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  • 1. ARI: Welcome to the Less Doing Podcast. Today my guest is Dr. Dominic D’Agostino, an assistant professor at the University of South Florida. His research involves ketogenic diets, metabolic syndromes, and some really cool stuff that we’re going to cover today. Dom, thanks for being on the show. DOMINIC: Thanks for having me, Ari. Appreciate it. ARI: Absolutely. Let’s jump right in. Let’s talk about what your focus of research is. I know that it’s changed a little from what it originally was supposed to be, right? So what’s your focus? DOMINIC: At the simplest level, we develop and test ketogenic diets and metabolic therapies, which include supplementation. Under that would be ketone supplementation for a variety of disorders, including seizures, Alzheimer’s disease, cancer, ALS, wound healing, just to name a few. But yeah, those are the major ones right now. So basically with an emphasis on diet and nutritional supplementation for these disorders, and less on drugs. We do a little bit of drug research, but it’s 90% diet. ARI: Now, how did you come across – from what you told me before, you originally were trying to find a better drug. So how did you get on the path of looking at nutrition, and specifically the ketogenic diet? DOMINIC: I was funded by the Department of Defense, and under them is the Office of Navy Research. Divers use a closed circuit rebreathing apparatus, the Navy Seals and Special Ops guys use that, and the advantage is that it’s very quiet; the disadvantage is that it can create seizures underwater, and these seizures are resistant to drugs. They’re very powerful, what we call grand mal seizures, or tonic-clonic seizures. And giving a Special Ops guy or a Navy Seal anti-seizure drugs is really not a good idea, because it can dull your senses and impair your performance. So I looked into alternative strategies to prevent this, to test in the lab, and I found the ketogenic diet was actually more effective than drugs for preventing seizures. It really blew my mind, the research behind this. So I focused on the ketogenic diet, not only that, but developing I guess you can say a ketogenic diet in a pill. The version that we’re testing is a ketone ester, so you take it orally. Within 15 minutes you have a level of ketones above and beyond what you could achieve with a ketogenic diet. The function of the ketones is that they provide an alternative fuel for the brain, and if the brain has lots of energy, it can actually withstand the oxygen toxicity that triggers a seizure. And the ketones themselves also have neuroprotective properties. So it led to that, developing a high power nutritional supplement based on the ketogenic diet. And then we found that ketones had all these other applications. Because they function as a very high, dense source of alternative energy for the brain, that they had applications in Alzheimer’s disease and in ALS. We’re looking at cancer now. Cancer cells have a defect that prevents them from using ketones for energy. They basically have dysfunctional mitochondria. The mitochondria is where the ketones are actually oxidized to make ATP. And wound healing, too. Ketones increase brain blood flow; they also increase blood flow to the periphery, and we can
  • 2. observe this. So they have a number of applications that just kind of exploded out of our seizure project. ARI: Wow. Without backing up too much, tell me what ketone esters are. DOMINIC: Your main ketone bodies that your liver produces under periods of carbohydrate restriction would be acetoacetate and beta-hydroxybutyrate. The function of these ketone bodies – think of them as like fats that are water-soluble. You stop eating or you restrict your carbohydrates and you deplete your carbohydrate stores, and your brain is craving some source of energy, and it can’t really use the fats very effectively because they can’t cross this blood- brain barrier, we call it. So the fats are converted to ketone molecules, which can get to the brain, and they provide energy to the brain. What we’ve done is taken basically the two ketone molecules, beta-hydroxybutyrate or acetoacetate, and we’ve made supplements out of them, either mineral salts of beta- hydroxybutyrate, or esters of acetoacetate. Essentially what an ester is is that you take the ketone molecule and combine it to something that stabilizes it so that when you ingest it orally, your body can break it down in a controlled fashion and it releases the ketone in a rapid and sustained fashion so you have elevated levels in the blood. And that ketone body is actually providing a super fuel to your tissues, and most importantly, your brain and heart. ARI: The fact that you’ve been able to isolate that – now, how is what you’ve created, the ketones in a pill, how is that different from taking MCT oil, for instance? DOMINIC: MCT oil, when you ingest it, it goes to your liver and is processed and broken down into – it can become ketone bodies through liver metabolism. The elevation of ketones that you get with MCT oil is relatively modest, maybe half of a millimolar or 1 millimolar, if you’re into measuring your blood, like I know a few guys out there are. Another problem with MCT is that you have this issue with tolerability. Some people can tolerate several tablespoonfuls, like me, actually. So I can get my ketones pretty high, actually, with MCT. Other people can’t even tolerate a teaspoon. They’re running to the bathroom with a teaspoon. So that’s a limitation. A fatty acid is something that really needs to be processed by the liver for your body to make ketones. The advantage is it’s a natural source, it’s cheap, it’s readily available. Ketone salts, or ketone esters, are kind of like straight up ketones. You take it and bam, you get rapid elevation of ketones. It might not be one or the other that’s optimal for whatever application you’re using it for, cognitive or physical performance, but we actually find that when you combine these things, a ketone salt or ester with an MCT oil, that they work kind of independently, but synergistically in a fashion that can help elevate and sustain ketones. So it’s not maybe one or the other, but a combination of the two will likely be your best bet. Depending on your application. ARI: That’s interesting. My first question with that then is can you overdose on ketones? Other than the [inaudible 00:07:38] thing.
