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The Melanie Avalon Biohacking Podcast Episode #170 - Dom D'Agostino

Dr. Dominic D’Agostino is an Associate Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine. He is also a Research Scientist at the Institute for Human and Machine Cognition (IHMC).  In addition to his teaching responsibilities, his laboratory develops and tests nutritional strategies and metabolic-based therapies for neurological disorders, cancer and metabolic optimization. He is conducting basic science research and human clinical trials. He has a personal interest in environmental medicine and methods to enhance safety and physiological resilience of military personnel in extreme environments.  His research is supported by the Office of Naval Research (ONR), Department of Defense (DoD), private organizations and nonprofit foundations.



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10:30 - NASA's NEMO

12:50 - the aquarius habitat and hyperbaric effect

17:55 - performance ketogenic diet

19:15 - cNS oxygen toxicity

21:25 - dom's research into the ketogenic diet 

23:45 - anti Seizure drugs vs keto

26:30 - what makes keto beneficial?

28:50 - Seizure control with other low carb diets

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The Melanie Avalon Biohacking Podcast Episode #38 - Connie Zack
The Science Of Sauna: Heat Shock Proteins, Heart Health, Chronic Pain, Detox, Weight Loss, Immunity, Traditional Vs. Infrared, And More!

31:00 - root cause in seizure

34:00 - the spectrum of ketosis

35:30 - Becoming fat adapted

37:20 - higher resting blood glucose on keto

38:00 - The dawn effect

41:50 - cryotherapy, ketones, and blood glucose

45:00 - why do we enter ketosis?

48:30 - acetyl coA

50:20 - starvation and Metabolic disorders that prevent ketosis

55:10 - the inuit

56:30 - long term ketosis

58:40 - is chronic ketosis healthy?

1:00:25 - fat adaptation through restricted carbs vs restricted dietary fat

1:04:40 - ketones and mitochondrial uncoupling

1:12:30 - lactate

1:15:20 - ketones to fuel the brain

1:18:00 - strict keto with carb cycling vs moderate carb keto

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1:24:15 - Ketone Bodies And Measuring Ketosis

1:30:30 - Acetone on the breath

1:34:10 - acetone for anti seizure effects

1:35:50 - personalizing the ketogenic diet for our genetics

1:38:15 - Exogenous ketones vs endogenous ketones

1:40:40 - salts vs esters

1:44:10 - can we become 'ketone resistant'?

1:45:55 - chasing ketones

1:47:45 - 'metabolic memory'

1:51:00 -  is keto pro-cancer or anti-cancer?

1:55:00 - pairing keto with cancer treatments

1:59:20 - metabolic psychology

2:00:15 - when will modern medicine use nutrition as medicine?


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Melanie Avalon: Hi, friends, welcome back to the show. I am so incredibly excited about the conversation that I'm about to have. I am here today, honestly with a legend, especially a legend, probably that a lot of my audience is very familiar with, especially with me hosting the Intermittent Fasting Podcast as well. And talking all the time about the ketogenic diet, ketones, metabolic flexibility, all of that, and I was actually thinking about this before we started recording. I think when people think ketones, probably the go-to source of information, I think, would be Dom D'Agostino. So, it is no surprise that ever since I started this show a few years ago, he was at the top of my list of somebody to interview. So, this is really a surreal moment right now. And it's actually kind of funny. I don't know if you remember this, Dom, but I've been like trying to find my way to you. So, I've been like asking all different people for an intro and I think two people the same day emailed you almost the exact same email connecting you or like offering to connect you to me, which was funny.

Dom D’Agostino: Yeah. Kirk Parsley and I forget who else.

Melanie Avalon: Brad Kearns. 

Dom D’Agostino: Oh, Brad Kearns. Yeah, I did his podcast recently.

Melanie Avalon: It's funny.

Dom D’Agostino: Yeah, two great guys that I know.

Melanie Avalon: Yeah. It was just funny because I've been asking Kirk for a while and then I asked Brad. And Kirk just happened to do it like the same day that Brad did. So, you got hit with all the emails. But in any case, for listeners who are not familiar, Dom D'Agostino, he's an associate professor with tenure at the University of South Florida and he teaches students of the Morsani College of Medicine, and the Department of Molecular Pharmacology and Physiology. And he focuses on an array of really incredible topics like neuropharmacology, medical biochemistry, physiology, neuroscience, and neuropharmacology. That should be a test for like young kids learning how to read and pronounce things. 

He is also a research scientist at the Institute for Human & Machine Cognition and he has a lab where he just does a myriad of incredible things that I'm sure we will talk about. And this is super cool, you are a research investigator and crew member on NASA's Extreme Environment Mission Operation. Where was that?

Dom D’Agostino: Yeah, so the NEEMO, NASA loves these acronyms. NASA Extreme Environment Mission Operation is space analog research project that they use for training astronauts and it's in the Aquarius habitat, which is off the coast, it's in the bottom of the Atlantic Ocean, and it's off Islamorada. You have to boat ride about an hour out and then you go underwater. And then the habitat is actually it's hyperbaric. So, it's at the same barometric pressure as the water you're down under. So, you stay in a hyperbaric environment and you live in what's called saturation. And it's an extreme environment, it takes like 17 hours for us to come back up from that level of pressure. So, yeah, it's off the coast. The Aquarius habitat, if you Google that, and NASA uses that habitat for training, and they also use the Neutral Buoyancy Lab at NASA in Houston to train astronauts underwater because it simulates neutral buoyancy.

Melanie Avalon: How long are you at that pressure?

Dom D’Agostino: My mission was the NEEMO 22 Mission and we were underwater for 10 days, and we have to do a variety of different tasks that NASA has in regards to your testing different types of equipment, different procedures. I did a lot of medical testing, microbiome changes and things like that, skin microbiome, blood measurements, things like that. And then my wife actually was on NEEMO 23, which was an all-female crew. Her commander was Samantha Cristoforetti and Jessica Watson, who will actually be going up to Space Station and doing a launch in April along with my commander, Kjell Lindgren, who is a medical doctor and astronaut. He was my commander for that. So, it's weird. It's like the whole NEEMO crew is reuniting and they're going to space. We're staying on the ground-

Melanie Avalon: Wow.

Dom D’Agostino: -because my wife and I are just scientists, and we assist with the project and organizing the research on the project, and we became the crew members too. You become aquanauts when you stay underwater for more than 24 hours. So, we officially are keen aquanauts.

Melanie Avalon: An aquanaut, that is so cool. Okay, I have a question. Actually, it's a parallel question for the ketogenic diet related to that. 10 days at that hyperbaric pressure, the findings that you find because normally when people are doing hyperbaric oxygen therapy or pressure chambers, I'm not using that terminology. Normally when they're doing that, they're doing sessions, more acute sessions, so the findings that you get doing an elongated session, do they apply to the benefits that you can get from acute sessions, or do things happen at a longer session that you can only get if you're doing a longer session?

Dom D’Agostino: With hyperbaric oxygen therapy, you get inside a chamber. And if it's a mono place chamber, the chamber is flushed with the air, which is 20% oxygen is flushed with 100% oxygen, and then that's pressurized, typically to above 1.5 atmospheres to 2 and then up to 3 atmospheres, maximum. And then you usually sustain that for about an hour or so, maybe 90 minutes or depending on the pressure. And then you do that, if it's for wound healing, for example, which is like an FDA approved application, probably one of the most common applications, you do that for like five days a week. And then if your recreational diving, you have things like decompression sickness, then you would just do one exposure. But the Aquarius habitat, you're breathing hyperbaric air, you're at about just about 3 atmospheres. And what you're breathing is the air, there's air that's pumped down into the habitat. And that air is at, we're at like 60 depending on 60 to 90 feet of sea water, depending on if we're doing the mission outside or inside the habitat. But hyperbaric air is not as high concentration as hyperbaric oxygen therapy, but you still have that pressure. So, your body is saturated with nitrogen and you're living in something called saturation, which means it takes a long time to decompress to get to the top. It's easier. 

My commander at the time actually, before we decompressed, he tweeted, it took longer for him. It only took like five hours to get from the International Space Station back down the ground. But it took 17 hours to get from this extreme environment to the surface. 

Melanie Avalon: Oh, wow. 

Dom D’Agostino: Because you have to do what's called The Stage Decompression, like overnight in this habitat to get back up to the top. Or if you were to just shoot up to the top after the end of the mission-

Melanie Avalon: Oh, what happened? 

Dom D’Agostino: -your blood would boil, and you would have a freaky painful death-

Melanie Avalon: Would you explode?

Dom D’Agostino: -from something called Decompression Sickness. So, the nitrogen would want to come out of solution and then that would get into your blood vessels. It would cause embolisms in your brain, in your heart and your pulmonary system, and you would die. So, you have to do a very, very calculated stage decompression where the first hour of the decompression you prebreathe oxygen to help with the denitrogenation.

Astronauts actually do an oxygen prebreathe before they do a spacewalk. A spacewalk is when they come out of the International Space Station, or whatever ship they're on. And then they'll work in space wearing a suit. But the suit is only pressurized to a quarter of an atmosphere. What they'll do typically and the astronaut, Mike Gernhardt, who I know actually worked on this protocol. They get on a bike and they breathe oxygen, and that helps them get more nitrogen out of their system. And then they suit up into the spacesuit, and then they go outside of the space station into space and do what's called the spacewalk. But the oxygen prebreathe serves the same function. It helps to denitrogenate the body, so you don't get decompression sickness or the bends.

Melanie Avalon: Did you experience any side effects from any of it? 

Dom D’Agostino: No, I didn’t. And part of the reason I stayed in a deep state of ketosis where my ketones were elevated above my glucose almost for the entire mission. And I took like saliva, I took urine samples to look at my neurotransmitters, I took tons of bloodwork to see how that environment changed me. Also, wore the Oura ring, which Oura sponsored it. All the crew members, the astronauts, they had, they're wearing the Oura ring. And they also wore the Polar V800 to get deep heart rate variability, which is a little more complex than the Oura ring. But it was good to compare that, and it basically validated Oura as like a great device for heart rate variability. And, yeah, we did tons of other measurements. We looked at psychological measurements and microbiome and skin microbiome and all these different things. But, yeah, the extreme environment, a lot of research that I do is actually creating a state of ketosis whether dietary or supplemental, to preserve performance resilience in environments to make it more safe to operate in that environment and also increase your performance, whether that be cognitive and physical performance.

Melanie Avalon: Which I have so many questions about. So, this is fantastic. Out of curiosity on that mission, were you just following a dietary approach to achieve that ketogenic state or were you supplementing with exogenous ketones or what were you doing? 

Dom D’Agostino: I did both. So, they have this astronaut food type things. This is like camping food that you can make. The rest of the crew, the idea was to see what happens to our bodies in extreme environment, eating what we normally eat. The crew basically gets to pick from an array of foods aligned with what they typically eat. But I was following a ketogenic diet. When I was in this actually, it was probably a little bit more ketogenic than normal. And I was eating a lot of sardines or no, I couldn't bring sardines. That's right. I wasn't allowed to bring sardines because of the smell, actually so I brought chicken. I know, it was funny.

