Dominic D’Agostino Transcript

Reposted from here

Written by Christopher Kelly

Oct. 3, 2014


Chris: Hello and welcome to the Nourish Balance Thrive podcast. I’m delighted today to be joined by Dominic D’agostino, PhD. Dominic is an assistant professor in University of South Florida. Dominic’s laboratory develops and tests nutritional and metabolic therapies including ketogenic diets and ketogenic agents for central nervous system, oxygen toxicity, epilepsy, metabolic disorders, Alzheimer’s disease, ALS, muscle wasting, and cancer. Hi, Dominic. Thank you so much for coming on today.

Dominic: Thanks for having me, Chris. I appreciate it.

Chris: This is great. I wanted to start by trying to better understand how ketones are produced in the body. So I think most people listening will understand that ketones are an alternative source of fuel. How the heck do they get produced?

Dominic: Yeah. That’s a good question. I think the best way to approach describing the process of ketosis is with fasting which would be physiological ketosis or even therapeutic ketosis. So this is different. I want to say right up front that what I’m going to be talking about is far different than diabetic ketoacidosis which is a metabolic disorder or derangement associated with the absence of insulin. So if your body lacks insulin, your glucose levels go really high, and your ketone levels are not regulated by the liver. So it’s a very dangerous situation that can result in coma and death. I’ll just stop there because it’s linked specifically to type 1 diabetes where the body cannot produce insulin.

Chris: Okay. I understand.

Dominic: As we approach the topic that we’re going to discuss which is nutritional ketosis, I’d like to start with fasting because when we simply stop eating our body will mobilize fatty acids for energy. The insulin levels will drop because insulin is not needed if you’re not putting in calories. That will stimulate a faster release of fatty acids for fuel. Our body is actually very fine tuned to adapt to using fatty acids for fuel but the brain doesn’t really transport fatty acids very well across the blood-brain barrier. So initially our brain will get starved of glucose and we go through I guess what you can call glucose withdrawal in the brain.

Chris: Is that what drives the process then? It’s not that insulin starts to drop and then you start mobilizing fatty acids; it’s really the energy levels. The brain senses that it doesn’t have enough energy and then something changes with insulin. Is that the way it works?

Dominic: Well, I think initially when you stop eating there’s a drop in blood glucose. Parallel to that is a drop in insulin. You start basically mobilizing more fats for energy. As the liver starts accumulating fatty acids for energy it starts converting some of them over to a water-soluble, fat-like molecule called ketone bodies, acetoacetate and beta-hydroxybutyrate.

Now, these molecules, unlike longer chain fatty acids, ketone bodies can rapidly transport across the blood-brain barrier. The brain has the metabolic flexibility to adapt from using glucose for fuel to transitioning to ketone bodies as source of energy. In some people it happens very rapidly, and other people it can take quite a long time, and these are people who just find fasting intolerable or very hard to do. These are also maybe the same people that find a carbohydrate restricted ketogenic diet difficult to adapt to.

Chris: Right. I just wanted to go back to your original interest in ketosis. I kind of missed that point. Ketones are just a means for an end, a solution to a problem for you. I think I’m right in thinking that that problem is anti-seizure and oxygen toxicity. What’s the mechanism there? How do these ketone bodies prevent seizure?

Dominic: Scientists have known this since the 1920s, and I guess you could date back to even 400 B.C. at the time of Hippocrates that fasting could control seizures. The mechanism early wasn’t understood until we were measuring ketones back in like the ’20s and ’30s. And even today with all our technology, the anticonvulsant, neuro-protective effects of ketosis are still a mystery and that’s a big aim for our laboratory to dissect or to elucidate the molecular and cellular mechanism of ketosis for preventing seizures.


Now, our lab is primarily funded by the Department of Defense and a part of that branch is the Office of Navy Research. They know the elite fighters here, the special operations divers, the Navy Seal Divers, they use a close-circuit rebreather. There’s a lot of advantages to using this kind of technology, but one disadvantage is that the high concentrations of oxygen, which it gets more concentrated as you dive down and become a greater hyperbaric environment, the high oxygen can overstimulate the brain and cause a seizure.

Now, I became interested in understanding why that occurs and also developing a strategy to prevent that. In the process of looking at potential options, various anti-epilepsy drugs and antioxidants maybe to prevent the oxygen free radicals which could be triggering, I stumbled across the ketogenic diet as a means to control seizures in kids that were resistant to drug treatment. It occurred to me — I was actually a big fan of low-carbohydrate dieting and I was like, wow, this is something I’m already very interested in, I wonder if it would work for oxygen-toxicity seizures. The military was not very fond of putting someone on a low-carbohydrate diet, believe it or not.

Chris: Right.

