#116 - AMA with Dom D'Agostino, Ph.D., Part I of II: Ketogenic diet, exogenous ketones, and exercise

Hey everyone, welcome to a Sneak Peek, Ask Me Anything or AMA episode of the Drive podcast. I'm your host, Peter Attia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to peterattiamd.com subscribe so without further delay, here's today's sneak peek of the Ask Me Anything episode. Hey everyone, welcome to a special Ask Me Anything episode. And when I say special, I am not kidding. You'll see why in a moment. This is going to be part of a two part series with Dom d'. Agostino. Now, some of you may know Dominic Dom's name, as he was, oh, I don't know, probably our fifth guest when this podcast kicked off in 2018. Dom's episode to this day remains one of our most popular episodes. And it's for that reason that we decided to go back and bring him back on in the format of a Q and A. We had this interview scheduled for a long time, and right when it was scheduled to happen, something came up. Something very important came up where I had to go away and I had to go away such that I couldn't actually do the interview. We all powwowed, contemplated, should we reschedule it for a little while. Dom had already set aside the time to do it, and in the end, the consensus view was why not have Bob Kaplan, who many of you know from this podcast, why not have Bob do it? Bob and Dom already have a great rapport. There's probably nothing here that Bob would do that I wouldn't do and vice versa. So Bob and Tom ended up doing just that and they ended up sitting down for a heck of a lot longer than anticipated. But both true to the sport, Bob wanted to go down every avenue and Dom left no stone unturned. And that's why it's being divided into two parts, so that a normal human being could actually listen to it in a reasonable sitting. Now, in the first episode, Bob and Tom cover a lot of questions, both general and specific, about ketogenic diets and ketosis. They also do a bit of a deep dive on the impact of ketosis on different forms of exercise. Now, as a reminder, Dom is an associate professor at the University of South Florida, where he teaches at the College of Medicine in the Department of Molecular Pharmacology and Physiology. He focuses on neuropharmacology, medical biochemistry, physiology, neuroscience, neuropharmacology. As a reminder I believe Dom actually got his PhD in neurobiology. For those of you who haven't listened to it, it might even be worth going back and listening to at least part of the first discussion I had with Dom in 2018, because it gives you an idea of how a neuroscientist became one of the most credible voices of on ketosis, ketogenic diets, and all things ketone related. Lastly, it is important to note that while Dom is answering specific questions and scenarios, he is not giving medical advice. Everything in this podcast is for general informational purposes only and does not constitute the practice of medicine, including the giving of medical advice. So without further delay, please enjoy part one of the AMA with Dom d'. Agostino.

All right, welcome to a very special AMA with Dom d'. Agostino. Dom, how you doing?

I'm doing well. Thanks for having me.

Absolutely. So it's been almost two years since you were on the podcast with Peter. I met you in New York at that time. I think it was the summer of 2018.

I know how time flies. I was just talking to my wife about that. She would ask me what I'm doing this week, and I was like, oh, I got the podcast with Peter. Peter. And she's like, didn't you just do one? And I mean, she was happy that it was on, but we were just amazed at how fast that time flew by. Yeah, the time in New York. So I give you credit for dealing with New York. It's always an adventure every time we go.

Absolutely. So since then, we certainly received a bundle of questions. And then Peter went on social media and asked if there were any questions for you, and particularly what you've been up to in the last couple of years. But maybe you could fill us in just in general a little bit about ketosis or how did you get into ketosis and what you've been up to in the last couple of years.

Sure.