  • 3. DOMINIC: Well, we’re doing studies now in our rodent models where we go very high in ketosis, and there is a level where you basically start to feel drunk. You feel sedated because your body’s dealing with – too much of anything will be toxic, right? The ketone bodies will start to – you’re probably familiar with diabetic ketoacidosis, or alcoholic ketoacidosis? ARI: Right, the fruity smell. DOMINIC: Yeah. These are a little different, because with diabetic ketoacidosis, your blood glucose is really high, like astronomically high, and your ketones are high. The combination of those two produces an acidic condition in the body. It can cause coma and death, even. Toxicity with a supplemental ketone would be very, very difficult. You’d have to consume a ton of the stuff, and your body has a great capacity to eliminate what it doesn’t need, and it would be expensive. The limitation to toxicity would be your gastrointestinal ability to absorb it and get it into the system. People talk about “If I can get my ketones up to 1 or 2 millimolar” – I was just on the line before you with some researchers who think 1 to 2 millimolar is the sweet spot for performance enhancement. That’s really not achievable with MCT. You get almost to 1, but with a ketone salt and a ketone ester, that’s very achievable. But you can also achieve 5 or 6. I believe that 5 or 6 millimolar would be good if you have, for example, severe seizures. But for performance enhancement, I think it’s putting – ketone bodies are mildly acidic, so at that level, it may be creating an acidic load that your body has to deal with. Although the salts of our ketone products are buffered with minerals that are very alkaline, so they’re kind of pH balanced, you could say. But I don’t think there’s any advantage to going over 3 millimolar of ketones. Many of the leading researchers would probably support that, like Jeff Volek, a colleague of mine. He would probably say, yeah, once you get above 3, your body’s just working to get rid of it, rather than – unless you’re really all-out sprinting or something like that, or maybe an Ironman athlete. Maybe 2 or 3. But your body’s using it so much, so it’d probably be hard to get up to that level if you’re in the middle of training or in the middle of cycling or whatever event you’re doing. ARI: I’ve done Ironman, and I looked at all sorts of different training methods, and metabolic efficiency was one that came up a lot. Now, I personally was self-directing, and I was basically on a diet that was almost 85% carbs at the time. Which was fine for me, honestly, except for the fact that I was eating every hour, basically. DOMINIC: That’s a disadvantage right there. ARI: Exactly. And had to eat on the bike and all that stuff. It was fine. Also, the remnants from that, because it’s completely different from what my diet is now, is that I got ridiculous sugar addiction once I stopped eating that level of carbs. And I don’t have an addictive personality. I know that from years of stuff, and I have legitimately had a battle with a sugar addiction since then.
