Your heart and your brain love ketones, and many would argue that the brain and the heart function more efficiently off ketones.
Dementia, Alzheimer's, should you be on a ketogenic diet to prevent those?
Yeah. So, the evidence is, the strongest evidence would say that quality of life can be improved with a ketogenic diet. Yes. But not as a standalone therapy. So,
I see. What does the research say about the ketogenic diet and cancer?
The ketogenic diet can take the foot off the gas pedal of cancer growth and minimize cancer growth.
Welcome back to the Dr. Layne Norton podcast. Today I have a very special guest, my friend Dr. Dominic D'Agostino. Dom is a professor at the Morsani College of Medicine at the University of South Florida. Now, I have known Dom for nearly 20 years, and I met him on the bodybuilding.com forums, and we actually met for the first time in person at a conference called Experimental Biology. And we've been friends ever since. And we've had interesting career arcs because I went off into entrepreneurship and he became a professor, and we both came back together in 2018 as invites for the Joe Rogan podcast because, as you're going to see, Dom has done a lot of research on the ketogenic diet and low carbohydrate diet for various different metabolic issues as well as cognitive function, cancer. And so I wanted to have him on the podcast to see how his views have evolved over the last few years. And we really dug into some very interesting topics. Not just cancer, not just metabolic health, not just cognition, but we also talked about meathead stuff. So, I think you guys are really going to like this podcast. So, here's my interview with Dr. Dominic D'Agostino. Dom, welcome back, man. It's been a minute.
It's been a while. I think the, well, not the last time we were on a podcast because we did one since then, but some people, these young kids that may not remember, you and I were on the Joe Rogan podcast together doing a debate. We were doing the debate on low carb, low fat, and so I'm really interested to get into that and see how much maybe our opinions have changed over the years.
But first of all, I just want to kind of give you a chance to, like, how did you get into researching this? I mean, you're primarily known for research in the ketogenic diet.
And then also exogenous ketones. How did you get into researching this? Like, what was your path to where you're at now?
Yeah, it's kind of a circuitous path, I guess. As I was saying before we jumped on, I majored in nutrition at Rutgers, and it was kind of thought even back then, I guess now still, it's like a bit of a soft science. And then double majored in biology. Then went to neuroscience and physiology and then got a postdoc fellowship studying oxygen toxicity seizures and, you know, doing pharmacological research and testing different drugs for that. Those powerful tonic seizures were largely, you know, refractory to different drugs. You had to use a really high sedating dose of an anti-seizure drug. And then I observed in the literature that ketogenic diets were used for pediatric drug-resistant seizures. So I got interested in diet therapies again, and it really interested me how a dietary therapy could change the neuropharmacology of the brain in a way that could have an anti-seizure effect. So I pitched a ketogenic diet to the Office of Navy Research, part of the Department of Defense. They did not like the idea of a high-fat diet being used by the warfighter. The adaptation to the diet wasn't really logistically feasible with the mission requirements and things like that. So they said, 'Well, go research a ketogenic diet in a pill.'
So, and why were they interested in, why were seizures a thing for the military?
Yeah, sorry about that. So a limitation to Navy SEAL diving with a closed circuit rebreather is oxygen toxicity seizures.
So oxygen is a stimulant. We're breathing 0.2 ATA of oxygen now. In a hyperbaric chamber, that's 100% oxygen. And then you increase the barometric pressure to, you know, two, three atmospheres, and that saturates your tissue with oxygen independent of hemoglobin, meaning like your hemoglobin's, you know, saturated, but the oxygen is in the plasma. And that, you know, oxygen is a stimulant. So if the partial pressure of oxygen increases in the brain, that becomes a hyperstimulant, and then that can trigger a seizure. And using this specialized equipment, a closed circuit rebreather, there's no bubbles. There's a stealth component to that. So when you're underwater, you can't detect the enemy coming, but the oxygen is in a closed circuit. So it's scrubbing out the CO2, but it's in a closed circuit. And a limit, if a SEAL had to dive down to like 100 ft of seawater to plant a mine, that would trigger an oxygen seizure within like a couple minutes, right? So that's a limitation. It's also a limitation for hyperbaric oxygen therapy, right? So you can only cap out that therapy to about three atmospheres. Theoretically, if you could push that to five or six, you could save someone with carbon monoxide poisoning. Hyperbaric oxygen therapy has 14 different FDA-approved applications, but the limitation to that is oxygen toxicity seizures. Right? So the idea then is to create a neuroprotective anti-seizure strategy that could be administered orally and be active within 30 minutes. And essentially that's what different forms of exogenous ketones can do. And that's the preclinical work that we did, moved to human studies at Duke University, and now that's still an ongoing project.
Okay. So, why does the ketogenic diet protect against seizures? And does that just apply to seizures with divers at depth, or is that something, because you said you were looking in the research literature. And as I understand, one of the most well-researched applications of the therapeutic ketogenic diet is for like seizures in kids.
Sure. Yeah. It's a 105-year-old therapy developed at the Mayo Clinic by Wilder. So basically the idea that they knew for centuries, millennia even, it's like in, you know, the Bible, in ancient texts, that fasting could control seizures. And they observed in subjects that just ate fat with just a minimal amount of protein to prevent protein malnutrition, that the metabolic physiology mimicked the state of fasting. So they couldn't measure insulin stuff back then, but they measured the presence of these ketone bodies in the breath and in the urine. So mostly in the urine, and then later on they could do blood measurements. So it was a diet that mimicked largely the physiology of fasting, and by doing that, it also shifts, your brain has the metabolic flexibility to adapt from using glucose as an energy source to using ketones. And after, you know, 7 days of fasting or 7 days of a very restrictive ketogenic diet, you're deriving 50% of brain energy metabolism from ketone bodies, beta-hydroxybutyrate and acetoacetate. And also your peripheral tissues are using it. Your heart and your brain love ketones, and they function, you know, many would argue, and I think the science would support it, that the brain and the heart function more efficiently off ketones.
Meaning that, yeah, I was going to say, how do you define efficiency?
Well, it was defined very meticulously by the late Dr. Richard Veech, who was a student of Hans Krebs. He was like an early mentor of mine. He was at the NIH. I went to his lab and his whole career was like trying to convince people that ketones were a superfuel, and he had a DARPA project that was, I think, 15 million plus dollars.
And it was a warfighter dominance program. So that caught my interest. I have to admit, just going online, I discovered that. Whoa. So someone's studying these exogenous ketones, I could potentially use that for oxygen toxicity. And not only do they, you know, dull your senses and make you sleepy like anti-seizure drugs, but they can actually, they're being used or developed for warfighter performance. So I was like, 'Oh, okay. Let me switch to this.' So, long story short, I acquired that ketone ester and it didn't work for oxygen toxicity, but actually the late Patrick Arnold, who recently passed away unfortunately, helped me develop different forms of ketone esters that elevate both acetoacetate and beta-hydroxybutyrate in more or less a one-to-one ratio, and that had tremendous anti-seizure neuroprotective effects. So we muddled around with different formulations and then stumbled upon this diester formulation that was, when acutely administered within 30 minutes to an hour, it mimicked the fasting physiology of someone who's been fasting for like 7 to 10 days. Meaning the ketones were elevated to 5. Glucose went down sharply. In rats, it was like 160 and it dropped down to like 50.