Melanie Avalon: That’s funny.

Dom D’Agostino: I had list of the things and they contacted me, and they're like don’t bring sardines. I was like, “Why?” It was like an email back and forth. “Okay, can you explain why I can't bring sardines?” Apparently, the smell can be kind of, in that particular undersea habitat, the smells are amplified. So, yeah, I had a lot of chicken and olive oil and coconut oil, and I brought ketone supplements down with me. And I would consume the ketone supplements, for example, like before the oxygen prebreathe, because we actually study CNS oxygen toxicity, which, when you're in ketosis, it protects against that, and we've published quite a bit in that area. And I would take the ketones before I did what was called an EVA. An EVA is Extravehicular Activity, where you go outside of the habitat, in the habitat you're dry, but you're pressurized. And then with an EVA, you suit up and then you work in the water outside that habitat for hours on end. You go down deeper too, so you're at a higher pressure and you're also under—you are very task loaded cognitively. And then you're also there's pretty high physical demands too, because you have to pull a cart and you have to drill into the ground and get samples of coral and build these corals. 

I remember a big project was the Coral Reef Foundation, where you would get samples of coral and then bring it back and do genetic analysis. But then you also basically make these coral trees to propagate certain types of coral that are endangered. I think siderastrea was one of them. There're a few different types of coral that we were working with. 

Melanie Avalon: That is so cool. Were you the only one doing a keto diet? 

Dom D’Agostino: Yeah. Everybody else was pretty interested, and there are astronauts that I communicate with that follow a low-carb ketogenic approach even on the station. But for me, I was the only one doing that. And the idea was to get baseline data because we had a whole bunch of experiments. What does this extreme environment do to our physiology, and then in other crews that were planning our other experiments, we can do an intervention, like change a dietary parameter, lower ketones or lower carbohydrates and elevate ketone levels and things like that. But I got a lot of data, and some of that we've published and we've got a couple other manuscripts we're working on.

Melanie Avalon: One other question just to get my audience more familiar with your work, and for me, personally, I'm super curious. What made you interested in this whole world of the ketogenic diet and ketones and what you're doing today? Was it like an epiphany one day, or--?

Dom D’Agostino: I did my PhD in neuroscience and physiology and then my postdoctoral fellowship was funded by the Office of Navy Research. And they were essentially funding me to develop technologies to understand oxygen toxicity seizures, which is a limitation for Navy SEAL divers that use a closed-circuit rebreather under stealth operations. So, the advantage of these rebreathers is that there're no bubbles when you're swimming, but the disadvantage is that it's high oxygen because it's closed circuit, and it was pure oxygen. 

We knew that if you go down more than 50 feet for even like 10 minutes, you could potentially have a seizure. We wanted to develop and understand how to predict these seizures and how to prevent them. In the process of doing that, I was very interested in different antioxidants and combining even like melatonin, I did some studies on melatonin, which is actually a really good antioxidant, has some interesting effects and other more antioxidants we use. And they tend to work good in the lab, but in practice, they don't seem to have good antiseizure effects. And then there's antiseizure drugs, but then they can dole your senses and make you sedated. You don't want to load up a warfighter with antiseizure drugs. So discovered that the ketogenic diet was actually used when drugs fail. So, I became interested in implementing a high-fat ketogenic diet but the military did not like the idea of giving a Navy SEAL a diet that was like 80%, 90% fat. 

So, then I embarked on this idea of developing a ketogenic diet and a drug which led me to develop ketone esters and ketone salts. And now, I mean, we have like a dozen different molecules that we're kind of playing around with formulate the optimal therapeutic ketosis approach. And different ketogenic strategies can be employed for different scenarios, whether it be anti-cancer effects, or antiseizure effects, or neuroprotective effects or blood glucose lowering effects. So, there're different approaches for that. 

Melanie Avalon: Speaking of the seizures and the drugs to normally to treat it and all that, I was reading your book, The Origin (and future) of the Ketogenic Diet that we're talking about before we were recording with Travis Christofferson. And it was really upsetting to read and-- not the whole book, but the concepts that you discussed about how these antiseizure drugs typically worked and their success rate compared to the ketogenic diet success rate. But basically, the doctors and the pharmaceutical companies-- they're not going to really suggest the ketogenic diet because there's not funding behind it, there's not a pharmaceutical motive there. And then on top of that, they say that it's hard to follow. So, they're making the choice for, especially like parents with kids with epilepsy, they're making the choice for them that the keto diet is not really an option because compliance is too difficult when the success rate is, I mean, looks like way, way better than those drugs.

Dom D’Agostino: Yeah. And actually works in like 70% of the patients where multiple drugs have failed in combination. So, it's working through a mechanism that's independent of any particular drug. It's interesting because it's pleiotropic, we say. The ketogenic diet is working synergistically. It's like many different mechanisms working synergistically together to enhance your brain function, balance your neurotransmitters, and really protect you from seizures. And the etiology of epilepsy and many seizure disorders is largely unknown. And the ketogenic diet works remarkably well for controlling seizures from a broad array of etiologies, or causes like it could be temporal lobe epilepsy, it could be absent seizures. It could be seizures from metabolic disorders like glucose transporter deficiency, or PDH deficiency. There're genetic disorders where there's a persistent genetic problem, but the ketogenic diet works even in the presence of a persistent genetic pathology, which is very interesting. So, you're not correcting the gene although we are looking at epigenetic changes. By following the diet, it changes your metabolic physiology, which changes your brain neuropharmacology and changes neurotransmitter systems that can then-- it has an antiseizure effect. And we don't know all the reasons why it has such a profound antiseizure effect but that's a lot of what we're doing in the lab now, is investigating that.

Melanie Avalon: Yeah, that actually speaks to a question I had, which was a more general question, but it's what you were just talking about, because the ketogenic diet is linked to so many different health benefits with an array of issues. So not just seizures. In general, is it mostly the benefits from the ketones, from the ketones signaling, from the low carb aspect of what you're cutting out? The weight loss on a ketogenic diet? Is there one thing that's more than the other or is it just a myriad of things? And is there a for each different disease-- is it a similar effect for all the different conditions or are some things it's a specific aspect of the ketogenic diet or ketones that are creating that health benefit?

Dom D’Agostino: It's such a good question. This has been the topic of workshops and seminars at the American Epilepsy Society, which is largely a huge event with tens of thousands of people, mostly sponsored by drug companies. But they have-- Within the American Epilepsy Society Conference, they have the special interest group on dietary therapies, which is the ketogenic diet. They don't even like to use the word ketogenic diet, they call it Special Interest Group on dietary therapies. But within that, all the experts come and we discuss this. And in some cases, it does appear that the seizure control correlates with the level of ketosis, but you can also say that seizure control, that the level of ketosis also correlates with decreased glucose availability, the level of ketosis will be inversely correlated with insulin. So, the lower we suppress the hormone insulin, the more our body is in fat burning mode. And as the liver burns tons of fat, then we make more ketones from that fat. But there's certain disorders like glucose transporter type 1 deficiency syndrome, where the glucose literally can't get across the blood-brain barrier. 

When a child has this disorder, they could be relatively catatonic and not be able to get up and move at all. But when they enter a state of ketosis it fires the brain back up again. And they become aware, they become alert, and they can regain function again. So, the ketones function as an alternative energy substrate, because the glucose cannot literally cross the blood-brain barrier, because the GLUT1 receptor is deficient in that. So that would be a case where ketones definitely matter. 

And then there're other disorders that are being studied, like absent seizures, and even like autism, things like that, where something called a low glycemic index diet, which is, high fat, moderate protein and low carb, but not low enough in carbohydrates to really produce high levels of ketones. There's just a moderate level of ketosis. And then this has antiseizure effects, too, not as much as a classical ketogenic diet. But what's interesting and established is that it's been shown that people can have seizure control with a lower carb diet, that's not necessarily ketogenic. So that's kind of interesting, too. It doesn't necessarily need to be highly ketogenic to have antiseizure effects for some disorders. Whereas other disorders you really need to get the ketone levels up high to control the seizures.

Melanie Avalon: Would whether or not somebody with epilepsy who goes on a ketogenic diet and then goes off and is okay, like, they don't have to go back on it versus those who the seizures come back, would that be indicating? I guess if it's a different type of seizure or a different root cause, like are there multiple root causes for seizures?

Dom D’Agostino: There are, yeah, Charlie Abrahams is probably a really good example. His father, Jim Abrahams, the Hollywood producer, who made the movie Airplane and Naked Gun. That story inspired me to study the ketogenic diet and to actually look at it. When I saw the movie First Do No Harm with Meryl Streep. Meryl Streep did a movie about the ketogenic diet which is interesting. And I saw it in 2008. And as a scientist, I was unaware that the diet was used for seizures. I just thought it was like in the fitness and bodybuilding circles people talked about the keto diet, but I didn't even know. I went through a nutrition program at Rutgers University, and we did not even really talk about the ketogenic diet as a medical therapy. But Charlie, Jim Abrahams found the ketogenic diet by going to the library, and got Charlie administered at Johns Hopkins where he got off all his medication, which had horrible side effects. Charlie was put on a very calculated ketogenic diet, four to one ratio, which is like 88% to 90% fat, and then his seizures were controlled. He followed the diet for a couple years, and then weaned off at the diet and never got seizures again. 

The ketogenic diet is the only therapy that we know of that you can follow it for a period of time, and you're able to wean the patient off of the diet over a particular time in some patients, and then the seizures never come back. Whereas if you stop drug therapy, then you have a rebound effect, and you have more seizures. The ketogenic diet, what that was telling me is that when you follow the diet, it may be repairing and rewiring the brain and balancing brain neurochemistry and metabolism in a way that's actually fixing the brain and curing epilepsy. And it seems pretty far-fetched, but that's what the literature was suggesting and the researchers at Johns Hopkins and Mayo Clinic and Duke and other places, show these are called super responders. Not everybody is like that, but I think about anywhere between 10% to 20%, around like 15% may have, are what considered super responders, which means they have rapid seizure control, and they adhere to the diet and it never comes back. They're able to manage it with the diet and then gradually wean off the diet, and then the seizures never come back.

Melanie Avalon: Another question, as you're talking about people in moderate levels of ketosis and potentially seeing benefits. There's definitely this idea, I mean, definitely, with me being the host of the Intermittent Fasting Podcast, a lot of the questions we get, there's this idea that you're in ketosis or you're not, like it's an on and off switch. Is it an on and off switch? Or, is it more like a dimmer?

Dom D’Agostino: Yeah, it is like a dimmer rheostat. You're thinking in like far as electronics. Yeah, it's a spectrum, which is largely a result of the carbohydrate restriction. As we dial in for our current clinical trial, where we're using continuous glucose monitoring with the Levels Health app, what we do with patients who are non-diabetic, we put CGMs on them and we measure a whole bunch of parameters, including psychological depression, we look at anxiety and things like that, and how that changes in addition to lots of bloodwork. And then you titrate the carbohydrates down over about four weeks. And we find we have better compliance, better adherence, and then people are just not-- and also less side effects because if you rapidly induce someone into ketosis with if they're on a low-fat diet, and they go to eating like 70%, 80% fat that can cause some side effects from fat intolerance. 