Dominic: So, they wanted to develop a ketogenic strategy in a formula or a pill, so that got me interested in developing agents that could produce fasting-level ketosis, i.e. providing ketones to the brain without severe dietary restriction, and then that led to things that we are testing for the military, these ketone supplementation — esters and mineral salts of ketones — which can mimic the effect of the diet. I’m a fan of the diet and I’m a fan of the ketone supplementation, and I think like using them together offers many advantages to military people depending on kind of what task you’re faced with, but also, I mean for therapeutic applications, we’re doing active research on that, and also for enhancing exercise performance.

Chris: Right.

Dominic: This is just a brand new area and I feel kind of lucky and fortunate to be kind of at the edge of exploring the potential of using this alternative form of energy — ketone bodies — as a way to augment and enhance physical performance and also cognitive performance or brain-energy metabolism, especially under conditions of environmental stress, which could be hypoxia, altitude if you’re in the mountains, or hyperoxia, you’re a deep-sea diver or under really harsh conditions where you’re just basically tapped out of energy. I think ketones can shine in those situations where your physiology is faced with extreme demands.

Chris: So how does that extend to traumatic brain injury then? Are the problems somehow related?

Dominic: Our lab likes to say that ketones are neuroprotective. If you have a child with seizure disorder, it doesn’t seem to depend to a large extent to what’s causing the seizure. It could be a brain injury, it could be brain tumor, it could be the etiology may be unknown.

The ketogenic diet seems to work for a variety of different seizure types, so I like to say it’s neuroprotective and its neuroprotective properties are linked to its ability to supply ketones as a form of energy to the brain. If someone has traumatic brain injury, the outcome of that person, the long-term outcome of that person will depend on the results of a PET scan. So you radiolabel glucose, sugar and you look to see how the brain metabolism is influenced immediately after or shortly after a brain injury event. If the brain is consuming 50% less glucose, that’s a pretty good indication that the brain is metabolically impaired from the injury and that the outcome is not going to be very good.


So ketones are a way to restore brain energy metabolism after an injury where there’s impaired glucose metabolism. And the faster you can restore brain energy metabolism you can mitigate and correct some of the secondary consequences that can lead to brain damage later on. I think people should — football players and combat war fighters should prophylactically take ketone supplementation in the event of getting a brain injury. Not only would it potentially protect them from brain injury but it would also potentially enhance their performance at the same time.

What I’m saying here is somewhat speculation but it’s also supported by some pretty good science. Some of the science is published and some of the science resides in areas where the public can’t get to it. I think that needs to be recognized that there’s a viable substance out there that may offer some significant neuroprotective effects. The science is good enough that government agencies would fund the development and testing of this.

My vision and my overarching goal is to bring this from the military realm to the therapeutic realm. So I think that there’s a lot of potential therapeutic applications to this and I would like to exploit that to the betterment of people out there who have a variety of disorders that could benefit from this.

Also, with my personal interest in sports and exercise in general, I think this would be a great tool, I guess you would say, for an elite athlete. I think elite athletes that kind of run the fine line of going into ketosis following exercise — it’s called post-exercise ketosis — these elite athletes, the data indicates that the more elite you are of an athlete the better that you may be able to use ketones for fuel and benefit from its use during competition or maybe even training.

Chris: Yeah, that was the original draw for me. Actually, the tipping point was hearing you speak on Dave Asprey’s Bulletproof podcast. That was — I just got to do this. This is just crazy. I just have to try it at least. But, yeah, you’ve now just made me realize that actually the supplements may be more useful for protecting my brain health than a polystyrene helmet that I wear.

Dominic: Yeah.

Chris: It’s an interesting idea. So, tell me about the keto-adaptation process. What exactly is going on at the cellular level when you lower your blood glucose and start using ketones as fuel, or fatty acids in general? What happens?

Dominic: Well, I think it’s safe to say that a lot of things happened, right?

Chris: Okay.

Dominic: And I think the most important things are that when glucose is limited, it turns on a genetic program if you will that upregulates a variety of pathways that allows your body, your brain in particular, and most of the other organs — interestingly, the liver doesn’t use ketones for energy. It makes ketones but it can’t use ketones for energy. So the rest of your physiology adapts to using these ketone bodies for fuel when glucose and insulin remain low. We’re interested in actually looking at the genes and the signaling pathways and especially the global metabolomic profile so how it’s influencing the flux of all the energy intermediates. We’re up to 3,000 we’re looking at.

I think it’s safe to say that as you transition into a keto-adapted state, there’s an upregulation of the transporter which is the monocarboxylic acid transporter. Studies have shown an increase in the transcription for this protein or the gene and also the translation of the protein.


So there’s more of this protein being produced and there’s a greater density of the transporter in areas where it can serve an important role like the blood-brain barrier on the surface of muscle cells which can ultimately result in a greater utilization of ketone bodies as an alternative fuel.