So yeah. And there's reasons for that that we can get into. But so glucose went way down, ketones were up, ketones become the dominant fuel for the brain. And in that context, so in the specific context of an extreme environment where you're throwing a massive amount of oxidative stress on the brain, ketones shine. So, and that's kind of like if you have a deficit, ketogenic diets can be remarkably therapeutic and effective. And if you have an extreme environment, hypoxia or hyperoxia, in that context, ketones as an alternative fuel to glucose, as not an alternative but an additive fuel. So it's not like you're switching, some of the terminology that people use when they talk about this is like switching from glucose to ketones, but glucose is always there. There's powerful homeostatic mechanisms that maintain our blood glucose.
Yeah, because you've got, like, red blood cells have no mitochondria. They're 100% obligate glucose users. Like, there are, you do need a certain amount of, I think it's around 120 grams a day of actual glucose, which your body can produce on its own. You don't have to take it in, but...
So that became compelling to me. Those first experiments that we did, we replicated it, and then I think we have at least a half dozen different seizure models. So inborn errors of metabolism, you know, glucose transporter type 1 deficiency syndrome, PDH complex deficiency syndrome. We studied Kabuki syndrome, Angelman syndrome, Pompe disease, which is glycogen storage disease type 2. So all these things are remarkably responsive to ketogenic therapy. So that could be a ketogenic diet or exogenous ketone therapy, exogenous ketones. And I'm of the opinion that a ketogenic diet should be coupled with exogenous ketones to further augment that therapeutic efficacy. But a lot of people don't do the diet. So a lot of people are unwilling or unable to do a ketogenic diet. So exogenous ketones can come into play.
And something that I did 15 years ago that I would not recommend doing now.
Listen, kids. When testing these things, it was some compelling research that was done by George Cahill and Oliver Owen at Harvard Medical School in 1967, where they fasted subjects for 40 days and they injected insulin, 20 IUs of insulin, into fasted subjects.
Pushed their glucose to 1 millimolar, which is like...
You would never get this through an IRB.
Well, they... wow. I think they knew the members of the IRB. So, 1967.
Different time. And what would 1 millimolar be? That'd be like 38... no, it's like 18 milligrams per deciliter. Oh my gosh. 1 millimolar glucose. That's almost... you're almost dead.
Yeah. And in that context, because they were fasted, their ketones were elevated for 40 days. They were fasted. So these were obese subjects, heavy subjects. So they injected them with 20 IUs of insulin IV, pushed their glucose down to 1 millimolar, 18 milligrams per deciliter, and they were asymptomatic for hypoglycemia. So that was really interesting and compelling research. And like 15 years ago, I tinkered around. I won't tell people how to do this, but was able to lower my glucose to a point where the meter just would not measure it. It just flashed low. And I did it after fasting, but also did it in the presence of exogenous ketones, with the idea that you could rescue someone from a hypoglycemic event, right? And then these little mini experiments that I did were very, they changed the trajectory of my career from shifting from pharmacology research to more metabolism and diet and metabolic therapy research.
So there's two things here. First of all, this is so much in the vein of scientists in the 60s, 70s. I'll never forget Peter Garlick, who I think you met him, the late Peter Garlick, who...
Dr. Don Layman was my adviser, but Peter was kind of a co-adviser for me.
Protein tracer study. Like protein metabolism.
Just to study this, man came up with the methods that we use to study protein metabolism.
I remember because you mentioned Garlick, and that's his first name, Dr. Garlick, and I was like, I got to research this guy, and I was pretty blown away.
Yeah. So his adviser was a guy named, um, I want to say Waterlow. And Waterlow started on radioactive isotopes to study protein metabolism. I think they were looking at radio-labeled, I think it was, I want to say it was a leucine derivative.
And he wouldn't... now you hear radioactive and people get freaked out, but there's different levels to radioactivity. You know, you're getting a certain amount of radioactivity just stepping outside, right? Most of these radioactive tracers are used in a lab to measure protein metabolism. You could inject it right into you and you'd be fine.
There's a decay time too. Yeah, they decay fast. So he had injected himself because he was trying to mess with something, and he went through, he was traveling, he was going to Miami, and he developed an embolism from the injection. And so he's like sweating and looking all... and he tells them what he did, just very matter-of-fact, 'I was looking at these radioactive isotopes.' So they take him and they put, they bring out the whole deal, you know. Like so his whole weekend was him basically being quarantined, you know.
But this is, you know, and then some of the, a lot of muscle physiology was studied originally in the Nordic countries, and I mean there was a guy who literally just sliced open his arm and was like looking at different stuff. I can't remember his name, but like this is very, scientists are very inquisitive.
Yeah, I mean those little whatever, N-of-1 experiments, pet experiments lead to ultimately like smaller pilot trials and then funded projects ultimately.
In our lab. So yeah, but I needed some validation. The animal work is compelling. You know, rodent models are really good. So I mean, yeah, you study rodents. So for seizures, they're really good. For cancer, not so good. I think they're informative but not predictable.
Well, seizure models are great. One of the things I tell people is when it comes to animal research, it depends on what you're studying, what animal you're using, and how well validated the model is. When it comes to like for protein metabolism, the rat is actually a very good model. When it comes to like digestion, pig, very good model for humans. Now, I'm not saying all of it translates, it doesn't, but a lot of it translates.
And I mean, just, you know, my PhD research was all in rats, and that actually all that stuff got later validated in humans. So I don't want to say all of it, but the vast majority of it got validated later in humans.
It's a very basic fundamental process, and it's, you know, it's physiology.
Yeah. But when it comes to cancer, those sorts of things, I mean, I've always been very critical of longevity studies in mice and rodents because, you know, rodents have a very different growth curve compared to humans. You know, like humans, you kind of reach your peak in terms of mass-wise, you know, in your 30s and 40s, and with the obesity epidemic, it's obviously different now, but for a long time it was, and then you kind of started this slow, slow drip, right? Rodents grow the entire course of their life. Like it doesn't stop. And then if you're trying to like, you know, I know that paper in, there was a paper in like 2014 that got a lot of play was calorie-equated fasting, you know, 16:8 fasting. I'm like, but you realize that 16 hours of fasting for an animal is the equivalent of like 3 weeks in a human. Like these are very, like it's, and it's hard to, yeah, and it's hard to really like, how much does that mean? So IACUC, which is like the animal IRB, like won't let you go beyond 24 hours. We tried to do that. But with intermittent fasting, you just come in and you feed them. With caloric restriction, it's important to, unless you have a very diligent student that comes in multiple times a day, you essentially come in and put five or six grams of food. They eat it within an hour, and then the 23 hours elapse, and then they eat it again. So when you're doing caloric restriction studies in rodents, you're really kind of studying intermittent fasting because they eat it, unless you have a machine. Now everything's probably automated, but this was our situation when we did, because we published studies and they're like, no, you have to go back and do a control with caloric restriction because we saw some ketogenic diet effects. So when we do that, just observing, the rats would eat everything within like two hours. So they were essentially, it was caloric restriction with intermittent fasting. And yeah, that impacts cancer growth.
Yeah, that's how we had to feed our rats was we meal-fed them. We trained them to meal-feed. So there'd be three meals, and they, like you said, they would eat it very, very quickly. They were very well trained at that point.
You went in there and fed three times per day for...
100. Yeah. My last experiment was 110 rats.
Three, three. And these diets, these diets were not chow diets. I made these diets myself, right? Mixed them all myself and weighed them all out. So yeah, it was...