A gradual approach just reducing carbohydrates from like 200 to 300 grams a day, which is normal for the Standard American Diet, down to 100 per day produces a really nice effect on glucose and insulin, and you become more metabolically flexible, that defined as being able to use all fuel sources, fat, ketones, glucose. And as you become more fat adapted, it's easier to transition someone from a lower carb diet into a state of ketosis. Like nutritional ketosis, where you have pretty profound suppression of the hormone insulin, your glycemic variability, if you look at your continuous glucose monitor trace throughout the day, it's essentially flat, much, much different than what you get with a standard American diet. 

We don't know if reducing fluctuations in glucose in nondiabetic people will have long lasting benefits if you do this all the time. But you get a hunch that it will, because if you look at the data for type 2 diabetics and type 1 diabetics, the wild postprandial glycemic excursions if you want to call that, are directly correlated with like longevity. It's like the more you're you have these wild glucose fluctuations, highs and lows, it can go too low, if you're a type 1 diabetic, especially if you're administering insulin, then that becomes a problem. We're of the opinion that if you can manage your blood glucose within certain parameters, you're also managing insulin and you're optimizing your metabolic health. And that's going to pay big dividends as we age and we're decreasing inflammation, we're decreasing glycation. We're improving a whole host of metabolic biomarkers that are tightly coupled with healthy aging and health span. There's not a whole lot of data using these continuous glucose monitoring devices in nondiabetics, so that's why I'm pretty heavily involved in that research now.

Melanie Avalon: I love CGMs, and we talk about it all the time on the shows. And, yes, so I'm definitely team CGM. What are your thoughts on people who are doing ketogenic diets, but they don't experience the swings as much, but they experience higher resting blood sugar levels than they might be otherwise?

Dom D’Agostino: We don't see this that much with our current group of people, our current cohort, I think, because we're transitioning them and I think it might be helpful to transition them. My views of that have changed a little bit. I think, definitely for compliance, and people do get side effects when they follow a ketogenic diet. So, I'm of the opinion now if you're not doing it for epilepsy, of course, where you need to get rapid seizure control to kind of ease into it more, my thoughts about that have changed. So, the dawn effect-- the dawn effect is when towards-- in the morning before we wake up and especially as soon as we wake up, we get a pulse of cortisol, which usually peaks in the morning and the body wants to be primed for the taking on the day, whether that’d be physical or cognitive tasks and it's a bit of a stress response when you wake up. So, glucagon, which is the counter regulatory hormones of insulin can be elevated and cortisol is higher also in the morning, and that can contribute to glycogenolysis, which is the breakdown in glycogen for glucose in the liver. We tend to see in some people, especially if they've eaten like a lot of food at night or carbs at night, and they have maybe higher glycogen stores in the liver, they'll have this this sort of spiking. 

In some people, it's higher and in other people they don't see it as much, but I would say about more than 50% of people do see a morning elevation in glucose, but it typically will taper off during the course of the day. I've been looking at dozens if not hundreds of CGM traces and I do see this elevation of baseline insulin in the morning or baseline glucose rather in the morning, but the insulin levels go down. So, if your insulin levels are down, then the insulin helps to facilitate glucose disposal. And if your insulin levels are suppressed, then more of that glucose may float around in circulation, but it's still within physiological ranges, typically not--

I think the important thing is, if you want to look at it over the course of the whole day, and generally speaking if you look at average glucose levels on a ketogenic diet, it goes down or hemoglobin A1c will go down. Glucose does not go to zero because we have all these counterregulatory mechanisms, to maintain-- homeostatic mechanisms to maintain blood glucose in some tissues and cells, like the red blood cells need glucose so we have, and then we can make glucose from the glycerol backbone of triglycerides, and some amino acids can make glucose too. Glucose levels, unless we really restrict total calories, or we do things like intermittent fasting, and that can bring it down over time. Glucose levels don't change a whole lot on eucaloric ketogenic diet. And in some people, they may trend up in the beginning, but they will typically, if you have someone who's type 2 diabetic and hyperglycemia, those typically comes down.

Melanie Avalon: So, it may be a case where, especially with people not having as much access to things like CGMs until now where this idea that the higher resting blood sugar is happening on ketogenic diets might be more that people historically on keto diets, were doing a finger prick. Just getting a snapshot a few times a day rather than getting the whole picture. 

Dom D’Agostino: Yeah, for currently cohort, what we encourage it, we just had another meeting about this, and I talked to a bunch of investigators doing low-carb ketogenic diet studies, they have them measure glucose before dinner later in the day, kind of a semi-fasted state before dinner and then that's kind of a better way to go about doing it.

Melanie Avalon: More telling. 

Dom D’Agostino: Yeah. The thing is to measure it at the same time every day and multiple times throughout the day. I think it's going to be important because these things change, triglycerides fluctuate throughout the day, hormones fluctuate throughout the day. If your glucose bumps up a little bit high in the morning if you start a ketogenic diet, it might be lower in the afternoon as it was with me. I'm usually like in the 60s in the afternoon, like low 70s and 60s throughout most of the day in the afternoon after 12.

Melanie Avalon: Have you done any studies on cryotherapy and how it affects blood sugar and ketones?

Dom D’Agostino: I use the hot tub at home. I finally got my hot tub. We have this old ancient pool concrete structure, and I got the hot tub and I tweaked it so it goes higher than normal, instead of 104. [crosstalk]

Melanie Avalon: Oh, nice.

Dom D’Agostino: -which is 110. So, I do heat therapy and I notice my CGM gets a big spike. But the sensor in the CGM, if you heat it up, it's going to give you a positive effect. And then I jump into the pool water, which is pretty cold and I go back and forth. And I notice when I jump in the water, I wear a Dexcom and I can't turn the alarm off. I think the alarm goes off like crazy all the time when I go in the pool and I come out and the thing’s beeping like crazy every single time. So, I think that's more of a sensor anomaly because if I prick my finger and check, I do have lower glucose when I switch back and forth. So, you're specifically talking about cryotherapy. 

So, going in cold water kind of does the same thing because it's bringing your core temperature down too. And if I do heat therapy, and I bring my core temperature up, the nice effect I see from that is that it lowers my blood pressure when I get out. I've been doing a lot of blood pressure measurements. But the cold therapy will stimulate, what's called your catecholamines, like your dopamine, epinephrine, norepinephrine, and by stimulating catecholamines you do two things, you're facilitating more fat burning effect, adrenaline will liberate fat from adipose, so you'll burn more fat, but you will-- also you might increase your glucose levels because adrenaline will stimulate glycogenolysis, which is the breakdown of glycogen for glucose. So, as a stress response you might see that.

Melanie Avalon: That was the reason I was asking because we were talking about spikes, and then I do cryotherapy almost every day. I did some before this actually. And when I'm wearing a CGM, it spikes so high. I didn't know if it was actually from the cryo or if it was from the sensor freaking out, but after it would go down and then ultimately go to lower levels than pre-cryo and stay lower throughout the rest of the day. 

Dom D’Agostino: Yeah, it could be just your sympathetic nervous system activation from the cryo depending on how low that is, but the sensor does, the sensors operate within a particular temperature range. So, to test that you could just prick your finger and use something like an Abbott Precision Xtra or the Keto-Mojo device, and then measure your blood glucose and ketones too, and blood glucose to see to check your sensor. 

When I put the sensor on, it's always running high relative to my finger prick device. So, then I usually have to calibrate it, but then I calibrate it, so it's about five points over, I have to bring it down because usually like 10 or 15 points high relative to my finger prick device for me. But I usually calibrate it so it runs a little bit high, so I'm not getting these alarms all the time for low glucose which happens quite often if you follow a ketogenic diet. 

Melanie Avalon: Oh, that would make sense. That's smart. That's funny. Okay, so stepping back a little for a bigger picture of, I love the question why, and I have a lot of why questions about why the body does ketosis and creates ketones and one of the biggest epiphanies I had recently, and you can tell me if I'm correct with this, but people often think that the reason the body enters ketosis is because we run out of glucose. So, we don't have energy because we don't have glucose. So, we have to make ketones. Basically, that we need to just access our fat, and so that's why we create ketones, but my newer understanding is that we're always probably burning fat with carbs in the Krebs cycle. And the reason we enter ketosis isn't because-- when we run out of carbs isn't because we don't have carbs to burn, it's because we can no longer burn fat because we don't have carbs to burn fat. Is that correct? That was like a mind blown moment for me.

Dom D’Agostino: Well, biochemically what happens is, the simplest way to explain it is that when you enter a state of ketosis, whether it’d be fasting ketosis or the ketogenic diet, the beta oxidation of fats are so high in the liver, you accumulate Acetyl-CoA and the accumulation of Acetyl-CoA gets directed into the path of ketogenesis, where two Acetyl-CoA molecules will condense enzymatically to what's called acetoacetate, and that's a ketone body and then through another enzyme the acetoacetate can convert to beta-hydroxybutyrate, which is another ketone. And then they both enter circulation in the blood, it's about a three to one, or four to one ratio beta-hydroxybutyrate to acetoacetate. But the reason that happens that your body makes ketones is, well, to preserve energy flow to the brain. That's probably the evolutionary reason why. But biochemically, what's happens is that the level of beta-oxidation of fatty acids in the liver is so high, you’ve got to do something with the Acetyl-CoA, and the Krebs cycle gets a bit backed up and the Acetyl-CoA then gets condensed and forms, goes down the ketogenesis path. 

And that's almost entirely dependent upon the suppression of the hormone insulin. So, if you were to get even just a little bit of sugar, or anything that increases insulin, insulin is a storage hormone, and you go quickly from a fat catabolic state primarily to an anabolic state. And so if you're fasting, for example, and you're in a high state of ketosis, and you inject the hormone insulin, it kind of can cause a dangerous scenario where your ketones will start to come down after a period of time, you’ll probably be protected from the hypoglycemia. And that has been shown in some early work. But that production of ketones is primarily a result of the lowering of the hormone insulin and that stimulates your fat burning so much. Ketones are a really good indicator that you are burning fat. In that case, Atkins was right, you get your ketones elevated and you know your body is in a fat burning state, you can't make ketones without burning excess fat. That's a statement that no metabolic physiologist would argue with.

Melanie Avalon: To clarify, so that Acetyl-CoA building up in the liver is coming from fat stores on our body or our diet?