Well, I guess, yeah, like I said, the last two years. And we are really trying to move the laboratory science into human applications. So we've been doing quite a bit on that front. And that has been pretty time consuming in regards to setting up all the IRB protocols. We're doing quite a bit with NASA Extreme Environments, Mission Operations Research, where I was a crew member for Mission 22 and my wife was a crew member for NEEMO, the acronym they used for that for NEEMO 23. And that involves looking at everything from cognitive function, body composition, gut microbiome, sleep, heart rate variability, stress. So we have like an IRB protocol for each one of these. And we're evaluating the effects of hyperbaric environments, extreme environments, on, on human physiology and all the things that I mentioned. And I just happen to be on a ketogenic diet for my thing. But we're trying to collect baseline data for future missions underwater where we can have an intervention, a dietary intervention, for example ketosis. So that has been a big focus of our research. Another space analog mission would be hi seas. So we're preparing for that. Of course, all this stuff is being on hold now because of COVID 19. So that's kind of outside the lab. Inside the lab we've focused a lot. My student now, Dr. Andrew Kutnik, last week actually he graduated and his research, PhD research was focusing on cancer cachexia. And we just got his manuscript, a massive manuscript published in High Impact Journal and really happy with that. And we have some interesting findings evolving out of that research looking at the effects of ketones on mitigating cancer, cachexia and wasting associated with metastatic cancer. In the model that actually Thomas Seyfried developed, we're looking at Kabuki syndrome, we're looking at various genetic diseases and developing ketone metabolic therapies as a means to treat these diseases, not only from a metabolic perspective, but as a means to influence epigenetic pathways that may be used to treat the disease. And the model that we're using, for example for Kabuki syndrome was developed at Johns Hopkins. So we were able to work with the folks there and get access to this animal model which we're breeding up. And things are on hold now. But we're doing pretty well on these experiments, getting them started up. And that's becoming another PhD dissertation for first year student of mine, Sarah Moss. And then we have a lot of little pet projects on the side I could talk about forever, but I think those kind of the main ones we're working on.

Cool. Well, we're going to double click on hyperbaric oxygen, cancer, cachexia and things like that. I know that there are some questions that came in on that, but first there were a few general questions for you. The first being is there a case for one to two months of ketosis a year if I am perfectly healthy and don't have any problems with carbs?

I kind of, I don't like to use this term, but you have to sometimes. It depends on the individual and what their goals are. But I do think there's definitely benefits that you can derive out of, I guess what you'd call intermittent Ketosis, the main thing is, I think one of the main benefits is that it promotes metabolic. And so having your body, we're relative, most people are adapted to frequent carbohydrate feedings. So your metabolism is not adapted to using fat as a major energy source during times of limited carbohydrate availability or calorie availability. So during periods of fasting by promoting metabolic flexibility. And I believe when you go into a state of ketosis, whether you do it with ketogenic diet or fasting, it actually activates a genetic program that actually can allow you to burn fat and make ketones more efficiently. And I think once, if you do that, a couple times, we have muscle memory work out. You take time off, it takes a little bit of time to get back to where you left off, but you get back to that level very, very quickly. And the same thing happens with your metabolism. I would say there's a metabolic memory associated with it. So the more you do it, the more benefits you derive from it over time. I think there's personal development reasons for intermittent ketosis. There's logistical reasons too. It could be a difficult period of your life that you don'. Have a lot of time just based on work or other priorities. And eating ketogenic actually saves time. I know Peter was doing something like a three day fast every month. I think that people could implement this idea. I think the same thing could be achieved. Instead of fasting, you could do six days, a restricted ketogenic diet every month. And I think you get the same benefits if you didn't want to just do fasting. If people have an aversion to fasting three days out of the month, the thing to target would be the glucose ketone index. And if you're doing, for example, intermittent ketosis, this guy has a question and you want to derive benefits of it similar to fasting. You could restrict calories like 50% on a ketogenic diet and do that for six days a month. And I believe you would achieve, at least for me, a glucose ketone index between 1 to 2. And if you do your blood work, you'll find that you'll have almost a similar level of insulin suppression, especially if you measure that insulin even during that week of feeding just prior to eating a meal. If you do restricted ketogenic diet and combine that with time restricted feeding, you're hitting all the major drivers of the benefits that you'd get from fasting, like suppressed mtor, suppressed insulin. Your body sensing low ATP, is probably stimulating autophagy. Although we don't have a good means to measure that. So that would be my suggestion. If you want to, don't have any problem with carbs, but you want to get some of the benefits of ketosis to maybe try once a month to do five or six days, or five to seven days, let's say, of a restricted ketogenic diet, which I think is pretty easy to do.

That makes sense. One thing that Peter was doing previously, he was doing one week fasts and he would sandwich it between two weeks, a week prior he would go on a ketogenic diet and then a week after he would go on a ketogenic diet. And one thing that I noticed too, just with my own playing around and probably other people have experienced this, is that if you're trying to dial in that glucose ketone index and I think is it like directionally, you want it basically one to one with glucose and ketones.

