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Ketones: The Fourth Macronutrient with Dr Dominic D'Agostino

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Ketones: The Fourth Macronutrient with Dr Dominic D'Agostino

There's so much more to 'keto' than its growing fame as the latest trending dietary buzzword.  The science emerging on ketones in healthcare is compelling and it's no wonder they’re being touted as the "fourth macronutrient".  

Today we are joined by Dr Dominic D'Agostino, a leading keto nutrition researcher who takes us through the growing body of evidence for ketone-focused clinical interventions. Ahead of his educational seminar series touring Australia in late 2019, Dom takes us through the history of keto nutrition to the many applications ranging from oncology, neurological disorders, cognition, performance and more.

Covered in this episode

[01:07] Introducing Dr Dominic D'Agostino
[02:10] The history of the ketogenic diet?
[07:33] Ketosis vs. keto-acidosis
[11:14] Key health issues keto is indicated for
[15:41] Vegetarianism and ketogenesis
[17:11] Ketosis and cancer research
[21:41] Ketones and the influence on immune signalling
[25:31] Ketones and the heart
[27:11] Ketones and cognitive function
[28:37] Political and agricultural change
[31:53] The trend towards greater acceptance
[36:29] Keto nutrition and kidney function
[38:14] Ketones: the fourth macronutrient?
[40:10] Myth busting coconut oil
[42:04] Emerging research: signalling properties of ketones
[44:08] The theory behind why keto nutrition helped Dom's eczema
[46:15] Breaking down the science for the average user: KetoNutrition.org
[48:44] The Institute for Human and Machine Cognition
[53:59] Australian seminar series with Dominic D'Agostino

    

Andrew: This is FX Medicine, I'm Andrew Whitfield-Cook. Joining us on the line today is Dr. Dominic D'Agostino. He's a tenured Associate Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida. He's also a Research Scientist at the Institute for Human & Machine Cognition. His laboratory develops and tests nutritional strategies and metabolic-based supplements for neurological disorders, seizures, cancer, and metabolic wellness.

He was the research investigator and crew member on NASA's extreme environment mission operation. And has a personal interest in environmental medicine, and methods to enhance safety and physiological resilience in extreme environments. His research is supported by the Office of Naval Research, Department of Defense, private organisations and foundations, and he's basically known as the Keto King. Welcome to FX Medicine Dom, how are you? 

Dominic: Thank you for having me. I'm doing well. 

Andrew: I know it's a popular term, but I want to go right back to nutritional ketosis. Because I remember when we learned physiology in nursing, and we at no stage covered ketosis as having benefit. So, can we do a quick review of this history? And when did it start to be used for therapy? Like I remember epilepsy, but when did it start to be used as a diet for wellness or for, indeed, therapeutic intervention? 

Dominic: Yeah, the clinical implementation of the ketogenic diet started about a century ago, you know, as a conventional approach, it really was the standard of care for epilepsy, and it is today for drug-resistant epilepsy. But there was no drugs to control epilepsy 100 years ago. So, it really was a very efficacious strategy to control a wide variety of seizure types. 

Andrew: That's right. But in my learning, the primary fuel of the brain cells was always, and only, glucose. And then I remember they said glutamine can act as a secondary fuel, but never ketones, which I find weird because it was used as therapy, as you say, 100 years ago. 

Dominic: Yeah, well, at the time, it wasn't really understood that...100 years ago the early 1920s, it was not really understood that ketones were acting as a metabolic fuel. But the diet did mimic the physiology of fasting. So, the Mayo Clinic really developed this diet as a strategy to mimic the metabolic state of fasting which produced these ketone bodies. And even back then, they thought of it as more or less a byproduct, a secondary byproduct of something else that was happening in the body.

I guess it was not until 1967 that Harvard Medical School in the lab of George Cahill discovered that ketone bodies were largely the fuel that the brain was relying on in a fasting state or a starvation state. And about 70% of brain energy metabolism was derived from ketone bodies, and it was a seminal study that really changed the way we thought about brain energy metabolism. Because prior to 1967, it was thought that glucose was really the exclusive fuel for the brain and maybe glutamine to a small extent or glutamate and maybe lactate, but they thought that was only, you know, maybe contributing maybe 2 to 5%. To discover that 70% of brain energy metabolism could be derived from ketone bodies, it really changed medical textbooks, but it didn't really take on. 

Andrew: This is what I find interesting because you're talking of a lag time of 30 years. That's amazing. 

Dominic: Yeah, and you know, it was really a few investigators who picked up on George Cahill's work and one of the investigators was Hans Krebs' student, Dr. Richard Veech, and he's at the NIH and he's up in years now, but really dedicated his life to studying ketones as an energetic fuel, a super fuel if you would. And the publications that he had over decades, really, I was drawn to those publications and the implications of this idea that we could, you know, provide an alternative energy source in the form of ketones. But the only way to achieve it was with starvation or prolonged fasting or this high fat ketogenic diet. 

