I want to have a two or a three-hour interview with him, but we had to cut it short. But we touched on some really interesting topics about the work he's doing with ketogenic diets and exogenous ketones on brain function, how his work in extreme environments can translate to regular disease processes that aren't in extreme environments, that people get and we need some better treatments for and how ketones can play a role in the specifics of the types of diet, the specific types of exogenous ketones, some of the protein sparing effects of ketones.
So we brush the surface and talk about some of these topics, but my hope is we're going to have him back for even more interviews in the future. But hopefully this will be a great introduction for you to Dr. Dom D'Agostino, all the amazing work he's doing and get a little sense of the personality, because he's really a great guy and I hope to hear more from him. Let's get started with the interview with Dr. Dom D'Agostino.
Dr. Dom, thanks so much for joining us.
So first of all with your name you've reached the status of Prince and Madonna of being known by just one name - Dom, and every knows who you're talking about. But, D'Agostino, when I hear D'Agostino I think lots of pasta in your upbringing. And now here you are as one of the most preeminent ketogenic diet and ketone researchers. So how did you make the transition from an Italian pasta family, assuming that assumption is right, to where you are today?
And the military Navy in particular, the major branch that we work with, they are interested in enhancing the safety and the resilience and performance of the military personnel under particular environments.
And what I have spent most of my time developing unique technologies to understand these environments, microscopy and telemetry and different things like that in hyperbaric chambers and as we developed these technologies and understood the biological process of oxygen toxicity, we realized that getting the body and in particular feeding the brain ketones or elevating your blood ketone levels would provide metabolic resilience in an extreme environment that could help the brain function and most importantly prevent a seizure under these extreme environments.
Or delay the onset to that seizure above and beyond what we could achieve with any pharmaceutical compound, which was my main focus - drug research.
Surprisingly I went through a nutrition program at Rutgers University in New Jersey and we didn't really talk about the ketogenic diet, at least its clinical applications. So in the process of trying to develop an anti-seizure neuroprotective strategy for oxygen toxicity, I went to the epilepsy research and I was also connected with people like Mike Dancer, who is a patient, an epilepsy patient, who was diagnosed with terminal epilepsy.
And at the time I got into this advice that he perhaps used a ketogenic diet and worked remarkably well for him. I connected with Johns Hopkins and other people who actually used the ketogenic diet clinically. And it became apparent that the ketogenic diet could potentially be used for these very powerful tonic-clonic seizures that limits Navy SEAL operations, because of the special rebreather unit that they use.
The office of Navy research, they were not very keen on a high-fat low carbohydrate diet as part of a war fighter strategy for enhancing performance. So, at the time Jeff Volek's work really wasn't popular yet and it was a hard sell for them in particular to fund a project. So they were like, why don't you come up with a ketogenic diet and a pill?
And this was 2008 and by coincidence Dr. Jong Rho who was at Barrow Neurological Institute at the time just happened to publish a review called the Ketogenic Diet And The Pill and he talked about that epilepsy world is trying to find something that could mimic the ketogenic diet, because it works better than any antiepileptic drug that we have right now. And he talked about exogenous ketones and the potential for that. So I got steered into Dr. Richard Veach and some work being done in Oxford by Karen Clark.
And Dr. Veach was a student upon scrub and a very well respected biochemist that developed and his whole life was really studying ketones. So it was interesting to me that these very high-level scientists were studying the therapeutic applications of ketones. Maybe it wasn't in the public domain at the time, but I saw that DARPA had funded quite a bit of money, millions of dollars, to develop these ketones for war fighter performance.
So I was like, okay there's a potential ketogenic agent that I could use for seizures and, you know, DARPA was funding it for performance. So let me see if it works in our seizure model. Surprisingly it didn't and this was a beta hydroxybutyrate mono ester. But then I connected with folks, Henry Brunengraber from Case Western and other chemists who could synthesize the compounds for me and tried a number of agents.
And the one agent that elevated beta hydroxybutyrate and acetoacetate, we discovered that that was remarkably neuroprotective.
So it can make it confusing for the individual in terms of what is doing the benefit, what is the key that's actually helping from a neurological standpoint.
You take ketone salts, mix some of the ketone esters and mixing ketogenic fats with ketone salts or ketone esters also seems to enhance the response. If you ingest a purely exogenous ketone... it's my belief and I think some data will support this... that you're turning off your own ketone production to some extent.
But if you mix a ketogenic fat like medium chain triglycerides with a ketone ester and deliver it orally, it simultaneously stimulates your own endogenous ketone production. Because you are producing hepatic ketogenesis by- for MCTs for example. And it also delays gastric absorption and extends that pharmacokinetic profile of that ketogenic agent, so it's elevated longer in the blood.
