About the guest: Dominic D'Agostino, PhD is a researcher and professor at the University of South Florida, where his lab studies metabolism, human biology, and related subjects.
Episode summary: Nick and Dr. D'Agostino discuss: ketosis and the ketogenic diet; effects of ketosis on diabetes, insulin resistance & metabolic health; effects on brain & mental health; relationship with exercise performance; cholesterol, LDL, triglycerides & other biomarkers; cancer; and more.
*This content is never meant to serve as medical advice.
Support M&M if you find value in this content.
Full audio only version: [Apple Podcasts] [Spotify] [Elsewhere]
Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Dominic D'Agostino 2:24
Sure, I am a professor at University of South Florida Morsani College of Medicine. I did my undergraduate in nutrition science and biology. And then I studied neuroscience and physiology with a focus on the neural control of autonomic regulation for my PhD, specifically in the context of the hypoxic response or response hypoxia. And then, as a postdoctoral fellow, I studied extreme environments. And then in my I have a more general kind of education background as a professor, I teach neuropharmacology. I teach nutrition, I teach physiology. And I teach medical students, PhD students, masters students and honors undergrad students. And I do about 50% teaching 50% research. And yeah, run our research lab and do teaching.
Nick Jikomes 3:23
What uh, what do you work on in the lab these days? What's the focus? Yeah,
Dominic D'Agostino 3:28
we have a lot of different projects. I should mention also cancer research we do. The last conference I came from was on an inborn error of metabolism called glycogen storage disease. Type two, which is also good Pompe Disease. There's a number of these inborn errors of metabolism, that these disease processes are highly receptive to ketogenic interventions that change metabolic physiology, brain energy metabolism. We've studied glucose transporter type one Deficiency Syndrome, Kabuki syndrome, which is a genetic disorder disorder, where the ketone bodies app act as epigenetic regulators on gene expression. I've studied Pompe Disease Angelman syndrome, I guess, I guess what you could say what pays the what has paid the bills in the in the lab and allowed me to expand into different applications is navy funding to develop ketogenic strategies to enhance warfighter resilience in extreme environments. So that would be like high oxygen environment associated in a high hyperbaric pressure environments. So we've I've worked in the capacity of looking at nanoscopic changes with atomic force microscopes to laser confocal to my study Use rat studies, collaborative pig studies, human studies where I've been a subject living in a hyperbaric environment, underwater for 10 days where I'm the subject. And I do research on astronauts because they train in these extreme environments in isolated extreme environments for their preparation for the space station. So that would be NASA's extreme environment. Mission operations are Nemo 22, and my wife was on Nemo 23. So we've studied everything from the mitochondria to like, the whole human and everything in between, or extreme environments,
Nick Jikomes 5:35
when you're in that hyperbaric environment. What what's it like? What happens? What are some of the the adaptations of the human body when when someone goes into those conditions?
Dominic D'Agostino 5:44
Yeah, you know, it's, you know, the human body is incredibly adaptable. I teach nutrition. So it's amazing that like, we can adapt to so many different nutritional things to eating just underprint plants to 100% meat. And it is remarkable how adaptive we are. Yeah, I was gonna say at least in the short term, but in the relatively long term, to changes in the composition of gases and pressure. So I was in the Aquarius habitat, which is off of the keys and Isla Murata about five, six miles off. And it's a it's it's a submerged habitat, that's down to about almost three atmospheres of pressure. So unlike a submarine, which stays at one atmosphere pressure, the submerge habitat for training is about three atmospheres of pressure. And then you can go outside of that, and do work. And that's that's called like EBA, or extra vehicular activity. If you're on the space station, and you go outside to Space Station to work on it, that's called an eta. So you get like, suited up to do EBA is to do different work things. So we measured, some of that's published them, it's not. But we have, for example, we were like the aura ring. So we look at sleep. Look at HRV, we were the polar v 800. So we get a little bit higher HRV. We look at the microbiome, how the microbiome changes and extreme like skin microbiome, the microbiome of the underwater habitat, which is kind of interesting. We look at blood, we do blood samples of like hormones, hscrp Different things like that we oh, we do my wife's a behavioral neuroscientist. So we look at stress. So we look at stress hormones, like cortisol, but also look at like, the impact of how allostatic load impacts, like different stress. So that we use like NIH toolbox, we look at depression, anxiety, you know, Gad seven, PHQ. Nine, we look at sleep. And then we do we'll actually take like, what's it called an iPad that's suited for underwater applications. And I dive I think they call it so we take the iPads, outside of the dry habitat, which is under pressure in the wet habitat, when we're all suited up to do the VAs. And we'll look at like reaction time and how, you know, this amount of pressure is impacting reaction time decision making a whole host of different things. We look at taste receptors, you know, it's because, you know, taste receptors can change under hyperbaric pressure. And of course, NASA has all their things. So actually, it's to vet out different procedures, different tools, for example, like we tested drill underwater, we go out and collect different corals like siter, Astria, and different like corals that may be endangered, and we bring them back. And we have a mini DNA analyzer and sequencer where we look at like, you know, the actual species, and then we actually go back and plant the corals and like a coral nursery to propagate certain species. So they like put us to work under there. But there's a whole host that's just like a little sample of objectives that we have. I'm more of like the biomedical guy, but then we have like engineers, and, you know, environmental biologists and stuff working with us, in addition to some of the top NASA astronauts, actually Buzz Aldrin, like, signed, right above my bunk that I was sleeping in. And so, so we've had some, like, you know, pretty big astronauts on those missions. So it's, it was really a, an amazing experience, you know, to work in that environment. And
Nick Jikomes 9:36
so, it sounds like there's a tie in here for for ketosis and the ketogenic diet. So when can you give people just a very brief overview of what ketosis is, and how you start to think about why changing your metabolic state like that would tie into, you know, making you more resilient in certain environments?
Dominic D'Agostino 9:54
Yeah, it's kind of a little bit counterintuitive, but I guess I'll start from the context of fasting. And we've known from millennia that when our bodies in a fasted state that can actually control seizures. We've known this for quite some time. But we didn't know the mechanism for how it does that. Right? So, you know, in the 1920s, the ketogenic diet was developed as a therapy for seizures, independent of the etiology of the seizure, being in a state of ketosis, provided an anti seizure effect. And a ketogenic diet is one that has a macronutrient ratio that is primarily fat, and has an adequate amount of protein to prevent protein malnutrition. So just enough, but not too much. It's kind of somewhat protein deficient actually. And essentially zero carbohydrates or maybe some indigestible fiber, you know, soluble and maybe insoluble fibers added to more like engineered ketogenic diet nowadays. So when when we eat that that has little or no impact on the hormone insulin relative to the fasting state, so it stimulates fatty acid oxidation in the muscles and in the liver. And beta oxidation of fatty acids in the liver contributes to the generation of ketone bodies, which deliver generates ketones but does not use the ketones as a fuel source, so they spill in circulation. And they, after a period of time of on the ketogenic diet or fasting, the ketones become the primary energy source for the brain in a fasted state. And on a strict ketogenic diet. Our blood glucose surprisingly, doesn't change much, because the homeostatic mechanisms that maintain blood glucose are very robust, I guess you would say. So we have things like the glycerol backbone of triglycerides becomes glucose gluconeogenic amino acids from skeletal muscle can become glucose. But the ketone bodies largely replace the need for glucose, so they become very glucose sparing. And they also have a profound anti catabolic effect. So they prevent the catabolism of skeletal muscle to liberate that gluconeogenic amino acids, so it decreases that need for that. And evolutionarily speaking, the being in a state of ketosis. One could think about like the ketone bodies, they they play a big role in allowing humans to stay in a fasted state for a protracted period of time without wasting away. So I always, I guess, Dr. George Cahill did a lot of the early starvation studies. And, you know, I was really into his research. And he was from Harvard Medical School, he did a number of interesting fasting studies where he fasted subjects for 40 days, back back, then you could get it approved by the IRB and the 60s. So it's also remarkable changes in brain energy metabolism, and the fuel use by the brain. So but but when you're in that in a state of ketosis, then those ketones kind of have, you know, the body is set up to protect skeletal muscle in a state of ketosis. So I think, and this comes up, quite often, the protein requirements needed in it on a ketogenic diet may be less because of the anti catabolic effects of ketone bodies.
Nick Jikomes 13:32
So when you're in ketosis, there's this anti catabolic effect, meaning that you will lose muscle mass more slowly than you otherwise would.
