The Peter Attia Drive - #120 - AMA with Dom D’Agostino, Ph.D., Part II of II: Ketosis for cancer and chronic disease, hyperbaric oxygen therapy, and the effect of ketosis on female health

Episode Date: July 20, 2020

In part 2 of this special AMA episode, ketosis expert Dom D’Agostino once again joins Bob Kaplan, Peter’s Head of Research, to discuss the impact of ketosis on various chronic diseases as well as the latest research on the metabolic management of cancer. Dom also discusses the numerous applications of hyperbaric oxygen therapy, provides insights into the application of ketosis on female health and performance, and much more. If you’re not a subscriber and listening on a podcast player, you’ll only be able to hear a preview of the AMA. If you’re a subscriber, you can now listen to this full episode on your private RSS feed or on the website show notes page.   We discuss: Update on Dom’s Press-pulse therapeutic strategy for the metabolic management of cancer [2:05]; Potential role for vitamin C in cancer treatment [12:45]; Glutamine targeting in cancer therapy—evidence that the mitochondria in cancer are damaged? [17:45]; Can a ketogenic diet lessen the toxicity of cancer therapies? [24:45]; 3BP—a promising agent in cancer therapy [26:45]; The relationship between cancer and ketogenic diets [29:30]; Hyperbaric oxygen therapy (HBOT)—primer, protocols, and therapeutic uses [33:30]; Is there a potential role for HBOT in treating COVID-19 patients? [44:15]; Non-cancer applications of HBOT [47:30]; The inverse relationship between glucose and ketones [50:30]; Is a ketogenic diet appropriate for type 1 diabetics? [54:00]; How ketosis may reduce the risk for Alzheimer’s disease and Parkinson’s disease [1:00:30]; Ketosis for females—considerations, fertility, performance, and the latest research [1:11:00]; Low-carb diets during pregnancy and postpartum [1:17:00]; A high-protein diet to counteract common hormonal issues associated with the ketogenic diet [1:21:15]; Nutritional tips for remaining metabolically flexible [1:22:45]; What is one belief Dom has changed his mind about? [1:26:45]; In utero experiments, and other interesting questions Dom wants to explore [1:29:45]; The anti-catabolic effect of ketones, cancer cachexia, and nutritional interventions for cancer patients [1:38:30]; What is the one interesting experiment Dom would do if money and time were not a barrier? [1:46:25]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/domdagostinoama02/ Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to a sneak peek, ask me anything, or AMA episode of the Drive Podcast. I'm your host, Peter Atia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to peteratia-md.com forward slash subscribe. So without further delay, here's today's sneak peek of the Ask Me Anything episode. Hey everyone, welcome to part 2 in our AMA series with Dom DeGustino. As a reminder, you'll note that this interview had been scheduled for a very long time, and just when it was about to happen, I had to go to Mars on a spaceship that did not contain a zoom setup, and I was unable to be a part of it,

but both Dom and Bob Kaplan might have researched graciously agreed to do it in my absence, and so you will once again be graced by the presence of Bob and Dom, my head of research graciously agreed to do it in my absence, and so you will once again be graced by the presence of Bob and Dom speaking instead of having to listen to me. In this second episode, Bob and Dom dive deep again, this time really focusing on the effects of ketosis on various chronic diseases, Dom's work with hyperbaric oxygen therapy and its numerous applications, as long as the applications of ketosis on female health and performance. This is a topic that I know very little about

outside of some reproduction, and also it's something that many of you have been asking about. And frankly, there's just not enough information out there on such topics. Dom is an associate professor at the University of South Florida where he teaches at the College of Medicine and in the Department of Molecular Pharmacology, Physiology.