There’s a variety of pathways that I could talk about but I think it kind of hinges upon the mitochondria too because as the ketones get into the cell, the mitochondria are able to generate more energy than they otherwise would be able to. Over weeks to months or even years there’s an increase in the number of mitochondria and there’s also an increase in the efficiency of the mitochondria’s ability to make energy.

Chris: Okay. So that’s the crucial piece for athletic performance too, right? I guess all of it is you get more energy per unit of oxygen, right? You just need less oxygen which is obviously the regulating factor in aerobic performance.

Dominic: Sure. That’s part of it. Yeah.

Chris: Okay. I hear people talking about how ketogenic diets can be stressful, and the adaptation process involves a flood of stress hormones. Is that true? Do you know anything about that?

Dominic: Yes. So initially what happens when you stop eating carbohydrates or when you start fasting, what happens is that your body senses that it’s hypoglycemic. That can set off, in some people especially that are adapted to a high carbohydrate diet — very adapted and sedentary — that’s like a massive stress response to your body. So your cortisol will go really high. You might get shaky. You might have even — psychologically, you might have a panicky feeling. You just feel unwell when you start doing this. Your body more or less kind of, in unscientific term, freaks out. So your stress hormones go high. Your sympathetic nervous system is activated. You have the fight-or-flight response.

Chris: Okay. So this is more straightforward than I thought. So we’ve been running lots of four-point cortisol tests on people that come into our practice. The reason is they are mostly over-trained athletes and we can find out from this test. That’s always been my understanding that whenever blood glucose in a non-keto-adapted individual drops below, say, 65, you’d start to see a stress response that would be not the normal process of regulating glucose.

We’re talking about the same thing then. We’re not talking about ketogenic diets being stressful in the long term. It’s just these initial periods where glucose might drop too low and there’s no other energy source to use.

Dominic: Yeah, yeah. So you have the scenario when you start carbohydrate-restricted ketogenic diet or fasting, you have the situation where your blood glucose goes low. The ketones are not there, really, to supply the alternative fuel so the body kind of launches a massive stress response so cortisol gets higher and that helps to elevate your blood glucose by breaking down protein. That’s a bad thing for an athlete because you’re breaking down muscle.

So I think another application of oral ketogenic supplements are that if someone wants to try the ketogenic diet, the first couple of days and probably the first couple of weeks, it would be much easier if they had a form of ketones that they could consume. That situation where it can be mitigated, I guess you would call it glucose withdrawal that the brain has can be mitigated to some extent.

Chris: So you could just get over that hump. But it’s just a hump, right? Once you’re over it and you’re able to use ketones as fuel, you don’t need to worry about the ketogenic diet being stressful in the long term.

Dominic: Yeah, yeah. Stress can be a good thing. So I’m interested into looking physiologically and biochemically how stress influences the body. If you take a normal healthy rested person and then run them to exhaustion or put them through a really hard training in the gym lifting weights and then you pull their blood out and look at everything, basically all the markers of inflammation will go up, the stress hormones go up. If you didn’t know that person worked out, you would basically look at his blood and say, “Man, this guy is really under stress.”


These are all bad things. All these markers of physiological health are going in the wrong direction. Stress hormones are up. Even glucose is high too with exercise. So the adaptation to that stress is what gives you the benefit, right? I think I’d like to use that analogy. It just kind of popped into my head. But I think if you exercise someone and everything goes in the wrong direction and there are a lot of bad things happen biochemically, but the adaptation to that stimulus is what the benefits that you’re going to get. I think the same thing, to a certain degree, happens when you initiate a ketogenic diet or fasting.

Now, some people say when you start this — the fat contains a lot of, shall we say, toxins. So when you fast, you’re releasing a lot of toxins in your body and your body is cleansing itself. I don’t know about that. People have put out theories but I basically just think your body senses it as a massive stress. Your glucose may actually even increase because your cortisol levels go up. Some cancer patients, especially ones that are overweight, if they want to therapeutically use this to metabolically manage a tumor and they start fasting, they get their blood glucose down, they may see a spike up in the first couple of days just because there’s a stress response but it’ll come back down in time.

The same thing happens with people. It may lead to a dysphoria or a feeling of not being well. I mean, it can actually make you feel sick and feel light-headed. That can be, for the most part, mitigated by taking in plenty of fluids and minerals and making sure your sodium is high and potassium is high and replace the electrolytes because when you start fasting or go on carbohydrate restriction, you lose a lot of water because insulin goes low really quick.

If you suppress the hormone, insulin, it has a diuretic effect. So you start losing a lot of water and that decreases your plasma volume, your blood volume, and it’ll make you — basically it’ll reduce blood flow to your brain just because your plasma volume is less. So you just want to make sure that you get in minerals and sodium. Soup broth is a good way to do that. It doesn’t have any calories.