Dominic D'Agostino 13:42
Yeah, I think that's a correct statement in the context of fasting. And in the context of a ketogenic diet, you can titrate the protein and to prevent any protein, any muscle loss, and then you could adjust the protein higher to build muscle and build protein. And that level of protein that's needed. It's still not, it's still not clear. And I think it's age dependent. You know, young, healthy relative to older people may be less because because protein because ketones are anti catabolic. But I also, I'm of the opinion that if you improve metabolic health, biomarkers, lower inflammation, you kind of reverse anabolic resistance in a way that you make your body more sensitive to the protein that you have. So, you know, no one really like thinks in these terms, but just coming from like the fitness but you could just see, like, like, even myself, for example, I could maintain and even build protein, if I improve my metabolic health, you know, and it's like, and I think there's a lot to unpack there, but but I think I think the point is that, like if we improve our metabolic health biomarker, I think we could especially in As we get older, and you have insulin resistant subjects that are anabolic resistant, if they improve their metabolic health, biomarkers and lower inflammation, they are more, they can be more anabolic to the given amount of protein. That makes sense. Yeah,
Nick Jikomes 15:15
I mean that that makes intuitive sense to me. Because if you imagine two people, and one of them has just a higher baseline level of inflammation, they just suffer from chronic inflammation, that inflammation is coming from immune system activity. And that's going to require some amino acids to power it. So like, you know, the amino acids you're consuming your diet, or going to some extent get get shuttled towards those things. So the extent to which you you reduce whole body inflammation, the more that's leftover for other things.
Dominic D'Agostino 15:45
Yeah, insulins working better, of course, you know, inflammatory, like, you know, TNF alpha, I think it used to be called kick axon, right? Because it was associated with muscle wasting, like many of these inflammatory cytokines and chemokine are catabolic. And if you keep them at a lower baseline level, then you could you favorably change the protein anabolism and anti catabolic state to anything.
Nick Jikomes 16:17
Why does Why does a traditional ketogenic diet involve adequate protein relatively low protein intake, rather than higher intake or to say in a slightly different way? What would be the difference in terms of the general metabolic response of a person, if they were on the classic strict ketogenic diet, so little to no carbs? relatively high fat intake and some protein intake versus someone who was on the exact same ketogenic diet, but they had higher protein intake?
Dominic D'Agostino 16:50
Yeah, it kind of varies between people, too. So I guess, broadly speaking, as we titrate in more protein from like, say, seven or 8%, which was kind of used in pediatric epilepsy upwards of 20 to 30%, we're going to see a proportional decrease in ketone production largely become because the protein stimulates insulin, not as much as carbohydrates, maybe about a third as much but a small increase in insulin is enough to decrease ketogenesis beta oxidation, but just by elevating insulin a little bit.
Nick Jikomes 17:32
So so because protein does affect insulin to some extent, basically, the protein content of your diet on a ketogenic diet or in a state of ketosis is going to affect the depth of ketosis in terms of how many ketone bodies are being produced. Yeah,
Dominic D'Agostino 17:49
and I think ketosis is inversely proportional to insulin, and insulin suppression is needed to sustain and maintain ketogenesis. So like, if you're in a state of ketosis, like the, you know, the famous Cahill study where they inject insulin 20 I use of insulin in fasted subjects to cause dramatic glucose uptake. So glucose disposal to where the blood levels of glucose went down to like one millimolar. But the subjects were asymptomatic for hypoglycemia. This is a fatal dose of insulin, but because they were fasted, and their ketones were elevated, they didn't die. So if you just go into the general population, and inject, you know, and have them fast for you know, six hours, inject them and 20 I use of insulin data, everybody would die. But these subjects were fasted is very bold, very bold experiment. And there was an extension of that experiment. It didn't make it into the peer reviewed publication, but I found it in a book where they injected the insulin. So they like they did the 40 day fasting, and that got published. And then it was like, you know, I found some figures in another book where they injected the insulin. And then I later talked to some of the investigators before they passed away a few years ago, but you know, they were asymptomatic for hypoglycemia. So it was a very dramatic demonstration, that the brain has a metabolic flexibility to adapt acutely from using a glucose to using ketone bodies. I mean, they had been adapted over time, but we can also we have the capacity to use ketones at any, anytime. So we could administer exogenous ketones, and then theoretically, lower blood glucose and be protected. And that became extremely interesting and exciting to me because nobody knew about that. And I became that actually changed the direction of my career to like study different strategies for ketosis.
Nick Jikomes 19:49
So when you're in a state of ketosis, you're using ketone bodies for energy, and there's this anti catabolic effect. So there's this protein sparing effect that comes with being in that state. If you're in a, if you're in a state of perfect energy balance, so you're getting just the amount of calories you need on a ketogenic diet, is your body going to nonetheless burn off body fat as a source of ketones?
Dominic D'Agostino 20:23
You will stay in energy. If you're an energy balance, I think that's the question you will have much, much greater flux of fat going into adipose and fat coming out of adipose. So the fat flux, if you will, and the fatty acid oxidation and ketogenesis will be ramped up as well. fatty acid oxidation enzymes, ketone transporters like the MCT, transporter, catalytic enzymes, all these things will be greatly augmented, and enhanced. But if you are an energy balance, and some people, many people would may argue this would be I don't think that your your fat levels will change unless you are like, very insulin resistant and obese and type two diabetes. And then you go on a ketogenic diet, maintain energy balance, and you tend to decrease inflammation and various cardio metabolic biomarkers that may favor body composition changes that could result in accruing more lean body mass relative to fat mass. So you may be, you know, have a body composition effect just by virtue of improving certain hormones to like, testosterone could go up, you know, especially in like obese. So I've seen this before where almost like, Yeah, but like a weight stable person, and their body composition changes, especially if they're doing resistance training. Yeah.
Nick Jikomes 21:53
Okay. So if you are an otherwise metabolically healthy person, and you go into ketosis via a ketogenic diet, you probably won't lose body fat if you're in energy balance. But if you go into negative energy balance, and you deprive yourself, because all of you, because you're in flux so much more, and there's just more turnover and metabolism of the fats in general, it sounds like you probably would see an accelerated body fat loss.
Dominic D'Agostino 22:24
I think so I think it would be maybe subtle compared to like, you know, a low carb diet or even, you know, yeah, I think that's I think that's fair, I think. And it all depends, of course, on the protein concentration, too, right, like? Yeah, I think, I think what you're getting at, I think, the early practitioners of low carb diets, and I think maybe some today feel that there's a metabolic advantage to being in a state of ketosis, that favors more favorable body composition alterations, you know, just by virtue of being in a state of ketosis. And I believe that there is some truth to that, especially if you take someone who is insulin resistant, and but I also for the average person, I think the it's, it's kind of negligible, like, you know, and the body composition changes will more reflect, like, you know, if you standardize for protein, and calories, and all things are equal, and you switch out carbohydrates to fat, I think it's pretty much the same. But I do think, you know, there may be some truth to a metabolic advantage of a ketogenic diet. I mean, you could you know, when you're you're urinating, you're you're urinating out ketones, it's ketone urea, and at the end of the day, that's about 150 calories of someone in ketosis. So there's like that there's like, you know, various uncoupling proteins that may be up regulated. And, and maybe, but but I think it's there's a lot of debate about this, and a lot of discussion, but I think it's kind of like in the weeds, you know,
Nick Jikomes 24:07
I want to talk a little bit about the time, the time course or time duration dependent effects of ketosis. So, you know, if someone starts a ketogenic diet, they go into ketosis. If they do that for like, a couple days, let's say someone cycles in and out of ketosis on a weekly basis, you know, for a couple of days, versus someone who's in a ketogenic on a ketogenic diet for an extended period of time, weeks, and weeks. Are there going to be any? Are there gonna be any differences beyond beyond just the time component here? Meaning, you know, if I stay in ketosis, day after day after day, are there metabolic adaptations and things that settle in after many days or even weeks?
Dominic D'Agostino 24:48
Yeah, yeah, absolutely. So I think, you know, there's epigenetic changes too, right? Because as we change metabolites or epigenetic signaling molecules, lactate even beta hydroxy butyrate you the longer you're in ketosis, the more you're changing mitochondrial function, mitochondrial biogenesis by altering PPA, our alpha and gamma and a number of different fatty acid oxidation enzymes are increasing. And essentially what you're doing initially, once you start a ketogenic diet, there's an increase in reactive oxygen species. And so an AI can increase things like NRF, two and various antioxidant enzymes, because you're forcing the mitochondria to work harder, you're decreasing glycolysis. And it's a stress to the mitochondria to make energy to meet the bioenergetic needs of the cell to make the ATP. So there's just like initial stress, and maybe that symptomatically people feel that in regard to the Keto flu, but I think maybe some other things are going on. But yeah, the longer you kind of maintain this dramatically altered physiological state, the more pressure you're putting on the mitochondria to force adaptations, which include mitochondrial biogenesis. And also mitochondrial efficiency over time. So I think you're increasing the mitochondrial capacity to make ATP independent of relying on glycolysis. And I think that has a lot of functional, you know, advantages. In regard to metabolic flexibility, you'd be you're more, you're more able to fast, you're more able to be more resilient under periods of limited carbohydrate availability, or even food availability. Like I found this out to be, you know, anecdotally, like you feel that and then animal data shows that and, you know, I would say not a whole lot of human data has has studied this. But, you know, I think it's a real phenomenon that the Keto adaptation, keto adaptation gets thrown around a lot. And I think we don't, not a lot of people have studied it. And I think that's an that's an antibody, I think people athletes, you know, kind of transition in and out of ketosis, especially like endurance athletes. So they're, in some ways, kind of keto adapted to begin with, they can transition in and out of ketosis, but the average sedentary person can't. So thrusting them into ketosis with fasting or a ketogenic diet can produce some pretty profound alterations, I think in mitochondrial stress and mitochondrial adaptations.