That's people watching this that...
Laborious. Yeah, full-time job.
And then I was weighing the animals every single day too. So I'm like taking them out of their cage, weighing them. Yeah, it was...
Layman was like, 'Yeah, nobody's going to be copying this experiment anytime soon.'
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Okay, I do want to touch on the neuroprotective effects. And so what's the mechanism behind that where when you've got oxygen toxicity or some of these issues that cause seizures, why is a ketogenic diet or ketones protective whereas, you know, glucose with those things causes a seizure?
Yeah. So it's not any one mechanism that really dominates. I think it's mechanisms and synergy, and I'll just mention the ones that we study. One, I mean, obviously, is the brain energetic mechanism. So in the context of a lot of oxidative stress and also neurodegenerative diseases and other neurometabolic pathologies, including inborn errors of metabolism, there's brain glucose hypometabolism. So, and that is, there's a governor that regulates glucose oxidation, the mitochondria, pyruvate dehydrogenase complex, also the glucose transporters for some inborn errors of metabolism, and also the GLUT3 transporter on neurons. So these can all come into play. So by feeding ketones, you feed an alternative fuel that could preserve and maintain brain energy metabolism in the context of impaired glucose metabolism. So that's one, and that's, you know, no one will dispute that, that's like old physiology.
So just to butt in, sorry, so because does it have anything to do with the fact that, okay, you know, oxygen's required for fat metabolism, you have a lot of oxygen present. I know nothing about this, so I'm very much simplifying. But glucose does not require oxygen metabolism. So there's something going on, is there something going on where, you know, the use of that...
Mitochondria in glycolysis? Yes. But in mitochondrial glucose oxidation, yeah, the mitochondria respire, right? But that's, you know, there's a lot of flexibility for fuel use, but yeah, for glycolysis, that's right. It's anaerobic.
Right. So you're providing this alternate fuel that basically allows the brain to get energy without triggering a seizure.
Yeah. It preserves the membrane potential in neurons. Membrane potential is like -60 millivolts. And you need a lot of energy, about, you know, the bulk majority of ATP in a cell is to maintain what's called the resting membrane potential. The membrane potential of cells, especially excitable cells like neurons and heart cells, the membrane potential basically sucks up most of the ATP, and you've got the ATP pump, you know...
Yeah, sodium-potassium pump. So that maintains the membrane potential, and that sucks up a lot of ATP. And if that membrane potential reduces, becomes depolarized, that activates neurons, they become excitable, and that can trigger a seizure. So if you get dehydrated, a cell that is not, a cell that's dehydrated is less energetic, and it basically can trigger a seizure. So if you are, you know, if you have any lack, your brain is extremely sensitive to the energetic state, and ketones can preserve brain energy metabolism in the context of low glucose, glucose hypometabolism. And so you have that going on, but you also have the conversion of more glutamate, which is an excitatory neurotransmitter, to GABA. And that happens because ketones, for reasons we don't fully understand, but there's people researching this, ketones activate glutamic acid decarboxylase, GAD65 and 67. And that, and we've replicated this in our lab, at least in mouse models. So it converts more glutamate, which is excitatory, to GABA, which is like, you know, GABA is a neurotransmitter that stimulates chloride-mediated postsynaptic inhibition, which it hyperpolarizes the membrane potential to make it more hyperpolarized, so away from depolarization. So you have more GABA, more energy, more ATP, more GABA. And you also have adenosine. That's something that we're looking at. But I think the literature would also support a reduction in neuroinflammation and seizures. A seizure can trigger neuroinflammation in the brain. If you have systemic inflammation, if you have an infection, if you have a virus, if you have an, like, you're going to get some degree of neuroinflammation that could give people a headache, could give people brain fog. And we know that neuroinflammation also triggers seizures too. So, and we published a paper in 2015 on the NLRP3 inflammasome, and the ketone body beta-hydroxybutyrate inhibits the formation of that inflammasome and also the activation of that inflammasome. And when that inflammasome is activated, it activates a cascade of inflammatory mediators including IL-1 beta, TNF-alpha, IL-1 beta predominantly. So that's three mechanisms there, but there are other mechanisms because ketones are ketones. These metabolites, not just ketones, lactate, these metabolites that are in circulation actually have their own receptor, the GPR109A receptor for ketones. They function almost like hormones.
Yeah. So, and I don't think people in the ketone world talk about it specifically, like ketones are like a hormone, but I think lactate, maybe even some of the amino acids, these metabolites in circulation have other receptors and signaling mechanisms that make them function as sort of a signaling role.
Well, it makes sense from a teleological perspective. I mean, leucine's this way, right? Leucine functions...
I didn't even think about that. Yeah, leucine is amazing signaling.
And, you know, you think about it from an evolutionary perspective, you would want to be able to sense what kind of state are we in, right?
And that's why you mentioned with ketogenic diet, but I say, you know, high-protein diet in some ways does mimic a calorie deficit because you're activating some of these things in the liver, you're up gluconeogenesis, glucagon's going up, like there's a lot of similarities here.
And I think, you know, being able to communicate between different tissues is, or to communicate to all the tissues.
This is the state overall that we're in. Okay, upregulate these things because, like for example, you have 20 amino acids.
For whatever reason, the body evolved to sense leucine as kind of the trigger for, okay, we have enough amino acids, enough essential amino acids, go run protein synthesis.
Right? If you have high lactate, that is indicative of a different physiological state, right? And so this whole milieu of metabolites, that completely makes sense to me that your body would recognize those. And then when it, I just want to put a bow on the discussion we had about membrane potential and everything. So for the lay people listening, essentially all your cells communicate with metabolites, with hormones, and also with electricity.
Electric, excitable cells. Yeah.
Right. And so if you, and that is very, that this is one of the reasons that sodium and potassium are so tightly controlled in the body, because if you get those things too high or too low, it will cause things to go awry very quickly.
And so maintaining a certain potential, as Dom said, is critical for those cells to function well. And if it gets too low, too high, bad stuff starts happening.
Yep. Yeah. So you could do different things like low calcium, high magnesium. So I trained as a patch-clamp electrophysiologist, which means like you have an electrode on a single neuron and you record from it, and you measure the action potential in current clamp, and in voltage clamp you measure like, you know, different currents and everything. So if we want to decrease the action potential, we do low calcium, high magnesium, and the magnesium sort of tempers down the NMDA receptor, it's called. So that quiets it down.
And that's also magnesium, if you take magnesium in the form of magnesium glycinate. So that does have a calming effect on the brain, and actually it's pretty good for seizure patients to take a relatively high dose of magnesium, to not be deficient in magnesium, that can actually cause seizures, but to actually supplement with magnesium too.
Yeah, it's good for sleep too. And magnesium, like you said, if you already have enough magnesium, adding more doesn't seem to do anything, but a lot of people are deficient in magnesium, so magnesium supplements are a good idea for a lot of people.
Um, okay. So, since we're on kind of neurons, I'm going to ask you about cancer, but I want to ask about obviously like when we're talking about this stuff, the people are going to ask dementia, Alzheimer's.
Should you be on a ketogenic diet to prevent those, or if you have those, is it useful to use? Like, what does the evidence say so far?