  • 4. I guess there’s two motivations for looking at a ketogenic diet. One would be if you have an actual disease, something like cancer or some other metabolic syndrome where you really need to starve your body of glucose. But then there’s this other side, which is performance-enhancing, cognitive-enhancing and energy-boosting. Personally, right now, my motivation for having ketones in my body – and I’m not saying ketogenic, because I’m certainly not. I am not low-carb, I’m not 85% carb. My current diet is pretty much high fat. My motivation is that my wife and I have a 22-month-old and twin 6-month-olds, and neither of us sleep very much, and I find that having high fat in my diet is pretty much the only way that I can not just get through the day, but actually really function at a high level. But I’m not getting the benefits of the disease-fighting aspect in that case, because I’m sort of cheating. DOMINIC: Well, you’re pushing your body from being a sugar burner to a fatty acid and perhaps ketone burner. I don’t know what your ketone levels are. But whenever you shift away from a glycolytic or glucose-based metabolism to a fatty acid metabolism, especially with your level of exercise performance, you’re forcing your mitochondria to be more efficient. You’re probably stimulating mitochondrial biogenesis. The healthier your mitochondria are, the greater capacity you have to deal with stress, the more efficient you can convert food into energy. In a high fat diet, your meal frequency goes way down, you’re satiated. I used to eat like six to eight meals a day, actually. I eat two now. I eat a breakfast and a dinner, and they’re spaced 12 hours apart, and I don’t get hungry during the day. I have some bulletproof coffee during the day, maybe some branched-chain aminos. But it’s extremely more practical. I cannot even fathom going back to my early pattern of eating, where I look at my watch and I see, “Okay, two and a half hours went by, I’ve got to eat.” With my lifestyle, I just can’t do that, with teaching and research and everything else I do. It would be very inconvenient to do that. And I understand where you’re coming from with being a family guy and juggling a lot of things in your training. I can see how that can be a very enormous practical advantage. But you probably are realizing the performance enhancement effects, too, of the high fat intake. ARI: But not necessarily the disease prevention aspects, right? Like the cancer or – I mean, I don’t have a seizure issue, but those kind of things. DOMINIC: Yeah. For cancer prevention, I think generally just a low carb diet is best. You may want to periodically do a fast, like a short-term fast, three to five days. What that does is, say you have precancerous cells in your body, if you go into fasting ketosis, it’s putting an enormous amount of metabolic stress on those cancer cells that are in your body and essentially purging them from your system through autophagy. Your body can deal with them. I think that was probably part of our normal evolution. We did that. But I tell people who don’t want to do a ketogenic diet, just prevention. Just eat low carb and periodically go into nutritional ketosis a couple times a year. For people who really don’t want to do a ketogenic diet, I think prevention’s a cure for cancer, and periodically going into ketosis could be a very effective strategy to prevent it. And just avoiding any kind of processed carbohydrates and keeping your blood sugar in check, exercise, just kind of the basic things. But
  • 5. a calorie-restricted ketogenic diet for the rest of your life is not very feasible. I actually think the body is best when you cycle it. You do periods of maybe overfeeding, if you have a goal to increase muscle size or strength, and then periods of under-eating is probably the best way the body works. ARI: I think that’s a very good way to frame it. You mentioned nutritional ketosis. For people who don’t really know what that is – because that’s not exactly the same as saying a ketogenic diet. We’re talking about an in between, aren’t we? DOMINIC: Nutritional ketosis is any nutritional method you use to elevate blood ketones. That’s my thing. But typically, historically, it’s been carbohydrate restriction. If you restrict carbohydrates, your glucose goes down, your liver glycogen gets depleted, and your liver starts pumping out these ketone bodies to replace glucose. ARI: Right, that’s the distinction that I want to make for everybody. With a ketogenic diet, it’s more of the idea of eliminating – not eliminating, but restricting severely carbohydrates and protein due to gluconogenesis for the purpose of cutting out glucose. Gluconogenesis being the process of your liver turning lean proteins into sugars. Nutritional ketosis is sort of the other side, where you’re just looking at raising the available ketones in your body. It’s very, very important to me that people realize this distinction, that you sort of can have your cake and eat it too. As long as it’s a low-carb cake. DOMINIC: Yeah. It really depends on what your goal is. If your goal is to manage seizures, you probably need to be on a strict ketogenic diet to optimize that. Cancer prevention, periodic carbohydrate restriction to induce ketosis could be optimal. If you are an athlete – this begs the question about – and I get this a lot in advanced athletes – sprinters, I don’t think should be on a ketogenic diet. Maybe a targeted ketogenic diet where you throw in carbs during the actual event just to maintain muscle glycogen. But for triathletes, I think adding a little bit of carbs in there, like Ben Greenfield does maybe 100 grams a day or 150, just to keep maybe your muscle glycogen topped off, may be optimal. You might be able to have your cake and eat it. Because I think he even registers ketones with a relatively high carb intake. If you’re real active, you can get away with it. You can save your carbs for your dinner. I did that for awhile. When I’m real active, I basically just go ketogenic all day, work out, go home and eat dinner, and just have a salad, vegetables, half a sweet potato, something like that. ARI: And that’s also another good point. My understanding is that triglycerides are a good indicator of your carb tolerance, right? DOMINIC: Yeah. I think they’re a great biomarker. ARI: Which is really cool. And anything under 100, as I understand, is considered to be pretty good. If you’re going above 100, then you’re probably having too much carbs. You know Jimmy Moore, cholesterol clarity guy?