Chris: Sorry. Can you name that again?

Dominic: What’s that?

Chris: Sorry.

Dominic: Soup like just bouillon.

Chris: Oh. Sorry. I thought you just named the name of a product. Yes. So bone broth is —

Dominic: Yeah. Bone broth. Yeah, yeah. That’s a great tool, or just simply a bouillon cube, beef bouillon or something like that. If you take someone who tries to do like a distilled water fast, it could be difficult for them because they’re losing a lot of minerals. I mean, your body has a lot of minerals to lose. I think it can help, especially initially, to replace some of those minerals so your blood pressure doesn’t drop too fast.

Chris: Yeah, I think I noticed this on the bike actually as an increased heart rate for the same given power. It went up quite a lot by 15 or maybe even 20 beats. It’s not all the time. I think the fluids thing is definitely connected. I’m not exactly sure how much salt or how much water it requires to solve the problem but I’m sure the two things are related.

Dominic: Yeah. As your fluid volume drops, yeah, your heart is going to have to pump a lot harder, obviously. Some people do report having palpitations or rapid heart rate. That can be largely attributed to a decrease in overall plasma volume from the diuretic effect of having suppressed insulin with carbohydrate restriction.

Chris: I’ve heard you talk about increased sensitivity. We spoke about this just briefly. I’d like you to describe that a little bit more. What do you mean by that increased sensitivity? We’re talking about cell receptocides, right?

Dominic: Yeah. Oh, sensitivity-wise?

Chris: Yes, sensitivity. What happens with the keto-adaptation process to become more sensitive?

Dominic: Yeah. Well, again, a lot of things happen. In regards to the topic that you’re interested in — muscle — with fasting or carbohydrate-restricted diet, in many athletes, there could be an increased sensitivity due to a greater number of glucose receptors on the surface of the membrane. So as glucose availability drops, one countermeasure that your body has is the production of more transporters and the translocation of that transporter to the cell membrane.


If your glucose levels drop by 30%, you may have an upregulation of 30% or more of the actual transporter to get it into the cell. So there’s a lot of compensatory mechanisms that your cells use to transport glucose, but over time, what you may find is that muscle cells in particular start adapting to using fatty acids for fuel. So you can take someone who’s carbohydrate-adapted and look at their respiratory quotient and determine that there can — burning primarily mostly carbohydrates for fuel and then take someone that’s keto-adapted — or fat and keto-adapted I like to say — and determine through a variety of measurements that they’re burning primarily fat for energy.

It’s interesting to me, and really fascinating. Jeff Volek, who’s now at the Ohio State University, is doing a lot of great work in this area with advanced athletes and showing that you could take two athletes to have completely different metabolic physiology, meaning that you have one guy basically using a different fuel source than the other guy or, largely, his fuel source is vastly different than the other guy and they’re performing at the same level. They’re both performing; they’re competitors against one another. I find that fascinating and the compensatory mechanisms —

So what I think we can learn from it is that we can identify what’s optimizing performance in a carb burn and what’s optimizing the performance in a keto-adapted person and try to find some kind of hybrid between the two, and can you have your cake and eat it? Can you be carb-adapted and also be able to use ketones and fatty acids more efficiently for fuel?

I think there’s a push in that direction. So basically, staying ketogenic during the day or for most of the time but during exercise maybe throw in sources of carbohydrates to function as an alternative fuel if you’re fat-adapted. I think it’s going to be different for each person and for the type of activity that they do.

Chris: Right.

Dominic: That’s where the art of really a good dietician who knows, who is savvy with low carb diets can really take a person and work with them to understand their physiology and then develop a program to — whether they think they’re maxed out. I think a good trainer can take a person, learn their physiology and increase their performance by 5% to 10%. And that’s a tremendous amount. I’ve seen that happen.

Chris: Yes. So that’s kind of where — you just described a lot of things that happen to me. So respiratory quotient is obviously something you need to go into the lab to measure, but I know coming from a real sugar-burner type background where I’d be experiencing those symptoms of hypoglycemia after even 40 minutes of not doing any maltodextrin or some sort of sugar-based food supplement to now where I can go on four- or five-, even six-hour rides on nothing at all and not feel hungry any time during that ride. I think that definitely — that was me. I mean, you just can’t be burning glycogen during that time. At least not entirely.

So I’ve been delighted with the difference it’s made to training. I seem to be going just as fast but for the racing, particularly at the moment, I’m doing cycle- cross races which is only a 45- or 60-minute race on a bike. The course is very twisted and turny. On the face of it, it looks like a time trial but actually it’s really a series of short sprints and so you’re constantly tapping into all that power and I’ve noticed a significant decrease in power, which is probably mostly actually just maybe I’ve not been training as hard. It’s very difficult to tease this out but knowing what you know, would you suggest adding back in some carbs then and when would you do that?