Nick Jikomes 27:37
Yeah, so So the state of metabolic health that you have to start with the amount of time that you exercise and the frequency and intensity of things like exercise, and fasting probably changes your ability to easily switch into and out of these different metabolic states without having unwanted side effects.
Dominic D'Agostino 27:59
Yeah, yeah. And I think the big driver is insulin and all this. So just being able to function while you're suppressing the hormone insulin and decreasing glycolysis that may decrease brain energy metabolism, because the brain is now you know, looking for energy, the liver may be sluggish and making ketones because you have to overcome some of the insulin resistance to really drive high levels of ketogenesis. But and that's to like that's where exogenous ketones can come into, or even medium chain triglycerides, ketogenic fats can can be helpful there for that initial transition. I see. So
Nick Jikomes 28:41
basically supplementing the body with those things through diet, while the body's endogenous mechanisms to ramp up ketone production.
Dominic D'Agostino 28:49
Yeah, and I think we've done a lot of work with ketone esters. And I think large doses of ketone esters may may reduce or suppress some of that. Those adaptations if they're consumed in large quantities. What I've found just through testing, that if you consume exogenous ketones were quickly elevate your ketones, where you have a Delta of like two millimolar, and that will elicit an insulin response. And that could decrease your own endogenous ketone production. Whereas if you take like smaller doses of like a ketone, electrolyte salt, I use keto start, which is like electrolytes, bound to beta hydroxy butyrate, and then consume it and just bump bump yourself up like one millimolar maybe two or three times a day that has no effect on insulin, but at the same time, is actually the presence of ketones in tissues tends to upregulate the transporters in the catalytic enzyme so you can actually enhance your keto adaptation by exogenous li up, you know, elevating your ketones over time, as long as You don't increase insulin, which tends to decrease your fat oxidation in the liver. So and you could do that with MCT, too, but or ideally the combination of MCT with like a ketone electrolyte, but large doses of ketone esters can like spike your ketones up, and then your ketones come down. And because you release insulin and your when your ketones come down your hypo ketogenic and hypoglycemic. So for me, I get a headache and that can like tank performance. So I've, you know, talked to athletes that are not aware of this, and then it can crush their performance. So I think, I guess the important messages that higher is not better, when it comes to I was of the opinion that it was when I get into this research. And for certain applications, it is like you want to get up into like the three to $4 million range.
Nick Jikomes 30:49
So sort of a certain amount of exogenous ketone ingestion can help your body adapt faster. But if you go higher than that amount, you can get an insulin response, and then the outcome will be very different.
Dominic D'Agostino 31:03
Yeah, because there's a lot of counter regulatory mechanisms. When you spike your ketone levels up, you know, you're elevating insulin, and a whole host of counter regulatory mechanisms that can kind of throw your body off, and you just don't feel well. So I think for certain therapeutic applications, I think we might need to get up into the higher ranges, but for people looking just to enhance their metabolic health performance, and for me, I just mostly use it for mental energy, clarity, you know, keeping energy levels high, when glucose and insulin are low. You can kind of hack that system if you want to use that term with exogenous ketones. And I think they become an important tool for that. And, you know, we study different disease models, and definitely see some pretty profound, you know, therapeutic applications of these molecules, mostly from the neuro like neuroscience, resilience, but also from the anti inflammatory effects, looking at epigenetic effects. And then we also studied cancer, we see some interesting anti cancer effects of ketones to
Nick Jikomes 32:13
given how widespread diabetes is how widespread insulin resistance is, and everything that you just told us. Are there any dangers for someone who has a type two diabetes and is strongly insulin insulin resistant? Are there any dangers or things that they should be aware of if they were going to say try a ketogenic diet?
Dominic D'Agostino 32:37
Well, I am a strong advocate for doing bloodwork, like for I do it quarterly, maybe a little bit over the top, but I think it's important to get like you're just your basic comprehensive metabolic panel, CBC CMP. Blood pressure. So actually, of all the different diets, you know, I've kind of took a deep dive on blood pressure, low carb diets and ketogenic diets have a much greater blood pressure lowering effect than for example, like a calorie restricted high carb diet. So that actually could mean and I've had people email me about this. If they don't change. If someone doesn't change their blood pressure medication and they go on a ketogenic diet, they can have, you know, get dizzy, they could be hassled blood pressure. Static hypotension is very common. Okay.
Nick Jikomes 33:27
So if they're on meds that lower blood pressure and they go on a ketogenic diet, that also lowers blood pressure, so you can lower it too much. Yeah, yeah.
Dominic D'Agostino 33:34
And I also think that some medications, especially like lipophilic compounds, tend to get more permeability to the blood brain barrier when you're on a ketogenic diet. So this is something that no one has studied, but just from investigators that look at like brain levels of certain drugs, like it's up pretty profoundly, I think, and, and anecdotally, when I experiment with, you know, different compounds and stuff, things that are more like affiliate, I just, I mean, a deep state of ketosis, it's just much, much stronger. So I know, it's either, you know, penetrating the blood brain barrier, or enhancing receptor function. Something's going on there. That's pretty profound. Years ago, I got invited to UBC pharmaceuticals in Belgium, either the drug Capra and Keppra. You know, the idea behind using the ketogenic diet for epilepsy is to replace drugs, but there was also an observation that certain anti anti epileptic drugs are enhanced by the ketogenic diet. So you could use like a very small dose and get in good effects. And I think that's a really interesting area of research that we're not really doing but I think should be funded. So the enhancement of, you know, different drugs, I guess using diet to enhance different drug therapies. Yeah,
Nick Jikomes 34:58
so I guess that's the basic idea. is, in certain metabolic states like ketosis, it might be that certain drugs, which are fat soluble, are actually more potent effectively because they're getting into the brain more efficiently or something else has changed.
Dominic D'Agostino 35:14
Absolutely, yeah, there's a lot going on there. And it's like people acknowledge it and recognize it. But there's not a whole lot of like, direct studies on that. And I think that that's important. There's a lot of interest in getting things across the blood brain barrier. Like with enzyme replacement therapy, for example, for glycogen storage diseases. I'm of the opinion that, you know, certain, there's certain ways to do that, uh, dietarily. Some of these compounds work better in like an acidic environment, you could use like IV ascorbic acid and things like that. So, yeah, I think there's a lot of a lot of potential to look at diet drug interactions, and I used to teach that subjects at the medical school. And also, another important thing is the effect of different drugs on nutritional status, which is something I also teach like, you know, proton pump inhibitors on vitamin B 12. You know, things like that. So I think people should appreciate some of these things,
Nick Jikomes 36:15
given the impact. ketosis has on insulin and blood glucose levels, is this. How widely is the ketogenic diet, accepted as a potential treatment avenue for things like diabetes as a tool to help stabilize blood glucose and decrease insulin resistance? Yeah,
Dominic D'Agostino 36:39
well, there's a lot of studies being done now. verta health has spearheaded many studies using low carb diets and ketogenic diet, or the metabolic management of type two diabetes, you know, and obesity, and some patients and I think if you were to go on like clinical trials.gov, now you go 10 years ago, there might have been one study now, I think there's over a dozen registered clinical trials on the use of ketogenic therapies for type two diabetes, you'll find trials on Alzheimer's, you know, muscle wasting weight loss. So the science is definitely emerging. And I think now we can, it's generally accepted that of the evidence based applications, I think there's about a dozen or more for ketogenic diet under that would be type two diabetes, for sure. And an emerging application is actually type one diabetes, which is kind of interesting, right? Because you have diabetic ketoacidosis. Dr. Belinda lenaerts, at Harvard has been studying low carb diets and ketogenic diets for type one diabetes. Kind of makes sense, because whenever you could use less insulin to manage type one diabetes, an endocrinologist would have to agree that that's a good thing. Right. And if you look at a type one diabetic patients CGM, a week of CGM data before and after transitioning from a standard American Diabetes Association, high carb diet to a ketogenic diet, it's like night and day. And typically, insulin requirements go down 50 to 80%. So and that has to be a good thing. Although there's a little bit of pushback, you know, from some people about lipid changes on a ketogenic diet, in particular LDL, and APB and there's some research on that that's kind of ongoing, and I think that's an interesting area of research that deserves more attention. And there's even a phenotype called the lean mass hyper responder, where you have very low triglycerides, very high HDL above 80. And you have astronomically elevated LDL and APB in some cases, you know, I think the cutoff point is like 200. APB but I've seen you know, 500, LDL 600 LDL and I
Nick Jikomes 39:07
guess what's interesting about this or potentially confusing about this in sort of the what's implicit and everything I think we're about to say is, we don't know the answers to all of these things. Yeah, but traditionally traditionally trained physician would consider Oh HDL high is good, triglycerides low is good. LDL high is bad, but in these particular people, you've got low triglycerides, which is good, you've got high triglycerides are high HDL, which would be considered fine, but then they also have very high LDL, which you would normally think of as a bad thing, but it doesn't seem to be in these people. Is that kind of what it looks like. Yeah,
Dominic D'Agostino 39:43
and well, you know, blood pressure glycemia you know, checklist you know, all these all these things are improving. But the elevation of LDL and a bo B which is causative for ascvd is, is high in many And I thought, you know, this was kind of a rare anomaly when we started doing this research, and noticed that people that sustained a ketogenic diet that had more of an athletic phenotype that were lean, hence the name, lean mass hyper responder, tend to present with this elevated LDL and a B. So it ties into a hypothesis or a theory called the lipid energy model. And I think it was posited or advanced by Dr. David Ludwig from Harvard, that the lipoproteins are functioning in lipid transport and lipid trafficking. So the idea is that, you know, if peripheral tissues are using astronomically, more fatty acids for fuel, so we need a lipid transport system, right, because fats need to be on a lipid protein to be transported. So you need more a greater carrying capacity for lipid trafficking, to have these greatly augmented fatty acid oxidation, which is observed at the level of skeletal muscle, the heart and peripheral tissue. So the fat needs to get there by some mechanism. And, and I'm simplifying it and there's a lot of you know, the
Nick Jikomes 41:16
ideas if you're using permanently fat for energy, and you're lean, meaning you're exercising a lot, your energy demands are high, you need a transport or like LDL, to actually get it through the body and to where it needs to go. Yep.