  • 6. DOMINIC: Yeah. Jimmy’s a great guy. ARI: Jimmy’s awesome, and I had a really cool interview with him. Of course, we had to start comparing numbers. What I thought was really funny, I think – yeah, this is what it was. When we had the interview, which was maybe a month or so ago, I had just had a blood test because I knew I was going to talk to him, and my triglyceride level was 57. Which is great, and I don’t think I’m low carb, but 57 is really good. I looked back at my blood results when I was 85% carb, when I was training for Ironman, and my triglycerides were 74. So apparently, I can handle quite a bit of carbs and still have ketones floating around. DOMINIC: Yeah. That’s probably because you were – it also depends on your calorie balance. If you’re in a high carbohydrate diet, but you’re at even a mild calorie deficit, like 10%, 20% for that week or something like that, your triglycerides are going to be low, because you’re pulling them from your system and oxidizing them as fuel. But keep in mind, I think one simple rule is that carbohydrates spare fats. So if you’re giving your body glucose as an energy source, then it’s going to say “I don’t want to use the fats because you’re giving me glucose.” They’re going to be spared in the blood and they’re going to register on your blood triglyceride reading. My triglycerides I think were really low, like 30s or 40s, when I fasted and then did a strict ketogenic diet. I think now they run around 50; 40 or 50. They’re still pretty low. Really low. ARI: Yeah, that’s really cool. Another thing I want to talk about, which may be slightly outside of your realm of research, but I’m sure you’re going to have a little opinion on it. The other motivation for me personally for being high fat is that I have found that a high fat diet – avocados, grass-fed butter, those kind of things have been very anti-inflammatory for me as someone with Crohn’s disease. But obviously, chronic inflammation is at the heart of so many illnesses. Am I making that up? DOMINIC: No, I’m glad you bring that up. It’s not something I talk about much, but I think it’s extremely important, and I think your case reflects it. The application of the ketogenic diet, or a low carbohydrate, high fat diet with quality foods like you mentioned will have a powerful anti- inflammatory effect on the body, which will be reflected in low C-reactive protein levels. Mine actually doesn’t even register, it’s so low. Whereas previous blood reports showed it was pretty elevated when I was on more high carb. I think the benefits of that cannot be overstated, and I think that you’re a walking example of that. I just see so many people who their muscles don’t ache, their GI problems are resolved, their brain fog is gone. And I think it’s a combination of controlling your blood glucose, and a ketogenic diet, high fat diet, tends to control your appetite, too, so you’re less likely to just overeat, and then you’re less likely to binge and less likely to have these blood glucose excursions, if you will, that go up into the dangerous zone. Which can kick on a whole host of inflammatory processes. You eliminate that process in your body, your blood glucose is stable, your body’s antioxidant mechanisms are more robust and upregulated from the fuel that you’re giving it, and your mitochondria are more healthy because you’re forcing your mitochondria to burn fat for energy.
  • 7. If you’re giving glucose, the mitochondria get sluggish, and our metabolic health really is reflected upon our mitochondrial health, which is much better if we’re on a fat-based, low carb diet. ARI: It’s really exciting for me to hear that, because for all the time that I’ve been doing the Less Doing stuff and wellness has been part of that, I never intended to – and I haven’t – created a diet, but I’m always recommending that people increase good fats. For a couple reasons, one of which is I feel like most people in the standard American diet simply don’t get enough good fats. They’re not eating the olive oil and the avocados, and certainly not the grass-fed butter. Simply increasing that, to me, is already a benefit. And it’s really great to see that there’s research to back that up. DOMINIC: Yeah, absolutely. ARI: What’s next in your research? What are you excited about? DOMINIC: A lot of things. Actually, everything. But yeah, I have some really great – my graduate students, my Ph.D. students are the ones driving the research, so it’s kind of a neat transition when you go from being a Ph.D. student to a postdoc to doing all your research and then getting more settled in a lab and getting students to do your research. I have research going on now and I can just pop into the lab and see blood ketones being measured, looking at tumor growth in one room. I have all these projects going on. I think I’m most excited about the cancer work, because it was so unexpected. I got into ketogenic diets, and I stumbled upon Thomas Seyfried’s work with the calorie-restricted ketogenic diet. We also had an observation that high levels of oxygen make cancer cells explode, and we didn’t see this with normal cells, so it was like we have to test this idea of combining the ketogenic diet with hyperbaric oxygen. And when we did, the results were so dramatic. We recently got that published. But now that we’ve developed ketone supplementation, ketone supplements tend to lower blood glucose. We don’t know exactly how it’s working, but we did a study, it’s under review now, showing that simple ketone supplementation, even to a standard diet with carbohydrates in it, has a profound