And I think the public fear of high fat, which is part of the diet, really prevented the ketogenic diet from taking hold. And that's an interesting story with politics and a lot of bad science behind it. But we had a fear, we demonised fat for such a long time, and I think that kept the medical community from embracing the therapeutic potential, of the ketogenic diet. 

Andrew: Indeed, you were not a fan of the ketogenic diet at the beginning as well were you?

Dominic: You know, not really. I thought of it, as... I knew about it from the fitness industry as a rapid weight loss diet, as a fad diet. It was in 2008 when I really got into studying anti-seizure effects that I discovered the literature on "PubMed." And then since then, the last 10 years, there's been an explosion of peer-reviewed research on "PubMed," an explosion of Google search too for the diet. 

And I think to a large extent, the popularity of the ketogenic diet is definitely due to influencers, you know, celebrities using the diet, but also the legitimacy has been kind of secured by the explosion of scientific publications on the ketogenic diet. You just have to go to "PubMed" and search. And that has been very interesting to me as a scientist. 

Andrew: One of the things that I got at the beginning was the robust argument against it, saying it'll destroy kidneys, and this is what happens with diabetics, and let's go into that. What's the difference between ketosis and ketoacidosis? 

Dominic: Yeah, it's a good question. So ketoacidosis is a pathological condition that is almost exclusively associated with a deficiency of insulin and that's characteristic of type 1 diabetes. Where the body does not make enough insulin, there's either a complete lack of insulin or insulin insufficiency. And in the context of you know, physiology where you cannot make insulin, when you're a type 1 diabetic and you don't inject insulin, basically the body becomes starved of energy of glucose because it cannot get glucose into the cells. So what it does as a survival mechanism is that you have run away ketogenesis. The liver makes massive amounts of ketones and your blood glucose is very high on top of that.

So you have very high ketones, 10 times higher than what you would get on nutritional ketosis with normal physiology, and you have very high glucose, which produces an acidotic condition, and if it's not corrected with injecting insulin, fluids, and electrolytes, you will die of a diabetic coma. So if you're not a type 1 diabetics, and you follow a ketogenic diet, or you fast, there's no, really, danger of getting into a state of ketoacidosis. And even if you are a type 1 diabetic...my PhD. student, for example, is type 1 diabetic and does quite well on a ketogenic diet because it keeps his blood glucose levels very stable. 

And recently out of Harvard Medical School, Dr. David Ludwig published an article that basically demonstrated a low carb ketogenic diet could be used for the metabolic management of type 1 diabetes. Which is something I actually didn't even, you know, consider talking about because it was such a controversial subject. But now that we have a publication to show that type 1 diabetics use much less insulin and can control their glucose much better on a lower carb ketogenic diet. So things have really, really changed over the last couple of years. 

Andrew: Absolutely. It's so funny how there's this turnaround. I guess the reason for the turnaround, as you say, is these investigators, but the change in the minds of the scientists. There's got to be something for these questioning minds to go, "Hang on." For instance, you just explained that it was the glucose really causing that acidotic condition, not the ketones, but the ketones were blamed.

Dominic: Yeah.

Andrew: How often do we see this? 

Dominic: So you know, when you're in nutritional ketosis, your ketones are in the 1 to 2 millimolar range, not the 10 to 20 millimolar range, and your glucose is relatively low and stable. Whereas if you have type 1 diabetes, your glucose is out of control and can even get up to 3 to 400 milligrams per decilitre or in millimoles that could be you know, 10 millimoles or more. And that makes your blood essentially like sludge, and it makes it very acidotic, and a very dangerous condition, actually. 

Andrew: So you mentioned diabetes type 1, diabetes mellitus type 1, what are some of the other emerging applications of nutritional ketosis? 

Dominic: There are many actually. Well, the low hanging fruit, I think, is really type 2 diabetes. And that could...I mean, another term for that could be carbohydrate intolerance, because essentially, that's what's happening. You know, people with type 2 diabetes are consuming a level of carbohydrates that's keeping your blood sugar sustained and elevated, and their insulin levels too. And there's a couple ways to correct that. One would be calorie restriction, you know. But a more feasible approach would be carbohydrate restriction, which would decrease the secretion of insulin and lower your blood glucose, and the postprandial elevation of glucose too that accompanies a meal. 

And there's a number of investigators and organisations working on treating this dietary disease, and I would call it a dietary disease, with diet, instead of treating a dietary disease with drugs, which really doesn't make any sense. It really makes sense to treat a dietary disease with diet. And so many Americans you know, really suffer from that and weight loss too, really. I mean, it's been around for a long time, using the ketogenic diet. But now we know there are many different forms of the ketogenic diet, and we have a better understanding of the types of fats. 

In the United States here hydrogenated fats were popular for a long time, oils rich in omega-6 fatty acids, which are pro-inflammatory, were used ubiquitously in many different food products. And now, you know, they're being minimised or limited. So we know how to formulate the ketogenic diet in ways that's healthy. And that can lead to not only a weight loss but a sustainment of that weight loss. You know, it's relatively easy to lose weight, but to have a lifestyle or dietary plan to sustain that weight loss, I really think is where low carb and ketogenic diets really shine, because they really help to regulate the appetite in a way that can moderate eating behaviour to sustain that weight loss. So that's two of the big ones, type 2 diabetes and weight loss. 