Dominic D'Agostino 41:29
And I will actually say that I just want to quickly say that I've never seen someone that's very low carb or ketogenic. That's an advanced athlete with low LDL, like, I've never, ever seen that. So I think it ties into supporting that hypothesis.
Nick Jikomes 41:45
Okay. And so that was kind of going to be related to my next question, which is, is this phenotype? Is it? How general is it? It sounds like most people if they're lean and athletic, and in eating a ketogenic diet, say they're probably going to have this general phenotype, or is it a subset of people with a certain genotype? In other words, certain lean athletic people won't display this pattern?
Dominic D'Agostino 42:11
Yeah, good question. I think we need more data. But I have communicated with so many people like hundreds. And like I said, I've never seen someone who's lean have a low BMI who has a high level of athletic capacity and performance, that strictly low carb or ketogenic that has even like a normal LDL, like it's almost always elevated. However, if you take someone with type two diabetes, obesity, metabolic syndrome, and their LDL at baseline is high, and you put them on a low carb ketogenic diet, LDL typically comes down. So we see that you know, as subjects who have a high BMI, and you put them on low carb or ketogenic that that biomarker and all the other biomarkers go in the right direction, but it's almost like you need like a train subject who has a very high fat oxidation capacity. And this lends itself. You know, I was a little skeptical when this theory kind of got thrown out there. But the more data I see, the more I see the data supporting case reports case series, and even RCTs supporting this idea.
Nick Jikomes 43:20
Yeah, I mean energy model. At the very least, this would seem to say to me that you know, the direction that things move, so the direction that LDL goes, does it go up? Does it go down? Your overall state of metabolic health, whether these things are good or bad, is probably highly context dependent. It depends on the individual and where they're starting in terms of their overall metabolic health. In other words, we can't just say, LDL up is always bad for everyone. That's probably not viable. Yeah. And if
Dominic D'Agostino 43:47
LDL is up and APBs up in someone who has a genetic predisposition for cardiovascular disease, I would be concerned about that, I guess the question we really need to ask if all other things are equal, right. And if someone has beautiful, you know, cardio metabolic biomarkers, and one person has an LDL, of 350, and an eight bow be of 160, where you have another subject who has a third level of that, you know, an LDL of 100, and a B of 50, or whatever. All things considered, is the person you know, with a lower LDL, enable be at a significantly reduced atherogenic risk. That those studies are ongoing, and I think they're important. They're important for the field of like for epilepsy, type two diabetes, Alzheimer's, because even the conference that I came back at, which is a rare inborn error of metabolism, some of the physicians and clinicians are they're very hesitant to put even kids on occasion Getting diet because of the potential elevation of not LDL, I'll say that if triglycerides start to go up on a ketogenic diet, that's a bad sign. That's, you know, the body's not adapting to burning fat for fuel, but usually it comes down after a period of time. Interesting.
Nick Jikomes 45:19
So what about so I want to ask one more question about LDL. So in again, in general, the sort of standard traditional thinking would be higher LDL is bad, lower LDL is good. But you know, we've got all of these weird patterns related to the lean mass hyper responders and other things that might make us conclude that's at least a little too simplistic. Another pattern I've seen that I would love to get your your take on, is just the relationship between total LDL levels and all cause mortality, because my, in my reading of the literature, the all cause mortality risk goes up if your LDL goes too high, but it also goes up if it goes too low. So there's there's this nonlinear relationship. Is that your understanding? And what do you make of that?
Dominic D'Agostino 46:07
Yeah, so Well, it's very context dependent. So in it very low LDL is a sign of another other disease processes. So I've looked at enough blood work from cancer patients, for example, where their LDL tanks and presumably, the expanding tumor mass of the patient is contingent upon sucking up LDL and using your fuel. And, and also, you know, I don't know if that excludes people on lipid lowering medication, too, right. So if they push it way down with a statin, then they probably have some comorbidities and things associated with it. And then there's a lot of discussion too, about, you know, people with higher LDL, decreasing all cause mortality, mortality up to a certain point. And I think that's what you mentioned, right? So that these people that may just be a function of people that are normal, healthy, maybe higher LDL may indicate that they have a more nutritious background, that they're getting better protein sources that you know, that they're living longer, because it just could be like, a healthy user bias, you know, they're there, their LDL is high, and they're living longer just because they're, they're healthy, and they're eating. But But I think I think the LDL thing gets a lot of wind, and I think there's other biomarkers, but we do have drugs to lower it. And I think, and I think for some people, definitely, if you have a predisposition for cardiovascular disease, I think it's important to adjust your diet or do a pharmaceutical intervention. I actually did an experiment with zodia Acetamide. And I did a genetic test with GB health Healthwatch, which indicated that I had a missense mutation and the NPC one L one transporter, which is in the gut, and that transports cholesterol. Presumably I have a gain of function, increase in the ability of that transporter, or maybe more transporters to hyper absorb cholesterol. So which, which I took basically I'm micro dosing Ezetimibe. And Ezetimibe is an inhibitor of the Niemann pick c one, like one receptor, or MPC, one L one receptor, and it's a specific cholesterol transporter in the intestines. So it plays a role in cholesterol absorption. And, and people have different levels of this and and there's like, you know, the niemand, there's MPC to and there's different there's Niemann picks disease, right? So that's like excess, you know, lipid in the brain, and there's, you know, various diseases associated with different versions of this transporter, but this particular transporter is in the gut, it's also in the liver. So that brings up the question when you take Zebadiah, or ezetimibe, is it impacting sort of liver cholesterol processing, but what I can say is that a very small dose of Zetta might as a standalone not not together with a statin dramatically lowered my APB and LDL. The lipid energy model may posit that this would decrease performance because that could potentially decrease lipid trafficking. So I think an interesting question would be to take some of the lean mass hyper responders that are high performance athletes and cut their APB LDL by by 60 to 80%. And then their time to exhaustion metabolic car, you know, performance measures. Oh, who's to see, I think that would be a valid test. I've discussed this on other podcasts. And I think that's experiments to be done. A good way to test that, but I personally did not see I cut my APB in half. And you would think you would feel something if I go from cholesterol 270 to like 105, right, and my AB AB from 165, to 80. Actually, I think I had an increase in performance and strength in some things, and I didn't alter my diet at all, I just took a very low dose of a drug that has very little if any side effects effects relative to like something like a statin. So, so this could be a pharmaceutical intervention that I may stick with. But I've transitioned off of it, and added some different forms of fiber, and also adjusting my diet a little bit, to see if I can maintain those numbers independent of drug therapy. So which is kind of like my ultimate goal
Nick Jikomes 51:03
is that is that something that's like a guiding principle for you in your life to try and minimize drug use unless you find it to be absolutely necessary
Dominic D'Agostino 51:14
for some drugs, so what I also observed is with the with Ezetimibe is that my liver enzymes went from the 20s to the upper 40s. And I do a lot of blood work. So I pretty much know my body. And and there was a couple of papers of like, you know, liver stress, I think a case report of someone with liver failure. So I could have some weird snip or genetic anomaly that makes me that basically, that is the inhibition of the MPC one L one is somehow causing liver stress. And because I'm taking a really low dose and to see that, but at the same time, I'm eating a lot of protein, you know, I train pretty heavy about three times a week. So that could be some I'm reproducing it. So I've transitioned off the low dose of Ezetimibe. And I'm going to do two months just with a psyllium fiber, and incorporating more nuts and decreasing my, my dietary cholesterol consumption, which is like three to 5000 milligrams per day, when I did like, my, when I calculated it, which is pretty high, even Paleolithic man had something like 500 milligrams a day. So it's like, you can't argue that like, you know, it's, it's out of, it's kind of unnatural, because I eat a ton of eggs, and like, you know, sometimes two or three pounds of beef. So like my total cholesterol consumption is kind of high. So I'm just, you know, I'm thinking more about longevity, as I approach 50, you know, just above the DSO. So getting these getting all my metabolic cardio metabolic biomarkers, in the optimal range is like my goal now, like it used to be like performance and strength goals. But now, the numbers that I focus on are my biomarkers for longevity.