anti-cancer effect and increases survival tremendously in a model of advanced metastatic cancer. So the cancer stuff is really exciting to me. Another thing is just developing and testing different ketone supplements that can be used for pathological conditions, but also applied to athletes to enhance performance. Working with University of Tampa right now in developing a protocol where we’re looking at advanced athletes, like advanced bodybuilders, and looking at the effect of the ketogenic diet and ketone supplementation in the form of MCT, and looking at strength and looking at metabolic biomarkers and looking at body composition. So this will be a really interesting study, because nothing like it has been done before. So I have a combination of things I’m really excited about, both rodent models and in human models. Just a lot of potential for what we call metabolic therapy, and not too many people are
  • 8. doing stuff like this. It’s kind of surprising. Well, I guess there’s not a lot of research for nutrition. That’s why I call it metabolic therapy, because if I write a grant and say I’m going to study the ketogenic diet or low carb diet, the funding agencies just kind of roll their eyes, like “Ugh, another diet study. This isn’t novel. This isn’t exciting.” But if I repackage it into metabolic therapy and innovative ways to elevate ketone metabolic substrate – so I have to use scientific jargon and terminology to win over the hearts of funding agencies, and it becomes kind of tricky. Luckily, we’ve had some really generous donations come in to the lab to really help our research along and been really fortunate to have a few generous people donate to our lab. ARI: That’s great. It’s got to be exciting, too, to be able to do research that you yourself can live, actually, as far as the diet. Because if you’re testing a new drug or something, you really can’t just pop that in your vein and see what happens. DOMINIC: Yeah. Say we do test a number of different drugs and they work, and then you have to file an investigational new drug report. It’s literally like millions of dollars to get that thing into the public hands, and like 10 years. And in our hands, I have the ability to test different things in our rodent model, and basically we’re finding that forcing your body to shift from one physiological state to another with nutrition has a powerful neuroprotective effect, anti-seizure effect. It basically is kicking on a genetic program in your body to confer protection against a number of different things. By enhancing your metabolism and persevering your mitochondrial function, it makes the nuclear genome do its thing better. So DNA repair mechanisms are more robust. Even by enhancing metabolism, it’s actually preserving the fidelity of your nuclear genome and preserving the function of your cells. I think that’s a real important thing to understand. There’s a lot of these targeted approaches, especially for cancer, but if you keep the nucleus of the cell healthy by keeping the bioenergetic state of the cells very robust and healthy, you’re going to prevent cancer, you’re going to prevent the early onset of many chronic diseases, and it can be used as an effective treatment, too. ARI: Wonderful. We’re out of time now. I just want to ask you the last question that I always ask everybody on the podcast, which is what are your top three personal productivity tips? What makes you more effective every day? DOMINIC: Productivity tips. Sleep I think is a big one. Sleep, actually. I just noticed, I went through a couple days without getting sleep and it taxed my productivity. Diet. A high fat, low carb diet decreases my meal frequency, and when I do, I have stable blood glucose. I just have more energy to do what I need to do, and less food preparation and all that stuff. So sleep, diet, and just downtime, quality downtime. I do walks with my girlfriend, play with my puppy during the day. I think I really need that downtime to kind of reboot and get my mind back into work mode where I can attack work. When I wake up in the morning, I just want to attack work like an animal. But only if I’m well-nourished and have proper sleep and have good downtime. Sometimes we lose track of those things when life gets busy, and we need to put things in perspective.
  • 9. ARI: That’s absolutely true. Dom, thank you for those. I think those were three great tips. Thank you for all that really amazing information. Where can people find out more about you and follow what you’re doing and what you’re eating? DOMINIC: (laughs) What I’m eating. You know, I keep a website called ketonutrition.org. It’s mostly because I get hammered with a lot of emails from patients just wanting more information, so I’ve compiled a lot of information on that ketonutrition, all one word, .org website. I’ve done a number of podcasts, so if you look at podcasts – I just did a TED Talk last week, so that’ll be up pretty soon, probably in about a month or so because they’ve got to edit it. Yeah, I would go there and just look at our research too. I probably have to edit that website and put more things up. But I really need to develop a website. I’ve been so busy with research, though, I need to actually do the research and get more studies done so I have something to show on the website. But we’re in the process of that. ARI: We’ll link to that in the show notes. DOMINIC: Okay, cool. ARI: Okay, again, Dom, thank you so much, and I hope we get a chance to talk to you again in the future. DOMINIC: Thanks. My pleasure being here. ARI: Have a good one. DOMINIC: Appreciate it. Bye.