Dominic: Yeah, that’s a good question. I think it really depends on the person’s physiology and their carbohydrate tolerance. You need to experiment. I know it doesn’t seem to answer the question but I think a person needs to take it upon themselves to try —


The ketogenic diet is a big, big radical shift for most people that are carbohydrate-performing athletes. And I think for them to give it an honest try, they’ve got to give it a minimum of like to four to six weeks to start to get the benefits, and I say like two to three months really. I think you keep getting benefits beyond a year, like the more you do the ketogenic diet, the more benefits you derive from it and the easier it becomes too on a day-to-day basis just to eat low carb, so I think that needs to be appreciated.

But I think I would really urge people to kind of do a self-experiment and measure out the kind of carbohydrates that they give themselves during exercise, pre- and intra-workout, and also even it’s a good idea and it’s relatively inexpensive to measure your blood glucose levels. So, if your glucose goes really high, it would indicate that you are giving your body more carbohydrates than it can use, so you want to be able to titrate in the carbohydrates and to ensure that your glucose levels do not go too high because you are kind of spilling over, if you will.

Chris: Yeah.

Dominic: A glucometer is a pretty useful performance enhancement tool and I’ve seen a couple of athletes that I know, all they use — they don’t even check ketone. They just use a glucometer and then basically they say they have been able to radically alter their body composition and also enhance their performance just by titrating in the carbohydrates.

Now, these people are not — well, one person is a ketogenic diet follower. Most of these are basically guys that follow a high carbohydrate diet and they titrate in the amount of carbohydrates they need simply by tracking their blood glucose response to a meal and then they know how much they can tolerate and they know how much would be needed to optimize their performance based on a combination of objective measurements with the glucose meter and subjective measurements, kind of how they feel and their GI tolerance and a variety of things.

Chris: That was an enormously useful tool for me, and there is really no reason — we talked about this before in the podcast, but there is really no reason not to do it. You can buy one of these meters for $7 from Amazon.

Dominic: Yeah.

Chris: So it’s just ridiculous not to even do it. Yeah, the other thing I have been using is UCAN SuperStarch, which I found has been really useful for this. So, I’m really sensitive to carbs and even a few squares of chocolate will send my blood glucose north of 120 but UCAN SuperStarch doesn’t do that. It really has minimal impact on my blood sugar at all. It’s almost unmeasurable, so that stuff would be an awesome trick.

Dominic: Yeah, I’ve tried a few of those resistant-type starches and had the similar experience. It never goes above 100 for me even if I take a pretty big dose.

ChrisI think it is actually it might be the second worst tasting substance after — maybe. I’m not sure. But while we are still talking about keto-adaption, I wanted to talk to you about oxidative stress. So, one of things I have been doing over the years is running this organic acids test. It’s made by Genova Diagnostics and they have a couple of markers on there where they are looking at these organic acids and the urine that claims to show levels of oxidative stress of both cell turnover and damage to the DNA itself. I’ve noticed a quite significant reduction in oxidative stress in switching to a ketogenic diet. Again, it is very difficult to tease out. There is no control obviously, but I’m right in thinking then that there is a plausible mechanism there that the ketogenic diet does reduce oxidative stress?

Dominic: Yeah, yeah. There is evidence in our lab and in other people’s labs that support it. There was a publication in science actually that suggested that — well, it didn’t suggest. It showed convincingly that beta-hydroxybutyrate, the primary ketone body is a powerful endogenous histone deacetylase inhibitor, HDAC inhibitor, I guess.

That’s a very hot area of pharmaceutical research is developing synthetic agents to work the same way to target histone deacetylase, and in doing so that can upregulate a number of endogenous antioxidant mechanisms and perhaps allowing your body to withstand the greater oxidative stress. We think that’s just one of the mechanisms involved in there that it can work acutely because we have actually given ketones and given induced oxidative stress and it can blunt that but I think over time it can also influence gene regulation that can provide the body with better antioxidant defenses and the science is pretty solid behind that.


Chris: Yeah, it’s fascinating.

Dominic: Really, I like the idea of pre-conditioning and helping your body kind of help itself, instead of throwing in exogenous antioxidants which, from the literature, just doesn’t really seem to do much. It’s just kind of confusing, and it can also block some of the adaptive responses that we want to occur, right? Oxidative stress could be a trigger for the adaptive response that can allow us to adapt to a subsequent challenge whether it be exercise or anything. I like the idea of coaxing our bodies or doing something through our physiology that can enhance that process, instead of just throwing in —

Chris: A crutch.