If you can achieve that, that's pretty good. I'm a little bit more loose on it. I think if you can achieve 1 to 2, just based on my observations from fasting to ketogenic diet, I think you start to derive a lot of benefits. And I quantify that through the level of insulin suppression. I've been able to kind of record from that. So I've been measuring, taking a lot of insulin measurements.

Yeah, that makes sense. So the second question, what are some books you'd recommend to get knowledgeable on modified keto? And I guess the preface there is that you do a form of a modified ketogenic diet. At least last time I spoke to you, you were doing that.

Yeah, that diet has been kind of evolved over the years. But some of the books that really influenced me that are kind of mandatory reading for people entering the lab are Jeff Bullock and Stephen Phinney's book the Art and Science of Low Carbohydrate Performance. That was a great. But since then, I guess since we've last spoke, a couple really good books have come out. The Ketogenic Bible is a fantastic comprehensive overview of the ketogenic diet and it's got everything from recipes, it breaks down the terminology, it's written for the layperson and the people really interested in the science too. Keto Answers is a great book for the layman and it really breaks down what a modified ketogenic diet is. Recipes, suggestions on a lot of tips, troubleshooting and things like that. Now if you really want to geek out on the science, I would definitely recommend. I know a lot of listeners are interested in the science, the ketogenic diet and metabolic therapies. So Google that term, ketogenic diet and metabolic therapies. Primary author would be Susan Massino. I am the editor of that. So kind of disclose that I do get royalties. It's from Oxford University Press, and it's a book that really delves into very deeply into the science. And I guess the book that had probably one of the biggest impact on me for the modified ketogenic diet or the modified Atkins, which sort of evolved around 2008, when I became aware of it, was more of a clinical book by Dr. Eric Kossoff from Johns Hopkins. So if you're interested in the modified ketogenic approach from a clinical perspective, just look up Eric Kossoff from Johns Hopkins and check out his book on the modified ketogenic diet. Okay, so they're all the books right now sitting next to me on my shelf. So the ones I'd recommend.

Yeah, I'd recommend those as well. Particularly the Art and Science of Low Carb Performance is not a pamphlet, but it's not a novel either.

No, it's a quick read.

Yeah. Update on ketone measurement devices. Breath, blood, et cetera. I guess I would say urine. I'm not sure if there are any.

Other ways to measure, but that about covers it. Yeah. The urine strips are actually something I don't discourage against, and I think they could be a good kind of yes or no if you're in ketosis and it gives you a relative reading, but I tend not to. The Siemens Multistick SG is pretty good and it gives you other parameters on the urine strip. But when it comes to blood meters, which I've used most often, the Precision extra remains one of the meters I use almost on a daily basis. Abbott Lab makes that. It's well validated. It's very reliable. It's got a track record. People publish with it. The newer device that's out is the Keto Mojo. And I have the Keto Mojo gki, which has the glucose ketone index sort of incorporated into the algorithm here. And what I find is that the Keto Mojo device, it's got a lot of pros, a lot of benefits to it. The strips are much cheaper. It does the gki, of course, it's a little bit larger, so it doesn't. It's a little bit bigger than the precision extra and it records higher beta hydroxybutyrate in the low ranges. So if I'm 0.5 on the Precision Extra, I'm usually like 0.9 or like a 1.1 with the keto mojo. Now, when my ketones get into like the 2 and 3 range, then they're pretty, they correlate. I think the keto mojo may be measuring slightly higher in the low ranges, but I also think that the precision extra may be measuring slightly lower in the range. For example, if I was 0.8 from an assay we do in the lab, I think the keto mojo would maybe have me at 1.0, whereas the precision extra would be 0.5. So I think there's somewhere in the middle is the correct one. But they're relatively, they're easy to use and I think they're devices that I use pretty much on a daily basis. The breath acetone meter. Now that's what I've been spending a lot of time evaluating that technology. Biosense makes this device and in regards to breath acetone meters, I would say it's like a next level kind of stuff. The breath acetone does correlate well with beta hydroxybutyrate from my measurements, if you're in a fasted state. So it's exceptionally good in a fasted state. There are some drawbacks to it. I think, for example, if I have wine or if you eat a meal, you're going to get a false positive, which means you're going to get an elevation. Breath ketones, that's outside of the spectrum where you're really at. And that suggests that it's picking up something other than breath acetone definitely picks up breath alcohol, but it is pretty reliable. I've used it hundreds of times and that would have been thousands of dollars worth of strips. And it correlates well, especially if you're into fasting. And if you're following a ketogenic diet and you just abstain from food or chewing gum or alcohol or whatever for a good hour, then the measurements are pretty. Correlate pretty well with beta hydroxybutyrate in the blood.