Andrew: Yeah, there's so many others. I want to get into those. So you said there's more many forms of the ketogenic diet now, so it's not just a standard thing, it's really how you respond, how the person responds. So, this would therefore always require testing. Correct? 

Dominic: Yeah, there's an art and a science to it, right? It used to be kind of like a cookie-cutter approach for epilepsy for many years. You know, you just put this amount of butter and heavy cream and you know, you mix a little egg, and it was very dairy based. Now, you know, some people don't do very well on a dairy-based ketogenic diet and do much better and a non-dairy ketogenic diet. 

But the classical ketogenic diet was 90% fat. And some of the emerging data, even in epilepsy, shows that a modified ketogenic diet which is 60% to 70% of fat, and more liberal in protein can be just as efficacious for seizure management. And that particular diet, because it's less extreme and more palatable, can be used for a wide range of applications too.

Andrew: Okay, but do you find many people go too high with protein levels which might interfere with growth signalling?

Dominic: It keeps you out of ketosis too once you get above... like the Atkins diet, different forms of it, was really a high protein diet and people kind of misinterpreted the ketogenic diet as a high protein diet, where really the original ketogenic diet was low in protein. It actually became problematic for paediatric population because it stunted their growth. 

Andrew: Ahh. 

Dominic: So now, instead of 8% or 10% protein for kids, they try to do more like 12% to 15%, which is still quite lower than the standard American diet. But getting a ketogenic diet in the 20% to 25% range of protein seems to work pretty well, even for seizure control, weight management, and a variety of other things. 

Andrew: And then obviously, protein, you know, the obvious sort of go-to there would be meats. What about vegans, vegetarians? How do they cope with a ketogenic diet, which has that moderate amount of protein in it? 

Dominic: I think it's challenging for a vegan to do it. But in the last couple years, there's been the availability of various plant protein isolates. You know, everything from hemp to pumpkin seed to rice and potato even. So these can sort of be incorporated into food and food products and even baking powders to supplement, you know, that protein...and various nut butters and things like that. So a vegetarian diet that would allow eggs and a little bit of dairy, that's actually much easier. 

Andrew: Yeah. 

Dominic: So you know, you can make a variety of things with egg, and egg protein is very good source of protein. So it becomes challenging with more of a plant-based vegan diet. I do have a blog article, one of our first articles ever in ketonutrition.org our website describe a plant-based ketogenic diet because so many people just think of bacon and eggs as the ketogenic diet. But it is evolving to the point where different meal plans are being developed that would allow access to the ketogenic diet for vegans and vegetarians. 

Andrew: Dom, what about cancer? I've heard of the work of Valter Longo using the ketogenic diet in cancer. Can you tell me what's happening in the research area of its use in cancer? 

Dominic: Sure, yeah. That's a very exciting area of research. I was introduced into the ketogenic diet for cancer by Thomas Seyfried, who wrote the book "Cancer as a Metabolic Disease." And it's a very in-depth, scientific book explaining how metabolic damage or damage to the mitochondria can trigger the activation of oncogenes, and ultimately, you know, lead to carcinogenesis and tumour formation. 

The idea would be or the implications would be that keeping our mitochondria healthy and our energy pathways healthy, would preserve genomic stability, and make it less likely... if the cells are energised, and energy is very important for DNA repair...if the bioenergetic state of the cell is high, it's much less likely to suffer insults that would then trigger mutations that would cause cancer.

So, this has implications not only for the treatment of cancer but also for the prevention of cancer. So Valter Longo and many others are doing clinical trials now. Ten years ago, there was maybe one or two government registered clinical trials, maybe one or two, and now there's about 25 to 30 registered clinical trials, ongoing trials using the ketogenic diet, usually as an adjuvant. In some cases as a standalone therapy when standard of care has failed, but typically, you know, sort of as an adjuvant.

And there's many reasons why the ketogenic diet works, because it's not only about lowering blood glucose, and you often hear, "Starve your cancer of glucose," you know, "go on a ketogenic diet."…I just looked now there's 31 clinical trials…So the ketogenic diet reduces insulin and IGF-1 signalling, which drive cancer growth and proliferation, it reduces inflammation, it reduces angiogenesis, it reduces invasiveness and metastasis of the cancer.

An interesting topic of cancer biologists is the alteration of gene expression by ketones. So, ketones can actually activate various gene pathways that can prevent cancer from growing and spreading. And that's a very hot topic. The ketogenic diet also enhances anti tumour immunity. Which means that if you're in a state of nutritional ketosis, it makes the immune system more vigilant to identifying cancer and helping your body rid itself of that cancer. So that's another benefit of the ketogenic diet. 

And it's protein sparing. So, when your ketones are elevated, it prevents muscle tissue from being broken down. And I think that's a whole project that we have. It's a PhD. project of my student looking at anti-cachexia effects of ketones.

Andrew: Yeah, which is really counterintuitive, one would think?

Dominic: Yes. 

