Dr. Dominic D’Agostino -Disease Modifying Effects of a Therapeutic Ketogenic Diet

Dr. Dominic D’Agostino
Research Scientist
Institute for Human and Machine Cognition

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 NASA’s 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.

TRANSCRIPT

Dr. Pompa:
Well Dom, welcome. I am so glad that we’re doing this teaching today because, my gosh, you have so much information that I wish I could just extract out of your brain in a second. But that’s why you’re at the next up and coming seminar because we’re going to get all that information that you’re doing on the research. Welcome and thank you for being here.

Dominic:
Thank you for having me. I appreciate it.

Dr. Pompa:
Dom, listen. You have so much research going on right now. But I do want to start with this because I think a lot of people watching this have heard your name. And yet, they’re not exactly sure what you do. But I want you to start for those who don’t know you well, how you got into this researching ketones, which by the way in our field right now is the hottest thing. If you Google ketones, ketosis, you’re the man behind a lot of these studies. How did you get into this?

Dominic:
Yeah. It goes back in 2004, I finished by PhD. And then I literally spent a year writing grants to get funding to study oxygen toxicity seizures. And these seizures are a limitation for our limitations for our Navy Seal divers using a closed circuit rebreather. The grants allowed me to understand brain energy metabolism and signaling as it pertained to an extreme environment. As we understood that more, I started looking into anti seizure strategies. And one of the things that got on my radar was the ketogenic diet. And I did not know the history of keto … I thought it was a fad weight loss diet. But it dates back to the 1920s, where the Mayo Clinic developed a very specific dietary protocol to mimic fasting, to mimic the metabolic state of fasting, which would elevate your blood ketones. And I saw that the data supporting this as an anti seizure strategy was really good.

About 2007 or 2008, I started pitching this to the Department of Defense, and ultimately got funded a little over 10 years ago. And now we’ve branched off into so many different areas from cancer, to rare genetic disorders, to wound healing, many different things we study, exercise performance.

Dr. Pompa:
It’s amazing. Years ago when I heard your research, I came out of my chair. And for years we talked about even: How do we turn these bad genes that get triggered via different stressors off? And I was excited because some of the research you were doing then and even more now is showing that these ketones have the ability to turn off genes, whether it be a cancer, be it whatever condition. Talk about some of that new research. I know you’re going to go into depth on some of this at the seminar.

Dominic:
Yeah. Sure. Well, I got into the cancer focus because understanding that brain cancer patients use anti seizure drugs to prevent the seizures they were getting from the brain tumor. I initially got interested in using it for that application. And the more I studied cancer biology and cancer metabolism, I realized that we could not only control the seizures, but being in a state of therapeutic ketosis profoundly altered and shifted your metabolic physiology to target the hallmarks of cancer, which is accelerated proliferation of cells, evasion of immune system, metastasis, angiogenesis, all of these things are altered by being in a state of nutritional ketosis that lowers blood glucose, lowers insulin, insulin’s a driver for cancer, and elevates ketones.

And the ketones work in different capacities. One of them, as you alluded to, is that they have specific signaling properties on cells. And they have receptors. They have signaling pathways. They have epigenetic effects. It’s an endogenous metabolite that has epigenetic effects. And one of those effects is suppressing various gene pathways associate with cancer growth and proliferation. And they function essentially as what’s known as a histone deacetylase inhibitor, type one, two, and three. And they work on a variety of genes influencing methylation rates on genes. In the seminar I can go into all the different pathways that’s on that.

Dr. Pompa:
Right. Look, I can tell you clinically, without putting people in a state of ketosis, we would never be able to help the conditions that we’re helping. I think for many years we just didn’t understand why. We just knew it worked. With a lot of your research, now we actually understand what’s going on. Talk a little bit about, this is one of my favorite topics, the neurodegenerative conditions, whether it be Alzheimer’s, Parkinson’s, or autism. These are massive epidemics. Of the research here with the neuro inflammation, if you will, and brain inflammation, nerve inflammation, just to keep it simple, it’s outstanding. Talk a little bit about that because some of your new research that you’re going to be discussing at the seminar goes into that.

