CLINICAL PEARLS - Dr. Dominic D'Agostino: Therapeutic Strategies with the Ketogenic Diet

Uh, there wasn't like a whole lot of opportunity at the time in the 1990s for nutrition, and I kind of wanted to go to med school. So I started majoring in biology too. And at the time, I remember 1994, I was an undergrad. I saw on Dateline NBC the Hollywood producer Jim Abrams, and he talked about how the ketogenic diet kind of saved his son that had drug-resistant epilepsy. And Jim later went on — he's a close friend of ours and we work with him when we host the Metabolic Health Summit. We hold a gala dinner and it goes to the Charlie Foundation. Charlie's story is very interesting. He was on many anti-seizure drugs and was kind of headed towards — I mean, he really had almost like terminal epilepsy, nothing was controlling it. And Jim went to the library and discovered the ketogenic diet was used, you know, a hundred years ago in the 1920s, and was able to get a team at Johns Hopkins to implement it in his son. And I found this to be fascinating, but it was not really — I was more interested in nutrition for different reasons, for sports and body composition reasons, when I was in undergrad. And then it kind of evolved to the point after my neuroscience training at Rutgers, I went on to study seizures and I revisited nutrition and I remembered the ketogenic diet was used for epilepsy. And we were studying military operational diving and a limitation of that is oxygen toxicity seizures. So I was able to incorporate ketogenic diet therapies and ways to induce therapeutic ketosis with different forms of ketones as a neuroprotective anti-seizure strategy. That was 2008, and it took me about two years to get like high-level federal funding for the projects. But for the last 15 years, I've been studying the ketogenic diet for seizures, but probably at least a half dozen or more different therapeutic applications. The ketogenic diet is unique in that it's the only diet that is characterized by an objective biomarker, and that would be blood ketone levels, urine ketones, or breath ketones. Right? So as ketone levels are elevated within a certain range, then that becomes clinical ketosis. I can go down the list too of the different applications that are currently being studied. It could be polycystic ovary syndrome, type 2 diabetes, weight loss — there was 25 clinical trials for weight loss — cancer and muscle wasting, 47 clinical trials on that, four on Parkinson's disease, over a dozen for Alzheimer's disease, of course epilepsy and different seizure disorders, migraines, Kabuki syndrome, which we study, Angelman syndrome, and then there's like a wide range of inborn errors of metabolism like the — we study that too. Glycogen synthesis disorder, you know, type two, Pompe disease, Marden-Walker syndrome, Prader-Willi syndrome, PDH deficiency, GLUT1 deficiency syndrome, Deater syndrome, Lennox-Gastaut syndrome — like all these things. Actually, some of the ones that I mentioned, the only therapy that exists for the disorder is the ketogenic diet for like PDH deficiency or GLUT1, and Lennox-Gastaut syndrome, it's often used. So these are all like evidence-based clinical applications, but then there's the like emerging applications. So that would be psychiatric disorders. One of them would be probably the psychiatric disorder that kills more people than anything else is actually anorexia, and my colleague Deanna Rancourt studies that at USF and is doing a study on that. Bipolar disorder, anxiety, autism, traumatic brain injury, type 1 diabetes — actually there's a clinical trial with a ketogenic diet for that. Non-alcoholic fatty liver disease, stroke, HIV dementia, alcohol withdrawal syndrome — there was two clinical trials on that — and chronic obstructive pulmonary disease, a study on that. So none of these — like most of what I just mentioned here was not being studied at all five or 10 years ago.

Uh, liver disease. So your liver is the site of production of ketones, and if you have liver failure, it's hard for your liver to be healthy enough to have that elevation of fat oxidation to make the ketones because you really need to ramp up fat oxidation. So pancreatitis would be one, fatty acid oxidation disorders, primary carnitine deficiency, carnitine palmitoyltransferase deficiency, CPT1A I believe. So carnitine actually plays an important role in moving fatty acids to the mitochondria. And what I actually — I see this quite often in the blood work of kids. When you do blood work and measure carnitine, it's often deficient because you're burning so much fat that actually your carnitine plays a role in transporting the fat into the mitochondria. So you're oxidizing and burning such huge amounts of fat that you're depleting your body of carnitine. So carnitine is often — clinically it's actually a supplement. So carnitine and potassium citrate to prevent the kidney stones. And so that's, you know, if you've had kidney stones in the past, you know, they'll tell you not to do the ketogenic diet. And there's definitely a high risk of kidney stones in the literature, but I think that has to do more like with the type of ketogenic diet they're using and also hydration. I think if you just correct for hydration and also take like an electrolyte supplement to just offset the mild metabolic acidosis, then in those studies where they even use potassium citrate, there's like no increase in kidney stones. It's about suppressing insulin, and just that alone, the benefits of that can be absolutely tremendous.