Dominic: Yeah, yeah. Antioxidant.

Chris: Okay. And then I wanted to ask you obviously about ketone supplements. We start with the most basic thing that’s pretty easy for everybody to get hold of, MCT oil, which is something I use quite a lot of now. How the heck does it work?

Dominic: Yes, MCTs are metabolized all different than long-chain fatty acids.

Chris: And then even different from coconut oil, right?

Dominic: Well, coconut oil is a mix of different fatty acids from six carbon up to 12 and 14, and it does have some CA and C10 but the medium chain — by straight medium chain fatty acids, it’s kind of the C8-C10, and that’s the carbon length of the molecule. It puts it in the current category as a medium length, they’re medium chain fatty acid. When these are consumed, they are rapidly transported to the liver.

I guess the simple way to explain it is that it stimulates the liver. It simulates fatty acid oxidations so much in the liver that you get an accumulation of acetyl-CoA, and that ultimately results in the condensing of acetyl-CoA to acetoacetate and ketone bodies. So you have accelerated fatty acid metabolism in the liver and that contributes to the accumulation of ketone bodies.

Chris: Okay, so it’s not actually the oil itself or necessarily the oil itself that’s being metabolized. It could be other fatty acids too that didn’t come from the MCT?

Dominic: Yeah, well, it’s the nature of the medium chain fatty acids and that they bypass the typical way that we are taught that fatty acids are metabolized or transported through chylomicrons and then through the lymphatic system. And then they have kind of a more circuitous way of transport in the body where if you drink MCTs, they go to your stomach and the small intestines and then rapidly sent to your liver and, through first pass metabolism, the liver gets a big hit of fatty acids. It burns them up if there’s very rapid metabolism. And because the metabolism is so rapid, you accumulate energy intermediates that are then transformed into ketone body pieces. And then these ketone bodies get to your blood stream and then they function as an alternative energy source.

Now, what’s interesting with MCTs is that you can eat a high carbohydrate diet and still able to achieve a mild level of ketosis if you take in enough MCTs. The problem with MCTs is that they can cause gastrointestinal distress probably in about 30% of people who take MCTs. I mean, everyone has a level. I’m talking about just 15-20 milliliters, like a tablespoon, will cause issues in about 25% to 30% of people.

In some people like me who have adapted over the years, I can probably take in a couple of tablespoonfuls and be okay. I can use them — on an empty stomach, it may unsettle my stomach and cause some issues but if I was to eat a small meal and take two tablespoons of MCT, I’d probably be fine.

Chris: Yeah, I’m the same way. I kind of got used to it. It was very sensitive at first and I think that’s really common from what I’ve heard from other people. But I’ve noticed with, say, Dave Asprey’s Bulletproof Brain Octane, if I have more than a tablespoon of that, it makes me really jittery, like kind of overstimulated. It’s quite strange.


Dominic: Yeah, like you had too much coffee or maybe even anxiety. I have experienced that too, the combination of caffeine and medium-chain triglycerides. We found in our most recent study — we’ll publish it soon — is that the medium-chain fatty acids actually cross the blood-brain barrier and go right to the brain unlike the longer chain fatty acids. So when we did experiments and harvested a brain tissue we found the levels are really high in the brain. So it’s advertised that these actually do go to the brain, and we found that to be the case.

Most of the fatty acids that you get from dairy or meat and steak they don’t have that ability to do that. Now, what does that mean? What are the practical implications of that? One implication is that if your blood glucose is low you can take MCTs, and not only will you generate ketones for your brain but the fatty acids, the medium-chain fatty acids themselves, will get to the brain.

I like to say that ketones keep the brain happy even when you are in a calorie deficient state. That’s really one of the benefits of using the ketogenic diet for weight loss is that by keeping the brain happy and the brain thinks it’s getting enough calories because its energy status is fulfilled by the ketone bodies, it makes it easier to regulate your appetite.

Now, appetite regulation is incredibly complex and I’m not really qualified to go into all the mechanisms because I simply don’t know, and people just don’t know all the factors related to behavior and appetite. But what I have seen documented in the literature and just anecdotally is that being in the state of ketosis makes it very easy to regulate what you eat and to regulate your appetite and that’s very important for long-term maintenance of weight loss. I mean, in the United States we don’t have a weight loss problem. Most people can lose weight, if given the effort, pretty easily. The problem results in keeping that weight off and I think carbohydrate restriction allows a person to regulate their appetite in a way that they can sustain that weight loss.

Chris: Do you think that could be a double-edged sword for athletes? Say, for me, where I’m regularly going out and doing long bike rides where I might burn, say, 3,000 calories but still feel just fine, not really feel like eating very much more food, do you think that could be a problem in the long term?