Dom D’Agostino: Yes. When we fast or we go into a state of ketosis, whether it’d be diet or fasting, then you're getting fatty acids to the liver through your adipose. For example, if your sympathetic nervous system is activated, it can activate hormone sensitive lipase and then the adipose tissue or like cells that contain the fat, and then you're liberating the fatty acids—the triglycerides and fatty acids from your system and these fats go in circulation and the fats are an amazing source of fuel for skeletal muscle, the heart preferentially burns fat for energy. The liver relies on fat for energy and many organ systems do. But the long chain fatty acids that are typically dietary and the fats that are stored in adipose do not readily cross the blood-brain barrier. What happens is that these long chain fats are broken down through a process called beta-oxidation and to their constituent molecule, which ultimately is Acetyl-CoA. And then the Acetyl-CoA is a breakdown product of fat, which is occurring at a very high rate in the liver. The liver is chock full of mitochondria and there's just like massive fat oxidation in the liver. Interestingly, the liver cannot use ketones as an energy source. The ketones that are produced in the liver get spilled into circulation and then they become fuel most importantly for the central nervous system, but also the heart.

Melanie Avalon: So, if a person was actually starving, and did not have excess body fat, would they stop being ketogenic because they wouldn't have the fat to create the ketone? I guess and they won't have any fuel, but would there be a level where they're just burning the fat to run their metabolism and they wouldn't actually go through the ketogenic process?

Dom D’Agostino: Even a lean person has a really high amount of energy stored as fat. I mean, you have to get towards contest bodybuilder which becomes dangerous when you're tapping into your essential fat. You get down to like 2% or 3%, which is extremely rare. Only in starvation effects do we see that or people who are manipulating it chronically to achieve certain body composition alterations associated with bodybuilding, and the use of bodybuilding drugs and stuff too, to achieve that. So, it's unlikely that you'll ever lower your body fat so low that body fat won't be available to make ketones. It becomes really rare. It happens in extreme athletics and things like that, but it's for the normal person, for 99.9% of the population, that's not going to happen. 

People have different disorders where you can enter a state of ketosis. Some people are better than others. There's, I think, 30 different enzymes associated with beta-oxidation of fatty acids and ketogenesis, there's beta-oxidation defects, where if someone fast they literally can't make ketones, and then they can go into a seizure. There's carnitine deficiency syndrome, CPT I, CPT II, there's a medium chain acid deficiency syndrome, which is called MCHAD, then there's LCHAD and SCHAD, which is long chain fat. There's a lot of different metabolic disorders that we teach and there're various disorders-- there are contraindications where people would not want to do a ketogenic diet, it can actually be deadly with someone with CPT I or carnitine deficiency or something like that, or even beta-oxidation defects. So, they have to be on a high-carb diet. These are rare disorders but it happens and I think it's also on a spectrum.

We may have some SNPs where we may not make as much certain fatty acid oxidation enzymes as the next person. That could be the person who just does not feel well on a ketogenic diet and then there's a variety of different enzymes too that are associated with the ketogenesis process. Some people can quickly get their ketones elevated and other people just cannot seem to get their ketones elevated as high. And that could be a consequence of the body's just using the ketones for fuel. So, they're cleared from the blood and they're not really picking it up. But you could have like thiolase deficiency, which is one of the ketogenesis enzymes, that's a potential disorder contributing that, but these are kind of rare or they're thought of as being rare, but I do believe that people have-- it's not an on or off thing. I think we have varying levels of these, but I do think we can train our metabolism to be a better fat metabolizer, better ketone producer and a better ketone utilizer simply by putting our body into a state of high fat oxidation and ketosis is actually changing the transporters where the monocarboxylic acid transporters, which gets the ketones across blood-brain barrier, across cell membranes and across mitochondrial membranes were stimulating even in an epigenetic way the production of ketolytic enzymes. The enzyme is responsible of basically converting ketones into our energy currency ATP. So, we can do that. 

When we just dial back the carbohydrates, that's actually increasing our fat oxidation, and then when we become ketogenic, then a whole slew of metabolic processes occur including the increased production of proteins that actually become transporters and ketolytic enzymes can be elevated. I'm kind of referencing animal studies, that's why studies are ongoing now taking muscle biopsies. The adaptation may be different in some people, and it might be different in the liver, it might be different in the calf muscle versus biceps or lat or something, there's probably tissue specific alterations that occur too that we need to appreciate.

Melanie Avalon: What do you think are the implications of-- is it the Inuit that actually, don’t they have a genetic predisposition to not enter ketosis despite being on a low-carb, high-fat diet?

Dom D’Agostino: There's different genetic predispositions for some people that essentially what happens is that they're very good at gluconeogenesis. So, they can convert more gluconeogenic amino acids like alanine into glucose. And I don't know if someone has done a really comprehensive study to show that. And the Inuit are basically carnivores, but eating whale blubber and seal fat and things like that. And it's pretty close to a ketogenic diet, but probably not even as high as in fat as a classical ketogenic diet. But, yeah I think they have evolved to basically convert protein and maybe even the glycerol backbone of triglycerides into more glucose. They become insulin resistant if you put them on higher carbohydrate diet. So, they have just as American Indians do. They have a predisposition for type 2 diabetes.

Melanie Avalon: I brought that up because I've heard that use as an argument to say, our bodies don't want to be in long-term ketosis because if you look at like this population that historically would have been on a long-term keto diet, they adapted genetically to not do that. Basically, I’ve just heard that argument. I don't know if you have thoughts about that. 

Dom D’Agostino: I would argue that there's still be in a mild state of ketosis. Even from the ketogenic diet literature, even the people who study it that are big advocates for the ketogenic diet will say that a medical ketogenic diet is not natural, and it's not a healthy diet. They will say that right up front. Like the leaders at Johns Hopkins, for example, Dr. Eric Kossoff and Mackenzie Cervenka, I think a quote out of their book, but at the same time that diet is optimal and super healthy for someone with epilepsy because it's controlling that condition without drugs. Now, there're modified variants, which the Hopkins crew has really spearheaded the modified ketogenic diet, which has more protein and allows for more fiber and a little more liberal with carbohydrates and things like that. The spectrum of ketogenic diets would be the five to one ketogenic diet, which is like over 90% fat to the modified Atkins diet, or the low glycemic index diet, which is a one to one ratio. One being in grams fat and the other one would be in grams protein and carbohydrates. And if you work out the ratios, it's like 60%-70% fat or something like that. But it just allows for more fibrous carbohydrates and more liberal with protein. 

I would argue that a ketogenic diet that was used clinically, the classical ketogenic diet is really so high in fat. Only very limited geographic regions would people follow a diet that was truly ketogenic. Chronic ketosis is probably not ideal when you're following like a medical ketogenic diet. It might not be optimal. I guess the question is, is it healthy? If we look at the community of patients that had to follow it, like glucose transporter deficiency, and then there's also people with epilepsy who had been on it for up to three decades. Their blood work and their carotid arteries and everything look fine and it great, so you would think that we demonize saturated fat and high-fat diets and stuff. And there's very few people that don't have epilepsy that follow the ketogenic--, but there are people that truly follow a medical ketogenic diet, which is extremely high in fat, and they'd been following for decades and their blood work looks remarkably great. One could argue that that's pretty good. 

There're a couple studies actually that shows the distensibility of the arterioles are a little bit reduced in some kids that follow the ketogenic diet. And then when they get off the ketogenic diet that distensibility comes back. People will point to that data but I think it's kind of weak. Also, some of the earlier studies with the ketogenic diet in kids show their triglycerides go up really high in LDL, but these early diets were basically like hydrogenated soybean oil mixed with like casein. Our knowledge of the ketogenic diet went just from a macronutrient ratio. Literally, it was like Crisco, like the majority of fat would be Crisco, like hydrogenated fats and so our knowledge of the types of fats has dramatically increased over time, and we know that switching out saturated with more monounsaturated, and getting more of a balanced fatty acid profile can have pretty big effects in improving lipid profile.

Melanie Avalon: Speaking to that, the dietary fat and then also looping it in with what you were talking about with, in a way teaching our mitochondria to burn fat, is there a difference in “teaching our mitochondria to burn fat” in just from going low carb, so like not really adding fats, so them just burning endogenous fat, compared to actually taking in fat. Does that teach the mitochondria to burn fat faster? Adapting metabolically to burning fat.

Dom D’Agostino: When we restrict carbohydrates, then the process to make energy that's independent of the mitochondria is glycolysis and there's a reduction in glycolysis and sugar metabolism for a number of reasons. One, you're just limiting glucose availability so glycolysis goes down. When you lower the hormone insulin that hormone is really the driver of glycolysis. The metabolism of sugar, which is independent, which occurs in the cytosol, independent of the mitochondria goes down. So, the mitochondria are stressed and actually can in the beginning create some oxidative stress and the mitochondria need to adapt to make energy to compensate, so that you get a little bit of energetic crisis, which triggers a robust increase in mitochondrial function and also mitochondrial biogenesis. And we know that chronic calorie restriction can increase the number of mitochondria, we call that mitochondrial biogenesis. And then over time, the mitochondria become more efficient, which in regards to their energy production, relative to their reactive oxygen species production. 

When we burn energy, some of the exhaust of the energy, so to speak, is reactive oxygen species or oxygen free radicals in the mitochondria, the primary one is superoxide. And then that can go to hydrogen peroxide, and then more reactive intermediates, like hydroxyl radical and that can oxidize membrane, lipids, proteins and nucleic acids. But when we follow a ketogenic diet or calorie restriction, we first stimulate-- it becomes a mitochondrial stress. And then maybe the word hormesis comes in here, where it's a hormetic effect where there's an adaptation to the chronically low levels of glycolysis. And the adaptation produces more energy through something called oxidative phosphorylation, which is exclusively dependent upon the mitochondria. Under normal conditions, like the skeletal muscle, I think derives about 80% to 90% of its ATP from the mitochondria. But like a cancer cell, for example, has defective mitochondrial function in regards to energy production. We'll default back to sugar metabolism for energy, but also for biosynthetic processes. Like cancer cells may rely almost 80% to 90% off sugar metabolism, independent of the mitochondria. 

There're big, big differences in mitochondrial function and mitochondrial health. Healthy mitochondria help to keep the energy status of the cell very high and if you have chronic damage to the mitochondria, the nucleus senses that there's an energetic stress and that energetic stress perceived by the nucleus may also be associated with excess reactive oxygen species and that could potentially kick on oncogenes and transform a normal cell to a cancer cell, like under certain conditions. For example, if you drink alcohol at high concentrations and you're hammering your liver with alcohol, a little bit of alcohol can have a hormetic effect and be very healthy and beneficial, but like chronic consumption of a toxin can damage the mitochondria and mitochondria senses an energetic crisis and it's the damage from that that actually can kick on-- can transform a normal cell into a cancer cell and that cancer cell has a widely different metabolism relative to healthy cells.

Melanie Avalon: I just finished reading Dr. Steven Gundry’s new book called Cracking the Keto Code and his thesis about ketones and the mitochondria is that ketones are not a super fuel. They're not efficient. It's not about how they “burn” cleanly. That it's basically all about how they do part of what you were just talking about with stimulating the mitochondria to create more mitochondria. His whole thesis is about mitochondrial uncoupling. To what extent is the role of ketones in our mitochondria about encouraging the mitochondria to uncouple and create energy that way versus the ketones themselves being a fuel source?