Yeah. So we study the signaling roles of ketones. So ketones are energy molecules that can provide a boost to your brain energy, but they also have pretty significant effects at impacting signaling pathways that are pathophysiologically linked to many different disorders. So when I first started studying the ketones, we actually measured oxidative stress, reactive oxygen species, and we developed — I developed an assay to measure superoxide in the brain and showed that under like high levels of oxygen, you know, these were elevated. And then the ketones were more effective than any drug that we looked at at lowering oxidative stress, like in the hippocampus, for example. We looked at the CA1 region. So a reduction in reactive oxygen species, a decrease in glutamate to GABA ratio. So one thing that happens from a signaling perspective is that the ketones, in ways we don't fully understand, activate an enzyme called glutamic acid decarboxylase. And that's the enzyme that converts — all the GABA that we have in our body is made from glutamate, and that's converted by glutamic acid decarboxylase, and they're GAD65 and 67. That's what we measure in the lab. We do western blots for that, and then that's sort of — these two different enzymes will dictate how much glutamate goes to GABA, and there's about a 30% elevation. What we focus on now is actually the epigenetic effects. So my PhD student, Sarah Moss, her PhD project is essentially the metabolic control of epigenetics, and specifically beta-hydroxybutyrate. So it affects histone enzymes as HDAC inhibitors. But what we're studying is something called beta-hydroxybutyrylation, where beta-hydroxybutyrate directly interacts with the histone and modifies the histone in a way to kick on gene expression. So this idea came from Dr. Bhatt at Johns Hopkins, and he studied the Kabuki mouse model, and he showed that he could rescue the mouse model with the ketogenic diet. And his speculation was, and he did some superficial testing, was that it was working by affecting gene expression. So our experiments are not to use the diet, but to use different exogenous ketone formulations because kids with Kabuki syndrome are very picky about what they eat. So we are designing sort of formulations where therapeutically you can ingest ketones, elevate beta-hydroxybutyrate, and then beta-hydroxybutyrate is a form of epigenetic therapy. So that's the project we're working on now. So all these different mechanisms are sort of — and it's probably not just one, but it's like many mechanisms in synergy.

Yeah, there's a couple things that I think can help, and these were kind of given to me by, you know, the dietitians over time. So carnitine, magnesium is going to be really important. Vitamin D3, of course, you want to make sure that — there's a paper, one or two papers showing that selenium was lower, but I think that had to do with the type of ketogenic diet they were on. If you're getting like, you know, fish and other like more of a balanced array of different protein sources, it probably won't be an issue. And then MCT oil, which you can buy pretty much anywhere, is going to be really — pretty much all clinicians now or dietitians really start to incorporate MCT because it really boosts the ketones. And for exogenous ketones, I am of the opinion to steer away from the ketone esters. We've done enough research that I feel that they should almost be in a category of like a drug because I mean we've never — I'll put it this way — we've unintentionally like sacrificed, you know, euthanized animals I guess you could say with a high-dose ketone ester. It can induce ketoacidosis, so that's a potential that people need to realize — you need a large dose. But we've never had that problem with, you know, ketone salts, and we've done studies where we have administered these things for a long duration of time. The blood work looks great, everything looks great. So ketone salt products — Keto Start is a really good one. As far as MCT oil, the powder is pretty useful too. Like I think Quest Nutrition makes like an MCT powder that's pretty useful and can be mixed with the ketone salts. Other than that, you know, you don't really need a lot of supplements on a ketogenic diet if you choose a good balance of food. You know, a good — I think it really is important to work with a dietitian on it. You know, some people will say an antioxidant supplement or just, you know, just a multivitamin supplement. So methylated B vitamins for some people need that. So I think, yeah, I'm kind of a minimalist when it comes to supplementation. But some of the supplements that I think have a really good track record are like creatine monohydrate — has like more research than any other supplement on the planet, has a lot of, you know, benefits to the brain and strength and body composition. But caffeine too, and I guess maybe some people will like to hear this: caffeine can greatly boost ketone production. And when you consume caffeine with MCT, it converts more of the MCT into ketones. It actually increases ketosis by 40%. And Stephen Cunnane — I mean, I observed this, but it was nice that, you know, a group did a study up in Canada. I think it was Stephen Cunnane's lab that showed that if you dose the MCT with caffeine, then that stimulates greater ketogenesis. There's also the amino acid taurine can help the liver produce ketones. So, and that should be taken not a small dose, like two to five grams per day, upwards of even eight grams per day. Taurine really doesn't have any — you could buy it bulk like online. So it's pretty cheap and it has a lot of other benefits too. And that could be, you know, if you're not producing ketones, the taurine has an effect on the liver. I think maybe even a therapeutic effect. And I've noticed that in people that just are not healthy, maybe they have like the precursor to alcoholic liver — like you get them on taurine or maybe an N-acetylcysteine in the beginning, but taurine can really help boost their liver production of ketones.