Dominic: It depends on what your sport is.

Chris: Right.

Dominic: Everyone likes to eat, right? I would say I start to lose weight when I just get too busy. I basically end up waking up and eat breakfast and I’m so busy at work with a lot of different things I don’t have time to eat and so I eat dinner. I basically eat two meals a day, spaced about 12 hours apart. I never could have imagined in my wildest dreams, when I was 18, 19, 20, consuming like six meals a day that I could ever do that.

Chris: Yeah.

Dominic: But a high fat ketogenic diet, I mean, it becomes very easy to do. Just because I don’t eat as much food I’ve lost a significant amount of weight. But I was pretty heavy. I had a lot of muscle because I was into powerlifting and everything. So I dropped from 250 pounds to 220, and then 220 is kind of what my body feels good at naturally.

It depends on your sport. For biking even, it involves maintaining a certain level of muscle mass although if you get too much muscle that’s extra weight you’re carrying around. So your power to weight ratio is important. I think when it comes to nutrition and the ketogenic diet, I think you can optimize your power to weight ratio with the ketogenic diet. So that comes into play for bikers and gymnasts and things like that.

Chris: Uh-hmm. The different types of ketones, there’s more than one type, right? What type exists at the moment?

Dominic: Well, there’s some actually excellent work that has been done at the NIH and Oxford University to develop and test an ester of beta-hydroxybutyrate. It’s not commercially available yet. So that’s beta-hydroxybutyrate ester.

Now, there’s a beta-hydroxybutyrate mineral salt that’s available as a product called KetoForce. All one word — KetoForce. That’s sold by Prototype Nutrition. That’s kind of one that we test in the lab. We find that when we combine that with MCT we get a really nice pharmacokinetic profile of the ketone bodies.


So the combination of MCTs, which are readily available and cheap, with KetoForce, and I think you need to experiment starting with a low dose and combining them together in a 1:1 ratio and then working up has been what seems to be working for athletes, advanced athletes that I’m in contact with. I have used the combination myself. It takes a while getting used to the taste of the KetoForce. It needs to be diluted to 5% to 10% solution to be palatable.

Chris: Yeah. That’s the one I’ve been using. It does. It tastes horrendous. But, yeah, I’ve learned more recently that you need to dilute the heck out of it and just drink lots of water with it. But, yeah, someone suggested to me. It was actually Chef Rachel. You know her. Rachel Albert suggested using a tiny bit of stevia and then some lemon juice and/or apple cider vinegar with 12 ounces of water. As you said, it tastes like lemonade which makes sense to me.

Dominic: Yeah, yeah. It tastes like a salty lemonade.

Chris: So why would you call it a poor man’s version of the esters? Where does that come from?

Dominic: Okay. So I described to you beta-hydroxybutyrate esters which are something developed for military applications at Oxford and NIH. We have developed — and then the ketone salts can elevate beta-hydroxybutyrate but to get levels up really high may be difficult to do with the salts unless you adapt over time and can tolerate a lot of it.

Now, another ketone ester that we have is acetoacetate. When you consume the acetoacetate ester, your body basically makes a 1:1 ratio. It elevates both ketone levels in the blood. We have done a lot of work with this in cancer research and also seizure studies with oxygen toxicity. So this would be acetoacetate ester, ketone ester.

Now, this is a pretty potent molecule for elevating ketones and sustaining levels of ketones for a long time. It tastes like jet fuel. I would not advice drinking it just because it tastes so bad. I mean, it can literally lead to a gag reflex. It smells that bad. So the palatability is an issue.

I think there’s a definite application for this for seizures. I also think the application exists for cancer. But it is expensive so to make esters of ketones involves a certain level of chemical expertise and also a manufacturing facility. As of now, that facility does not exist. The science is accumulating and I think with enough interest and science to back it up there’ll ultimately be ketone esters that are affordable. They’ll probably stay in the realm of military applications, the very elite level athletes.

In the meantime though, I think a product like KetoForce, which is a ketone mineral salt, and then maybe some variations of that in the future, may ultimately close the gap. KetoForce is derived from natural substances. You may have a naturally derived ketogenic supplement that closes the gap and is basically as potent as a ketone ester.

But I don’t necessarily believe getting your ketone levels up to like 5 millimolar is going to give you more advantage than like 2 millimolar. As your ketone levels get too high, it also produces a mild metabolic acidosis that your body has to deal with. So that’s kind of a debate and I think it needs to be further studied. What’s the optimal level of ketones? I think anecdotally and from the data that I’ve seen, I think somewhere between 1.5 and 3 is optimal.

Chris: Okay. Why does my blood glucose drop so dramatically? I’m not very good at keeping it low. It’s often the 80s. High 80s is pretty normal for me. But when I take the KetoForce, it knocks 20 points of my blood glucose almost straight away. So what’s going on there?