Dom D’Agostino: Well, we need to appreciate ketone bodies, beta-hydroxybutyrate and acetoacetate. Beta-hydroxybutyrate is a very good energetic fuel. So, that's why in a fasting state, ketones become the primary source of energy for the brain. And early work done in different model systems, for example, the working heart preparation work done by Dr. Richard Veech, he had trained under Hans Krebs, and did a lot of work in cardiovascular system and on the energetic effects of ketone bodies. When you metabolize ketones as an energy source, in the mitochondria it produces a favorable energetic profile relative to glucose, biochemical terms, the delta G of ATP hydrolysis is higher for ketones relative to glucose. 

In a working heart preparation, what that translates to is about a 25% increase in the hydraulic efficiency of the heart if you're burning ketones relative to glucose. This is well known. I don’t know if he knows about that, but we know that this is well known in the heart. A little bit hard to do a working brain preparation, working heart preparations a little bit easier experimentally. I can tell you from if you take ketones and give them to cells, and then you remove glucose, normal healthy cells with good mitochondria can function in the absence of glucose, which is really remarkable. If you have cancer cells, and you are growing cancer cells with glucose and ketones, and then you remove the glucose and leave the ketones, all the cancer cells die. At least the brain cancer cell lines that have that people look at.

Some cancer cells may be metabolically flexible to use ketones as an energy source or biosynthetic fuel. But as cancer becomes more aggressive, it sort of defaults to a more glycolytic phenotype. And not only relies on glucose, it needs high levels of glucose to sustain life. We believe, I think, the field at large kind of believes that ketones are superior energy source in many ways, in regards to producing ATP with a less reactive oxygen species production. So that is pretty much well known, at least in the heart and in other tissues too. But ketone bodies are also powerful signaling molecules that can change the activation and expression of different enzymes called histone deacetylase enzymes, so they can function through histone deacetylase inhibition. And that can actually activate genes and whole gene programs, which confer protection to cells. And it can actually upregulate endogenous antioxidant enzymes, like superoxide dismutase can be increased and catalase, which are enzymes that have endogenous antioxidant function. 

We also-- A project in the lab that we're working on now that is a PhD dissertation project is actually looking at the direct effect of ketones on the histones, which are basically histones can prevent the activation of certain genes and through interaction of beta-hydroxybutyrate with the histone, it can actually activate different gene pathways. And we're actually looking at ketone bodies as epigenetic regulators for certain diseases. One of them being Kabuki syndrome. So, yeah, ketones have a wide-- there's a ketone receptor, the GPR109A receptor is a receptor for ketone bodies. Ketones have a plethora of different signaling effects that we're just starting to understand. The literature is pretty nascent on this. And as we understand more, pharmaceutical companies are becoming increasingly interested, especially in the ability of certain ketone bodies like beta-hydroxybutyrate to inhibit inflammatory pathways.

There was a paper published in Nature Medicine showing that beta-hydroxybutyrate can suppress the NLRP3 inflammasome. When that signal protein complex gets activated, that sets off a cytokine storm and an activation and elevation of things like IL 1 beta, TNF alpha, and IL6 and things like that. It's thought that the effects of fasting and it’s that elevation of beta-hydroxybutyrate that contributes to much of the anti-inflammatory effects of fasting.

Melanie Avalon: Yeah, I'm interviewing him on Monday and he basically tries to dismantle everything that you just said about ketones, their role actually as a fuel and their benefits. And he just focuses on the signaling aspect of them and how that's really what's going on. So rather than it being additive, he makes it like this is what's actually happening. So, this is helpful. 

Dom D’Agostino: I'll have to look at his book. We've known, for example, the early work by Dr. George Cahill from Harvard Medical School, where they fasted subjects for an extended period of time, 40 days, and they injected them with insulin to rapidly lower blood glucose. And the subjects were asymptomatic for hypoglycemia because their ketone bodies were elevated in their blood. So, if ketones were not functioning as a remarkable alternative energy substrate, all those subjects would have died. You can't live if your glucose is one millimolar. And you don't have ketones elevated that it's going to be universally fatal. So, that was in 1967. It actually changed some of the medical textbooks, because at that time we thought that the brain was exclusively dependent upon glucose. And we knew that the levels of glucose largely remained relatively stable even when you're fasting, like it goes drops down to like three millimolar, maybe dips a little bit here and there. But one way to basically dispose off glucose and not make it available to the brain is to do an insulin shock, which is in the case of the Cahill study, they injected 20 IUs of insulin, which rapidly caused what would be fatal hypoglycemia, but because ketones were elevated, and sustained at about four or five millimolar. The subjects were asymptomatic for hypoglycemia. This is really, really important. 

When I read that, I had to talk to him, I had to talk to Dr. Veech and I realized that I would like to leverage exogenous ketones as a way to bring people back from hypoglycemic shock. It's kind of what was happening too in diabetic ketoacidosis. And that's another thing that we could talk about, but the ketones do serve as a function to preserve. There are warning signs definitely. Yeah, but there's no doubt, I think every metabolic physiologist would agree that ketones are a very remarkable alternative energy substrate. Lactate is too. I think lactate is underappreciated.

Melanie Avalon: I agree. Sorry. [laughs] I'm fascinated by lactate.

Dom D’Agostino: I was too. Before I focused on ketones, I focused on lactate because I was into mountain biking and I used a product called Saito Max and it had alpha poly L-lactate. And I became interested in lactate as a fuel. This is back in the early 90s, like 1991, 1992. So, I just kind of dating myself, but I was back in high school, I got into mountain biking and I would go to the library and look up lactate as a fuel. And then I became interested in administering exogenous lactate to protect the brain from hypoxia. If there was like stroke or brain injury or infants become hypoxic, you'd give them lactate. So, that was like the original idea I became interested in. And then I did some studies with lactate, but I eventually got steered into ketones because it interested me that ketones could get elevated into millimolar concentrations, lactate too, but you have to exercise really hard to bring that up. Lactate ketones and glucose are all super remarkable fuels for the brain. And if anybody argues against that then they don't understand physiology. 

Melanie Avalon: So, it's interesting because one of the people he quotes, he quotes Owen and Cahill, one of their studies where they found that after a three-day fast, the muscles were using-- switched to using free fatty acids instead of the ketones and so the argument--

Dom D’Agostino: Muscles, yes, because you're sparing it for the brain. 

Melanie Avalon: Okay, so that wouldn't really apply to the--

Dom D’Agostino: No. The ketones are for the brain, really. Muscles are incredibly metabolically flexible. You get into a state of ketosis and then your muscles will start using ketones. But it's like we got to spare these ketones for the brain, the muscles are incredibly hungry for fatty acids too, for fat as fuel. Evolutionarily speaking, it's the ketones, their primary focus is to preserve the central nervous system and to make it so we are lucid that we have brain energy, so we can go forage for food and resources in the face of starvation. That's why we were able to live. Dr. Stephen Cunnane wrote a great book on this, it's called Survival Of The Fattest, he’d be a great person to have on, he has a whole book on the evolution of fat as a fuel for human metabolism.

Melanie Avalon: I didn't actually read the article, but I saw it referenced in an article that I was reading and it was saying that it's actually possible that the brain could feel completely on ketones. But ethically, we can never do studies to test that. Do you have any thoughts on that?

Dom D’Agostino: I don't believe that's the case. I think glucose is so such a ubiquitous fuel. And we have so many, the homeostatic mechanisms that our body has to maintain glucose levels are very, very robust. And that's why we can fast for 40 days, and our glucose is still like two or three millimolar. And that's a significant amount of energy in the blood. I get asked that question a lot, could the ketones be the 100% fuel? I think there's certain organ systems to think I maybe the kidneys, and maybe there're organs that probably need a certain percentage of fuel, red blood cells, they don't have mitochondria, because it makes them a little bit--. If they had mitochondria, they'd be bigger, and they wouldn't be able to get into the little, tiny nooks and cranny blood vessels where they need to get to. So, they leverage exclusively glycolysis for their energy systems. So, if we went to zero glucose I think it would be toxic to the body. 

A good example of that there are drugs that are trying to mimic the ketogenic diet, and one is 2-deoxy -glucose, and that inhibits glycolysis and it becomes cardiotoxic. If once you increase the dose, unfortunately, the dose that becomes a very effective dose for controlling seizures and also for inhibiting cancer growth, then you get to the dose that becomes cardiotoxic. Although it's a useful tool, and I think it like 25 milligrams per kilogram or something like that if I remember correctly, has a pretty profound effect. But then you start when you're inhibiting glycolysis that's not a good thing to do. And also chronic ketosis inhibits a rate-limiting enzyme associated with glucose oxidation, that enzyme is pyruvate dehydrogenase complex.

Athletes that are chronically doing ketosis when they go and do sprinting exercises or anaerobic exercise, they could be somewhat limited. Their glycolytic systems are compromised, because they're inhibiting pyruvate dehydrogenase complex. I think to bring that enzyme system back and to keep glycolytic flux functioning, just adding a little bit of carbs in, like, I typically do 50 to 75 grams of carbs a day. Yesterday, I probably did 100. We went to a Mexican restaurant, but I think adding some carbs in here and there is probably good for the person who's just doing ketogenic diet as a lifestyle.

Melanie Avalon: What are your thoughts on, so that option, option A, the ketogenic diet as a lifestyle with slightly more carbs versus super low carb, but doing the cycling so having like a carbing up a day?

Dom D’Agostino: I think either option, it becomes very context dependent on what your goals are. The ketogenic diet really shines in the context of caloric deficit. I think that if you're on a ketogenic diet and trying to gain weight, like muscle, I guess, or gain muscle size, getting surplus amount of calories on a ketogenic diet is probably not very good because it's going to be fat, and you're probably going to back up in the liver. But if you are seeking to reduce your-- to lose weight, to lose fat as fast as possible, and to retain your strength, I think there are advantages to a ketogenic diet for that context. And that becomes-- it seems like what a lot of people want to do. It's like maybe they've gained some weight and they want to follow a dietary pattern. And that could be ketosis during the week. I don't like the idea of just carbing up but I think to refeed carbohydrates with a calculated amount, like maybe keeping 50 grams of carbs, Monday through Friday, but bumping it up to like 150 on the weekends or something like that, which I think I've done in the past, worked kind of well for me, so there're different ways to go about doing it, but it depends on your goals. 

