#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

Foreign. Hey everyone, welcome to a Sneak Peek, Ask Me Anything or AMA episode of the Drive podcast. I'm your host, Peter Attia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to Peteratti md.com subscribe so without further delay, here's today's sneak peek of the Ask Me Anything episode. Hey everyone, welcome to Part two in our AMA series with Dom d'. Agostino. 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, 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 neuropharmacology, medical biochemistry, physiology, neuroscience and neuropharmacology. He's also a research scientist at the Institute for Human and Machine Cognition to assist with their efforts towards optimizing the safety, health, health and resilience of warfighters and astronauts. Lastly, it's important to note that while Dom is answering specific questions and scenarios, he is not giving medical advice. Everything in this podcast is for general informational purposes only and does not constitute the practice of medicine, including the giving of medical advice. So without further delay, please enjoy part two of the AMA with Dom d'. Agostino.

So we're going to switch gears to ketosis and disease and the first up is cancer and a lot of questions around Updates on Press Pulse therapy since a couple years ago. When you're on the podcast, you mentioned the Press Pulse in the paper that you did with Tom Seyfried.

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, 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 I see other PIs or professors, they just get students, and they're just kind of stuck with them for five years. But I've got the upper echelons, 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 ketogenic diet studies, like Tom Seyffert, 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 of using, I guess, what you'd 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 glutathione. So the pentose phosphate pathway, for example, generates more glutathione in cancer cells, and that is being fed by glucose. So if you reduce glucose availability, inhibit 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 hyperbaric chamber for Department of Defense and Office of Navy Research related projects on CNS oxygen tox toxicity, which manifests as seizures. 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 dihydroethinium is taken up into the cells and then reacts with superoxide anion and forms this ethidium cation which binds to nucleic acids and it lights up. So the lighting up inside the cell as the cells light 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 superoxide anion production, 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. This is looking AT cells. So Dr. Angela Pove, 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 Seyfried developed. 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 metabolism, Tom Seyfford 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 2. That sets the stage, slows tumor growth and proliferation and makes the tumor more vulnerable to what I mentioned, hyperbaric oxygen therapy, but other cancer specific metabolic drugs. And we really want to try the PI3 kinase inhibitors that Lou Cantley is on. I just started listening to the last podcast, fantastic podcast podcast you guys did with him. We've been using two deoxyglucose which is basically also inhibits hexakinase and inhibits glycolysis. Three Bromopyruvate is something we want to use. We've used DCA metformin. 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 we're also interested in. And so there's all these things out there, but we haven't really put it together into a therapy. You need to test these things sort of in isolation and then combine certain things together. But how they all work together. The Press Pulse 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. It was Valter Longo study looking at fasting with IV vitamin C I believe. And it showed in Kras, basically tumors that are aggressive and very hard to treat, that had the Kras mutation. He had remarkable effects. It was a mouse study I believe and I still. It's on my desk. I got to read it 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, then fasting. I have to look at all the protocols that were used, but I think they use prednisone too. 40 milligrams per day, which is kind of high. But come to find out that can trigger apoptosis in 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, 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 authors pointed it out that the woman had. She had a couple of episodes, correct my pronunciation, myasthenia gravis. 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 of 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. She went down to £80. 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 want to call it, the tumor burden. They're measuring it in cubic centimeters. It slowly progressed. It was pretty stable. It looked, 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 different sized balls. And it looked like it went from a football to a golf ball or something to that effect, where it almost seemed like the ketogenic diet. I was wondering, it's almost 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 kg 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 somewhat similar. And so then you think the tumor cell part of the defense is the upregulation 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 effect of vitamin C and down to the redox pathways that I don't even think about it as an antioxidant anymore. We use really high concentrations. That's right. So hyperbaric oxygen. It's well known that radiation therapy kills cancer cells by 80 to 90% just through ROS generation, maybe 10, at most 20% just by directly nicking the DNA like double strand nicks. But you're generating reactive oxygen species. And then they are tox 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 and outstrip their 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. This is well known and accepted. But what isn't really firmly established is that if you have hyperbaric oxygen therapy before or after radiation therapy, like say you have hyperbaric oxygen and then you get out of the chamber and go have radiation, the P.O. the tumor will drop, but you'll have a residual elevation of reactive oxygen species for hours after 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 am 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 of 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 Fenton reaction. So if you remember biochemistry or organic chem. So the Fenton 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 and 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 dihydroascorbic 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 cel. So if you elevate vitamin C ascorbic 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. And in cancer cells, because tumors have a lot of free iron, because there's a lot of heme cells are necrotic cells are dying in tumors all the time just because they're 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 really, really high. And vitamin C is really sort of 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. We've published it in abstract form. I had a super awesome undergraduate, Janine de Blasi, who she did her honors undergraduate with me, but then went to Oxford to study cancer and radiation. And now she's at Moffitt Cancer center under a different mentor. But I would love to 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, 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 the teleology, but they're addicted to glutamine. I remember he did a paper recently. He has, like you said, the VMM3 glioblastoma mice.