Yeah. So, the evidence is, as is always the case, it's ongoing. If you look at, you know, systematic reviews and meta-analysis, the data is pretty strong. These are not really top-tier large-scale randomized clinical trials, but there are randomized clinical trials on ketogenic diets and also on exogenous ketones, mostly MCT. There's quite a few studies on MCT. So pretty much any neurodegenerative disease is in some way pathophysiologically linked to brain glucose hypometabolism. So is it the chicken or the egg? So is the beta-amyloid causing, you know, the pathology that's impairing, you know, brain blood flow and the functioning of neurons in a way that's decreasing glucose utilization? So that's one argument, but the data is emerging to suggest that energy metabolism and neuroinflammation is sort of the initial cause, and the downstream epiphenomenon then is the accumulation of the toxic, you know, amyloid and tangles, you know, over time. So, but from a practical perspective, glucose hypometabolism is a hallmark characteristic of Alzheimer's disease, mild cognitive impairment. So that presents an opportunity then to give a metabolic-based therapy that could come in and rescue, well, people who study exotics say rescue, but sort of mitigate the brain energy metabolism bottleneck. And so you could preserve and maintain brain energy metabolism if you elevate and increase circulating ketones. And that does a number of other things too. It does. So when you have circulating beta-hydroxybutyrate, that increases cardiac output. So that will increase brain blood flow. It relaxes the vascular endothelium, new research is showing nitric oxide. But it seems to impact the endothelium in a way that could be the glycocalyx or something. But we observed this in our wound healing model, when you give it and you do a Doppler blood flow measurement, it's like, you know, 25% increase with acute ketosis. So that has been observed previously, originally in fasting patients and ketogenic diets, and now exogenous ketones. And interestingly, so there's two forms of beta-hydroxybutyrate. So this is a little bit technical, but maybe you'll appreciate it. So they're called enantiomers, the stereoisomers. So yeah, so you have the D-beta-hydroxybutyrate and the L-beta-hydroxybutyrate.
And I just want to butt in as somebody who did biochemistry and organic chemistry research as an undergraduate. There's a reason he's showing you his hands.
So enantiomers, they have the same atom-to-atom connectivity. So both these molecules are beta-hydroxybutyrate. But enantiomers are non-superimposable mirror images. Meaning my hands are the same, but I can't put them on top of each other and have them match.
And so there are molecules like that. In fact, the amino acids, all the amino acids that we take in, the natural form is the L-enantiomer, or isomer rather. There's also a D-isomer, but that is not what the body uses.
So there's a lot of interesting, Adam Hartman at NIH studies the D-enantiomer for epilepsy, like emerging research on D.
Yeah. Oh, interesting. So you were saying there's an enantiomer of beta-hydroxybutyrate, and so I'm assuming these enantiomers may have differential effects.
They do. Yeah. It is really interesting, and this is like I've kind of been on this, I guess, for, you know, ever since we've been studying, because we were looking at racemic beta-hydroxybutyrate, and there was some evidence from NIH and others that the D-form or the R-form, depending upon the nomenclature...
Chemists like to do everything like three or four times. There's a bunch of...
It's to make matters worse, like beta-hydroxybutyrate is technically not even a ketone, acetoacetate is, but that's another, because it was named by a physiologist.
Yeah, nomenclature in biochemistry is an absolute mess. If you look up any molecule, it has like five different names.
Yeah, it's nuts. So, yeah, we have the D-beta-hydroxybutyrate and the L, and they are enantiomers. They're mirror images of one another, and the D gets utilized as an energy source very efficiently, very rapidly. It gets burned as fuel very quickly and can energize cells. Whereas the L-beta-hydroxybutyrate, for reasons we don't fully know, if someone's on a ketogenic diet with elevated ketones, the heart has like 30%, 34% L-beta-hydroxybutyrate. So there's a racemase enzyme that converts the D over to L, or some mechanism that we don't fully understand, but L seems to be kind of important. But the L-beta-hydroxybutyrate is a little bit resistant to ketolysis, which means it doesn't get burned up as energy. So people thought it was like a useless kind of molecule. But come to find out, if you administer both of them, the D and the L, the L stays in circulation about four or five times longer. And there's also a four to five times increase in cardiac output if you administer the L over the D.
And that's because the L seems to retain for the most part the signaling properties of the primary ketone body. So it's sticking around longer. It can function more as a signaling molecule as opposed to just energy.
Yeah. So that's kind of like, you know, and everybody's, you know, people are scrambling to make patents on this and to make it like the drug form of beta-hydroxybutyrate. It's been around for a long time, and one could argue that your body does make it, and it seems to concentrate in the heart and some other tissues. And there's some really elegant studies published in the Journal of the American Heart Association, Circulation is one of them, where they administer this in pigs and the cardiac output goes up. I think there's a human study too.
So when you say cardiac output, what do you, what's the measurement they're using?
Yeah, just like the hydraulic efficiency of the heart, and they're looking at peripheral vascular resistance.
So the cardiac output will correlate to a reduction in peripheral vascular resistance. So peripheral vascular resistance is like kinking the hose, and if you unkink the hose, you...
have a bigger, you know, unrestricted flow, and the L-beta-hydroxybutyrate appears to be superior to that. And actually, who's the protein guy? Jose Antonio.
Yeah, Jose Antonio just published a randomized controlled trial using a small dose of ketones. It was something like three grams of L versus the D, and the L, I believe, was superior for reaction time, and they only used three grams. And he's typically a protein guy, so it was interesting to see that he published this, and it was more convincing coming from him, I think. So the L actually showed enhanced reaction time, and then the D slightly increased strength. I think they were both like a trend for increased strength, but the main effect was the L, this reaction time was increased in his study, and that was, I think, a 40-something-subject RCT just published, and it was in like an issue that has a DOI number. It kind of gets hidden, but that just came out recently. So, yeah, we have two different ketones. I favor actually taking both of them because you have the D that could be used as energy, and the L stays in circulation and has anti-inflammatory effects, maybe some vasodilation effects. And that's an emerging area of research right now, the two isomers. So, cool. Dr. Grove would be very happy with me using my organic chemistry isomer and enantiomer language.
I hated Orgo. I got through it and did well, but it was just tough.
It's tough. It's tough. That is what they call the med school filtration. That's where about 60, 70% of med students, if they drop out, they drop out in that class.
Or pre-med students, rather.
Okay. Want to talk about cancer?
Yep. So this is something that, you know, you were talking about 15 years ago when I first started doing camps and you came and spoke, and I remember everybody was getting their mind blown. I'm sure your kind of understanding of things has evolved a lot. What does the research say about the ketogenic diet and cancer, exogenous ketones and cancer? What's the strongest evidence here?
The strongest evidence would say that a ketogenic diet is feasible. Pilot studies show that it's feasible. Pilot studies show that quality of life can be improved with a ketogenic diet. There does not exist, to my knowledge, large randomized controlled trials, but if you go on to clinicaltrials.gov and type in ketogenic diet, you actually get over 500 registered clinical trials. So, you know, when I gave that camp, there might have been two. So we got 500 registered clinical trials, and of them, about 40 registered clinical trials are using the ketogenic diet as an adjuvant. There might be two or three trials using it as late-stage cancer for advanced metastatic cancer for quality of life. But for the most part, ketogenic, we now use, well, for grants we don't use the word ketogenic diet, we use ketone metabolic therapy because that can encompass a diet and a supplement approach. But the data would indicate that...