He focuses on Neuro Pharmacology, Medical Biochemistry, Physiology, Neuroscience, and Neuro Pharmacology. He's also a research scientist at the Institute for Human and Machine Cognition to assist with their efforts towards optimizing the safety, health, and resilience of warfighters and astronauts. Lastly, it's important to note that while DOM is answering specific questions and scenarios, is not giving medical advice. Everything in this podcast is for general informational purposes only and does not constitute the practice of medicine, including the giving of medical advice. So without further delay, please enjoy Part 2 of the AMA with DOM, digistina. of the AMA with Dom Dagestina. So we're going to switch gears to ketosis and disease.

And the first step is cancer. And a lot of questions around updates on press pulse therapy since a couple of years ago when you're on the podcast, you mentioned the press pulse and the paper that you did with Tom Seafried. Talk about that a little bit. I have to say I was not formally trained as a cancer biologist or cancer researcher. It just sort of fell in my lap. So to speak, I guess around 2010.

And I think maybe I went into that on the first podcast. And I have to say I've been extremely lucky to have brilliant students come into my lab. And that has made all the difference in the world. Because there's the other PIs or professors, they just get students that, and they're to kind of stuck with them for five years. But I've got the upper echelons, like the top of the top students in the program I always have. And not only are they brilliant, they just have a genuine interest in this topic. So they were able to basically be the engines behind a lot of the research that we did.

That started laying the groundwork, I think, or the groundwork was already sort of laid because people were already doing key to genetic diet studies like Tom Sayford, who's been on the podcast before. But we sort of picked it up and took it in other directions. And we kind of worked on that press pulse review that sort of encompasses this idea using, I guess we just call ketone metabolic therapy or therapeutic ketosis and other modalities to compromise tumor growth and proliferation. And that weakens the tumor, if we're talking about a solid tumor, to be more amenable to other modalities,

which could be the one thing that we experimented on years ago that one of the first papers we put out was the ketogenic diet and hyperbaric oxygen therapy. And there are a number of reasons why they are synergistic. So being in a state of therapeutic ketosis suppresses insulin signaling, which drives PI3 kinase, it lowers glucose availability to the tumor, it elevates ketone bodies, which as an alternative fuel cannot be readily utilized by cancers, most cancers as a source of fuel, perhaps anabolic processes,

but they are not a good fuel source for cancer cells, most cancer cells. And they also do things like they impair antioxidant pathways that the tumors use to defend itself. And a tumor is resilient because it has upregulated endogenous antioxidant pathways by high levels of glutathion. So the pentose phosphate pathway, for example, generates more glutathion in cancer cells.

And that is being fed by glucose. So if you reduce glucose availability and hibit insulin, which enhances glycolysis, so you're suppressing glycolysis, you're creating a scenario where if you give an oxidative challenge with hyperbaric oxygen therapy, you can potentially kill the cancer cells. So this is what I observed using a hyperbaric laser scanning confocal microscope. So we adapted this technology for use inside a hyperbric chamber for Department of Defense and Office of Navy Research related projects on CNS oxygen toxicity, which manifests as seizure. So we are looking at a variety of different cell types, and one cell type curiously had a tremendous oxidative burst, and we were measuring superoxide anion with dihydroethidium. So with dihydroethidium is taken up into the cells and then reacts with superoxide anion

and forms this athidium cation, which binds to nucleic acids and it lights up. So the lighting up inside the cell as the cell flight up that indicates reactive oxygen species are being produced. And when I started looking at the first cell was U87 glioblastoma cells, and these were taken from like a 40-some-odd-year-old glioblastoma patient, and now it's a cell line that a lot of people use.