Nick Jikomes 53:02
And so So given the comment you just made about your cholesterol intake. So you eat a lot of eggs and things like this. What is the relationship between dietary cholesterol and blood cholesterol levels in general? Slash, if you eat a lot of dietary cholesterol, what are the main things in the body that's going to drive?
Dominic D'Agostino 53:24
Yeah, so for most people, unless you have like, a mutation in the NPC 101 receptor, are not hyper absorbers. So taking a drug like Zebadiah, or is that a MEID? At least if you look at the studies as a standalone may drop LDL like 10%. So typically, what they do is add it to a statin. But the more I talk to people, there must be a lot of people that are hyper absorbers because I feel like maybe the pharmaceutical industry added Zinnia to some of the statin drugs to make them look better. Just because I talked to so many people who, who took zodia Or is Edomite. And they had a profound decrease in their their LDL and their APB not everybody, but but quite a few people more than you would expect based on the literature. So but generally speaking, and everyone's a bit different, that dietary cholesterol, so things like eggs have other components in it that can maybe enhance cholesterol and excretion of cholesterol, through bile acids and things like that. So generally speaking, dietary cholesterol plays a minimal role in LDL and a B, if you go to the literature, but in some people, for me example, I think as an example, I think it plays a pretty profound role in AP and LDL.
Nick Jikomes 54:55
I'm going back to the subject of ketosis and the ketones on a diet with respect to insulin resistance, insulin resistance and diabetes, what is your general take on the dietary recommendations we get from official institutions? You know, big, big institutions like the American Diabetes Association. They generally don't seem to recommend things like the ketogenic diet, they recommend other diets. I'm not sure. How would you characterize the recommendations? And and what do you make of them?
Dominic D'Agostino 55:28
Yeah. Well, I'm actually interviewing Nina teicholz. On this later today. The recommendations are definitely biased towards a carbohydrate centric diet. There's like, No, I mean, I grew up farming, you know. And then you get subsidies for growing certain crops and wheat and things like that. So I think for political reasons, and maybe some historical reasons for scientists like Ancel Keys and everything demonizing saturated fat, animal protein. I think there's a bias there. But I think the big the big problem is processed food hyper palatable food. But But I do think simple. It doesn't have to be ketogenic. And it doesn't have to be very low carb, but simply titrating the amount of carbohydrates into the individual. And how do we do that we do that through. One way to do it, it might sound a little bit over the top is but for normal, healthy people to wear a continuous glucose monitor, or someone who just has some weight to lose, because if we're spiking glucose and having big post postprandial excursions in glucose, we're simultaneously releasing insulin at levels that we should not be doing like that are almost super physiological. And those repeated spikes in glucose and insulin are going to have big consequences on our metabolic health over time, and I think everyone pretty much agrees with that. Well, the literature for type two diabetes strongly agrees that glucose and insulin spikes profoundly impact metabolic health, but it just has not been studied in non diabetics, because non diabetics don't wear CGM. But I think, but I'm an advocate of at least, you know, for people who want to improve their metabolic health, especially people who have type two diabetes in the family to slap on a CGM. Have their doctors prescribe it, and then actually eat their normal diet and to see what's going on. And if they're getting postprandial excursions in the two and three hundreds, which many people are by eating the standard American diet, then they have to think about, you know, going low carb or reducing carbohydrates.
Nick Jikomes 57:40
Yeah, a story I've shared multiple times on the podcast is, I don't have diabetes, I'm, I think anyone would consider me pretty healthy. I wore CGM a couple years ago, for a couple of weeks. And, you know, I was eating what I thought was, you know, heart healthy, green based cereal, it wasn't you know, wasn't Froot Loops, it was, you know, some, you know, whole grain bran cereal. And that, that spiked me more than anything. Yeah,
Dominic D'Agostino 58:08
oatmeal, oatmeal spikes me a lot, I grew up on oatmeal, fruit, like, even like an orange or something like that. But if you miss, mix the meal with protein and fiber that has a significant attenuation, you know, in the glycemic spike. But, you know, I think, and also fat too, so protein, fat, and fiber is pretty much all you need. And then you can adjust carbohydrates accordingly. You know, and then but but then you and I think this is more important for people as we age as we become increasingly more, you know, insulin resistant, as a consequence of age, which I think is to some extent true. But for like the, for the high school kid for the college kid for the athletic, younger people, they can probably do well on a high carbohydrate diet and not see any overt consequences. Although I don't know we do have an obesity crisis with with kids. So. So there's some insulin resistance and metabolic dysfunction going on there that we need to address. And I think addressing it with a guidelines would be the way to do it. I think the low hanging fruit is really like sugar sweetened beverages, and just hyper processed food, you know, are just, and just eliminating that especially. I mean, that's that's the first thing that we need to target and not put everybody on a ketogenic diet.
Nick Jikomes 59:40
And so for you, like where do you where do you draw that line between hyper processed and less processed? Because like, for example, if I go back to the American Diabetes Association, they've got a voluminous website filled with snack and meal recommendations. One of them that I have, you know, Top of Mind is there's one that's you know, multi grain, Cheerios and chocolate chips. Like what? Like, where does that come from? And is that hyper processed? Is that mildly processed food? How do you think about that? Well,
Dominic D'Agostino 1:00:13
I think it like in terms of like the 8020 rule, so single ingredient, whole food diet, right? So it could be that simple, right? Whatever you're eating could just be like a single ingredient. And that would if we did that, like 80% of our diet was Whole Foods, single ingredient, you know, things then that would probably solve the problem. But you know, I eat processed food sometimes too. And, you know, we went out for Mexican food the other day, maybe it had some like tacos and things like that. And, and would be totally fine. But I think the large majority of people are getting 80% of their calories, not 20% 80% of their calories off. processed food, which includes anything made, you know, any kind of bread, any kind of chip, any kind of cereal is considered process where ingestion of the food triggers and absorption of carbohydrates and spike of glucose above and beyond what our bodies are used to experience through millennia of evolution. So in the last 100 years, like, we've not changed at all, you know, pretty much from a metabolic perspective, and but our food system has changed, like significantly. And not everybody has to radically implement dietary changes, but the large majority of people really do and I don't think they recognize the impact of the processed food as and I think they would recognize that they simply were a CGM, which is becoming a really important, we did a study where we use continuous glucose monitor as a behavioral tool. And it was not done for. We also we coupled it with a low carb diet, which had a profound effect. And the CGM had, it was a little bit within the noise. But we didn't have the statistical significance in the sample size to really get the power that we needed to validate CGM as a as a behavioral tool. But I think for many people, simply wearing a CGM, once every quarter, or once or twice a year, can be a powerful behavioral tool to to allow them to understand what processed food is doing to their system.
Nick Jikomes 1:02:34
And to give people a little bit more of a concrete sense of what low versus high carbohydrate diet means. Can you give us just a rough estimate? Like what, what percentage of calories is the average American getting from carbohydrates? And what would you consider to be roughly a low carb diet?
Dominic D'Agostino 1:02:51
Yeah, I think the literature may describe low carb is like under 30%, which is still kind of high carb from the ketogenic world. But according to the guidelines, the standard American diet is anywhere from 60 to 70%. carbohydrate, and and that may be fine, like for some people, depending upon the selection of carbohydrates that they're eating. But I think it is in I think contributes to the the obesity and type two diabetes problem that we have. And as we age, I think the guidelines should kind of be different as we age, or if we have pre diabetes, and especially if we have type two diabetes, and type one diabetes, but the guidelines are just kind of blanketed and just apply to everybody. So I think I think it's safe to say that a high school athlete has a different ability to a different carbohydrate tolerance than like a 50 or 60 year old, but the guidelines were the same, right?