Yeah. Better get funded. So that's, we recently got an R01 grant, and submitted 30% the first time. That's pretty good for an R01. But an R21. So a ketone metabolic therapy would encompass just elevating and sustaining ketones throughout the therapy, and that could be done intermittently or continuously. And there's some evidence, a lot of evidence mostly in preclinical models, showing enhancement of, you know, it can enhance chemotherapy, radiation, immune therapy, including checkpoint inhibitors and CAR-T therapy. So some of these have then the preclinical animal model data.
So you're, sorry, just to touch on that. So you're saying basically the standard of care, that in some cases the ketogenic diet can improve the responses to standard of care.
Yes. But not as a standalone therapy. So it is not used, definitely not like part of standard of care, but studies have been done in the case where standard of care has failed. There have been trials with advanced, you know, metastatic cancer where it shows improvement in quality of life, and, you know, there was a lot of preclinical animal model data on a variety of different types of cancer. So those preclinical animal model data led to pilot trials showing improved quality of life and feasibility for certain kinds of ketogenic diets for certain kinds of cancers. And then that has moved to the use of a ketogenic diet as an adjuvant to enhance, you know, the standard of care, and the standard of care could be in the form of temozolomide and radiation therapy. And with the added benefit, if you have a brain cancer, then you have the brain cancer patients are always put on anti-seizure drugs. So you have the anti-seizure effect, you know, that's overlaying also the neuroprotective. So it's kind of protecting your normal brain cells and restricting, not eliminating, restricting and minimizing the growth of cancer cells that have a very high glucose dependency. So we call that the Warburg phenotype. So cancers that are more hot on an FDG PET scan, which is like a labeled glucose, and you can do a positron emission tomography scan to show if it's very hot and very, very high intensity on a PET scan, that cancer has, you know, accelerated glucose metabolism. What a ketogenic diet does...
Just going to step in real quick. So basically they have you drink a solution, right, that is labeled glucose. So we're talking about, you know, isotopically labeled glucose or whatever. This is, I think, different. But then they can put you on a scan and it essentially lights you up. Like if you have very, they use it to detect cancer because cancers in general do use more glucose than other cells. So they can detect tumors with it. But based on the intensity, you're saying, of how much you fluoresce or light up or whatever it is, the more intense it means that those cancers are using more glucose than your standard cancer and maybe more responsive to this. Is that about right?
Upwards to 10, 20, and even 100 times more glucose metabolism relative to the tissue around it. And that's why an FDG PET is a very useful tool for looking at the location and the aggressiveness of the tumor, and then also predicting its response to ketogenic therapy. So a ketogenic therapy then lowers glycolysis, and it also lowers circulating lactate, and lactate is an oncometabolite. So lactate levels correlate with cancer growth and metabolism. Makes sense because it's a product of glucose metabolism.
Yeah. But also glycogen, well, glucose, glycerol, amino acids, I think glutamine can also, you know, form lactate.
So, substrate-level, you know, metabolism, phosphorylation. So, you have the ketogenic diet can lower insulin and IGF-1. So that's one thing, especially if it's protein restricted. So it's lowering insulin, IGF-1, glycolysis, lactate, reducing inflammation, and elevating ketones. And then ketones, because they are metabolized exclusively in the mitochondria by certain pathways that are often defective or minimal in cancer cells, cancer cells, especially more aggressive cancer cells and many types of cancer cells, can't use ketones as an energy source. However, there is data, radiolabel data, to indicate that ketones could be part of the biosynthesis of certain, like the membrane and things like that. But I think Dr. Thomas Seyfried was the first to sort of pioneer this idea, and I think the data supports that ketones are a very poor fuel, if used at all, for cancer metabolism. And that is so the ketogenic diet can take the foot off the gas pedal of cancer growth and minimize cancer growth. And also the emerging research, most of the research being done now is showing the effect on the adaptive immune system. So natural killer cells are being increased, and that could just be by changing different parameters of our metabolic health can do that too, you know, with different types of diet therapies. So that was sort of my thinking, but then other data came in and showed that no, beta-hydroxybutyrate specifically tends to, for example, expand CAR-T cell survival and enhance various adaptive immune response parameters that can help people respond to things called checkpoint inhibitors and CAR-T therapy. So that's probably the most, you know, as of the last five years, and you look at ketogenic therapies and cancer, a lot of people are focusing on that, like using ketone metabolic therapies to enhance immune therapies.
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Yeah. So I have a dog in this race, or a dog in this hunt, because my mother has multiple myeloma and has had it for 11 years, and has actually one of the more aggressive refractory types of it, which just goes to show how tough my mom is. And she's gone through CAR-T therapy multiple times.
It was a while. I remember meeting with your mom.
Yeah. Yeah. You actually, you were the one who got...
It was 11 years ago on Thanksgiving when she told the family.
And yeah, like, you know, she had somebody at IU she went to, and he was fine. But then, you know, we felt like she got some advice that was a little bit too aggressive for where she was at. They were wanting to do a donor transplant, which has a very high mortality rate. And so anyways, you know, you linked us with Moffitt and Dr. Bose, and they have done just a fantastic job for her. So...
My mom is not ketogenic, but she does take care of herself. I think so, just not even pushback, just to contextualize. I think one of the important things to point out here is that there appears to be mechanisms by which the ketogenic diet can improve things. But keep in mind that a lot of times when we're looking at these things, we don't really have control groups because it's hard to do randomized controlled trials on this kind of stuff because you're literally dealing with people's lives. And so we can't... super hard... we can't be like, well, we're going to put people on this one healthy diet. People don't understand that. And then we're going to put the other, and we're just going to see who dies faster, like that. I mean, can you do that in drug trials? Yes. But those are with unproven drugs that you don't know, right? With diet, it's much more difficult. These are not just people who don't exist. These are somebody's mom, somebody's dad, somebody's kid, right? Like they're not waiting around. Gee, I wonder how I can help mankind the most. Like, I don't want to die, right? So it is hard to conduct these studies. And what we do know about cancer with nutrition that's very clear is that a Western diet is not the best diet, that's high in processed foods, high in calories, a lot of adiposity, or, you know, people who are overweight or obese have lower survival rates with cancer, more likely to get cancer. If you have a healthy diet, if you maintain a healthy body weight, if you have good body composition, especially good skeletal muscle mass, much in fact, skeletal muscle mass, much more likely to survive cancer. It is one of the biggest predictors of cancer survival if you have more muscle mass. All that being said, from my understanding of things, you know, you'll have people say something like, I see this content sometimes, the Warburg hypothesis says this, and they've been hiding a cure for cancer, or the cure is the ketogenic diet. But my understanding is one of the hallmarks of a lot of cancers is that they are very adaptable and they can find different substrates to use, amino acids, maybe ketones in some specific instances. And I think, would you agree with this statement that people say cancer is not one disease, it is a group of diseases that result in one commonality, which is uncontrolled cell growth, but the things that cause it, contribute to it, and help it grow can be vastly different between cancers.
So, when people say a cure for cancer, I don't know if we're ever going to find like a cure broad across the spectrum, but we'll probably find a lot of therapies for individual cancers that will work well. So, all that being said, are there some cancers that respond better to ketogenic diets than others? Are there some that don't respond well to it? And what would your best recommendation be?
Yeah, I mean, I'm glad you brought that up because sometimes people who get cancer think that it's something that they did, something that they caused. So there are many... and there's a lot of shame out there that gets dumped on cancer, but well, what do they do? Well, do they do, well, they drink Diet Coke or they did this or they... and it's...