The intensity of the cell indicative of superoxyan anaproduction skyrocketed above and beyond anything I'd ever seen before. And then the more hyperbaric oxygen I gave, I saw the mitochondria starting to disappear. They lit up, too, because they have their own DNA. It was mitochondrial superoxide. I think we went on to look and explore and use various mitochondrial specific superoxide detectors. But the cells started dying, and I didn't see that

in other cell model systems, so we figured something was going on there, and this is looking at cells, so Dr. Angela Poff, who was one of my first PhD students, studied the ketogenic diet with hyperbaric oxygen, delivered at 2.5 atmospheres of oxygen, 60 minutes, three times a week. And that protocol combined with a modified ketogenic diet proved to decrease tumor burden and extend lifespan in this animal model of metastatic cancer, which is the VMM3 model that

Thomas Safry developed. And I think it's a remarkable model of metastatic cancer. So now there are many different things that you can combine in press pulse therapy. So I think the idea would be to, from a press perspective, going back to the glucose ketone index and that paper, if you just Google glucose ketone index, and maybe I think it was in nutrition and metabolism, Tom Saferd published this, and really laid out all the science to support that a glucose ketone index, the lower that is, ideally in the 1 to 2 range, below 1, if possible. Getting a glucose ketone index, which is the level of glucose over the level of ketone

in millimolar concentrations to 1 or two, that sets the stage, slows tumor growth and proliferation, and makes the tumor more vulnerable to what I mentioned hyperberecoxygen therapy, but other cancer-specific metabolic drugs. And we really want to try the PI-3 kinase inhibitors that Lou can't leave us on. I just started listening to the last podcast, fantastic podcast you guys did with him. We've been using 2Doxyglucose, which is basically also inhibits hexa kinase and inhibits glycolysis. 3-bromo pyruvate is something we want to use. We have used DCA, MEP4-MEN. We've done experiments with vitamin C,

high doses of vitamin C, and that was a project of one of my undergraduates. To publish that work, vitamin C has some interesting effects, and then there's the SGLT2 inhibitors that were also interested in. So there's all these things out there, but we haven't really put it together into a therapy. We're just, you need to test these things sort of in isolation and then combine certain things together, but how they all work together, the press polls review that we published was more of an idea, and it was sort of in the preclinical stages. But there are a number of papers coming out. One just came out

this morning in science communications looking at a Walter Longo study, looking at fasting with IV vitamin C, I believe. And it showed in K-RAS, basically tumors that are aggressive and very hard to treat that have the K-RAS mutation. He had remarkable effects. Oh, it was a mouth study. I believe in it. It's on my desk. I got it read because it just came out this morning. I saw it just showing a remarkable effect, completely non-toxic, combination of fasting with vitamin C, intravenous vitamin C. And there was also another paper that came out, just came out like a week or two ago, metastatic thymoma. Female, she was 37 years old, I believe, very difficult to treat cancer, not a curable cancer at all. Pretty light, like maybe 50 or 60 kilograms. Stage 4A, and she did

fasting, ketogenic diet, and fasting. I have to look at all the protocols that were used, but I think they use prednisone two, 40 milligrams per day, which is kind of high. But come to find out that can trigger apoptosis and cancer cells, but they had like a 90%, 96% decrease in tumor burden with this therapy. And it was like using relatively non-toxic approach. I mean, there was some drugs throughout, some immune-based therapies, And it was like using relatively non-toxic approach. I mean, there was some drugs throughout some immune-based therapies, but it was basically water fasting with ketogenic diet and then periodic water fasting with different immune-based therapies. So it's another paper on my desk. I got to read.

Tom actually emailed that paper to me. Yeah, I recently read it and it was remarkable. And one thing that I noticed, the author's pointed it out, that the woman had, she had a couple of episodes, correct my pronunciation, myastenia grabis. So she had a couple of those cases and it looked like during those two cases that something, the remark was something about a remarkable decrease in her intake, a food or oral intake. And on the second, her second episode, she lost about, I think it was about 15 kilograms. And like you said, she was already, let's say she was like 110 pounds,

she went down to 80 pounds. And the second, I don't know if it was the second imaging or one of the later imaging, her tumor went from, it looked like, whatever you wanna call it, the tumor burden, they were measuring it in cubic centimeters. It slowly progressed, it was pretty stable, it looked like whatever you want to call it, the tumor burden, they're measuring it in cubic centimeters. It slowly progressed, it was pretty stable it looked like, and I want to say, it sounded like, and if you look at the pictures, it looked like she had an extra lung in terms of the