Andrew: You know, the standard way would think you need more carbs you know, to provide more energy to stop cachexia. It's not necessarily so. You need to be protein sparing, muscle mass sparing. 

Dominic: Yeah, and that's how we could fast too. So that's a really important consideration. If we fasted and we didn't make ketones, our body would catabolise the skeletal muscle to make glucose and we would waste away. But because we have...even a lean person has 20 or 30,000 calories of fat. If we liberate that fat, then we make ketone bodies from the fat. And those ketone bodies, prevent our body from needing massive amounts of glucose to run the brain and the heart. Because your heart and your brain run really efficiently, off ketone bodies. So it's very protein sparing and that's probably why humans could withstand fairly long periods of starvation, they could do quite well, you know, in a state of fasting ketosis.

Andrew: Just something you mentioned before about the immune system in cancer. So do you know of any research that's showing say, a decrease in tumour associated macrophages using the keto nutrition?

Dominic: I know TNF-α and IL-1β, I mean, these pro-inflammatory drivers...

Andrew: Hijackers of the immune system, yeah.

Dominic: Yeah, are kind of knocked down and sort of the natural killer cells and various...and it really depends on the individual patient. But Adrienne Scheck is doing a lot of work in this area and we just started working in this area. But it tends to augment the immune system in a way that, because it's knocking down some of the pro-inflammatory cytokines, the immune system becomes more sensitive to detecting the presence of cancer in the body, and that's sort of the ongoing theory. That's how it's playing out in the animal model work, and now human trials are looking at this. 

Andrew: Dom, just going back to obesity, which is obviously, you know, convenience, our 21st century...it's the scourge of health in our 21st century, "living." And it's been said that our generation is going to be the longest living and perhaps our children aren't going to live as long. I was very interested by the work of Professor Robert Lustig, who was, you know, definitely anti-sugar. He told me that we measure HbA1c, but indeed there's other lysine links, I think it was along the haemoglobin [molecule]. Do you ever look further than just the standard testing when you're investigating the benefits of keto nutrition and the effects on glucose?

Dominic: You know, we don't go too far down into the weeds in that regard. What we do do is look at… we do a very comprehensive cytokine assay where we look at 60 different you know, cytokines. We do have a standard kit where we look at you know, haemoglobin A1c, insulin, you know, glucose, ketones, you know, a lipid profile, and...I mentioned insulin. And we look at all this, you know, in a snapshot... And triglycerides too, of course.

Andrew: Yep, yep.

Dominic: And we try to keep it relatively simple in regards to the metabolic profile because the other things are just kind of a little bit too variable and the cytokines too can be variable. But that's giving us a lot of insight into how the immune system is kind of augmented. 

Andrew: Yeah. 

Dominic: You know, we do have the tools for that, but we haven't really delved too deep into some of the other aspects. Well, I guess we do in regards to global metabolomic profiling. So we actually look at like, you know, up to 4,000 different metabolites. And typically, you see a lot of things that don't make sense. But out of the 4,000, typically you see about 70 to 80 different metabolites that do shift in really significant ways. 

So we're sitting on a lot of data right now I can't really talk about, but we will be publishing soon, where we essentially take the blood, we take muscle tissue, we take the liver, we take the brain, we take the heart, and we look at up to 4,000, different metabolites, you know, using a variety of different approaches and also bioinformatics to analyse that data to make sense of how it's shifting. 

Andrew: I can see the keto nutrition being quite useful even in things like cardiovascular disease where the heart muscle needs energy. You know, heart failure is a massive issue. I could just see this being such a benefit.

Dominic: Yeah. And you know Richard Veech, I mentioned him, the student of Hans Krebs, did work back in...I think it was published about 20 years ago showing the hydraulic efficiency of the heart is about 25% greater when your heart is burning ketones, relative to glucose. So, this was a profound change. And especially since, with ketones, you don't need insulin, that you can actually generate ATP without the presence of insulin. So, ketones are very good for the heart. The heart burns fatty acids really well, it burns ketones really well.

And the brain, some argue the brain functions more efficiently off ketones than it does with the glucose. We do know the ageing brain gradually uses glucose less efficiently. You know, even in a healthy individual, the glucose metabolism in the brain will decrease with ageing, and that's not the case with ketones. The ability of the ageing brain to use ketones does not decline with age. And this is work by Stephen Cunnane in Canada who's shown this doing a dual PET scan. So that's some pretty exciting work basically demonstrating that ketones could help maybe restore brain energy metabolism, you know, that's associated with cognitive decline with ageing.

Andrew: You know, again, keto is never in the orthodox world considered for, you know, dementia, which is a massive scourge in our society. It's a fear, indeed, for the future. 

Dominic: Yes, it is. And, you know, we don't have a cure for Alzheimer's disease, which is a terrible disease, and I've known people who've had it. So, I think prevention is key too, but we do know that ketones offer the ability to increase brain energy metabolism, and help to symptomatically...it can, right now, help with Alzheimer's disease. And I think there's different...people have... The etiology of Alzheimer's disease is largely unknown. 