A couple years ago I had a. What was it called? Ketonics, which I think was measuring acetone. And it wasn't. What should I say, quantitative. It basically gave you a. I think it was a green, a yellow or a red. And I think green meant that you're probably not in ketosis. And then yellow was moderate and then red was something along the lines of deep ketosis. I don't know if this correlates with maybe the urine strips or something like that. Is the one that you have. Is there something that you can quantify in terms of the Amount of acetone?

Yes. They have aces and 10 aces. You might see some of the measurements I've been posting on Instagram. 10acs would correlate to 1.0 beta hydroxybutyrate pretty much. So it's like an order of magnitude above and I think I got that right. But you might want to check out the specs on the website. So, yeah, it's just in order of magnitude higher, the numbers. And these numbers were developed to sort of correlate to beta hydroxybutyrate. I think that's how it's more or less calibrated, sort of in that way, the algorithm. And they've done quite a bit of work at BioScience to make the meter reliable, which I'm on my third one now, I have to say, because the first two, I think were sort of beta versions. Just sent the other one back and I have a new one now, but I carry it with me in my pocket. It's been to many countries, it worked well and it's reliable. So the ketonics meter, I think, has gradually become more quantitative, so you might want to check to see the latest version of that. Although I have to say that the BioSense breath acetone meter is the most quantitative breath meter that I've seen so far, and they've done quite a bit of research. One other drawback is that it takes about a minute or two to calibrate, so you have to press it and kind of wait to blow in it. If you're kind of impatient, you could probably take a blood measurement a little bit quicker. And if it's windy out or you're outside things, sometimes it get an error reading. But generally I'm testing at my desk, I'm testing inside. And, you know, I do like measuring blood, but this is a very close second to my favorite measuring device if I'm going to quantify ketosis. Breath acetone is a very strong indicator of fat oxidation. So if you're just using it as you're following a ketogenic diet, burning fat, that acetone is basically was derived from fat. So you have. It's a very good quantitative measurement of fat oxidation. Also, from the clinical perspective, which I'm most excited about is that a lot of kids do not like to get their finger pricked. Obviously, a device like this is very appealing to children who have epilepsy and breath acetone correlates really well with seizure control. So I'm excited that this technology can make it into the clinical realm, especially in epilepsy Yeah.

I was going to ask you actually between beta hydroxybutyrate, acetoacetate and acetone, if it's actually telling you something a little bit different physiologically or biochemically, that maybe one may tell you a little bit more about availability versus utilization. And it sounds like with the acetone it might actually tell you a little bit more about the ketones that you're actually burning. And I think you mentioned this, that instead of a glucose tolerance test, you thought of like a ketone tolerance test. When you think about it, if you're utilizing the ketones quite efficiently, then, and this is one of those things that I think some people get into ketosis, meaning they get into the diet or ketogenic diets, and it's almost like a challenge to see how high you can get your bhb, like how high are your ketones. But in some ways you think, well, maybe I want to utilize those things and if I'm utilizing them, then maybe it will be. The substrate might be small, lower for bhb. But it sounds like that's right, that the acetone tells you a little bit more about the utilization of ketones versus maybe bhp.