I understand what people are doing. So, I'm sorry I cut you off, but I think this is very important because it makes me upset where you're going with it. Because you're already fighting for your life and now you're being told it was your fault. And the reason it happens is people want to rationalize they got it because of something they did because it makes them feel better that, well, it won't happen to me. And the reality is a large percentage of cancers are genetically driven. A large percentage are environmentally driven, that are environmental things possibly outside our control. Your genetic predisposition is probably huge. And there are some things that are...
And there are some things that are... yes. Like if you were overweight or obese, higher risk of cancer. If you have poor metabolic health, higher risk of cancer. I actually don't know the direct citation, but I'm pretty sure that's true. But yeah, just because you get cancer, it doesn't mean that you did something. Like take the BRCA gene for instance. If you test positive for the BRCA gene mutation, basically they say just get a mastectomy now because you're going to get cancer. It's like a 99, I think it's like a 99%. If you've got a certain mutation, this isn't cancer, but like with Alzheimer's, you have an APOE4 mutation. Screen, get checked. I mean, you got to be on top of that. So, there's no way to prevent cancer, but screening is probably the important. So, emphasize screening.
The American Cancer Society came out. They have a flagship journal. It's an over 500 impact factor. I didn't even know that was possible. But they did...
Yeah. They did a very, very comprehensive review on preventable risk factors for cancer. And of the 12 you could like directly, I think nine of them you could directly link them to metabolism. So, you know, obesity, type 2 diabetes, even things that were loosely like H. pylori, like that were...
Yeah, that's actually true. So there's, um, viruses can cause cancer.
I was going there. So viruses too. Epstein-Barr, cytomegalovirus, herpes simplex virus, HIV, Kaposi's sarcoma is associated with that. So, yeah, a lot of viruses too. And also, I mean, there's evidence that ketogenic therapies can reduce viral load and also various infections like Lyme disease is almost completely glycolytic. So if you're in a state of ketosis, it can, you know, Borrelia kind of thrives off glucose and inflammation. So, but interestingly, like, you know, we like to study brain cancer, and for people who have brain cancer, for the different types, so just going back, so the preventable things, so that, you know, diet and exercise and just metabolic health are very powerful preventative for GI cancers. Liver cancer since 1980, it's went up three to fivefold. Liver cancer since 1980...
Three to, yeah, at least three times. I think it's more since 1980, it's like five times higher, so liver cancer.
So, GI cancers are on the rise. Colon cancer, especially in young people, on the rise. That's up like three times in the last 40 years, like three times higher.
You can probably directly trace that back to the, you know, fiber and processed foods and blood glucose and...
I think so. Yeah. And endometrial cancer, even like lung. So there are, you know, there are ways if you stay on top of your metabolic health, the diet, exercise, these are things that can help prevent cancer. And then screening. So that's important to put out. But for things like glioblastoma, brain cancers, some of the things that we study, there's no indication that there's any way to prevent them, and they tend to happen like in people that are like super healthy, right? I mean, the only things that they show in the literature, and it's very loosely tied to like radiation exposures and environmental conditions, and maybe so there's cytomegalovirus, there's a drug, valancy, where that was given to GBM patients and they survive like two to three times longer with this drug for, I could be getting the name wrong, it's val...
Valganciclovir, yeah, for glioblastoma. And it's like everybody was like in shock, and it came out in a legit high-impact journal, and now we're trying to replicate the data. And, you know, Thomas Seyfried talked about, you know, he has, you know, cancer as a metabolic disease and showing things that can attack the mitochondria. And many of the viruses that cause cancer, they not only impact the nuclear genome, but the mitochondria take the biggest hit.
Yeah, because mitochondria has its own DNA.
And there's components of the mitochondria that are very sensitive to viral load, the inflammation that the virus causes. So you have progressive mitochondrial damage by these viruses triggering an energetic crisis. The nucleus can sense the energetic crisis, and that's the retrograde response. So the nucleus talks to the mitochondria, and then that can kick on oncogenes, and the oncogenes are basically the cell survival hardwired system, and that gradually converts a normal healthy cell to a cancer cell if it activates the complement of oncogenes, then when it starts dividing. And so that's the general sequence of events, and then the cell eventually shifts from oxidative metabolism to more glycolysis over time. And there's a lot of details that I skipped there, but that's the essence of it, is that there are various things in our environment, could be toxins, radiation, but also viruses. And I think Epstein-Barr, cytomegalovirus, like...
So like if you have, you know, a viral load and you have, you know, Epstein-Barr, I mean, I think taking an antiviral, if you have like shingles and things like that, I think it's a good idea to get the shingles vaccine or to get various antiviral drugs. Well, now they're saying they might be able to basically not completely get rid of, but like I think like cervical cancer, you know, getting the HPV vaccine.
I forgot to mention that.
Yeah. Oh, yeah. If you like, it is very most...
I feel comfortable in saying that most cervical cancers are from HPV.
And so like if you're a young person, you should really just get that vaccine.
Absolutely. Like you really just should, especially before you become sexually active. I realize we're talking to a very small percentage of my population right now, but parents, if you have kids, I feel very comfortable in saying that that will save a lot of lives.
And what you said about screening, I'm just going to tell a story real quick because, so our friend Ted Fletcher, I don't know if you remember him, friend of mine from college. So Ted had back pain for a long time. Couldn't figure out what it was. And he'd been having it for like six months, like really bad back pain. And finally a really good physician said, 'You know what? It's probably not this, but why don't we get a PET scan just to rule it out?' And he lit up like a Christmas tree. He had stage 4 non-Hodgkin's lymphoma.
And fortunately, Ted was young, strong, had a lot of muscle.
And they were able to treat it very aggressively.
Healthy and with a lot of muscle. Doctors look at you and they're like, 'We can blast this thing.' Yeah, we can. The standard of care is much more effective and way less likely to give you negative side effects when you have more muscle. Muscle, the research that has shown this, I'm sure you've seen, is very clear that muscle is so protective when you have cancer.
And so Ted survived and has been cancer-free for, gosh, it's got to be 15 years. But my mother remembered his story because he told her this story at dinner one night. Years later, my mom's having upper back pain and she went, she got an X-ray done, she got an MRI done, and she goes, 'I want a PET scan.' And they put her on, that's how they found her multiple myeloma.
Oh, really? I didn't know that.
That's how they found it. And what I would tell people is, if there's something that's going on and you feel off, you have pain that doesn't feel right, you have, you know, something's going on. If you're in touch with your body, you know your body, you know something's not right, go get screened.
Go get screened. Most likely it's nothing, but it may, if it is something, that may save your life because so many of these cancers, there's even, I mean, pancreatic cancer is considered one of the worst, but if you catch some of these cancers early, a lot of them, I would say even most of them, are treatable and curable, especially with today's treatments that they have. But you got to get, if you start to get to like stage three, stage four, once they've hit the bloodstream and they've got their own vascularization and everything, it gets much, much more difficult.
Yeah.
Yeah. I mean, driving over here, there was a discussion about GRAIL, so the blood-based system that takes your blood and actually can identify, you know, cancer cells. And the advantage of that, I mean, it could detect if you have cancer or not, but a variety of different types of cancer. So the origin of that cancer and the cell type. So they can go zoom in, for example, on the kidney, on the liver, or something like that. And I do think that that's the future.