And I think there's a subtype of Alzheimer's, that's very responsive to these metabolic interventions. And I would say anywhere from 30% to 50% of people with Alzheimer's disease have a fairly significant, you know, response to a metabolic intervention like diet, especially ketones, elevating blood ketones. And this is a very active area of research right now. Some of it's published, and some of it is ongoing studies, clinical trials that are being conducted now that take several years before the final data are collected. But I'm aware of some studies that look very, very encouraging. 

Andrew: You were mentioning earlier that the types of oils that we use, you know, the different fatty acids, makeups, of the various oils that we use is changing over time. There was a really great film "That Sugar Film," which exposed that it was a political arena or a sort of support of the farming industry, the agricultural industry way back in the sort of '50s and '60s, which had this sort of high fructose corn syrup come as being the subsidised go-to cash crop for our farmers. Are you finding that that's changing, that the political landscape, the support, the actual farming practices are changing? Or is this from the other end, from the demand? 

Dominic: Yeah, well, I think, you know, there's... I mean, demand will dictate, you know, the suppliers, you know. 

Andrew: Yep, sure. 

Dominic: I'm on my farm right now. So, we have a 24-acre farm here, and what we're deciding to grow is kind of dictated by the demand of the stores around us, you know, what selling, what prices and so on. So we are actually considering growing avocados here, you know, because that's in pretty high demand and they sell very well here. And you know, 10 years ago that really wasn't the case. 

So I do see a lot of low carb options in recipes around, especially in the northeast, but we're in Florida here. But I was up in the northeast. So, a lot of gluten-free options, most restaurants in New York, you know, have these things. So I grew up farming all my life, and we grew wheat and potatoes and all sorts of carbs. And I think the landscape is changing. Government is continuing to subsidise farmers to grow certain crops and corn and wheat and things, and I think it's starting to shift where they're starting to subsidise more vegetables, like instead of grains. And I'm actually...you know, from the Agricultural Association, starting to see various subsidies for farmers to grow different types of crops that would be more in line with less carbohydrates and less grains and more vegetables that could be part of a low carb ketogenic sort of diet. 

And that's interesting to see. And that has actually happened over the last 5 years, maybe 10 years, but over the last 5 years, increased subsidies for different types of crops, less subsidies for grains and more subsidies for vegetables that would be more in line with low carb diet. 

Andrew: That's an amazingly quick change from a political landscape.

Dominic: It's slow, but it is changing in that way, and it's driven by a number of factors, but it is starting to change. And that's good, and maybe...I think there'll be a tipping point where, you know, as the change happens, the change will start to happen faster, especially if it's driven by the demand. 

Andrew: Obviously, you see this sort of patient/person. You know, you've got this avid interest in keto nutrition, so you're sort of honed towards that. Let's call it selection bias. But do you see that more and more the average American is becoming interested in lessening their waistline and looking at options like keto nutrition?

Dominic: Yeah, I think so. I live a little bit in the bubble of academia and people that are more kind of up on this area of science, and I definitely see it. I mean, in my travels, I run across people who are just...they've heard about low carb and ketogenic diets and they're interested in understanding more. And people genuinely become engaged and interested in things that can make them look better. 

Andrew: Yep. 

Dominic: You know, I'm interested in making people healthier and feel better, but generally, our society is very interested in looks. And if it can make you lose weight and give you more energy, that will get their attention. And that does happen, I mean, that's happened with me. The ketogenic diet is not for everybody. It's not a one size fits all, you really need to experiment and find out what works for you. But it's pretty clear what is not working, what's not working is processed carbohydrates, sort of, this processed food. So a shift towards this way of eating can really make a big difference in a person's health and well being. 

Andrew: What about the shift in, as you say, academia? What about dietitians who, you know...traditionally, it was carbs all the way, we're still in Australia seeing this resistance. Indeed, a forward-thinking dietitian here, proposed to a study group, if you like, that they should be looking at keto nutrition for...or could be looking at keto nutrition as an adjunct in cancer therapy, and he was booed off stage, basically. Do you find that the orthodox teaching of nutrition is changing? 

Dominic: Yeah, I think it's being driven and it should be driven by the science. You know, not only the basic science but the clinical science. And, you know, one of the big news networks here is public radio, NPR. "Science Friday," last Friday had Dr. David Ludwig on from Harvard Medical School, and his 20 minute segment was that ‘not all calories are created equal.’ And he studies the low carb diet and ketogenic diet for obesity and weight loss. And you know, that was a nationally aired radio program, and now a podcast.

And yesterday, I was on NPR on "Florida Matters" NPR WUSF with a dietitian who really was trained conventionally. And she is kind of coming... You know, I didn't know how it was going to go during the interview because I didn't know... But she was really warming up to low carb and ketogenic diets and actually acknowledges it now, as a registered...she's a PhD. and a registered dietitian, as a very effective weight loss and weight maintenance strategy. 

So that was comforting. I thought maybe they were doing a point-counterpoint. But it actually was a very, you know, nice conversation to have and just acknowledging that this is a viable strategy that is not detrimental to your health, and it actually has many health benefits. 