Dominic: Yeah, I saw that too. We see it in our experiments we do with animals and a number of people, blood work I’ve looked at and see the same thing. I think the glucose lowering effect of ketones is, really, from a therapeutic perspective it’s very interesting to me and — I don’t know why it happens. I think there are maybe two reasons why. The liver output of glucose is reduced so as you take in ketones, it decreases gluconeogenesis. That could be beneficial because it could stop the breakdown of muscle — skeletal muscle protein, for example.


Another potential thing could be that it’s enhancing insulin sensitivity. And also the ketones, if it gets high enough, could cause a small release of insulin which could allow for greater glucose uptake. But I really think it’s working by inhibiting the liver’s output of glucose — gluconeogenesis. I think it’s working that way. The drug, Metformin, works that way. It can lower glucose in that way. I think the data that I’ve seen coming out suggests — because if it was an insulin mechanism, you’d be able to look at insulin. It’ll be higher, and we haven’t seen that. So it appears to be just reducing the liver’s output of glucose.

Chris: That would also make sense with the Superstarch. I’ve noticed a similar but milder effect with the Superstarch so it’s almost — it’s counterintuitive. You consume 100 grams of carbohydrate as a Superstarch and then you’d expect to see that as a glucose response. But, normally, what I see is, especially if I do a hard ride where you’re going above the threshold where you could reasonably expect to be using fat, that you start to see some stress response and maybe some — obviously, the liver starts kicking in and producing some glucose.

It’s really common for me to check my blood glucose after I get back from a ride and it’s lower after I’ve used Superstarch than it would have been had I not taken anything at all. I wonder if that’s consistent as well like that. The hepatic output continues even after you get off the bike obviously. And I don’t know, but it’s interesting.

Dominic: Yeah, so maybe in some way it’s altering hormones in a way that helps you better utilize glucose for fuel, so your insulin sensitivity might go up. So that’s another thing that we want to look at.

Chris: So that’s kind of one of the ways. Do you think then it’s still useful to keep carbohydrate in the diet so, even if you’re aiming for ketosis, you shouldn’t be aiming for zero carbs?

Dominic: That’s a good question. I think it really comes down to the person needs to experiment. But I don’t think there’s any harm of transitioning into a ketogenic diet just by gradually reducing carbohydrates. That’s one way to do it, or you can abruptly do it, just 25 grams of carbs or less, or 20 grams of carbs or less and just go full steam at it. But I think the important thing to recognize that you need to fully assess the low carb diet on performance. You need to stick with it for at least six weeks and then give it a try and don’t be afraid of fat. Fat is your friend. Fat is a great fuel.

Chris: Yeah, absolutely. And so what about strength-based athletes then? I mean, this is all good news for me as a cyclist trying to go up a steep hill, but if I’m a strength race guy like really into cross-fit or body building or something like that, do you think that the carbs are required to make gains in those areas?

Dominic: Yeah, that’s a great question. I’m looking at the time now. I got to go give another talk. I’d like to leave off on this because just where I called you, I’m actually working on a manuscript right now, which is a compilation of our data in body builders or performance athletes or power lifters that did a ketogenic diet and that did a pretty comprehensive measurement of blood and body composition and strength.

I’ll kind of give you the bottom line is that the data is very interesting and suggests that if someone is embarking on maximizing their power to weight ratio, the ketogenic diet definitely has some advantages. And we found that there was no disadvantage at all in regards to losing muscle. There was no muscle loss. The people in the study actually gained muscle on a ketogenic diet. So I think this will be the first study to show that you can gain muscle on a ketogenic diet, and the level, the amount of fat that they lost was greater too than the western diet that they consumed.

Chris: Wow. That’s very interesting. I look forward to seeing that. Will we see that in public or is that going to be another –?

Dominic: Yeah. Yeah, yeah. That’s being prepared for peer reviewed study.

Chris: Wonderful. Thank you. Well, thank you so much for your time today. It’s greatly appreciated. I know it’s extremely valuable and I — yeah. This has been fantastic. Thank you.


Dominic: Thanks for having me, Chris. I appreciate it. You had some great questions. I love what I do and I enjoy talking about my research so I really appreciate the opportunity and would love to do a follow-up too as our research advances.

Chris: Absolutely.

Dominic: Thanks. It was great meeting you too at the Ancestral Health Symposium. I really enjoyed talking with you there.

Chris: Likewise. Thank you. Okay then, Dominic. Cheers then.

Dominic: Okay. Cheers. Talk to you soon.

Chris: Bye.

Dominic: Bye-bye.

[0:55:33]End of Audio

More on Dominic D’Agostino

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About the Author Michael Lantz (Big Papa)

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