I also encourage people to measure, do bloodwork and figure out what makes them feel good, and then measure then. I remember testing the ketogenic diet, and I was like, “Man, today, I feel really, really good.” And I will actually take measurements and it's like, “Okay, this is how I feel when my blood glucose is like this,” before I was wearing a CGM. I follow the real strict ketogenic diet, and it just didn't feel well. I felt a little bit of a headache. And then my ketones were higher, like three or four, I was really strict. And I realized that I had to be less strict with the ketogenic diet. And I was a little bit more liberal with the protein and even adding back in some carbohydrates, mostly in the form of fiber, like salads and some fibrous vegetables, and then I felt better, but my ketones level dropped to one millimolar, which is really the sweet spot for me where, I think, I'm getting the benefits of getting fiber in which is probably good for your gut microbiome and gut health. But also adding more protein in, which I needed, when I first started experimenting with the ketogenic diet, I had the book from Johns Hopkins. So, I was doing the medical ketogenic diet to understand what it was all about. And then I migrated to the modified Atkins diet, and then we started just formulating my own personalized ketogenic diet based on my blood work and how I felt,

Melanie Avalon: Yeah. I've experienced that as well. So, if I go very low carb and even add in lots of MCTs, I can get my blood ketones up really high, but I feel much better actually doing intermittent fasting with a pretty high carb-intake night. I feel really good with that. But speaking to all of that, I'm so excited, you brought this all up. For people actually wanting to measure this, that there're so many options. Well, there's not so many, so we can check blood ketones, breath ketones with acetone, urinary ketones, can we walk through the three ketone bodies? I guess I should clarify because I guess there's lots of different types of ketones, but ketone bodies would be the three that we'd be looking at, acetoacetate, BHB, and acetone.

Dom D’Agostino: Yeah. BHB is actually not a ketone. 

Melanie Avalon: Oh, it's not? Is it a transporter mechanism?

Dom D’Agostino: To the physiologist, yeah, it's a ketone body. But the ketone is basically like a type of chemical bond between molecules. And there're ketones everywhere throughout the body. But when we're talking about the ketogenic diet, yes, it's right, that's primarily beta-hydroxybutyrate, acetoacetate and then acetone, which is a breakdown product of acetoacetate. It can spontaneously what we call decarboxylate and lose a carbon and then becomes acetone. And acetone is volatile, which means that like when it's in solution it gets into air, it goes into the gas phase. We can blow it off in our breath. Traditionally, in epilepsy world urine ketone measurements were used, and then blood ketone monitoring systems became available. And now, I've been using a breath ketone device made by Biosense or made by Readout Health rather. The company's Readout Health, and the product is Biosense.

Melanie Avalon: I've had them on this show. 

Dom D’Agostino: Yeah. I was very skeptical, especially the first couple units didn't work or the battery's running down. But then I've used these things for years now. I feel breath acetone really correlates with your fat oxidation state, and more so than beta-hydroxybutyrate because if I'm sitting at my desk all day like working and I'm fasting, and I've done three-day fast in different versions of the ketogenic diet, things like that, my beta-hydroxybutyrate will be elevated, but then I start moving around and become active and I feel have very quick and robust tissue disposal beta-hydroxybutyrate, because you're using that as fuel. Acetone not so much. So, it tends to be a little bit more stable. I notice that I could taste acetone when I'm really in a deep state of ketosis, and I know my body is just pulling off its fat stores. And then that's registering very high on the Biosense device. But if I'm active, and I'm in a calorie deficit, my tissues are sucking up the beta-hydroxybutyrate for fuel, so it's not really showing on the meter as much as it should. 

What I have learned over the years, I see this in athletes. I just can't get into a state of ketosis, but their bodies are so hungry, especially if they're in a calorie deficit that the ketones are being sucked up in the tissues and use as fuel. Especially if you're in a resting state, that's when your ketones are elevated. But if you're moving around and your metabolism is fast, there tends to be this disconnect over time. And then Peter Attia, I think, also reported this. We had an email going back and forth, we're almost identical in the way our response is. Like beta-hydroxybutyrate will start to come up and it'll be one millimolar, and that'll correlate to three, or that'll correlate to 10 ACEs, the reading on the Biosense meter will be 10 and that will correlate to one millimolar beta-hydroxybutyrate on the blood meter. But as you prolong your fast, or if you're in a calorie deficit, the acetone-- my acetone levels might max out the meter to 40. It literally couldn't go any higher. 

And then my blood ketone levels were the highest they got during like a three-day fast, were like 2.2 2.5. I think a couple of times they bumped up because it fluctuates to like three or four. But largely, I mean, there wasn't a tight correlation between beta-hydroxybutyrate and breath acetone. And that's my interpretation and it might be more complex, but my simple interpretation is that my body was using the ketones for fuel, because I could quickly lower beta-hydroxybutyrate with just some mild activity, I can see it drop down. I could be at my desk, and I measure it, and I'm like, three, and then I take a brisk walk just around the house, and I'm back down the one with a brisk walk, whereas my acetone levels will stay elevated, which makes sense, because you're burning more fat. 

I also like the Biosense device because I've literally taken thousands of measurements on it. And that would have been thousands of strips, which would have been multiple thousands of dollars. So, yeah, I've done many experiments, and you can puff into this thing many, many times throughout the day and then it goes into the app, which is a great-- the app is fantastic that they have for that device. And it just becomes more cost effective because your ketones fluctuate dramatically. So, you really need to measure like three to five times a day, three, minimum, five times a day to really get an overall picture of what's happening during the day in regards to ketosis. And that would be expensive and even painful if you're pricking your finger all the time, which I do anyway. But I think for people that just want a ketone monitoring system, as an index of their fat burning state-- I'll put it this way, you can't have elevated breath ketones and not be in a high state of fat burning. It's reassuring to me to see that and rewarding, I guess is the word to see the breath ketone so high because the carbons from that acetone are really in the fat in your body. Acetone that you're blowing off is completely a result of fat from your body or if you're fasting or from dietary fat if you're eating.

Melanie Avalon: What's actually happening, the acetone you said is coming from the acetoacetate in the bloodstream?

Dom D’Agostino: Yeah, in circulation, beta-hydroxybutyrate is reduced and more stable in circulation. Whereas acetoacetate and we have to figure out resourceful ways to measure this because it can be kind of tricky and acetone is also very tricky to measure in the blood, but we've done it and we've published on it. So, your body's producing beta-hydroxybutyrate and acetoacetate in about a four to one or three to one ratio. And that acetoacetate in circulation will spontaneously decarboxylate to acetone. It's pretty similar in every body. I think metabolic physiology in regards to this is pretty similar in most people. Although I've come across some people, they can't get anything on the meter, and they claim that they're in ketosis.

Melanie Avalon: That was going to be my question, does the environment-- the thing that makes me not nervous, but if it's random, then isn't it sort of random? What causes it to create acetone?

Dom D’Agostino: I guess the word spontaneous. It's spontaneously decarboxylating, but it occurs at a very stable rate all the time. There're a couple of papers that look into this. The best estimate is about 20%. 20% of the acetoacetate in circulation will spontaneously decarboxylate to acetone and then it makes its way to the lungs, which is a huge surface area. So, we can pick it up in our breath in fairly high concentration parts per million it's pretty high. It becomes a very reliable means to monitor ketosis, and breath acetone, not only correlates very high with fat oxidation, I became very interested in acetone and we started measuring in the blood, although it's a tricky protocol to really get it reliably, but I became very interested in breath acetone because acetone correlated with seizure control. There was a lot of arguments about saying ketones don't correlate with seizure control, but the data with acetone seem pretty strong, stronger than the other ketone bodies. So, I became very interested in acetone as a correlation for antiseizure effects. Actually, that led us to developing ketone esters that elevated beta-hydroxybutyrate and acetoacetate. 

The one ketone ester that I've put a lot of time and effort into, is 1,3 butanediol acetoacetate diester. That's a real long name, but when you ingest it, it produces a one-to-one ratio of beta-hydroxybutyrate and acetoacetate in the blood, and then that acetoacetate spontaneously decarboxylates to acetone and then we get a blood measurement of acetone about one millimolar. If ketones get up to like five millimolar. In that state-- That's incredibly antiseizure and neuroprotective in that state, at least in the model of oxygen toxicity, and then we’ve tested a couple other models, too. It was important for us. I guess, the message was it was important for us to not only elevate beta-hydroxybutyrate, but to also elevate acetoacetate to get the antiseizure effects because it seemed to correlate very well with acetone.

Melanie Avalon: Is the acetone in that case completely correlational or is it actually having any of the beneficial effects itself?

Dom D’Agostino: Well, it's generally thought in the field that acetone is like a byproduct and we just blow it out and it doesn't really have a physiological effect, but there're papers showing the acetone can be incorporated to go back into like Acetyl-CoA and go into other biosynthetic processes. I'm of the opinion that acetone affects many different things, and probably the gating function of certain ion channels, which play a role in excitability of cells like neurons. So, yeah, like in particular, maybe potassium channels. I've been interested in this and I've got certain theories that are more speculation, but acetoacetate and beta-hydroxybutyrate are fantastic fuels. And they also have some interesting signaling effects. Acetone was always thought of as this byproduct that we just blow off. But I'm of the opinion because of its high correlation with antiseizure effects, which is also could just point back to acetoacetate. It has some biological function that's important for the things that we're studying, and I'm trying to figure that out.

Well, there are studies showing that if you inject just small amounts of acetone, it has antiseizure effects. There's a direct effect. Acetone, when it gets real high it'll start to produce like a narcotic effect. But when you're on a ketogenic diet, you have sub-narcotic levels of acetone and you're still a strong antiseizure effect.

Melanie Avalon: You were saying earlier how some people just don't seem to ever register the acetone as much. Could they have high acetoacetate, but not have high acetone? And then in that situation, do you think they might not see the beneficial effects that they had seizures? That's a lot of hypotheticals.

Dom D’Agostino: Yeah, I don't know. Well, the way to really answer this is to do metabolomics. We do have some metabolomics data, we're sitting on some blood data now. I didn't get a lot of data and didn't know how to make sense of it. But bioinformatics processing is improving. In some ways, we are a unique metabolic entity, and we may have different metabolic response to the same ketogenic diet. It's going to be important to personalize low-carb diets and ketogenic diets to not only our lifestyle, but to our genetics. And we're not there yet, but different tools and technologies are emerging that will allow us to adjust our nutrition, which is the most important thing for our health. I teach to the medical students, and it's unfortunate that nutrition is not part of the medical curriculum, per se, although we do have a course, scholarly concentration nutrition, where we get into the importance of nutrition, like for health, for lifestyle, it's like the biggest-- I mean we all agree it's one of the most important things to keep people off drugs and out of the clinic. The immense burden on our healthcare system is due to poor nutrition or overnutrition. It's going to be important to understand the utility of ketogenic diets and utility of just low-carb diets, and to have tools to be able to personalize that. 

The National Institutes of Health, they fund nutrition research, and the federal government focus, they've actually are steering more money towards nutrition, but with a focus on personalizing nutrition has been like the big thrust. And we'll see where that goes. I think it's a good thing to focus on, but I do think they should focus more on low carb diets and looking at the utility of low-carb diets and directing more funding towards that.

Melanie Avalon: Well, speaking to that, so the role of diet versus exogenous ketones versus pharmaceuticals and things like that, does the body know at all? If they're like the ketones, does it know if they came from what you ate versus from exogenous ketones? And does it matter or is it literally just once it's there, it's there? 