So the landscape is changing. And in my undergrad, I went through a conventional registered dietitian nutrition science program, and the diet was not looked upon fondly. I think now, in nutrition programs, because the diet is so popular in the media, and people recognise that it does work, and it really changes many aspects of your health, that they are incorporating this into a discussion into nutrition programs. And it will probably be part of the curriculum as things move along, as the science emerges. 

Andrew: Yeah.

Dominic: think it should really be driven by the science. And like I said, there was an explosion of peer-reviewed science over the last 10 years. But it takes about 10 years to change the medical textbooks and the nutrition science textbooks. 

Andrew: Can keto nutrition be of benefit in existing renal disease? Like especially further along in say type 2 diabetes when people are on insulin? 

Dominic: So, you know, your kidneys filter the blood, and the more stuff you have in the blood, the harder it is on your kidneys, right? So, you know, there's a fear...I think, to some extent, a legitimate fear of high protein diets for the kidneys and people who have pre-existing kidney disease. And some people mistakenly think that the ketogenic diet is high protein, and it's really not. And the ketones that are elevated in the blood are very mild metabolic acidosis that the body can deal with very easily. 

If you were to sprint, you know, and run down the street, you would create a much stronger acid load in your blood, than the ketogenic diet. So, it's not a stress to your kidneys. But what the ketogenic diet does to help your kidneys is clear that glucose out of your blood, or just by virtue of decreasing the source of the glucose, that brings the glucose levels down, and that does a good thing for your kidneys. 

So high levels of glucose can destroy your kidneys. It really strains the filtration system of the kidneys and stimulates a lot of pro-inflammatory processes that could damage the filtration. And your glomerular filtration rate can rapidly go down, you know if you have uncontrolled type 2 diabetes. And I think that could be reversed and managed very effectively with a ketogenic diet. 

Andrew: Ketones have also been described as the fourth macronutrient. What's this about?

Dominic: Yeah, you know, I've always thought about it that way and have mentioned it on various podcasts, and I think the term is kind of starting to take hold. The macronutrients are, you know, protein, carbohydrates, and fat. You know, classically, that's the macronutrients. So now we have ketone bodies that could be in the form of, you know, β-hydroxybutyrate salts and esters, and there's also ketogenic fats like coconut oil derived MCT oil. And ketones are calorie containing molecules that can be consumed orally and they give our body a source of energy. So, we have to classify them. And so I think it will be up to, you know, the industry to figure out how to classify these calorie containing molecules. 

In the early 1960s into the '70s, NASA looked at high energy dense space food, synthetic space food. And they looked at things like 1,3-Butanediol, which is one step away from a ketone, but it converts very rapidly to ketones in the body. And they didn't really know what to call it, you know. It was not an alcohol, it was a glycol or a diol. And now we have molecules that are essentially the natural form of ketones that our body makes, and we can consume them, and they're calorie containing. So, I think of them as like a super fuel. So, we can consume them, and they can enhance metabolic processes in our body to give us energy. And I think they are something that...we're just on the cusp of understanding what would be optimal as far as what kind of ketone formulas, you know, would be optimal for different applications and how to use utilise these things most efficiently. 

Andrew: You mentioned coconut oil, which has been lambasted by many cardiologists as being, you know, a cardiovascular risk in itself. Can you comment on that please and start to dispel this myth? 

Dominic: Yeah, sure. Well, coconut oil gets a bad rap because it is technically a saturated fat. And you know, saturated fat has been demonised for decades, almost half a century. And a lot of it was driven by Ancel Keys, and a lot of bad science kind of contributed to that. 

But coconut oil is really a healthy oil. It has many different properties to it. When you consume coconut oil, it does get metabolised a bit differently. So instead of being packaged into chylomicrons, a good percentage of the oil can be transported directly to the liver and be oxidised and be burnt more rapidly, and some of it is converted to ketone bodies more rapidly. 

Andrew: Yep. 

Dominic: So, fat in the form of coconut oil is less likely to be stored as fat in your body, and more likely to be converted into energy than other forms of long-chain fats. 

Some people fear that, you know, saturated fats can elevate your LDL cholesterol and that that could be atherogenic or cause heart disease, and the support for that...there's very little if any support for that. Actually, coconut oil has a wide range of health benefits from converting to ketones... Lauric acid, a component of coconut oil can boost your immune system. You can use coconut oil for a variety of different applications, and it's a healthy fat. And I think the data supports that. 

Andrew: Yep. And the signalling properties of ketones. Can you explain a little bit further about this? 

Dominic: Sure. And that's a recent development. It did not exist when I started studying this 10 years ago. But over the last five to six years, we've identified β-hydroxybutyrate, one of the ketone molecules, functions as an endogenous histone deacetylase inhibitor. Essentially, what it means is that, you know, we have...histone deacetylation strengthens the bond between DNA and histones, thereby repressing the genes in these regions. So if you have a histone deacetylase inhibitor, that can actually increase methylation and actually turn on the expression of different genes. And ketones tend to turn on the expression of genes that have protective properties in our body.