Nick Jikomes 1:03:50
So I have a number of questions related to ketosis, ketogenic diet and brain and mental health. I want to start off by just sort of asking you broadly, you know, what's going on in that world right now? What do you think is interesting, and what do you think is sort of the most important aspect of how ketosis can help with certain either certain forms of psychiatric illness? We're just sort of overall brain function.
Dominic D'Agostino 1:04:16
Yeah. So there has been an explosion of research on ketogenic diets, and I think it's because there's so many mechanisms that the ketogenic diet works through just real briefly like we study reactive oxygen species. So oxidative stress goes down, a decreasing glycolytic flux, a decrease in insulin. It changes the neurotransmitter balance. So the glutamate to GABA balance, adenosine receptor signaling, NAD, everybody's talking about NAD supplements. So ketogenic diets profoundly change NAD levels, suppresses inflammation, and also like epigenetic signaling. So that's I mean, these are Like the things that we study, but if we go to like the human clinical trials in 2010, I remember looking like, Are there any studies looking at cancer, and there was like, maybe one or two. And now there's, if we look at cancer and like muscle wasting, and I put them under, like cancer cachexia, there's like three dozen, I think. So there has been an explosion of research in the evidence based applications for human clinical trials. And if you go to clinical trials.gov, there's about 490 clinical trials if you just type in ketogenic diet. So just to put this in context, about 1015 years ago, there was like six, right, so so it's gonna take a while for this research to hit PubMed. So I think, you know, there are a lot of people were like, remember, the ketogenic diet was a fad a few years ago, now, you don't hear anything about it. But I think if you look at PubMed, and you're looking at clinical trials.gov, the research is exponentially increasing. Yeah.
Nick Jikomes 1:05:58
So So just in terms of the volume that's out there, unpublished and unfinished. Over the two years, there's gonna be a lot of new information.
Dominic D'Agostino 1:06:05
Oh, yeah. Yeah. And type two diabetes, like you mentioned about two does or know about a dozen clinical trials. Even for things like migraine, of course, inborn errors of metabolism. There's that Parkinson's, Alzheimer's disease, quite a few clinical trials. And then what you alluded to the emerging applications of the ketogenic diet are very interesting, especially in metabolic psychiatry. The psychiatric diseases include bipolar, schizophrenia, depression, anxiety. The psychiatric disease that kills more people than anyone is, is anorexia. So there's actually really trials on Yeah, kills more people than than anyone. So there's some very compelling case reports on using ketogenic diets for anorexia and also coupling it with ketamine. So the synergy between ketogenic diet and ketamine seems to be very efficacious for managing anorexia and that's a really interesting area of research. So that's, that's actually kind of that's actually five technical trials.
Nick Jikomes 1:07:12
Yeah. I mean, the last thing you mentioned is kind of interesting given, you know, there's a brand new paper out where they've developed a new drug that's sort of a dual GLP, one NMDA receptor antagonist drug, which is what ketamine is. So that's kind of interesting.
Dominic D'Agostino 1:07:27
Oh, yeah, that's right. Yeah. Ketamine works through NMDA. Yeah, agonist, right. So the antagonist. Oh, auntie, yeah, that's when the antagonists like, okay, yep. Interesting. I
Nick Jikomes 1:07:39
haven't actually read that paper yet. But it looks really interesting. Everyone, everyone is chirping about it right now. Yeah, that's
Dominic D'Agostino 1:07:45
really interesting. So first, schizophrenia, like I teach those lectures in neuro farm. There's like the NMDA receptor hypo function hypothesis, you know, for schizophrenia. And then, for the NMDA receptor, there's like many different ways to modulate it. There's like the glycine co agonist that you need, you know, and then, yeah, I did a lot of electrophysiology and patch, clamping as a PhD student. And we would always use like high magnesium, low calcium to block like synaptic activity and manipulating magnesium and other different blockers of the NMDA. So yeah, that's a really interesting area of research, I think, yeah.
Nick Jikomes 1:08:26
One thing I want to get you talking about a little bit is, okay, so there's, there's all these interesting results and hints, at least, that lots of different brain functions related to all sorts of different neuro psychiatric diseases seem to be modified by ketogenic diets or being in ketosis. I want to get people thinking about like, why that is why we would, you know, maybe see such a diversity here. And one of the things that you mentioned, is affected by ketosis is the excitatory inhibitory balance of the brain the ratio of GABA to glutamate, can you talk a little bit more about what that is and why that's sort of a central thing to brain function?
Dominic D'Agostino 1:09:08
Yeah, sure. Well, in regards to epilepsy, we know that many I guess you could even extend it to all different neurological neurodegenerative diseases and neurological diseases are in some way patho physiologically linked to glutamate, hyper excitability. So Alzheimer's disease, you have a seizure, glutamate goes through the roof, you know, bipolar or schizophrenia, there's like a dysregulation of neurotransmitter balance with glutamates, the most abundant neurotransmitter in the system and glutamate is converted to GABA via an enzyme Glutamic acid decarboxylase. And then there's different enzymes that make that Gad, 65 and 67. As we looked at these proteins and see that they are elevated, they're elevated in the context of a ketogenic diet, and then Gad, 65 and 67 are also elevated in the context of supplemental ketones. So, so being in a state of ketosis increases the conversion of glutamate to GABA, and many anti seizure drugs and by GABA Trin work through a GABAergic mechanism. So and I think that has to do in many ways just by impacting metabolic control in the brain by restoring normal metabolic control is impacting the Krebs cycle in various intermediates. And upstream metabolites, like alpha ketoglutarate, influencing the conversion of glutamate to GABA. So and I think that's so you have brain energy metabolism is significantly restored, and an imbalance just through the ketones. So that's one. And by virtue of restoring energetic flux in the brain, that's restoring neurotransmitter systems. So like many of the enzymes are made in the mitochondria, like monoamine oxidase, for example, is like, as you know, is a mitochondrial enzyme. So by improving and enhancing mitochondrial function, and various intermediates, we're improving, replenishing neurotransmitter systems, and also restoring some of the enzymatic pathways associated with neurotransmitter homeostasis. So that that's, that's a key thing, but also oxidative stress, to my early experiments, were taking hippocampal slices, and exposing them to graded levels of oxygen and then hitting them with different, you know, different toxins and things like that. And then that ultimately led to studies with ketones showing that ketones could preserve mitochondrial function at the same time knocking down reactive oxygen species, so superoxide, dismutase, catalase glutathione, all these things tend to be increased and in balance. And then we'd looked at adenosine, a one receptor signaling. So that's another thing. When we did metabolomics in the blood, and in the brain, we saw adenosine goes way up. And we didn't really expect that. But that was an interesting observation. So sent us down the rabbit hole of looking at adenosine receptor signaling, which is pretty complex. And maybe I won't get into it, but I'll I'll say that adenosine is a very powerful basal dilator. So I think some of the, the increase in brain blood flow associated with fasting and acute ketosis is due in part two, an elevation of adenosine causing a vasodilation effect. And that increase in brain blood flow is impacting brain energy metabolism. So a lot of people don't know that. But it's like, I think that's important to acknowledge. And there's other theories that people are putting out there about NAD levels, which are significantly impacted by like fasting and ketogenic diets in which direction and elevation of available NAD. Were in the context of ketosis. So I think that comes into play. And then of course, I'll have to add like the we did a study it was published in Nature Medicine, I formulated the diet, but it was looking at the NL RP three inflammasome. And there was some early work done at Yale showing that fasting suppresses the NLR, p3 inflammasome, and then IOM beta. And they the same lab reproduced the study using supplemental ketosis. So beta hydroxy, butyrate, was the molecule that was responsible for suppressing this inflammasome that when it assembles and becomes activated, stimulates il one beta. And then beta hydroxybutyrate suppresses that. So I think neurological diseases like bipolar schizophrenia, especially depression are associated with neuro inflammation. And I think ketones play a role in suppressing that.
Nick Jikomes 1:14:25
So if BHB is one of the ketones that can be sufficient to trigger some of these effects. Does that say that? So if someone's not on a ketogenic diet, they're not in a strong state of ketosis. They're eating, let's just say moderate carb intake. If you supplement with BHB, can that reproduce some of the effects of being in full blown ketosis?
Dominic D'Agostino 1:14:52
Some of the effects Yeah, I think my opinion is that therapeutic ketosis is much more beneficial. In the context of some kind of energy deficit, or neurological dysregulation, it tends to work really well. However, we've done studies on, you know, normal, healthy animal animals, and we see, like beneficial effects, you know, in some of these biomarkers. So I think the more metabolic li dysfunctional and neurologically dysregulated the more opportunity to use ketogenic therapies, as you know, up therapy. And that could be there's many different ways to implement many different types of ketogenic diets, ketogenic fats and exogenous ketones. So there's different ways to go about doing that.