Dom D’Agostino: Well, good question. I was extremely skeptical about this idea of just drinking ketones and then getting benefits. But I did study with immense enthusiasm. The ketone ester literature, which was you know, Dr. Richard Veech and Dr. [unintelligible [01:26:09] and a few others, Dr. Theodore Van Itallie, George Cahill, these were all just icons and metabolic physiologists. There're not really iconic metabolic physiologists now, they're more like biochemist, but you really need to understand physiology to understand the role of ketones in metabolism. Your question is a good one in regards to, is it all just about the ketones? 

There are certain things that happen when we're fasting and go into ketosis there are certain things that happen with a eucaloric ketogenic diet as a means to produce ketosis. And then there are definitely things that happen when you ingest exogenous ketones whether that’d be ketone esters. A lot of my research now is going towards ketone electrolyte salts. Having an electrolyte array that's beneficial to the body and those electrolytes are bound to ketones. We're really formulating things now in the ketone salts. There're overlapping things, but it’s also distinct. When you're fasting, you're in a calorie deficit, and that produces a caloric restriction effect. But interestingly, the ketogenic diet suppresses insulin and IGF-1 and some pathways that mimic caloric restriction. And then you have exogenous ketones, which interestingly lower blood glucose, ketone esters in high concentrations will actually increase insulin. I'm of the opinion that's probably not a good thing unless medically-- the rise in insulin is pretty small and you need a ketone ester at a large dose. I try to double dose ketone salts and I see only a little blip in my blood insulin. 

Melanie Avalon: What are salts versus esters, just for listeners that are not familiar?

Dom D’Agostino: Sure. You can make a ketone ester by taking ketone bodies and then binding them to a molecule with an ester bond. Typically, there are a couple. One is, 1,3 butanediol, which is a molecule in and of itself converts to ketones, but you can take 1,3 butanediol and then do a transesterification. And then you can bind beta-hydroxybutyrate and acetoacetate, either one to 1,3 butanediol and when you ingest that it gets broken down in the gut-- in the liver, and it releases the ketone bodies, beta-hydroxybutyrate and acetoacetate and then the 1,3 butanediol gets metabolized in the liver to beta-hydroxybutyrate. So, that's a ketone ester. 

You can also take glycerol and add acetoacetate or beta-hydroxybutyrate to glycerol. And that will produce a mild acidosis, and actually it's able to get your ketones elevated higher. It's almost like a dose-dependent effect. And then a ketone salt is actually we're taking in electrolytes like sodium, potassium, calcium, and magnesium. So, these are electrolytes. And these will ionically bond to the ketones, beta-hydroxybutyrate. You can bind them to acetoacetate, but it's less stable. So, they're not very common. So, you can have a sodium beta-hydroxybutyrate salt, you could have a potassium beta-hydroxybutyrate salt, calcium or magnesium beta-hydroxybutyrate salt. And then you can put these in certain ratios. The formulation that we use is similar to the electrolyte formulation of the product LMNT, which Robb Wolf has. I love that.

Melanie Avalon: I had him on three times.

Dom D’Agostino: Yeah, it's one of the first things I drink when I get up. Maybe this is to his credit, we found that that electrolyte ratio is actually the most tolerable in that specific ratio. We bind the beta-hydroxybutyrate to the electrolytes in that ratio and it's pretty tolerable and you can get levels up into like the one millimolar and even two millimolar range. And I think that's ideal. I have access to all different types of ketones and I can elevate mine up to 10 millimolar. But I feel sick, like, I don't feel well once I get up to three or four or five millimolar. But I do feel enhanced and optimized, so it's all about biohacking. I do feel that I am truly biohacking just by bumping my ketone levels up to about 1 to 1.5 with like a ketone salt, and you're also delivering electrolytes, which are probably a little bit deficient if you're low carb anyway, because you tend to excrete more electrolytes if you're on a ketogenic diet or low carb. So, that's my typical regimen. I take a couple servings of ketone salts per day and basically to deliver electrolytes and ketones at key times during the day. 

After this podcast, I make a workout, and I'll just have usually like a half a packet of ketone salts, and I'll mix some creatine in with that. And I do think there're some supplements too, that are important with the ketogenic diet, because we see it come up in bloodwork, like carnitine. So, I'll usually put some carnitine-- Acetyl-L-carnitine with the mix and drink that and that's a good zero sugar pre-workout, actually, especially with a little bit of caffeine. 

Melanie Avalon: Could a person become ketone resistant? Like they become insulin resistant? Like the equivalent of having too much blood sugar all the time, having too much ketones all the time?

Dom D’Agostino: I would say no. If you have robust mitochondrial health and metabolic activity, your body is going to be hungry for ketones. What we see in sedentary people, if you do-- I like to call it a ketone tolerance test. If you take people who just don't exercise much, like couch potato people, and you have them ingest ketones, the ketones get elevated, and they stay elevated in the blood a lot longer than someone who's an athlete, especially if you ingest the ketones and then get on a bike and ride or you do some kind of physical activity, those ketones get cleared very fast in elite level athletes, so it's just indicative of high ketone disposal into the tissues. Whereas a sedentary person did not transport it as fast, and that could be due-- the ketone transporter is a monocarboxylic acid transporter, which may be upregulated in athletes if they're making lactate, because it also co-transports lactate. So, yeah, we probably have much more robust ketone transport systems and ketolytic enzymes, and people who are more metabolically flexible and adapted to ketogenic diets.

Melanie Avalon: So, that actually speaks to, because a lot of my listeners on the Intermittent Fasting Podcast, feel like they have to chase ketones, like they really want high ketone levels. And we were talking before this about how I was listening to Rhonda Patrick on Joe Rogan and she was talking about doing keto and really needing to keep eating fat to keep her ketone levels up. So, is that something people need to be doing?

Dom D’Agostino: Rhonda and I had that conversation. I'll be meeting with her next week and doing some podcasts with her. Yeah, you do. A lot of people are chasing ketones, unless you're using it to manage a chronic disorder or something, I'm not of the opinion that everybody should be in a state of chronic ketosis. But say you're going to pull the ketogenic trigger and do one week out of a month of ketosis or a modified fasting diet, or a fasting mimicking diet, Valter Longo. It is very remarkable in the data, it supports that if you do that for one week out of a month, then you have this extended benefits over a couple of weeks. So, theoretically, yeah, you can follow-- I wouldn't follow any diet, but you can follow a more relaxed diet, and then periodically go into ketosis. 

I tend to do a modified version of a ketogenic diet just because I feel I have higher productivity, higher more stable energy levels. There're a lot of health benefits. I incorporate a level of carbohydrates that would typically maybe put most people out of ketosis, like between 100 to 75 grams per day, but the carbs are usually higher in fiber, but then I supplement ketones periodically throughout the day, just in a drink of ketone salts, similar to the electrolytes you get from element or something like that. So, I think of the salts of having two important functions of restoring electrolytes and just delivering a high energy source of fuel at the same time.

Melanie Avalon: Do you think people have any sort of metabolic memory? Like if they've done a ketogenic diet once, is it easier to do it again?

Dom D’Agostino: Yeah. That's an important point. And I think just like muscle memory, when you build up and get to a certain strength or conditioning, cardiovascular, you take time off, you can get back to that point like two or three times faster. And I think the same holds true, if we train our metabolism to be a strong fat burner or ketone producer, and we take time off. I know anecdotally, we would hear people, they would get into ketosis much faster, I know I do. If I take time off, which I usually don't. But in animal models, we see this too. So, if you put animals on a ketogenic diet, and then take them off, and then put them back on again, the levels of ketones will be elevated quite faster, a lot faster.

It seems that doing ketosis for a period of time makes the body more metabolically flexible when you revisit that again, and you'll talk to people who diet down for a contest or to make weight for a certain sport. And the first time they do it is kind of hard, and the more they do it-- and there could be a learning curve thing to this too. But I'm of the opinion that the more you do a ketogenic diet, and the more you do low carb and train your body to burn fat, the easier it gets, and probably the more benefits you derive from it, too, if you don't take it to extremes.

Melanie Avalon: Speaking of the animals, I just finished reading The Forever Dog, Dr. Karen Becker. She's going to come on the show, but she talks in her book about the cancer retreat for dogs where they do a lot of studies with dogs and cancer and ketogenic diets.

Dom D’Agostino: Yeah, I had that book. My wife is reading the book now. And they have an amazing free eBook that you can just download, and it tells you step by step on how to make the ideal food, low-carb ketogenic food for your dogs. I'm big fan of Karen Becker. And the KetoPet Sanctuary and what they've done to really promote low-carb nutrition for dogs, especially dogs that have cancer. We know that it's a very powerful adjuvant when you add it to therapy, and it could be a way to manage cancer and reduce tumors, eliminate them altogether, occasionally. When I got into studying the ketogenic diet for cancer, there wasn't too many people. Thomas Seyfried was doing it. Dr. Adrienne Scheck was doing it. And there were a few clinical trials, pediatric patients, but now if you go to clinicaltrials.gov, and just type in a “ketogenic diet and cancer,” you get dozens of studies. A new animal model study showed that there's checkpoint inhibitors PD1 and showed that the ketogenic diet can enhance the effects of some of these immune-based drugs too, which is a whole new direction. I didn't think about it toward until more recently. A lot of potential for ketogenic diets in veterinary medicine, and expanding application for different types of cancer too.

Melanie Avalon: Are there some cancers that are likely to be exacerbated by a ketogenic diet? Say, like the tumors that fuel on ketones?

Dom D’Agostino: There's no doubt that there's probably some cancers that would not be responsive. But when I think about ketogenic diet, I don't think about starving the cancer of glucose or elevating ketones, isn't it? When I think about a ketogenic diet for cancer management or as an adjuvant, I think about it as suppressing the hormone insulin, mTOR, PI 3-kinase pathway. So, I think of it as a way to change metabolic hormones that would marginalize and restrict tumor growth. And then, by limiting glucose availability, suppressing the hormone insulin and insulin-related signaling and elevating ketones too, because, I think they do have some anti-cancer effects that can put the brakes or at least let the foot off the gas pedal of cancer growth and then the cancer becomes more vulnerable to other modalities that can kill cancer cells. And that could be chemo and radiation or immune-based therapies, like these PD1 inhibitors, checkpoint inhibitors is a new area. 

And also the PI 3-kinase inhibitor drugs, Dr. Lewis Cantley has been researching drugs that target cancer metabolism including PI 3-kinase inhibitors. When we take these drugs, they tend to have a counter regulatory effect and they increase insulin unfortunately that was one of the side effects but these drugs work not so great in and of themselves, but when they're coupled and combined with a ketogenic diet, the ketogenic diet suppresses the hormone insulin and actually unleashes the therapeutic potential of PI 3-kinase inhibitors. So, there's some evidence for that and that could be a new direction. I view the ketogenic diet as a foundational sort of dietary approach that can be used for a wide variety of cancers. 