So they have the ability to methylate, and this is a new finding. We're studying this in the context of Kabuki syndrome. It's a rare disorder, where the ketone body β-hydroxybutyrate has a therapeutic effect. So, we're studying that. 

The ketone body β-hydroxybutyrate also suppresses an inflammasome called the NLRP3 inflammasome that's related to autoimmune disorders and also age-related chronic disorders.

Andrew: Okay. 

Dominic: So, the ketone suppresses that inflammatory pathway and thereby can suppress systemic inflammation associated with a wide variety of age-related chronic diseases. So, these are very hot areas of research right now. 

And it's important to acknowledge that the ketones are not working by altering energy metabolism, they're working more like a hormone or a drug and impacting different receptors and different pathways independent of metabolism. So that's a new and exciting area of research that were involved in right now. 

Andrew: So, I'm going to take this back to something that you've mentioned previously in podcasts and interviews. And that is that you use keto nutrition and you've found that your dermatitis just went. Are you now sort of, I guess, awakening to the fact that it might not just be the fats that you're intaking as, "Oh, it's making my skin more lush," but indeed it's having an anti-inflammatory signalling effect?

Dominic: Yeah, for sure. And it could be just like, elimination of things, you know, in a normal diet. I was eating more dairy, and I was eating grains, you know, 10 years ago or more. 

Andrew: Yep. 

Dominic: And I had eczema, which is, you know, a skin problem that I suffered with for a long time. And it was only until I got sugar and grains out of my diet and decreased the amount of dairy protein. I still consume dairy every day but more dairy fat and not...a little bit of dairy...a little bit of cheese here and there. But I think it was really lowering the carbohydrates and elevating my ketone bodies that rid my body of inflammation, that I had like 10 years ago on a higher carb diet. 

And I think it's a combination of eliminating pro-inflammatory foods and also elevating anti-inflammatory metabolites like ketones in the blood. And it's just had a profound effect on my systemic inflammation because my hs-C-reactive protein (hs-CRP) is almost non-detectable now and it was always kind of on the high end of normal, prior to doing this. 

Andrew: Wow, yeah. 

Dominic: And I really do think that keeping inflammation as low as possible, systemic inflammation, is really an important thing for health and longevity, over time. Because inflammation can wreak havoc on your body and your joints and even your brain, you know, over time. So, I think you're doing your body a good thing by following a nutrition program that keeps inflammation low. And your skin will thank you too, yeah. 

Andrew: You know, you've got a high level of intellect, a high level of education. How does the average punter, though, start keto nutrition? Because I can see there's some pitfalls. People might think, as you mentioned, cheese, you know, "Oh, it's high in fat, so therefore, it's good." What are the pitfalls that you see, practitioners and indeed lay people doing? And where are the best resources that they can get that really like up to the minute with the various types of keto diets? 

Dominic: Yeah, you know, we publish in peer review journals and that's a good thing. But I think, most importantly, over the last year or so I started a blog and a website ketonutrition.org, where I try to break down the science to the point where it can be actionable for the average person. 

Like today, we published a blog article, actually just within the last hour, called the "Ketogenic Diet for Weight Loss." Right? And it’s really… we have a chapter in a new ebook that really takes it step by step on how to implement this approach, you know?

Although I study more the neurological diseases and cancer, I realise that most people kind of come to this approach for weight loss. So, I spent probably a half a year just reading the research, reading what books are out there, and just kind of sat down and worked on this with my assistant, Christie, and we come up with a chapter in a book called "Fat Loss Forever." And in that in that book, we have a chapter, "The Ketogenic Diet For Weight Loss."

So we are really working hard not only in the lab but outside the lab to make this information more accessible to people. So KetoNutrition, our website, has information, and on that website, we have a bunch of different links to other people's sites that we kind of vetted out and feel is really good information. There's a lot of bad information out there.

Andrew: Yeah. 

Dominic: So we try to weed through what's good and bad and try to compile that into kind of one website that has all the links on there. And of course, some of the podcasts that I do have show notes in there. And there's show notes... You know, I talk about ketogenic diet like this but I have show notes to support some of the things that I'm talking about, and I think that helps people. 

Andrew: Yeah, I've got to say, talk about a poster child for keto nutrition, you're certainly that. I have one last question for you, though, and that is something about the institute that you're working. It's the Institute for Human & Machine Cognition?

Dominic: Yeah. Well, Dr. Ken Ford who's an interesting academic person, I mean, he's probably one of the smartest people that I know. And he worked for NASA, and he also worked for the President's Defense Science Board for quite some time. He started this institute as an expert in artificial intelligence. And actually, he had epilepsy growing up, and he used the ketogenic diet for decades now, to manage that. And he was also a very high-level wrestler. But his main sort of focus was robotics and artificial intelligence. And he worked with DARPA on a number of different projects, including humanoid robots. 

So as he developed various autonomous systems, he realised that it was equally important to enhance the human's capability to function in extreme environments. So, a big part of the research that the Institute for Human & Machine Cognition is doing is enhancing, you know, human performance and resilience in extreme environments. And I play a role in that, as does my colleague, Dr. Dawn Kernagis. We were both Aquanauts in NASA's extreme environment mission operations, so we have that in common.