Dominic:
Yeah. Sure. It was back 2009, so nine year … We’re in 2019 now, 10 years ago. Actually, the Alzheimer’s association recognized the work by Dr. Mary Newport. And she wrote a book Alzheimer’s disease, What if There Was a Cure? And that book really talked about treating her husband, Steve Newport, with coconut oil and MCT oil as a way to manage the symptoms of his Alzheimer’s disease. And ultimately, he went on a ketone ester. His story is documented in Mary’s book. And that book inspired me. And then I connected with the Alzheimer’s Research Institute here, and really directed part of my focus from seizures, which it was already clinically established as a standard of care for that, to neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, ALS.

The ketone bodies have a very neuroprotective property in that they enhance the energy currency of the cells, the ability to make ATP. And you can derive more ATP from ketone bodies than you can with glucose. And your brain can use glucose or ketones. In a fasted state, you start to switch over to using more ketones. And in that state, that physiological state of therapeutic fasting, your brain has access to ketone bodies. And that has anti seizure effects. It has the beta-hydroxybutyrate is a ketone. It turns on brain derived neurotropic factor. And that can stimulate learning and memory. Mark Mattson at the NIH studies that. There’s a variety of investigators, all within the US now over the last 10 years that are looking at the neuroprotective disease modifying effects of ketones.

It’s working in a variety of different capacities, not only giving the brain an alternative form of energy, but also reducing neuro inflammation, which may be a driver for many of these, especially age related chronic disorders. It looks now … 20 years ago, we were focusing on oxidative stress or reactive oxygen species. But really, the focus in the field from a global perspective has been looking at neuro inflammation as a major trigger for many of these age related chronic diseases. And that’s a big focus of what we’re doing now.

Dr. Pompa:
You know, Dom, you’re the science guy, [inaudible 00:08:05] guy, but I love reading research like yours and applying it. One thing I can say is, and tell me if I’m right on this, when we look at ancient cultures, they were always forced into times of ketosis or famine, for that matter, which drive ketones. It seems like even the average person just by going through putting themselves in times of ketosis, even if they don’t stay there, it seems like they have a major reset in their brain and their body. Is there clinical evidence of that? Mean that, as humans, are we meant to be in these times of ketosis? Because of everything you’re saying, there’s neurodegenerative reset, there’s the epigenetic reset. Are we missing this in today’s day and age because we don’t go into ketosis? We don’t have to. We have plenty of food.

Dominic:
Yeah. I think we’re missing it. Also, you have to figure that our baseline state is reset to a level that’s probably producing a variety of maladies. We are really promoting sort of a chronic sickening state by allowing ourselves to these frequent feedings of processed food. And it’s really the over consumption of food that’s leading to weight gain and obesity. And the quality of the food absolutely is essential there. But we did not, as a species, eat three to five meals a day, day in and day out, of high carbohydrate meals. We largely silenced the metabolic state and even the genetic program that’s activated upon entering short-term fasting, or you might want to call it therapeutic fasting. That really has a remarkable effect on the body, on shifting the metabolism. And when that happens, the more you do it, the easier it gets. The first time you fast, it might be kind of difficult and challenging. But the more you do it, the easier it gets because it’s really hard wiring your system.

We’re already hard wired, but it’s opening up those metabolic pathways to be more receptive to those states. It’s stimulating fat oxidation enzymes. It’s stimulating ketogenic enzymes that allow your body to produce the ketones and your cells to utilize those ketones over time. You up regulate the transporters. Essentially, the more you do it, the easier it gets and the more benefits you derive from it. You’ve just got to do it.

Dr. Pompa:
Absolutely. And I’m going to be discussing this at the seminar, how to do it, strategies that we discovered as a group of doctors on how to do it, and moving in and out of that state. And I can tell you it does get easier. I can move into ketosis in one day. Even if I’m out for a few months, literally in a day I can be back into a ketotic state. I’m going to be teaching on how that happens, that metabolic flexibility. But that’s what our ancestors did. They weren’t always in a state of ketosis. They were in and out. When they had plenty, they ate plenty.