mass that you could see right in the sternum in that area. So it went from something like 600 cubic centimeters to, I don't know if it was like 30, I went on Google and tried to figure out how does that compare to like different size balls and it looked like it went from like a football to a golf ball or there's something to that effect where it almost seemed like the ketogenic diet I was wondering, it's almost like paired with this idea of coley's toxins, that kind of thing, that she had this episode but essentially I don't know how long she was fasting for but if she lost 15 kilograms during that time, and it also looked like her tumor just was being wiped out

over that period of time. But there's a few case studies like that too that I know that Tom's been a co-author on. I don't know if you mentioned it in your podcast or his, yeah, his, like a person with triple negative breast cancer and somebody with glioblastoma, but I wanted to come back to something too. You mentioned vitamin C. You mentioned IV vitamin C, and I know that in the previous podcast, this was eye-opening. When you talked about radiation and perhaps up to 80% of its effects are the reactive oxygen species that something like radiation can induce, and it sounds like hyperbaric oxygen

is somewhat similar. And so then you think the tumor cell, part of the defense is the up regulation of all these antioxidants. And a lot of people will think about vitamin C and they'll go, well, wait a minute, vitamin C is an antioxidant. I also think is it at IV doses, it can be a pro-oxidant,

is that part of why you think it might be effective? Yeah, I'm so into the pro-oxidant effective vitamin C and down to the redox pathways that I don't even think about as an antioxidant anymore. We use really high concentrations. So that's right. So hyperbaric oxygen, so it's well known that radiation therapy kills cancer cells by 80 to 90% just through Ross generation. Maybe 10 at most 20% just by directly nicking the DNA, like double-strand nicks, but you're generating

reactivoxid species, and then they are toxic tumor cells. So the efficacy of radiation therapy is proportional to the PO2 of the tumor. So if you oxygenate the tumor and then radiate it, you're going to do a lot more damage. It's directly proportional to oxygenation. So tumors tend to grow an outstriptor blood supply so they're hypoxic. So when you radiate them, they become resistant to radiation because they're hypoxic. So if you were to have hyperbaric oxygen therapy during radiation, like a targeted radiation, we know that that would dramatically sensitize it. Like this is well known and accepted. But what isn't really firmly established is that if you have hyperberecoxygen therapy before or after radiation therapy, like say you have hyperberecoxygen and then you get out of the

chamber and go have radiation, the PO of the tumor will drop, but you'll have a residual elevation of reactive oxygen species for hours after. So and it'll be somewhat site-specific increase in reactive oxygen species because various mitochondrial abnormalities, I should say, there's a debate whether the mitochondria are damaged or they are not damaged. I'm 100% certain that the mitochondria are aberrant in a way. So they are dysregulated in a way that they overproduce oxygen reactive oxygen species in response to an elevation of the PO2 at the tissue. So this is well documented. And it occurs because there's defects in the mitochondrial electron transport chain.

There's a lot of free heme available. That free iron that's available drives the fentanyl reaction. So if you remember biochemistry or organic chem, so the fentanyl reaction is when you have a lot of free iron, it drives the production of hydroxyl radical, which is like a super reactive oxygen species. And that can kill cancer cells very dramatically. So the combination of hyperbaric oxygen therapy, radiation, IV vitamin C, or if you were to take radiation out of it and just do hyperbaric oxygen and IV vitamin C, can be a potent pro-oxidant therapy. So another interesting thing about dihydroescorbic acid is that it uses, which is the oxidized kind of form of vitamin C, is that

it uses the glucose transporter to get inside cells. So if you elevate vitamin C or scorbic acid into millimolar concentrations in the blood using an IV route, it functions as a glucose antagonist. So you are not only inhibiting glucose transport and you might actually get some hypoglycemic symptoms out of it. So I did when I had IV vitamin C. So you are delivering a glucose antagonist that's also dramatically increasing reactive oxygen species in cancer cells because tumors have a lot of free iron because there's a lot of heme cells are chronic cells are dying in tumors all the time Just because there's not is or hypoxic, but they're proliferating