So I work with IHMC to develop strategies, including a ketogenic strategy, to enhance warfighter performance, astronaut health and safety and things like that. 

So check out their website. Also check out "STEM-Talk." IHMC interviews a lot of scientists that study keto nutrition and astronauts, and a number of different influential individuals in the world that really cover a range of topics. So that's called "STEM-Talk" podcast and there's also a lecture series. So you can find out more about IHMC from the lecture series and "STEM-Talk."

Andrew: This is brilliant stuff. I said one last question and no, it's not going to be. So one thing... because like you do scuba diving. Correct? You do underwater exploration.

Dominic: I love it, yeah.

Andrew: So do you find that keto nutrition...when you're talking about working with, you know, high-level elite military personnel, do you find that keto nutrition might help with things like fear reactions, trauma recovery, things like that?

Dominic: Yeah, I do. I think enhancing your metabolic resilience can make you better in performing cognitively and physically under austere environments where you have limited food availability and also where the partial pressure of oxygen may be lower, for example at altitude, or higher, your extreme environments where you're breathing high-pressure oxygen. 

And also many of the you know, detrimental effects that could impact a warfighter has to do with systemic inflammation, you know, fatigue, recovery. So these are why IHMC and other institutes are really looking at the effects of these nutritional interventions on performance and recovery. Because the ability to recover from trauma, from...you mentioned fear response. Actually, we had an article published today in "Journal of Online Video Experiments" on the anxiolytic effects of ketones, experimenting on using the elevated plus maze. So that looks at anxiety and fear reactions. And just today, we published an article really demonstrating from a video perspective, and we walk people through the entire experimental protocol, how ketone supplementation, elevating ketones, can reduce the fear response. And actually make the anxiety and fear reaction attenuated in a number of models systems. So, a lot of applications.

Andrew: Oh, I can see the big applications. I'm thinking even mood disorders, personality disorders, break down, psychiatric disorders, indeed. 

Dominic: Yep, that's the next frontier. We actually...we're working on a review article for that and hope to have that published soon, so we've recently submitted it. 

So I post these things on social media on Facebook or Twitter. So hopefully that review article will be published soon. And it's a good overview of the potential for nutrition with emphasis on ketogenic nutrition for psychiatric disorders. 

Andrew: Indeed, you're coming back to Australia for a seminar series to discuss the science of nutritional ketosis in October, November 2019. Correct? 

Dominic: Yes. I'm very excited about that. 

Andrew: Tell us a little bit about what practitioners can expect to learn?

Dominic: Yeah, well, I'm working on sort of the itinerary for that, and I want to hit on every possible angle of ketogenic nutrition and the various applications, and really listening to and wanting to hear what the audience...we're sort of putting together the itinerary based on what people want to hear, right? 

So I think some of the low-hanging fruit would be weight loss and of course, you know, type 2 diabetes, inflammation. My background is neurological diseases, seizure disorders, and also cancer. And we have active programs in sort of all those things that I mentioned. 

And I think most importantly, too, I want to have, you know, specific talks on practical implementation, and practical applications of this. Like how do you do it? You know, start with this step, and here's an example of a typical meal plan. If you were a vegetarian, here's an example of a meal plan for that if you want to follow a plant-based ketogenic diet. So here's some examples of that. Here's how you measure your blood ketones. Here's some of the equipment that we use that's commercially available. Things like that. Here's some of the, you know, ketone supplements and ketogenic foods that can help you along your journey implementing this approach. So hope to hit on a wide range of things.

Andrew: I could talk to you for hours and I think I will at the seminar series. I think I'm going to have to Shanghai...

Dominic: I hope you do. I look forward to it.

Andrew: Well, I remember at the Symposium you were positively mobbed after your stage presentation. It was just very interesting to see. 

Dominic: I love seeing that, that level of interest. And I know keto is becoming quite big over there. So that's great to see too, and as it's taking over here like every day, you know, you hear more and more about it, so it's not just me. 

Andrew: Yeah, I love the science that you're bringing to it. So you're validating the uses and saying, "Look," where it can be useful and where it can't. 

Dominic, thank you so much for joining us on FX Medicine today. As I said, I could talk to you for hours. There's so many other areas we could delve into. Maybe again, at another stage, you and I can hit it off on FX Medicine. 

Dominic: That sounds great. I'm ready anytime you are. Thank you. Thanks for having me, Andrew. 

Andrew: This is FX Medicine, I'm Andrew Whitfield-Cook.



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Dr Dominic D'Agostino

Dr. Dominic D'Agostino is a tenured Associate Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine. He is also a Research Scientist at the Institute for Human and Machine Cognition (IHMC). His laboratory develops and tests nutritional strategies and metabolic-based supplements for neurological disorders, seizures, cancer and metabolic wellness. He was a research investigator and crew member on NASAs Extreme Environment Mission Operation (NEEMO 22) and has a personal interest in environmental medicine and methods to enhance safety and physiological resilience in extreme environments. His research is supported by the Office of Naval Research (ONR), Department of Defense (DoD), private organizations and foundations.