Nick Jikomes 1:15:39
I'm also interested in whether or not ketosis can be performed sort of sustained, can lead to sustained resetting of cells. So for example, is there any evidence out there any work being done that shows that if someone goes into ketosis for, say, a number of weeks, that there are metabolic changes in cells that actually sustain themselves even when they come out of ketosis and start eating a different type of diet?
Dominic D'Agostino 1:16:07
Well, to answer that question, the more we're in ketosis, the better. We have an enhanced ability to transport and utilize ketones as an energy source. And so I would say yes, but under that sort of context, that and other people were of the opinion, too. And I remember reaching out to the late Dr. Richard Veatch, because I was under the opinion that he needed to adapt to a ketogenic diet to start feeling any any benefits over time. And I remember talking with him early on, because he had developed the ketone, mono Ester, and and talking with him and saying, No, you're, you know, he was very adamant that your body always had the ability, your brain always had the ability to use ketones as an energy source, and you could acutely lower it, and in five to 10 minutes, as your ketones Elevate, then your brain has that fuel and could be optimized. And then that he also did some seminal work to show that the hydraulic efficiency of the heart, for example, was significantly increased, you know, by burning beta hydroxy butyrate as a fuel, that would be difficult experiment to reproduce in the brain. Because yeah, are working hard preparation, but he was more or less under the impression that the same metabolic enhancement would happen in the brain, too. So your question is, like, you know, if you sustain that chronically, will that lead to favorable changes in like, the neurons in the brain? I think it would, but not sure that has been sufficiently answered experimentally. I see.
Nick Jikomes 1:17:48
Going to cancer. So you mentioned there's some interesting work being done with respect to ketosis and cancer, what's going on there? And maybe maybe it's a starting point, can you just give people a little primer on cancer cell metabolism? are cancer cells primarily using glucose? Does their metabolism work in a different way from non cancer cells? And then how does the ketosis tie in to that?
Dominic D'Agostino 1:18:13
Yeah, I think maybe start with like, you know, one of the imaging technologies that is important for identifying the location and aggressiveness of tumors would be the FDG PET scan. So we use we have been using that imaging technology for decades to identify cancer but not using that information to target the tumors. So the more aggressive and metastatic and invasive the cancer, the hotter it is on a fluorodeoxyglucose PET scan. So when you're imaging a tumor, and it's much, much higher intensity on a on a PET scan, that's basically showing glucose uptake in the tumor. And that's what we call essentially the Warburg effect, or the word Warburg phenotype, for particular for the cancer metabolism. So the Warburg effect is, you know, I guess it could be described as I don't want to get too technical, but disarray like impaired mitochondrial oxidative phosphorylation with compensatory fermentation. So, Warburg, and many people debate this. In some ways, we all agree that the Warburg effect happens, but we, there's a debate on sort of the reason why it happens. And I think the truth is somewhere in the middle, and to be honest, but the Warburg effect in Dallas cancer cells in the tumor to basically hijack various intermediates and direct them to the expanding biomass of the tumor. So the Warburg effect is essentially using fermentable fuels like glutamine, like glucose and glutamine as an energy The source but also as biosynthetic precursors for to develop membrane to develop, you know components of the cell as the cell expands. And the fermentation pathway also allows the tumor to grow in a low oxygen environment, a very low oxygen environment. And if you were to like if like for a glioblastoma for example, a very aggressive tumor, if you were to just like go in there and take a sample of the tumor, what you would see is that all the mitochondria are aberrant in some way. So, the mitochondrial structure and the function is significantly changed in cancer cells that present with this Warburg phenomenon. So, what that means from a high level, you know, from a translatable level is that we can target the Warburg effect by decreasing glucose availability, decreasing circulating insulin, which is a growth factor activates, you know, mTOR pathway and, and, you know, the PI three kinase pathway is something that has been various drugs being developed for that. And, and when the tumor is metabolizing, these fermentable fuels, it's dumping lactic acid into the microenvironment. And that acidification drives the invasiveness and the growth of the tumor. So limiting glucose availability and fermentable fuels is like the first thing you could do that take the your foot off the gas pedal, right, and ketogenic diets do a number of things, they lower glucose availability, they lower insulin, they lower inflammation, they reduce reactive oxygen species signaling, they decrease inflammatory drivers of the tumor and, and they make the tumor more vulnerable to standard of care therapies that includes chemotherapy, radiation, more recently, immune based therapies. So even two weeks of a ketogenic diet augments the adaptive immune system and can enhance the ability of certain drugs like checkpoint inhibitors, PD one and inhibitors in particular, and augment their responsiveness. So there was a study published, I believe nature, medicine or communications were the comparative vegan diet, which increased the innate immunity and a ketogenic diet, which greatly augmented the adaptive immunity. And the adaptive immunity is kind of interesting, because that has implications for immune therapies in particular checkpoint inhibitors. So that has actually become a hot area of research in cancer research with ketogenic diets now.
Nick Jikomes 1:22:47
So it seems like there's there's a dual benefit to being in ketosis with respect to cancer. On the one hand, you're sort of minimizing the fuel the cancer itself can use to keep that growing. And on the other hand, it seems to enhance some of these therapies, we have that attack the cancer. Yeah,
Dominic D'Agostino 1:23:05
and you could also add that the ketones and being in ketosis protects the normal healthy cells, too. So especially if you're getting like radiation therapy, great work was done by Dr. Adrienne scheck, where she like, did whole brain radiation of animals in ketosis, even like without a tumor and, like, protected their brains, like, you know, without being in ketosis, like all the animals died, and if they're in a state of ketosis, like they all lived, so there's like radiation protection issues there. That's why, you know, organizations like NASA have some interest in ketogenic therapies because their ability to protect against radiation environments, extreme environments. And, yeah, the anti inflammatory effects too, I think, are an important component because chemotherapy and radiation produced profound inflammation is at the site at the tumor site and systemically and if we can protect the body from the collateral damage from the inflammation, that's going to be like an important thing to do. And the ketones have their own anti cancer effects, I think through reduce things, certain glycolytic pathways. They have neuro protection, anti inflammatory effects, and you know, and it can be said that some tumor cells may use ketones, maybe not so much as an energy source, but could be incorporated into like lipid biosynthesis. So there are some cells that some types of cancers that may be much more amenable to ketogenic therapies than other types of cancers. And I think I'm actually we're very interested in like, glioblastoma and cancers that are receptive, but I'm equally interested in cancers that are not, you know, to figure out why. Yeah,
Nick Jikomes 1:24:58
so it sounds like it's so Seems like there's at least some evidence that at least intermittently going into and out of ketosis could have preventative benefits with respect to cancer.
Dominic D'Agostino 1:25:09
I think so, yeah. It hasn't been studied. But you could say that any intervention that would like significantly improve metabolic biomarkers, inflammation, mitochondrial health, you could say that with fasting, you could say that with caloric restriction. However, I think we believe that, you know, being in a deep state of ketosis, pushing insulin really low, potentially triggering things like autophagy mitophagy, that, that this could potentially, you know, target pre cancer cells, or cancer stem cells, and could also increase the adaptive immune system or enhance the immune system in a way to make the immune system more vigilant in identifying and neutralizing precancerous cells. So there's been, you know, animal work that suggests that, but I'm not sure of any human Well, the one human study, the two week diet intervention showing, you know, big changes in immune markers of adaptive immunity. That was just a pilot study. But yeah, we're hoping to expand on that working with Moffitt Cancer Center to sort of expand upon that with checkpoint inhibitors.
Nick Jikomes 1:26:24
It's no secret that many, many people are over consuming sugar in general. Obviously, that ties into the cancer stuff we were just talking about that ties into insulin resistance, it ties into just general health. You definitely don't want to be consuming too much sugar, but sugar added sugars are in all sorts of things. What is your general view on sugar substitutes everything from you know, so called non caloric sweeteners, things like Splenda to other sugar alternatives? Are they actually better? Are we substituting one bad thing for a different type of bad thing? Are there any good, truly healthy sugar substitutes?
Dominic D'Agostino 1:27:02
Yeah, yeah. Glad you asked that. I am of the opinion that artificial sweeteners like saccharin, aspartame, sucralose are a better alternative are a suitable alternative to sugar in different foods? I don't think they're ideal. But I don't think it's like the lesser of two evils. Right. So I don't I don't think there's any, you know, beneficial effects. But I think the data supporting that they are the data supporting that they're pathological or, you know, bad. And so I just don't think the data is there, especially in regards to cancer. I think there was a lot of discussion about aspartame and cancer. And I did a deep dive actually, we did like a little social post with the Moffitt Cancer Center CEO. And I think I know aspartame, I believe was designated potential cause of cancer, but so are other things like other food things that we eat. So I'm not too concerned with artificial sweeteners, but I think we should limit them because I do think they have an impact on our brain, our brains, desire for hyper palatable foods, and I think they could stimulate brain pathways dopaminergic pathways maybe to seek sweeter foods. So I think the jury's still out. The effects on the microbiome, I think are still under investigation. And I think, I think it's safe to say that they're not completely benign in regards to changing the microbiome, so they can change your microbiome, but it's not entirely clear whether that can be pathological or maybe even beneficial. I am a big fan of allulose. So allulose is an epimer or fructose. It uses the glucose five transporter, and there are some types of cancer cells that over express the glut five transporter, and we're doing some experiments in our lab now to looking at it in the absence and presence of allulose. And getting some interesting data to suggest that allulose could be potentially used in a ketogenic diet formulation as a sugar a natural sugar based alternative. So it's a rare sugar. It's not artificial, it's found in things like figs and some fruits and maybe QE. So how you lose consumed at 20 grams in a single bolus is probably like your tolerability limit. So if you want to incorporate allulose, I would suggest you know, start with like five grams and work out from there.