Yeah, yeah. It's a glioblastoma that metastasizes, so it's transformed in a way to become highly metastatic. If you inject it into the flank, then you even have brain, meth, the 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. So I remember Tom told me, if you can cure cancer in this model system, then you've cured cancer. And we're still trying to do that because it's such an aggressive form of cancer. And we just published a paper. First author was my graduate student. He just graduated, Andrew Kutnik. And he demonstrated in that it's an amazing model to study cancer cachexia. 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. 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 cachexia, 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 this to Gary Taubes. Gary shared this with me where he said he was talking about the field of cancer in 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 Tom's mice. And Tom's like, I'll give him the VMM3s. You try curing 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 will 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. Glutamine antagonist. Glutamine inhibitor, yeah.

Inhibitor antagonist, yep.

Six Diazo, five Nora L, leucine, something. Something to that effect, right? Yeah. And it's one of those things, if you look at a Kaplan Meier curve, 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 at 100 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. Yeah, 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 Kaplan Meier curve 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 implanted, they're between about 15 days, all the mice are dead with a standard diet. And he's made some headway with the ketogenic diet and he says it's not a cure all. It's not. At least it's not curing 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 may be taking in oxygen, but it's not producing ATP via oxfos. It may be that the tumor's not just getting energy from the Warburg 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 in that class, which was really fun. I course director for 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 cancer as a metabolic disease. And big question I think that actually Peter gets, and I'm sure you get as well, is with all the stuff that you have going on, you're writing grants, you're doing this, you're doing that, you're teaching. How do you keep up with the literature? How do you stay abreast of everything? And he essentially has every one of his students come up 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 he might be fooling himself. It's pretty fascinating. Obviously he's very passionate about it.

Journal club is a good way to do that. And there is no lack of papers out there and brilliant scientists out there who, 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 of the tumor. Those needs need to be met. And the mitochondria are transformed into ways that achieves that goal. And of course, glycolysis is elevated tremendously. And then glutaminolysis too, drives a lot of the anabolic processes and also ATP generation too, 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 don on the standard diet at least. Again, we're talking about mice. 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 peek AMA episode of the Drive. If you're interested in hearing the complete version of this ama, you'll want to become a member. We created the membership program to bring you more in depth exclusive content without relying on paid ads. Membership benefits are many and beyond the complete episodes of the AMA each month. They include the ridiculously comprehensive podcast show notes that detail every topic, paper, person and thing we discuss on each episode of the Drive. Access to our private podcast feed, the Qualys, which were a super short podcast, typically less than five minutes, released every Tuesday through Friday, which highlight the best questions, topics and tactics discussed on previous episodes of the Drive. This is particularly important for those of you who haven't heard all of the back episodes becomes a great way to go back and filter and decide which ones you want to listen to in detail. Really steep discount codes for products I use and believe in but for which I don't get paid to endorse and benefits that we continue to add over time. If you want to learn more and access these member only benefits, head over to Peterattiamd.com forward/subscribe. Lastly, if you're already a member but you're hearing this, it means you haven't downloaded our member only podcast feed where you can get the full access to the AMA and you don't have to listen to this. You can Download that@peterattiamd.com members. You can find me on Twitter, Instagram and Facebook, all with the ID PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare care services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or Advise, please visit PeterAttiamD.com about where I keep an up to date and active list of such companies.

Sam.