in Neuroscience some of these simple measures. What would you recommend, like for someone who has never tried any of these ketone exogenous, ketone esters? What would be a good one to start when you're dealing with, let's say, subjects you want to do a pilot trial, just to look at simple stuff like PVT and whatnot that is tolerable to them, that would have an acute effect, and if not an acute effect maybe was it seven days or 14 days of supplementation what would be a good one to try?

Speaker 3: 41:55

Yeah, well, you might want to just try the. So MCT will elevate your ketones too. So they've been around a long time. So I'll just kind of say that you know, because people are like, well, I don't want to buy, you know, a ketone supplement. However, the beta hydroxybutyrate is, like you know, a substance that your body makes anyway and the electrolytes are something. However, the ketone esters do have one prebutane dial and that's a synthetic molecule. You know that essentially. So I would start with an electrolyte beta hydroxybutyrate product.

Speaker 3: 42:26

Keto start by audacious nutrition is pretty good. I think you can get on Amazon and then, like, amazon has their own brand, nutricost or whatever. There's a couple of different brands out there, but it's called keto start. It was start. So the advantage of that is that you can deliver up to 20 grams of beta hydroxybutyrate and the electrolytes are balanced, that it doesn't give you GI issues. And then it it's really sweet because it's it uses monk fruit. That's another thing. It doesn't use, like you know, some people have issues with artificial sweeteners not so much me, but you know, I think the jury's kind of still out on that and some domains like microbiome or, you know, stimulating hunger or things like that. But it uses. Actually I'm drinking now. It's a little bit hyper sweet but it has monk fruit electrolytes and ketones as a like. A lot of the other products we use are rethritol, that doesn't settle well in my stomach, or sucralose, which is kind of like hyper sweet. And then the main issue limitation with a lot of these ketones salts on the market are the electrolytes. I drink it and it just goes right through me and you know I just go. It gives you like pretty bad diarrhea or some other issues. So it's really important to nail the electrolyte ratios and I think the tolerability will really enhance, you know, the absorption, obviously, of the ketones. So yeah, and I would start, you know, 10, one packet would be 10 grams of beta hydroxypeterite. That's about the threshold for starting to you'll feel it.

Speaker 3: 44:03

And the ketones also seem to be synergistic when it's mixed with caffeine. Not a lot Like. I think you can get keto start with or without caffeine, but it has maybe, like the caffeine version, maybe 70 milligrams of caffeine, like it's enough to feel it. But there's a couple of publications out showing that you know, ketones alone or caffeine alone and the two together. It's not added additive, it's actually like synergistic, right. And then you could also you could also mix the exogenous, the ketone salts, with MCT, and those two together can actually further elevate your ketones. And the MCT tends to delay gastric absorption, so it extends the pharmacokinetic profile we say, to the right or the area under the curve. So instead of a really rapid rise you get more of a slow elevation. So if you have like a four hour event or six hour event, you want to might mix the electrolyte, the keto start with an MCT. However, if you're doing like a quick one hour workout, like you know, the keto and salt electrolytes would be good to take.

Speaker 1: 45:15

But these will help with reaction time.

Speaker 3: 45:18

Yeah, yeah, I think I mean there's not a whole lot of things that people agree about as far as in the performance domain. Like I said, I think I think these also need to be used as a training aid. But when given acutely, especially in the context of mental fatigue or training to exhaustion, then that will then increase, like psychomotor, visual interaction, time, decision making, stuff like that.

Speaker 2: 45:44

I'm going to need you to help me construct a study with this administration on reaction time, because we have access to about 50 or 60 fighters here and we actually could do this. The challenges, the challenges you know. Measuring reaction time would have reasonable, like we said, a coordinated peripheral motor response as opposed to a finger tap. But nevertheless, I'm working on that right now but this would be wonderful to investigate.

Speaker 3: 46:08

Yeah, yeah, there's also like there's different studies that I was in, kind of our last and there was. Are you familiar with the incongruent flanker?

Speaker 2: 46:19

Yes, yeah, yeah yeah.

Speaker 3: 46:22

I think that you know it's looking at just cognitive processing and in that domain. So I think and we did a lot of different tests I'll have to look back to see, like with NASA. I was part of a space analog mission where we look at but they have a different program than NASA TLX and also Joggle Are you familiar with Joggle? Yep, yeah, we've used that with Dr Tartar only. Yeah, my wife, this is her domain, she's a behavioral neuroscientist. So we'll, like we get the licenses for all them and we get like the iPad set up and we actually do that like in a dry environment and we do it like in an undersea environment where we have like a dive iPad where, like, you can do the stuff, you can work on the iPad underwater.

Speaker 2: 47:05

Very cool.

Speaker 3: 47:07

Yeah, yeah. And look at, you know, in extreme environments so, and again, that's where being inestidic, he tells us, is neuroprotective and performance enhancing in these extreme environments. And that's what kind of like that's my career has been carved out just studying these extreme environments and I think it has cross, you know, carryover effect to many other domains like fighting.

Speaker 1: 47:29

Yeah, fighting is about as extreme as you get, tony. Yeah, it can be, yeah.

Speaker 2: 47:36

All we got to do now is just do it in about 30 below zero, and then it can't get any more extreme.

Speaker 1: 47:43

Hey, dom, in the interest of time I think we're close to our time limit here I wanted to address one last question in terms of any common questions or misconceptions about the ketogenic diet, because it's something that comes up a lot in social media. So what would be the common ones that you need to debunk?