Nick Jikomes 1:29:47
What do you mean by tolerability?
Dominic D'Agostino 1:29:49
So the ability to absorb allulose in the gut is contingent upon the presence of the glut five transporter. So if you're not sufficiently absorbing it all it can cause an osmotic shift give you diarrhea, maybe it's fermentable give some people some gas. But I think of all the different sweeteners out there, artificial and natural, I think allulose is the most promising for a number of reasons that it is a natural sugar it, it's kind of self limiting in that you can't like it's not hyper palatable. So it has a nice mild sweet taste, but it's not like super hyper sweet like super sucralose. It's transported through the glut five transporter, because it's an epi mer fructose, which uses the glut five, and it lowers blood glucose, which is very interesting. So I've wear a CGM, and I consume allulose. And my glucose actually goes down. It has very little if any insulin response, which is another benefit. And oh, and I think a lot of people are very interested in allulose, because it triggers the release of GLP. One. So there's a Nature Communications paper showing that an equivalent of the human equivalent would be like me consuming I think, 30 or 40 grams, but there was a 500% increase in the release of of GLP. One. So I think and people do report it has a appetite suppressing effect. So you have this rare sugar that's mildly sweet, lowers blood glucose has virtually no insulin response, and is a GLP one mimetic almost like a natural ozempic. So there, there are reasons why I'll have to disclose that I am a research advisor for the company RX sugar, and they make allulose products. I was slow to come on board. But the thing that got me on board was the peer reviewed literature. I was like, I want to study this. So we're studying it from the context of from the cancer research right now, because I think it could be we have a potential natural sugar that could be good, further enhance ketogenic therapies, make them more palatable and make them more efficacious, especially in cancers that overexpressed the glut five transporter.
Nick Jikomes 1:32:07
Interesting. So what it sounds like, Well, what do you how do you manage your own diet in your own life? Are you in a perpetual state of ketosis? Are you going? Are you going in none of it intermittently? How do you how do you manage your own metabolic states week to week?
Dominic D'Agostino 1:32:25
Yeah, I do a low carb diet that's kind of puts me into ketosis. I think a mild state and like, you know, how
Nick Jikomes 1:32:31
low is low carb?
Dominic D'Agostino 1:32:34
Well, today, I've had no carbs like almost 230, right. I had just some salmon and eggs for breakfast maybe eight hours ago. So I'm in a state of ketosis now, maybe like to milli molar. I do consume, like I have. ketogenic exogenous ketones that I'll SIP throughout the day, especially if I have a long day teaching, or something like that, and but typically eat about three meals a day, each meal is pretty low in carbohydrates. And I tend to get more of my carbohydrates in the form of vegetables and fruits towards the end of the day. The carbohydrates that I consume are salads, broccoli, avocados, blueberries, some dark chocolate, maybe an apple here and there. So usually about 7080 grams of carbs. This works great for me, I feel like it optimizes my microbiome, if I don't have that fiber in. I just feel that my microbiome and my gut mobility motility is not as optimal as it would be otherwise. So there's a big discussion with fiber. And do you think fiber is beneficial? I take as I mentioned, psyllium husk fiber at nighttime before bed. So yeah, I don't I'm not overly obsessive about tracking. But I've tracked in the past, and my diet is so routine that I pretty much know give or take 5% of the macros so. So I'm getting about 200 grams of protein a day, maybe 220 to some days, 250 grams of fat per day, maybe 80 grams, 50 to 80 grams of carbs a day, high fiber, carbs,
Nick Jikomes 1:34:11
so you're getting comparable levels of protein and fat, and much, much lower carb intake. Yeah,
Dominic D'Agostino 1:34:18
yeah, for sure. Yeah. And carbs may go up on weekends, if you know, we're out and about and doing stuff and eating out. But, but generally speaking, yeah, it's pretty, pretty much low carbs. There'll be some days where I'm working really long hours in the lab or at the office, and I don't have any carbs at all. I'll just come home at night and maybe have like, almost a zero carb day, but on average, it's pretty, pretty consistent like 50 to 80 grams today. Is
Nick Jikomes 1:34:44
there any work that's been done with respect to ketogenic diets and headache or migraines?
Dominic D'Agostino 1:34:51
Yeah. Dr. Elena gross. In Europe she has she was a migraine sufferer and He kind of developed a ketogenic product that is actually beneficial for migraines. And we co authored a review together, basically showing that migraines kind of proposing this hypothesis that migraines are like a sign of an energetic crisis in the brain, and also inflammation. And a lot of people respond positively to ketogenic therapies for migraine. I'll say that some people do get migraines from being starting a ketogenic diet, but I think that's more or less when they part of the transition phase, maybe the electrolytes are off or things like that. And I get quite a few emails from people who try exogenous ketones, and they tell me it relieves their migraines when nothing else helps. So I think if there are people out there with migraines, going into ketosis could be really beneficial. Interesting.
Nick Jikomes 1:35:54
What are you know, one or two of the things that you're working on the lab today that you think are particularly interesting that will have results for in say, the next year or so? What's what's on the horizon for you?
Dominic D'Agostino 1:36:07
Yeah, I would say, Well, I'm very interested in and this is broadly speaking of, I think there's a lot of potential for innovation of the diet composition. So you know, we've kind of just default to like the standard ketogenic diet just with macronutrient ratios. And I think, I think evidence is coming out that a higher protein ketogenic diet, not like the 10 to 12%, but upwards of 20% can be more favorable in regards like we call it a modified supplemented ketogenic diet, we got modified because it's got higher protein, and we call it supplemented, because we supplement medium chain triglyceride fats as a significant percentage of the fat component of the diet, but can also further enhance the ketogenic potential of the diet by incorporating exogenous ketones and ketone esters are can be beneficial, but ketone electrolyte salts are probably much better for the everyday person so and ketone esters and things like when three butane dial need to be metabolized by the liver, it does create a beta hydroxy, butyrate, aldehyde, and some some things that could be potentially toxic. So I think they're good and like the acute setting, maybe like military operations. But I think, you know, a ketogenic diet that's engineered that has specific fatty acid profile with omega threes. MCT is higher protein and also prebiotic fiber. And then different different types of fiber and maybe some resistant starch. And I'm just speaking very broadly here is like a step function above the ketogenic diets that are used now in like epilepsy clinics. And I think there's a lot of potential for innovation there. So we're working and designing these diets more or less for, for like different inborn errors of metabolism, but also for, for use in cancer studies. So I think in that the higher protein component is also going to be important, but not not really high protein, especially in cancer, because you could be driving some processes that could fuel cancer. So there's like a fine line there in optimizing that protein content. So on the cancer front, yeah, diet optimization, diet engineering. But also, I would say, just thinking broadly, medical education is a big thing, what we're focusing on, and that's why, you know, I co host the metabolic health summit and metabolic health initiative. So a big part of what we're doing, even from a lab perspective, is getting, you know, top tier medical students and PhD students and postdocs to actually work with us in the lab. So they can go on and into their academic careers and clinical careers, and be advocates for dietary approaches, and metabolic health optimization. And that could be not necessarily ketogenic diet, but just being aware of the metabolic biomarkers and the power of diet, the power of exercise the power of tracking glycemia with a CGM, like there's so many components to this that are just not yet recognized by the mainstream medical community.
Nick Jikomes 1:39:21
All right, well, we've covered a covered a lot. Thanks. Thanks so much for your time. Always glad to talk to you. For those listening. I've talked to Dominic once before the podcast. We covered some different topics in that one. So if you want to learn more, check that one out. Any final thoughts? You want to leave people with anything you want to reiterate that we went over?
Dominic D'Agostino 1:39:40
No, I think well, if you want to take a deeper dive on what we talked about, my website is keto nutrition, dot o RG and then the the metabolic health summit is a summit that we co host and it was in Clearwater, Florida a few months ago. We have a lot of top tier speakers, and many of those speakers are on the minimum Like link podcast where we take a deep dive into many different topics that we covered here. So, yeah, so for your listeners that want more information just check out their sites
Ketosis & Ketogenic Diet: Brain & Mental Health, Metabolism, Diet & Exercise, Cancer, Diabetes | Dominic D'Agostino | #158