Rhonda: So to bring it back to the magic pill, I'm kind of interested. So let's say someone like me that my diet is mostly, I eat a lot of plants, a lot of greens, broad spectrum, carrots, I eat a lot of vegetables. So I get a ton of fiber. I eat a lot of fish. And I do eat, like, beans, so I'm not adverse to legumes or even to oats. I like fiber. Let's say, I wanted to, I'm, like, super-interested in beta-hydroxybutyrate because I've been following a lot of the research from Eric's lab and I want to get some of those benefits. I want to increase my FOXO3. I want to reduce my lipid peroxidation, I want some of that signaling effect. Plus, I want to beta-hydroxybutyrate to be around to get to the brain, things like that. Can I potentially take a beta-hydroxybutyrate, whatever delivery source powder, pill, whatever it is, and potentially achieve some of those same benefits that you get from nutritional ketosis or ketosis from fasting? Let's say, but I don't eat a lot of, I don't eat refined carbs, so I'm not getting a huge insulin spike for the most part. So do you know?

Dom: So, yeah, you want to have your cake and eat it? But you don't eat cake, right?

Rhonda: But I don't eat cake. No, I just eat fiber.

Dom: You want to have your carbs. Yeah, that's that's really what we're working on right now and understanding in a head-to-head comparison to see if we can derive the same kind of benefits from ketone supplementation as we kind of with the ketogenic diet. We know the first kind of convincing studies of this that we did was with CNS oxygen toxicity in our rat model, and in that case, the rats were eating a high-carbohydrate standard rodent chow model, and we administered via an oral route a ketone supplement in the form of a ketone ester. That's probably one of the more powerful forms of exogenous ketones that we've developed. And that had the ability to prevent CNS oxygen toxicity from happening for almost, over 500% delay in that time to CNS oxygen toxicity. And that could not be achieved with fasting, it could not be achieved with anti-seizure drugs. So when it comes to enhancing and preserving brain energy metabolism in the face of a tremendous oxidative stress that breaks down brain energy metabolism, we're able to enhance that, preserve that. So we've also studied in our animal model of cancer, metastatic cancer simply giving ketones to the animals on a high-carbohydrate diet, it was almost unexpected the level of enhanced survival that we had with ketone supplementation.

Rhonda: What kinds of tumor is it?

Dom: This is a model of metastatic cancer and the primary tumor, it was derived from a glioblastoma, the GBM. And that tumor cell line is so aggressive that when it's injected or implanted into the flank of the animal, there's rapid systemic metastasis to all the organs and the brain. And the model that was developed by Professor Tom Seyfried at Boston College.

Rhonda: Didn't he publish a paper on...?

Dom: It made the cover of the "International Journal of Cancer." Yeah, when I wanted to this study initially, I wanted to do a brain tumor model, like with our diet and our stuff. He sort of wouldn't let me use the model. He's like, "Well, use this model of metastatic cancer because it's the most aggressive thing out there and no one will..." He's like, "If you create a cure, something that can cure this animal with metastatic cancer, you basically stumbled upon something that has the potential to cure cancer." So that, kind of, intrigued me. So I knew working with his model would be kind of difficult because the tumor burden...the animal has died so quick from the tumor burden, but it allowed us to screen a variety of things and just using this model understanding that in aggressive metastatic cancer, the cells are highly glycolytic, and they're highly in favor of using glucose and glutamine probably as an energy source. We're looking at ways to target glutamine, but have not really, kind of, implemented that yet in a combination therapy. But regardless, the animals are eating a high-carbohydrate diet with ketone supplementation and it reduced tumor growth and proliferation. We think that the ketones may be altering glucose metabolism.

Rhonda: They induce cell death?

Dom: Well, we think so. There's more, like, sort of, apoptosis in the tumors that were there, but just overall, there's just less tumor growth and less tumor burden and enhanced, most importantly, a 50% to 60% increase in survival time in animals that are supplemented with this. And it wasn't...although the animals tend to eat a little bit less if they're in ketosis, naturally, which makes a ketone supplement kind of an attractive thing for people that are dieting because when you're sending energy to the brain in the form of ketones, it has sort of a satiating effect on your body and it, kind of, shuts off that hypoglycemic trigger that makes you want to binge or crave food.

Rhonda: So is it changing ghrelin and leptin signaling, or...?

Dom: We think so. Yeah, we think so. That's the next thing to look at. It does impact the satiety centers of the brain. It's not like you don't want to eat, but you have control over your appetite.

Rhonda: You know what? I just thought of it. Lauric acid, which is C12, suppresses ghrelin in the gut, which is the hunger hormone... That's kind of interesting, right?

Dom: Is that specific for lauric acid?

Rhonda: It's specific.

Dom: I knew with certain fats. Really, lauric acid? That's interesting.

Rhonda: It is.

Dom: I'll look that up.

Rhonda: Sorry to interrupt. [crosstalk 00:59:39] Let's continue because this is really cool. So you fed them a normal high-carbohydrate diet, gave them this ketone ester, as we were talking about.

Dom: Ketone ester, the same ketone ester, which is.

Rhonda: The tumor burden was decreased, survival time increased.

Dom: Yep, yep. And so that was another demonstration, and the data looked very similar to the ketogenic diet. So we did the study.

Rhonda: They're eating less, you said, right?

Dom: They were eating slightly less, so we went back. We were thinking, "Well, maybe we're just getting a calorie-restriction effect," because if you have a mouse model or any kind of cancer model and you overfeed it the tumors are going to grow faster, and if you underfeed it you're going to restrict some of the tumor growth. So they were eating a little bit less, but a maybe only 10% drop in body weight. So we went back and we did a calorie-restriction control experiment, and although there was a decrease in tumor, it was nothing like the ketone supplement. So ketones we know undoubtedly they have anti-cancer effects, and it could be maybe through their expression of their gene expression as a histone deacetylase inhibitor. We think that they inhibit glycolysis. We think that they influence a number of pathways associated with cancer growth.

Rhonda: Did you measure mitochondrial respiration?

Dom: Of the tumor and the tissue or...?

Rhonda: Just, yeah, of, or any tissue, like, so let's say, did you give them ketones in this....

Dom: We looked at ROS production. Yeah, it can sort of knock down reactive oxygen species production.

Rhonda: In the tumor? Or in...

Dom: In normal tissue, yeah. And now it's kind of interesting, too, that in the tumor tissue in previous experiments, I showed that it could knock it down significantly, but I think in the paper that we published, there was a slight decrease in ROS production.

Rhonda: Yeah, that's interesting.

Dom: We don't know, we do...our experiments are sort of like a top-down approach. We find out what works and then, we're mechanistically going after it and we're doing -omics work metabolomic in particular, and western blots and assays. So now we're going after the mechanism, and if we understand the mechanism, we can, kind of, work backwards and tweak the molecule or adjust the diet in ways that may enhance the therapeutic effects.

Rhonda: It would be really interesting to do some of... I don't know if you can radio label these ketone esters and see if, like...

Dom: Yeah, that's another thing we'll look at.

Rhonda:...are they being used as a carbon source for ATP? Are they being used for something else, right, like...?

Dom: Tracer studies. That's what we want to do. Yeah, we're going to partner with a company that has, sort of, the market on doing these tracer fate associations. I think even doing a 13-Carbon glucose tracer fate association study where we give this, and we give ketones we look at the fate of glucose in the presence and absence of ketones and see how that may be influencing...

Rhonda: There you go, is it going to the pentose phosphate? I mean, this is all stuff I really want to know, so I'm, like, super-excited someone is doing it...