Speaker 3: 48:03

Yeah, good question. Well, I get the question. I get a lot. Does the ketogenic diet work? Like? What do you mean by work? It's so like context dependent, right, but I think I hear quite often that high fat diets are bad right, and a ketogenic diet is a high fat diet. So we work with different clinical organizations where ketogenic diets may really have a therapeutic effect or maybe a performance enhancing effect.

Speaker 3: 48:35

Actually, the military this is why they're like no high fat diets are bad. Try to develop a ketogenic diet in a pill. So that sent me down the rabbit hole of developing exogenous ketones and that's, I'm kind of like, the reason they came to market right. So but I was not of the opinion that high fat diets are bad. If they were bad, I mean, there's people on you know ketogenic diets for 30 years for inborn areas of metabolism and they have perfect cardiovascular health and 80% fat diet. So I think high fat diets can be bad in the context of a Western diet where it's not a carbohydrate restricted, ketogenic diet. And, of course, high fat diets are hyper palatable. And the big thing is that a higher fat diet can lead to more calories consumed and more weight gained over time. So it's more of a calorie, you know, an excess calorie thing or an energy toxicity thing.

Speaker 3: 49:32

So if someone says high fat diets are bad, I quickly sort of point them to the literature of ketogenic diets and their therapeutic effects and their emerging applications, which are tremendous, even like feels, like metabolic psychiatry, for example, which was theme in a conference that we just held in Clearwater, the metabolic health summit. I'm a co-host for that. We had a whole. You know, now there's like dozens of studies at major institutions studying ketogenic diets for bipolar schizophrenia, depression, anxiety. This did not exist five years ago.

Speaker 3: 50:05

So I'm talking about like NIH sponsored, like research. So that's a very rapidly emerging area that I'd also like to point people to because just to keep an eye on it. But yeah, I would say the big thing is that there's a stigma that high fat diets are bad and but that's very context dependent, in the context of carbohydrate restriction and caloric you know, temperance, I guess you would say. Or keeping a eucaloric, a eucaloric high fat diet in the form of a ketogenic diet is no worse than a eucaloric mixed diet on health so, and I think there's some remarkable potential benefits to that.

Speaker 1: 50:47

So let's go to know Tony and case you embark on your ketogenic diet.

Speaker 2: 50:52

Well, I did it for about six months and it was kind of fun. I you know, cognitively I did feel really good. I mean it was a little bit of a struggle from the peripheral side, on the wrestling side, you know, a little burning there, like probably needed a little more glycogen downstairs, but brain felt really good. And to Dom's points earlier, by the way, my blood work was spectacular my triglyceride. I was eating cream cheese and avocado for lunch and my my triglycerides were 38.

Speaker 3: 51:24

38. Wow 38.

Speaker 2: 51:26

I mean that's like a 95 pound female yoga. Yeah.

Speaker 3: 51:32

That's remarkable that you can like triple your fat intake but your triglycerides are like cut in half. And that's that really surprised me when I did the ketogenic diet. Actually, one of them the disturbing side effect or potential side effect of the ketogenic diet and people that are not adapting is that their triglycerides can dramatically increase and that's basically showing like some kind of fatty acid oxidation bottleneck or maybe they might have a SNP for a fatty acid oxidation disorder, so that in that case I would tell people not to do the ketogenic diet. But so you know, with with wrestling and fighting and things like that, what I would say is that people really got to give it like two to three months for you to ramp up those metabolic adaptations, to actually even feel normal.

Speaker 3: 52:19

I mean, when I started going to the gym and working out, I my strength took a dip and I guess it was about two to three months. Did it come back up again where I felt like everything filled back out my muscle glycogen. So there was some adaptations there. Jeff Ollick is studying that and a few other people are studying it, but I think it's a very interesting, you know, field of research, these metabolic adaptations and metabolic flexibility. You know, I think you've probably had Mike T Nelson on, you know it talks about metabolic flexibility a lot yeah.

Speaker 3: 52:50

Mike's a great guy. He is.

Speaker 1: 52:52

So tell, tell the audience where they can find you if you're going to be speaking at a conference. Anything coming up this year, yeah.

Speaker 3: 53:00

Well, well, we just hosted the metabolic health summit in Clearwater, Florida. We had like 700, 670 people, I think, attend that. That was a growing conference. The metabolic link podcast is actually associated with that. It's ACCME approved information so you can get medical education credits with that. My website is keto nutritionorg. Ketone Technologies is the site that I have for consulting and scientific research and, yeah, I have a bunch of different conferences coming up, you know, and I can't remember them all, but yeah intense teaching schedule on top of conferences, but I do really believe that education outreach is super important and I thank you for letting me be on your platform for talking about this topic.

Speaker 3: 53:53

Appreciate- it.

Speaker 2: 53:54

Yeah, it's fantastic and, by the way, I'm planning on 20, I'm already lobbying for this and I am on the board. So plan on 2025, coming over the outside of the state, potentially talking about ketogenic diet and athletic performance and cognitive processing and reaction time. Joey, I think that'd be great. I agree. Society for Neurosport, Neuroscience yeah.

Speaker 1: 54:14

I agree. Yeah Well, tom. Hey, thank you so much for being on the Sports Science Dudes it's been an hour of really informative and cool stuff. I've actually learned more this hour about the ketogenic diet than I knew even prior, because it's a category that's always confused me, but you've helped clear up some of the confusion, so appreciate your time. Tom, thank you so much. Thanks for having me guys Appreciate it.

Speaker 3: 54:41

Bye.