I believe that’s missing today. Talk about ketones from an antiaging standpoint, everything you just said, antiinflammatory, that’s all antiaging. But I can tell you in the last, whatever, eight years of my life, moving in an out of this state, forcing my ketones up either via fasting or just in a state of ketosis, my cellular age when looking at a telomere test has dropped dramatically. Now again, I do a lot of things. But I know that the ketones are a big part of it. Talk about that.

Dominic:
Yeah. That’s probably one of the biggest emerging topics right now of therapeutic ketosis. I was out in San Francisco, and I know the Buck Institute is heavily vested into this idea of using ketones as an anti aging compound. And probably they’re most interested in it because we now know from the work that was done at Yale, and we were part of kind of constructing the diets for that, that beta-hydroxybutyrate is-

Dr. Pompa:
Which is a blood ketone. We find it in the blood when we measure.

Dominic:
A ketone body, yeah. That’s playing a large role in the benefits of fasting. Different institutes, like the Buck Institute and John Newman is there, and a prolific scientist in the geriatric department is really looking at strategies that can do a number of things. They can increase insulin sensitivity, lower insulin at the same time, lower blood glucose, probably more importantly, turn on a variety of genetic pathways through the epigenetic effect that … And these gene pathways are associated with longevity. There’s [inaudible 00:12:55], we’ve known for many years, things like BDNF, super oxide dismutase, catalase. A variety of these pathways are up regulated and sustained up regulation in the presence of relatively low levels of beta-hydroxybutyrate into that .5 to one millimolar range is where you really start to take on a number of these pathways, including receptor pathways.

The G protein couples receptor 109-A, and there’s 40 … The G protein couples receptor 41 and 43, when these are activated, they actually produce an antiinflammatory effect. And we know that if we can suppress inflammation systemically in our body, especially neurologically, that can play a really key role in health span, longevity, our health span, and really delaying the onset of chronic diseases, but at this point are kind of inevitable until we find the true fountain of youth. I think the most powerful thing that we have out there in the world right now, I mean, there’s many scientists investing millions of dollars looking into a drug. I think fasting, or the ketogenic diet, or even supplemental ketones are a way to really promote that physiological state that would be enhancing our longevity and our health span.

Dr. Pompa:
Yeah. No doubt about it. Talk a little bit about this. One of the things we just interviewed Nasha Winters. She talked about the number one growing cancer right now in people under the age of 35. And it’s these glioblastomas, brain cancer, brain tumors. Talk a little bit about that because some of your new research is really dialing into this. And by the way, this up and coming seminar, we have a major focus on cancer. Right? Talk a little bit about that because I believe that we’re seeing this explosion of these brain cancers, possibly because of this. Your research and others are showing that ketones have a very protective effect against this type of radiation, radiation in general. Talk about that.

Dominic:
Yeah. I think anything that can dysregulate the electrical activity in the brain, and electrical activity, next Monday my lecture to the medical students will be on action potentials and the membrane potential of neurons. Neurons are like little batteries. And they have a membrane potential of about negative 60 millivolts. And when they’re depolarized, they send communications to other neurons in a neuro network, essentially your brain. Anything that disrupts the electrical activity of the brain will disrupt the membrane potential. And the bio energetic capacity of the cell is intimately associated with the resting membrane potential.

And if you disrupt the membrane potential, that can disrupt the energy pathways, including ATP. And the genomic, I should say stability or fidelity of the nuclear genome of the cell is tightly linked to the electrical activity and also to the energetic state of the cell. Things like cell phones, chemical carcinogens, stress, neuro inflammation, disrupts the membrane potential. That disrupts the energy pathways. If you block the ATP levels in the cell, the DNA repair in the nucleus does not maintain the fidelity of that nuclear genome. And what happens is the cell senses that and kicks on oncogenes, that are like a stress response. And those oncogenes actually create, they transform a normal cell into a cancer cell. That’s sort of the metabolic theory in a nut shell, what I just described.

Disrupt that with various disruptive agents in our environment, and that could be electrical activity. It could be carcinogens, radiation, inflammation. These are some of the provocative things that can actually trigger a normal cell to a cancer cell. And as you mentioned, GBM, glioblastoma, is on the rise. And there’s a couple provocative things in our environment that may be contributing to that.