My original interest was to just use it for brain cancers because people with brain tumors have seizures, so it made sense. I communicate with patients that had side effects with antiepileptic drugs. And then, as I started researching this topic, I stumbled upon papers by Thomas Seyfried and Adrienne Scheck, and they would be great people to have on your podcast that show that they had these ketogenic diets had remarkable anticancer effects. And then that actually set off my enthusiasm for researching this. And then I had a PhD student come along, Dr. Angela Poff, and she was like, “I want to do my PhD dissertation on this.” So, the more research we did looking at ketogenic diets, ketone supplementation, and also hyperbaric oxygen therapy, which seems to synergize with the ketogenic diet, we saw remarkable effects in our model system. So, it's still we do quite a bit of research that we currently do is focused on cancer.

Melanie Avalon: So, I have an idea for how pharmaceutical companies could turn this into a drug sort of. Well, definitely for keto from fasting, may be keto from diet. They could make a pill, and instead of all of the reasoning going into the actual makeups of the pill, it would all go into the instructions. So, for example, you have to take this pill on an empty stomach with a certain eating window that actually would be prescribing fasting, or it could be like for the diet, they can say that you have to have this pill with this certain type of diet.

Dom D’Agostino: Yeah. So, the exogenous ketones produce many of the effects of ketogenic diets, so they lower blood glucose remarkably low. Work done by Thomas Seyfried has have looked at the glucose ketone index. And if we look at all the different cancer studies that have been done in animal models and humans, the most beneficial effects seem to be achieved when you get the lowest glucose ketone index. What that translates to is the lower the glucose, and the higher the ketones, the better the therapeutic effect, that diet intervention had at restricting, eliminating cancer growth. And a pill would do that. 

We know that when you ingest a ketone ester or ketone salts that you're lowering glucose and elevating ketones, and with the ketone salts if the total rise in ketones are not above two millimolar, then you're not increasing insulin. And I think that's going to be important too when we deliver. And then there may be drugs that could just stimulate fat oxidation and ketone production in the liver. And there're a couple of drugs that may do that, but the drugs maybe have side effects. So, I think that work needs to be done. I'm not going to name the pharmaceutical companies, but I've traveled and went to a variety of different pharmaceutical companies, like the more popular ones, and they want me to give a summary of the ketogenic diet, all the mechanisms, so they can make a ketogenic diet in a pill. And it's hard to do that because the summary slide is showing a dozen different mechanisms potentially working in synergy to produce the effects we see in the clinical endpoints, which is like lowering blood glucose, reducing inflammation, having antiseizure effects. It's doing it through a variety of mechanisms. So, it's going to be hard to make a drug that does that.

Melanie Avalon: I was thinking that pill could actually be a placebo. So, the instructions for taking the pill, it would make the people fast, so they would think the pill was a pill, but actually, it was just placebo, and it would make them fast every day, and then that could be the treatment.

Dom D’Agostino: So, the pill then would be like an appetite suppressant. 

Melanie Avalon: [unintelligible [01:44:24] anything in the pill. It would just be like it has to be taken on an empty stomach. It can't be taken within four hours of food, either—like take in the morning on an empty stomach and then wait like four hours to eat, so then you're forcing people into a 16-hour fast.

Dom D’Agostino: That's a good idea. It's really a good idea. They don't figure it out. But, yeah, there are remarkable effects to placebo as we were just discussing this in one of my classes that the placebo pill. I also believe just in following people over the years that if the person implementing the approach truly, truly believes that it's helping them, then it's more likely to help them. I think there's neuro-psychoimmunology. I know our brains can change our physiology and many, many hormone systems and things like that. I do believe there's a major effect belief in whatever you're doing, if you believe that it's beneficial and having a therapeutic effect, it's more likely to work. 

I've just seen in enough patients that I've communicated with that that's the case. And I think it goes above and beyond the science of what I know it should do. Like I've seen cancers kind of go into remission, and like doctors saying, “Wow, this diet seems to be working,” in pretty much all cases, the patient was like completely convinced that it was going to help them. So, just do the communications. I guess there's just some where they believed it, and it didn't help or, but it just seems like the feedback that I'm getting, like, over the years that when patients really implement it and follow through, and they believe it, then you just get these remarkable effects, therapeutic effects.

Melanie Avalon: Yeah. I just interviewed Shamini Jain, I think. She wrote a book called Healing Ourselves. And it was all about this, like the biofield science and the placebo effect. She talks about studies looking at all of that and people's belief definitely plays a huge role.

Dom D’Agostino: It does need to be studied too. Also, when we get on a ketogenic diet, or low carb, or dietary intervention, ideally low carb, it's changing our psychology. So, there's a whole field emerging called metabolic psychiatry. And Dr. Christopher Palmer from Harvard was a speaker at the Metabolic Health Summit. And we also have a number of speakers and are going to really increase this theme at the Metabolic Health Summit, which is bringing together clinicians, basic science researchers and companies too, that support this kind of field. This idea that there's not too many, the toolboxes are not very good for things like bipolar disorder, and depression, anxiety, and things like that. And dietary interventions have very profound effects. And they could be used as an adjuvant or maybe even in some cases standalone intervention for some people. So, there's a lot of really cutting-edge research going on right now for psychiatric conditions, and using this dietary approach for that.

Melanie Avalon: What do you think is the biggest barrier to, like, there actually being a paradigm shift where conventional medicine is using these therapeutic dietary approaches more? Do you think it's possible?

Dom D’Agostino: Yeah, the big hurdle is implementation is hard. Most doctors don't have a nutrition team. They don't have registered dieticians at their fingertip that can put patients on a ketogenic diet and make them comply and we don't know if they are complying. You send them home with diet instructions, a pamphlet, or even have them go through a workshop to understand the diet. But that's where I actually think continuous glucose monitors, or Abbott came out with the Lingo device or Lingo that measured glucose, ketones, lactate, and alcohol.

Melanie Avalon: Oh, really? I want that. Levels needs to make access to that.

Dom D’Agostino: Yeah, the Consumer Electronics Conference, the keynote was on that by the CEO of Apple, or CEO of Abbott rather. Yeah, putting these monitoring devices on patients, sending them home, so the data just goes to a cloud. And actually, you can just look and see if they're following the diet or not. Yeah, it's going to be super important. It's going to be a game changer, I think. And then for them to have an app, like the Levels Health app. I use that where they can just press a button and have access to a nutritionist, and they can see the effect of a particular diet or amount of food on their glycemic response. And they say, “Okay, well, I shouldn't do that,” or, “I'll eat another meal instead of that.” It becomes very rewarding to them, they gamify the whole process, and then it inspires them because they have more control over their condition. So, I think these bio-wearables and these emerging technologies, where there's multi-analyte sensors are going to be game changers for managing people with epilepsy or type 2 diabetes and other disorders where the ketogenic diet is a therapy. It's going to be super important to monitor them to make sure they're complying, but also to optimize the approach to say, “Oh, you might add a little bit of fat or your ketones are actually too high, maybe you can add a little bit more protein to have that data is going to be really important.

Melanie Avalon: Wow, I am very excited. And, wow, thank you. This has been so, so amazing. And for listeners, we even had to figure it out for like half an hour before this, we were having technical difficulties. So, thank you so much for your time. I cannot thank you enough. I can't thank you enough for your work and all that you're doing. It's just really, really profound and life changing. Is there anything else you want to touch on, any resources you want to put out there for listeners? Anything else on your mind?

Dom D’Agostino: No, I want to thank you for giving me this platform to speak and thank you for the invitation. I really appreciate it. It's people like you that are getting the information out there, and people are hearing it, because I do these podcasts, and so many people respond back to me saying, “Oh, I heard you on this, and I started doing this.” And, yeah, it's really made a difference. So, thank you for that. If people want to find out more about what I do, I have an informational website called ketonutrition.org. People always ask me about what ketone supplements should I take and this and that, the one that I personally use is by Audacious Nutrition. It's called KETOSTART. And it's just an electrolyte formulation, that's bound to ketones. So, I like that. 

And, yeah, I'm a big advocate of using continuous glucose monitoring devices and I think people could just sign up and just use it for four weeks, and then that will give them like a ton of information. I wear mine all the time because I'm always testing things, but I'm a big advocate for that. Oh, one last thing, because I get a lot of questions about diabetic ketoacidosis. Diabetic ketoacidosis will not occur if you're not type 1 diabetic. So, diabetic ketoacidosis occurs in the absence of insulin. So, I just wanted to throw that out there because it's usually-- I get a lot of hands when I give talks at conferences, and people are like, “Well, what about diabetic ketoacidosis? That becomes only a problem in the context of type 1 diabetes. But at the same time, the ketogenic diet is actually being used as a therapy now for type 1 diabetes, and you can look that up. There's like literature and studies going on, and even a group that's advocating low-carb diets for type 1 diabetes. 

This a Facebook group that goes by the name of Typeonegrit. So, my student or former PhD student, Dr. Andrew Koutnik was a member of that and kind of network to that community. But it's kind of funny, because when I used to give talks on ketogenic diets, I would say, “First and foremost, if you're type 1 diabetic, don't even think about this approach.” But now, low-carb diets and ketogenic diets are being used to manage type 1 diabetes to reduce the amount of insulin that they need to manage their glucose within tight ranges. So, yeah, the field is changing a lot. And I never thought that would happen, but we do have publications now supporting the use of these diets and type 1 diabetes community.

Melanie Avalon: Very exciting. For listeners, again, the show notes will be at melanieavalon.com/ketogenicdiet, there'll be a transcript there. And I'll put links to everything we touched on. I'll put links to my interviews with Levels and Biosense and LMNT and Oura and Valter Longo and all of that for people who want to learn more. I promise this is the very last question I ask every single guest on the show this question to end it. And it's just because I realized more and more each day how important mindset is. So, what is something that you're grateful for?

Dom D’Agostino: Oh, man, so many things. Yeah, we had this discussion last night with friends. I do a gratitude practice every day. And I like to focus on something like very, very specific every day, and then that gives me appreciation. There're many different things, but the health of my parents, so my parents are getting up in age, and they'll be visiting very soon. So, I'm super excited about that, because I haven't been able to see them with COVID and other issues. But, yeah, I'm just really grateful for the health of my family and my friends, who also support the work that we do, too. So, I'm just trying to pick one thing, but as soon as I get off on this podcast, my wife is cooking dinner, and I smell it now. So, I'm super grateful for the meal that she's cooking me right now, and super grateful to enjoy--

Melanie Avalon: The ketogenic meal, I presume? 

Dom D’Agostino: Well, she doesn't eat ketogenic, but dinner is usually pretty ketogenic. But I'm super grateful for the smell I'm smelling now and the meal that we're about to have together, and the walk that we do with our dogs after the meal each night.

Melanie Avalon: I love that. Well, thank you so much, Dom. This has been amazing. I so, so appreciate it. I will eagerly continue to follow all of your work and this has been amazing. So, hopefully, we can talk again in the future and just thank you. I cannot thank you enough.

Dom D’Agostino: I enjoyed it. Thank you for having me, Melanie. 

Melanie Avalon: Thank you. Bye.

Dom D’Agostino: Bye-bye.

[Transcript provided by SpeechDocs Podcast Transcription]

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