So you just take a blood test and be able to find it.
Yeah. So GRAIL is, you know, it's rapidly advancing with AI analytics too, I think is helping, but the sensitivity and specificity is getting higher. Five, ten years ago, not so much, but I think it's evolving to that. There's also like, you know, whole body like prenuvo body scans and things like that that people can consider, especially if you're like over 50 and you want to get like all these tests and something just doesn't feel right. They're kind of pricey, about $2,500, but and then you have the risk of false positives too. Go in there and do some intervention without it. But I think there's emerging, you know, screening technologies. And now actually my wife did, she did, now they have an ultrasound instead of getting a mammogram, they have high-resolution ultrasound that can look at the breasts and look at other tissues that are, you know, five years ago they weren't up to snuff, but now, you know, now they're actually approaching that of, you know, the standard tests. So different tests that less radiation and things like that. So, yeah, but screening, there's no way to cure cancer as of now, but screening, getting it early is one way to do that.
Yeah. So I'm sorry, we took off a track. We talked about glioblastoma. Are there other cancers that you would consider pretty responsive to ketogenic diet or ketones?
Yeah, I think I would say like probably more than half of them. So endometrial cancer, different GI, pancreatic cancer, lung cancer, which is something that we're initiating a trial on, kidney cancers, maybe different types of sarcomas, but they're not known yet. Of course, different types of brain cancers, and there's, you know, there's different types of brain cancers, and they're kind of like the low-hanging fruit. And we tend to focus on things that, cancers that the standard of care is not good already, right? I mean, but for multiple myeloma, for blood cancers, lymphoma, leukemia, yeah, breast cancer is one too. I think there, breast cancer, well, for screening is important too, but breast cancer is also in that group. And there's so many different varieties of breast cancer, right?
So that needs, you have to consider the health of the patient, this for diet, well, standard of care and dietary therapies, the health of the patient, the tumor type, and their ability to just like follow a ketogenic diet, you know, and just a dietary therapy as an adjunct. So these are all things that need to be considered that we have to consider for a clinical trial, but for, you know, oncologists too.
So my next question is, how do you balance the benefits of a ketogenic diet or fasting with the risk of cancer cachexia and knowing what we know about muscle and its protective effect? How do you balance those two things?
Yeah. Well, I think first and foremost, you don't really consider a strict dietary protocol, a ketogenic diet, if someone is like really low weight, like under a BMI of 19. So that kind of excludes them from like a trial that something like we would do. But protein is central, right? And then muscle is going to be, so muscle, if there's any activity that they can do, they need to prioritize protein and some form of activity. Doesn't have to be exercise. It just has to be physical movement to maintain and preserve that muscle. Super important. And yeah, so cachexia is different than sarcopenia, but with cancer typically you can get cancer-induced cachexia, and then you can have chemotherapy-induced muscle wasting layered on top of age-related sarcopenia, you know, and low appetite.
The anorexic effect of the chemo and then the immobility of being bedridden. So all these synergize together for rapid skeletal muscle wasting. And once someone becomes immobilized and they can't move around, then that's tightly linked with poor outcomes. Like that's really hard to recover from that. So preserving and maintaining muscle is probably the most important thing for a cancer patient. And especially like, I mean, we're doing a clinical trial on lung cancer. Lung cancer is pretty heavy. You know, cachexia, there's certain types of cancer like pancreatic cancer. Different types of cancers are more tightly linked to cachexia. So we do know Dr. Andrew Kuczynski's work was actually looking at ketone therapy in the form of exogenous ketones mitigating cancer cachexia in our metastatic cancer model. So proven to be effective in that preclinical model. And that was published in the Journal of Cachexia, Sarcopenia and Muscle. Good journal. He did a lot of studies, a lot of supplementary data associated with that. In addition to that model, he did a second model of injecting lipopolysaccharide, LPS. So LPS causes massive systemic inflammation, and that causes anorexia and muscle wasting. And he was able to largely mitigate a lot of the muscle wasting and inflammation. The inflammation is kind of like the driver for the muscle wasting. So you get inflammation from cancer with TNF-alpha. TNF-alpha, the original name for that was cachectin. So that was named cachectin, then later named TNF-alpha. So with cancer you have these bursts of inflammatory cytokines that cause muscle wasting, and then the inflammation, and then the poor nutrition, the immobility, all these kind of synergize. So dietary therapies can lower inflammation, improve metabolic health, and that improves insulin sensitivity and helps preserve skeletal muscle. But also the ketones, if we fasted for two weeks and we didn't make ketones, we would catabolize skeletal muscle. We would liberate alanine and we would liberate a lot of glucogenic amino acids to preserve glucose homeostasis. So what the body has evolved to do is to enhance beta-oxidation of fatty acids. Even a lean person has like 20,000 calories of fat on them to liberate the fat, convert that to ketones, these water-soluble fat molecules that can then preserve and maintain energy to the brain without catabolizing skeletal muscle. So if you come in with ketones, which may actually have some anti-cancer effects, but it's also preventing the skeletal muscle catabolism. Ketones are not anabolic, and well, there's one study that shows that it preserves leucine...
Yeah, actually the IV infusion showed that it preserves branched-chain amino acids in humans.
But so ketones, we think of them as being primarily anti-catabolic, especially in the context of muscle wasting and cachexia specifically. So that's where I think it's beneficial.
And I mean, when it comes to cachexia as well, I mean, there's also evidence that the proteasome becomes overactive and protein degradation is very well elevated. There's actually some research, and like, I'm not a big fan of HMB anymore, but if there is strong evidence for HMB, it's actually in cancer patients. I think in situations where protein degradation, specifically the ubiquitin-proteasome system is upregulated. So, just for those out there, if you're interested, the proteasome is this big barrel-like complex, and ubiquitin is a protein that gets tagged on proteins that are old, need to be degraded, broken down. And so when they get tagged with ubiquitin, usually polyubiquitinated, usually multiple times, the proteasome targets them, breaks them down into their constituent amino acids, and those amino acids can be recycled. And in cancer specifically, the proteasome can actually be overactive, especially in skeletal muscle, and again contributes to this. You have inactivity, anorexia, where people are not hungry at all, especially with some of the standards of care, some of the downsides to those. So yeah, protein-centric.
Can absorb, like, so if you're, you know, inhibiting rapidly dividing cells with chemotherapy, that's your gut cells too. So it inhibits...
Absorption. That's a big, big problem. So yeah, TPN, you can do TPN, but then that's difficult because it prevents as much activity.
There's a lot of things that go into this, and I think one of the things I would, I want to get your take, and I think that you'll probably agree with me, is what you choose to do depends on, it's going to depend on a lot of factors. And you cannot make blanket statements like, well, if you have cancer, go on the ketogenic diet or this is the best diet for you. If you are somebody who is able to be active, you can stick to a ketogenic diet, you can do that, you have a cancer that responds well to that, and you are able to keep your protein up, you're able to keep your calories up, then that may be a very good choice for you. If you're somebody who's relatively frail, you don't have a lot of muscle mass, you are feeling very anorectic, you're not able to get in much calories on this, then I'm sorry. Yeah. Protein shake and ice cream might actually be a better choice for you. Do you know what I'm saying? Like when it comes to this kind of stuff...
Instead of protein shake, I would say like a whey or whey isolate.
With, you know, MCT, you can mix it like an MCT powder and mix that up. And...