So you have dead cells and live cells, but the important thing is that there's a lot of heme iron Available a lot of free iron so reactive oxygen species is like really really high and vitamin C is really sort of driving Driving that reaction in addition to the glucose antagonist effect. So, we're pretty enthusiastic about Vitamin C. We've done quite a bit of work. We need to publish more of it, publish it in abstract form. I had a super awesome undergraduate, Janine DiBlasi, who she did her honors undergraduate with me, but then went to Oxford to study cancer and radiation. And now she's at Moffit Cancer Center under a different mentor, but I would love to kind

of reinvigorate her honors undergrad project and start doing more vitamin C work. But yeah, that's a really important component now we think to press pulse concept of cancer management. And I think this is probably part of the original press pulse, but I know that Tom's done some work subsequent to that. I don't know if you're involved with that or you're aware of this as well, where he talks about mitochondrial substrate level phosphorylation with glutamine. And so he thinks that the tumor cells are, I think that that's actually, that's not controversial, that you'll read papers if you look up PubMed and you type in glutamine addiction tumor cells are, I think that that's actually, that's not controversial, that you'll read papers

if you look up PubMed and you type in glutamine addiction, tumor cells, you'll see a lot of papers come up on that and that they, tumor cells, quote unquote, love. I don't like to use like the teleology, but they're addicted to glutamine. I remember he did a paper recently, he has, like you said, the VMM3, Gleoblastoma mice.

Yeah, yeah. It's a Gleblastoma mice. Yeah, yeah. It's a glialblastoma that metastasizes. So it's transformed in a way to become highly metastatic. If you eject it into the flank, then you even have brain met still lung liver. It is the most deadly animal model of cancer that I know about. And so it makes it kind of a fantastic model system to study. I remember Tom told me,

if you can cure cancer in this model system, then you've cured cancer. We're still trying to do that because it's such an aggressive form of cancer. We just published a paper. First author was my graduate student. He just graduated Andrew Kutnik. He demonstrated in that it's an amazing model to study cancer cacaxia.

So not only is the VMM3 model, probably one of the best models of metastatic cancer, and we need way more research into metastatic cancer. Studying just a consolidated tumor, whether it shrinks, is not really that informative, because people really don't die of a tumor. They die of metastasis and invasiveness of the cancer. This is a tool to do that. So I'd encourage cancer researchers out there to use this model. It's really good.

Now, we've demonstrated through the work of my former grad student, now Dr. Andrew Kutnik, that it's an amazing model, the best model that we know of in my opinion, to study cancer cacaxia, which is a really important understudied phenomenon of cancers. It's funny. I was going to mention the same thing that what I heard, I think this is actually an Italian, I can't remember the guy's name, an Italian researcher, he may have told us to Gary Tobs, Gary shared this with me where he said, he's talking about the field of cancer and mice and said, if you can't cure cancer in a mouse, you need to get out of this field because it's so easy.

And then I would think to like, Tom's mice and Tom's like, I'll give him the VMM3s. You try carrying cancer in that mouse. You come back to me and you tell me how that is. But Tom, he did a paper, it was 2019, I would be able to pull this, it was nature communications. And he combined his ketogenic diet,

calorie-restricted ketogenic diet, and he looked at, and he's done that study before, where he looks at just the ketogenic restricted diet versus standard diet. And then he looked at, I think, standard diet, plus dawn, which is a glutamine, either glutamine and tagging is glutamineamine antagonist, glutamine inhibitor. Yeah, inhibitor antagonist.