Dr. Pompa:
Yeah. Exactly. You explained basically what’s happening at the cellular level, why we’re seeing explosions of different cancers. Toxins drive that and so does radiation. It really all causes a depletion in the cellular energy. My R number three of what we need to do to fix the cell is restoring the cellular energy because it has such an impact on even the genetics, turning on the bad genes when that energy drops, driving inflammation when that energy drops, and then creating a bad cell. That’s it. It’s as simple as that. Now ketones can actually be a factor of stopping that process. Obviously, it gives the cell a new energy and it bypasses that broken energy pathway. Is that the number one reason why ketones have such an impact?

Dominic:
Yeah. That’s definitely one of the reasons. The brain makes energy from glucose using a variety of pathways that I mentioned, correctly, are circumvented by a ketone metabolism. Two of the big ones are the glucose transporter, the GLUT3 transporter is on the membrane of the neuron. And that transports the glucose across that membrane. That gets internalized when our brains are under inflammation. And that internalization of the transporter prevents the glucose from [inaudible 00:18:53] into the cells, so our brains become starved.

And there’s also an enzyme called pyruvate dehydrogenase complex. And that gets inactivated and we produce less of it in a state of neuro inflammation. And Parkinson’s disease and Alzheimer’s disease and traumatic brain injury, a hallmark characteristic is lower levels of pyruvate dehydrogenase complex. Ketones totally bypass that. Actually, if you have the genetic disorder called PDH deficiency, the actual standard of care for that disorder is the ketogenic diet. That’s a good example of it working in a very specific case. But it’s a general hallmark of many neurodegenerative diseases that are pathophysiologic-ly linked to energy dysregulation from glucose hypometabolism. I know I used a lot of big words there, but the brain [crosstalk 00:19:51] does not use glucose efficiently as we age, and it uses ketones very efficiently as we age.

Dr. Pompa:
I was just going to say that. I was going to say, for those watching this. By the way, this is the first seminar where we’re actually doing a full day of the public. Share this with your doctor friends. They need to hear this new information that Dom’s going to be talking about, myself, and others. But share it to friends and family that either have cancer concerns or just general health concerns. They need to be at the seminar. And by the way, you have a link here to bring you to the seminar, find out more about the up and coming seminar that we’re talking about.

Really making it simple is this, we’re bio hacking the energy system of the cell to go around these pathways that potentially could be broken. But even if they’re not, I believe that the average human is just missing these times of ketosis. We need to go around these systems to create, really, to keep the cellular energy what it should be, or the cells themselves. You don’t have to understand the science. The fact is that we need more of these states, and your research is proving that. Give us one thing that you’re going to discuss at the seminar, something new, something to excite the people why they need to be there. Talk a little bit about that.

Dominic:
Yeah. Man, there’s so many. I have to think about what would be the best thing. I think the most relevant topic that I can think of is the new data that we have coming out, it’s not even published yet. But it’s showing the profound blood glucose lowering effect of metabolic strategies, specifically you could do it with fasting, ketogenic diet, and supplemental ketones too. That’s a new-

Dr. Pompa:
And you’re going to be talking about that as well.

Dominic:
A new development on our end, and the effect is probably much bigger than we’d thought it would be. And it’s become one of the hallmark characteristics of getting into a state of therapeutic ketosis is that lowering of blood glucose. And we have new data on ways to achieve that, that I think will have a readily implementable and actionable and translatable to humans. We have that animal cell data, animal data, and human data. I think that would be of interest to the public.

Dr. Pompa:
I think you’re right. One of the things that I know Thomas Seyfried. You’ve worked closely with Thomas. I got from Thomas then, saw clinically is, as well as he saw clinically is the fact that if you don’t get that glucose down, the utilization of the ketones just isn’t there. It’s a really important factor that we lower the glucose so our cells can actually use the ketones.

Dominic:
Yeah. The glucose ketone index is actually a single biomarker that he developed and has a paper, Nutrition Metabolism. We talk about the metabolic zone in our studies. And if you can achieve the metabolic zone, which is a glucose ketone index of, say, between one and two. That means basically lowering your glucose levels from four or five down to 3.5 or three. And then elevating your ketone levels up to about three and in millimolar range. Three millimolar in glucose is 70 milligrams per deciliter. And you can do that with the ketogenic diet and other forms of fasting. Get your ketone levels to three millimolar.