Yeah, I mean, whey has everything that you really need, and then maybe some lipid formulation that's not going to spike as much as your glucose and insulin. So keeping insulin, glucose, lactate as low as possible, but most importantly, just your, like the same thing that's healthy for your cardiovascular, emphasize, optimize your cardiometabolic biomarkers and your body composition, and that's going to be the big lever that's going to help you get through, you know, cancer.
Absolutely. And I think we'd both agree that like prevention or the state you were in when you, again, Ted was a healthy guy, had great metabolic health, everything going for him for...
Right, because what happens oftentimes is people get to 50, 60, 70, or they're younger but in very poor health, and oncologists will look at them and go, well, we can't blast them with treatment the way we can blast a healthy person because they're not going to survive the treatment.
I've seen it. I've seen people killed by the standard of care. I mean...
It's toxic, and you know, I mean, I think my colleague Thomas Seyfried would argue that a large majority of cancer patients are killed by the standard of care. You know, I mean, they're going in with a Hail Mary...
To be fair, they would have probably died from the cancer.
Yeah. Yeah. But in an effort to save them...
The chemo can kill them as well.
Yep. And it's a hard kind of trade-off, and you have to kind of look at the more information we have. And I do think AI is advancing to the way where it's starting to make decisions and identifying this drug and that drug. We didn't talk about, there's the ketogenic diet, but what we're doing is actually a very comprehensive, like the future is like metabolic-based therapies where you have a whole toolbox of metabolic drugs. We don't have time to get into it, but things that, I mean, you know, metformin, for example, it's used in over 200 clinical trials for cancer, and it seems to be a good, you know, adjuvant. But you have even drugs I don't know, talk about, but like mebendazole, ivermectin, glycolysis inhibitors, glutamine agents that can lower glutamine like 6-diazo-5-oxo-L-norleucine, also has some...
epigenetic effects too. So there's an hyperbaric oxygen. So that's a little bit harder to implement, but it tends to synergize. Well, it actually is if you have radiation therapy, hyperbaric oxygen would be covered by your insurance for radiation necrosis, but it sensitizes the tumor to radiation.
Yeah. I think again my the advantage my mom had like genetically she has all the disadvantages of multiple. She has the more aggressive form. It's more refractory to treatment, all those mutations. But my mom was active and very healthy when she got it. And her doctor, her oncologist said, "Your biggest advantage is you're going to be able to tolerate the treatment that we're going to give you."
If you were frail or if you were obese or if you had any of these co-orbidities, most people multiple myeloma specifically is a is a more later in life cancer for most people. And typically in people who are obese actually it's it's usually more of a obese cancer.
Um and so it is hard for those folks to tolerate some of those really hard treatments but my mom was able to do it.
And again like I have a I'm writing my first book and I have a figure in the book of uh long-term cancer survival probability
with high muscle versus low muscle. They separated into quartiles. So the top quart so the top 25% of muscle versus the bottom 25% on a 10-year survival probability is double the survival chance if you are in the highest quartile the top 25% of muscle mass.
Yeah, going into the cancer if you when you get diagnosed with cancer.
It is basically a linear association with your probability of surviving.
Yeah, you cannot overstate that. I think that's like such an important thing for people to consider and then you know when they get cancer and they're already like you know pretty frail to begin with and that you know that the time to start is now. Now build build your muscle currency, you know, and deposit it in the bank and just get just build as much resilience as possible because something's going to creep up on you whether you're not neurodegenerative disease, cardiovascular or cancer.
And muscle protects against all that all that like there's there's like a
I think it was something like um people with more muscle mass have a 68% lower risk of Alzheimer's and dementia. Um there's and this just muscle is a very inhospitable environment for disease on a per weight basis.
I believe sarcomas or muscle cancers are the lowest.
They're very rare. Especially when you consider
Yeah. But especially when you consider the fact that muscle skeletal muscle is one of your
If not the largest tissue you have mass-wise.
Uh pretty close to it for most people. Yeah.
So the fact that muscle cancers are relatively rare is pretty surprising. But when you understand the the microenvironment of muscle cells, they're very different than other cells. And not only that, but they send out myokines.
Which there is good evidence that those are anti-tumorigenic as well.
Yeah. Yeah. I mean it's it's muscle is an endocrine organ and you stimulate your releasing factors. And um I just think if if I have uh I like I like active recovery because if it's it's a day that I'm like sore from deadlift or squats or something like that and I just get moving and just start, you know, go for a brisk walk or something like that, I just feel like I'm clearing out.
Well, the research actually supports that active recovery is better than passive that it's it's better.
Yeah. I mean, I'm a huge fan. I mean, I just do that just working around the the farm and stuff, but that's is like crazy because if I just sit around all day after like a really heavy session the day before, I just feel like I'm just wasting away like it's accumulating like toxins in my muscles.
So, for those who don't know, Dom is kind of a true Renaissance man because he lives on a farm. He is a very very well-known scientist uh very successful in uh research and also strong as hell. Uh, I've seen this man deadlift 700 lb so many times in the gym wearing blue jeans after fasting for 48 hours
Coming from work. Yeah. Just popped by the gym. Yeah.
You're in there for like two hours ripping 700.
You're there for 30 minutes. Yeah.
Um, so now I you mentioned this in the lead in here and I wanted to talk about this because do you think there are any how do you think muscle hypertrophy
Segues with like fasting and the ketogenic diet because you have your own experience with this and I I'd be interested to to hear your take on it.
Well, a ketogenic diet is not optimal. Like, if you have a if you're in the, you know, if your goal is maximal muscle size and strength, uh, a ketogenic diet can, you know, result in some muscle gain and strength over time, but I think restricting carbohydrates is going to reduce the anabolic response to some degree, which would largely be dependent upon protein. And I do think that you could switch out carbs and fats and be fine. And especially for someone like my age where I don't really don't aspire to be, you know, as big as I was, as strong as I was back in the past. But uh but yeah, I I think where ketogenic low carb diets shine is for body composition alteration. So, I do think that you could uh and it could and maybe we could debate this, but I think if you're if you've bulked up and you you want to do a recomp, I do think a low carb ketogenic ketogenicish diet uh could be superior for many people for body composition alterations to preserve muscle and maximize fat loss. Uh maybe you could debate that, but I do think that that a well-constructed high protein low carb ketogenic diet is optimal for recomp. Uh and I think the added benefit is that if you have elevated circulating ketones, that that diet has uh an appetite suppressant effect. And it might not be the ketones, but I think it could be the protein, maybe the fat, but also I'm in favor of fiber, too. So, uh, high high to moderate protein.
Moderate to high fat and instead of carbs, I just think of fiber, you know, like broccoli, salads, blueberries, I pretty much have every night. So, I I could do a diet like that and kind of And I've strayed away from a strict ketogenic diet because
So, you're not worried about the toxins in plants then?
No, not me. I've never I've never seen any kind of broccoli study that shows other than gas maybe other like a negative outcome. Uh but for like you know if you do the FODMAP diet
Yeah. Yeah. And in fact honestly I think so many people who go carnivore and feel better they had some kind of FODMAP sensitivity and what happens is they essentially did an elimination diet stop being so gassy and bloated and having these GI symptoms and felt better. But the idea is with a elimination diet that then you start adding things back in because I think you and I would both agree that one of the best dietary like dietary components that you can eat is is fiber.
And especially like prevention of cancer uh even even people who have cancer.