And a kind of think that's the future. We're really at the cusp of figuring these things out and we have a long way to go. But we have started moving things into human clinical trials, which I will be talking about today actually; some of the work we're doing at Duke, who is a collaborator of mine.
If I mentioned the top 4, 1 would be- it's enhancing brain energy metabolism and contributing to brain homeostasis and balancing energy in the areas of the brain maybe deficient in glucose metabolism, glucose hypometabolism.
And when you're on a ketogenic diet, for reasons we don't completely understand it activates an enzyme called glutamic acid decarboxylase. And that converts glutamate, a hyper activity enzyme, stimulatory neurotransmitter to GABA, which is an inhibitory brain stabilizing neurotransmitter, that from neuroscience perspective hyperpolarizes the membrane potential of neurons and quiets the brain down.
We know that ketones are remarkably anti-inflammatory and inflammation in the brain can lead to anxiety, inflammation in the brain can lead to seizures, inflammation in the brain can lead to headaches. Ketone bodies do have a remarkable anti-inflammatory effect that we've just published a paper on that in animal models and we can use things like LPS, lipopolysaccharide, to stimulate that inflammation.
So, and then the gut microbiome, we can get into other things, but I just mention four things: brain energy metabolism, neurotransmitters, adenosine receptor signaling and inflammation. Are four things that we know, we have really good preclinical animal model work to demonstrate that being in a state of ketosis alters these things and in a way that would be neuroprotective and anti-anticonvulsant.
That's not probably more than modified Atkins diet. So when you're talking about a ketogenic diet for neurologic protection, does it matter the specific type of diet? And does the degree of ketone elevation matter as well do you think?
Many of the patients can transfer to a modified ketogenic approach, which is more liberal in protein and just making a diet more liberal in protein for example from 10% to 20% that's a very big change and it makes the diet much more feasible for the parents and it's quality of life thing.
And remarkably now we realize that the diet does not have to be as strict as we once thought it was and you can also incorporate into the diet fats that are ketogenic, like medium chain triglycerides and get the same level of ketosis that you would for example with a classical or more restrictive ketogenic diet.
So our minds are changing about this and new studies are starting to come out. I chaired the American Epilepsy Society special interest group on dietary therapies where it's more of a mainstream conference and evidence is starting to accumulate that a more modified ketogenic diet approach may be advantageous for compliance and maybe even efficacy too.
So, that gives me a little bit of confidence, what we're seeing in the lab will translate into human clinical trials, which we have now for Angelman syndrome, a registered clinical trial. One will be starting up for epilepsy. We have one, I'll be talking about today, using nutritional ketosis to enhance neuroprotection in extreme environments, which would be high oxygen environment.
And we do this in a lab at Duke University. I was actually amazed that it got approved by the IRB, because it's a rather extreme protocol that I'll be presenting today. But we are, you know, diving subjects now and implementing not only ketogenic diet, but ketone supplementation. And that was really the vision I had like 10 years ago when I started seeing the animal model work and it was very compelling, the neuro-protection that we were seeing.
So it's very satisfying to me that we're able to move things into the clinical realm with registered clinical trials now, but we do have a lot of work to do. And only the things that have been done now are mostly pilot studies, where we're recruiting, you know, more subjects to do large-scale clinical trials and ultimately multicenter clinical trials. And the direction to go at least for now is for epilepsy and seizure disorders, because there are so much data already in that, but we're also pushing to get some studies, clinical trials, for brain tumor patients too.
When you've depleted your glycogen stores you make proportionally more ketone bodies through the suppression of insulin. The hormone insulin stimulates hepatic fat oxidation and then you make more ketones. The ketone bodies do largely replace glucose as a primary energy source during prolonged fasting. You know, after about a week or more.
So they become uniquely anti-catabolic because they're simply supplying an energy source and that allows your body to spare amino acids, in particular gluconeogenic amino acids so your skeletal muscle will catabolize. If those ketone bodies were not there, we would waste away much faster. So that's well-established. Dr. George Cahill has written a number of nice reviews on that.
I think where ketones will shine is prolonged use of ketones can help perhaps with adaptive effects of exercise training, perhaps in the context of a calorie deficit, but I think the anti-catabolic effects of ketones are pretty real and I think the science will support that over time.
From an evolutionary standpoint we know that ketones really allow us to do and maintain prolonged fasting. And there are a number- my student Andrew Koutnik, who has just finished the PhD with me, his whole PhD project was basically studying the anti-catabolic effects of ketone bodies. And we wrote a review published in Cell with Dr. Brendan Egan that is an overview, maybe we don't have time to get into, and it mechanistically goes through all the potential anti-catabolic effects that ketones can have.
I do enjoy testing products and also enjoy testing devices like breath acetone meters or blood ketone meters and use those devices to test the products. And that's a fun thing that I do and kind of do it on my off time. I really like to do not only bench research, but also live this lifestyle and it's become sort of a passion to do both.