Yeah. Six diazzo, five, Nora L. Lucine, something that affects it. Yeah. And it's one of those things, if you look at a cappin myocurve, if you know how those work, where every death of a mouse or an organism or an individual is going to tick the little plot down towards percent survival to zero. And I looked at, it's probably the first figure in the paper.

And he has the mice that are calorie-restricted ketogenic diet plus dawn. And it's like this purple line. And it starts right at the top of the hundred. And it just goes all the way, just a horizontal line. None of the mice are dead. I just remember emailing him saying like, did you follow it up? I don't know why this reminds me of Seinfeld.

There's an episode of Seinfeld where they're almost on an empty tank of gas and they want to see how far they can take it. They're test driving a car. And I just thought, tell me the end of that story. I'm not sure how long they lasted, but his cap of my occur went out 40 days and there's no deaths. And if you look at standard diet,

I think this is pretty typical that the mice after and planted, they're between about 15 days, all the mice are dead with a standard diet. And he's made some headway with a ketogenic diet. He says it's not a cure. All it's not, at least it's not carrying cancer in these mice. And then he added this glutamine inhibitor, which is pretty interesting, I think. That would probably be his pushback on this idea that a lot of people talk about the cancer cells having normal mitochondria, and I think their justification is that it's

consuming oxygen. And so it's that you'll see OCR, oxygen consumption rate. But I think what Tom is arguing is that yes, it's maybe taking in oxygen, but it's not producing ATP via oxfoss. It may be that the tumors, not just getting energy from the warberg effect or aerobic fermentation, but it also might be fermentation of glutamine. And I remember, full disclosure, I sat in on Tom's class twice

at BC. He was kind enough to let me sit there. That's awesome. It was great. I taught in that class one time. I gave a departmental lecture, sat in that class, which was really fun. I course director for a kind of a metabolism

and signaling course, and we went over Tom's papers and stuff, but the whole course was not on cancer, but it was fun, it was a similar kind of course, they were the best kind of courses. So I'm sure it was a lot of very spirited discussion. Oh, absolutely. It's pretty brilliant what he does actually. So he has his cancers and metabolic disease, your experience? I think it's a lot of experience with your experience with your experience with your experience. I think it's a lot of experience with your experience with your experience with your experience.

I think it's a lot of experience with your experience with a paper that tries to essentially shoot down his hypothesis as cancer is a mitochondrial metabolic disease. And so it's actually a brilliant way for him to keep up with the latest research and the things that how you might be fooling himself. It's pretty fascinating. Obviously he's very passionate about it. So journal club is a good way to do that.

And there is no lack of papers out there. And brilliant scientists out there who basically are presenting work showing that cancer is perfectly normal. And the mitochondria are perfectly healthy in cancer cells. So I think there's sort of a happy medium. And we know that the mitochondria are transformed in ways to enhance biosynthetic processes. The expanding biomass at the tumor, those needs need to be met and the mitochondria transformed into ways that achieved that goal. And of course glycolysis is elevated tremendously and then glutamine alisus too, drive a lot of the anabolic processes and also ATP generation two to some extent. So targeting glutamine with dawn is a very great strategy in theory, but dawn is toxic.

So I mean, it's a dose dependent thing, but we need to come up with better molecules that could reduce glutamine levels in the blood and tissue, and also just function as a glutamine antagonist. Yeah. He mentioned, I think it's mentioned in that paper that, giving Dawn on the standard diet, at least again, we're talking about mice, it was the toxicity, I think, was a lot higher than the ketogenic diet. And I'm actually, I'm thinking about, if you have any thoughts on either radiation or

hyperbaric oxygen, that if you're doing either one of those interventions, do you think that there's a benefit of being in a state of ketosis while you're actually receiving either intervention? Yeah, absolutely. Thank you for listening to today's sneak peak AMA episode of the drive. If you're interested in hearing the complete version of this AMA, you'll want to become a member. We created a membership program to bring you more in-depth, exclusive content without relying

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