And that one to one ratio is a glucose ketone index of one. And we know from dozens of studies that that’s a very powerful neuro protective state to be in. It protects against seizures. It protects age related chronic disorders. And from the perspective of cancer, it has profound anti cancer effects, essentially targeting all the hallmarks of cancer. I will be talking about different ways to achieve that glucose ketone index, lowering glucose, lowering insulin, and elevating ketones.

Dr. Pompa:
Well, that’s perfect because I’m going to be showing them … That target range, I give Thomas credit for teaching me that. And we utilize that clinically to try to get people to that one to one ratio of glucose and ketones. Just really, for me, I say that it really is an indicator of when you start to at least move into maximum autophagy because the way that Thomas explained it to me, how he came up with it is when they saw the tumors really starting to shrink is when he hit that ratio. And when he was moving away from that ratio, he would see the tumors not shrinking. For me, it’s a representation of, hey, I’m in maximum autophagy if I hit that ratio. That’s kind of what I talked about in my book as well.

Dominic:
Yeah. Autophagy is another factor that we can discuss. It’s interesting. And you had mentioned the elevation of ketones also inhibit glycolysis pathways. Not only are you decreasing glycolysis because you’re decreasing glucose availability. And you’re also decreasing insulin. If insulin’s elevated, that stimulates glycolysis. But because you lower insulin, that lowers glycolysis. You decrease glucose availability. If you’re fasting and a ketogenic diet, that lowers glycolysis. But the ketones themselves actually inhibit different metabolic pathways including hexokinase and hexokinase two that are actually part of that glycolytic process. We’re just starting to delve in and understand mechanistically all the different aspects. And the more we understand it mechanistically, the more we can tweak the system for specific disorders and even specific kinds of cancers.

Dr. Pompa:
Well, one of the fun things we do at the seminars, we intermittent fast the people during the day. We take their morning glucose and ketones. And then we take them before their first meal. We want to see that glucose dropping and ketones rising, which is indicative of all the fun stuff that we’re talking about here happening in the body, moving towards that one to one ratio. It’s something that we do with everyone at the seminar. You talking about that target ratio, that index, is really going to be helpful for me because I’m usually the one trying to teach all that. You’re going to take the science on that.

Dominic:
It’s a very powerful tool. And I think once you understand it, it almost becomes fun to implement it and to actually see that you have control of your metabolic physiology, which alters so many different things in your body including how you feel on a daily basis, your energy levels, and of course your longevity is a big factor. It’s going to have a mass … It’s going to pay big dividends on your health span and longevity over time.

Dr. Pompa:
Yeah. It is fun because you would get a poll from the audience too, of my glucose was rising. My ketones were doing the opposite thing. Metabolically, you may have gotten stressed out or [inaudible 00:27:05] threw it off. But if you didn’t do that, then metabolically there’s something going on here. We have to figure that out.

Dominic:
It’s also interesting how our psychological state can impact our blood glucose. If you wear a glucose monitor, and you’re thrown into a stressful situation, I have seen … Yeah, because these are things that we measure in the lab. You can actually see a pretty profound spike in your glucose levels in response to stress.

Dr. Pompa:
Oh, yeah. No doubt. When people send me their values, I’m like, “Did something odd happen that day?” Yeah. My son da, da, da, da. Well, that’s why your glucose was up and your ketones plummeted. Well, we’re going to teach you more about that at the seminar. Dom, you’re a wealth of knowledge. This is an important seminar, folks, to be at. Share this video with friends, family, and other doctors because it’s going to be amazing. I can’t wait to hear your new research. Everybody needs to hear it. Dom, thank you for your contribution, honestly, in this area. And I really mean that. It’s been a wealth of knowledge there. Everything you put out, I love to read, so thank you for that.

Dominic:
I appreciate being part of this. Thank you.

Dr. Pompa:
Yep. And by the way, folks, again on this page, you can click and you always get the best deal here when you go to the seminar on these videos that we put out. So do that, and we’ll see you at the seminar. Thanks Dom.

Dominic:
Thank you.