Yeah, you bring up a good point. I think if beta hydroxybutyrate stays circulating in the blood longer, it's more likely to. You're going to have more acetone as well. And that can spontaneously decarboxylate or acetoacetate, I should say. And you maintain a ratio of about 4 to 1 in some measurements. I've seen people at 6 to 1 beta hydroxybutyrate to acetoacetate. So if your acetoacetate is elevated in the blood, that spontaneously decarboxylates to acetone and that's what. It's very volatile, so you're breathing that off. But in regards to the ketone tolerance test, yeah, if you're using ketones at a fast rate, there'll be less beta hydroxybutyrate and acetoacetate available for spontaneous decarboxylation. So that volatile organic compound's not going to show up in the breath. So if you exercise, acetone goes down. I did yesterday and noticed that a workout can really lower my acetone level breath ketone as it does with blood beta hydroxybutyrate. But if I work my metabolism up and I come back to my desk and I'm sitting there and you have that post exercise elevation in metabolism, then you start seeing that acetone starting to shoot back up again when you're at rest because the ketones are. You've ramped up metabolism, fat oxidation, ketogenesis, and you start building up ketones, but you're not using them. And athletes do really well, I guess you could say, on a ketone tolerance test. Because if you give them a bolus of exogenous ketones, they clear it from the system pretty quick, and they clear it very quick when they start exercising, so. Which is a really good indication that they're using that metabolic substrate for fuel.

You talked about this a lot. George Cahill, his study, the 40 days of fasting. And he looked at what he looked at. He looked at beta hydroxybutyrate. And I think on the same graph, he had acetoacetate and free fatty acids. I don't think that he had acetone. But maybe a future question. I don't know if it's in here, but something about free fatty acids and acetoacetate seemed pretty close, that they were pretty close together as far as substrates. But gets into the idea of how many free fatty acids are we burning compared to maybe ketones as well, and the interplay between those two.

Yeah, there's some interesting dynamics going on for sure. And I think you'll notice a couple things from that work. You'll notice that, well, they didn't measure acetone because it's very hard to measure. We've just doing the experimental procedure to store the blood to make an acetone measurement possible through gas chromatography and mass spec is quite an achievement. So it's kind of hard to do because it's volatile, but you'll see that glucose was relatively stable throughout. Another diagram on the same subjects demonstrates an injection of insulin or IV infusion of 20ius of insulin. You see fatty acids in the blood go down, ketones go sharply down. So you see a lot of that. Ketogenesis and fat mobilization for fuel is really a function of insulin suppression. I think that's really important to note, and that has implications for other things like do exogenous ketones elevate insulin? And so if you take exogenous ketones, will it promote a decrease in your own endogenous ketone production? And I think it's really important to understand what's going on in the liver and what's going on in muscle and what's going on in the brain when you're delivering exogenous ketones, which we think have many therapeutic applications and everyday applications. So that's. I've been focusing a lot sort of on some personal studies on that now. And also in the lab we're looking at that.

So let's get into we got a couple questions around genes. The first one is very broad. It says what genes are not good for keto? They're eg for example fto. I'm wondering if this is around maybe like the PPARS and fto and I think some people have talked about this and how they handle saturated fat and fats in the diet and things like that. Are you aware of any of this.

Literature thank you for listening to today's sneak peek AMA episode of the Drive. If you're interested in hearing the complete version of this ama, you'll want to become a member. We created the membership program to bring you more in depth exclusive content without relying on paid ads. Membership benefits are many and beyond the complete episodes of the AMA each month. They include the following ridiculously comprehensive podcast show notes that detail every topic, paper, person and thing we discuss on each episode of the Drive. Access to our private podcast feed the Qualys, which are a super short podcast, typically less than five minutes, released every Tuesday through Friday, which highlight the the best questions, topics and tactics discussed on previous episodes of the Drive. This is particularly important for those of you who haven't heard all of the back episodes becomes a great way to go back and filter and decide which ones you want to listen to in detail. Really steep discount codes for products I use and believe in but for which I don't get paid to endorse and benefits that we continue to add over time. If you want to learn more and access these member only benefits, head over to Peter Attia md. Subscribe. Lastly, if you're already a member but you're hearing this, it means you haven't downloaded our member only podcast feed where you can get the full access to the AMA and you don't have to listen to this, you can Download that@peterattiamd.com members you can find me on Twitter, Instagram and Facebook, all with the ID Peteratti md. You can also leave us a review on Apple Podcast or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or Advise, please visit PeterAttiamD.com about where I keep an up to date and active list of such companies.

It.