Dr. Patrick: So speaking of the nervous system, this is one area where in my opinion ketosis, ketogenic diets really shine. What has thoroughly convinced me is, you know, just the overwhelming evidence that you've talked about with the effects on the brain and epilepsy and other types of brain disorders but also some of the preclinical studies that have come out of our mutual friend Dr. Eric Verdin, and I know John Ramsey also did some publications where they fed mice. In the case of Dr. Verdin's study, midlife, they started a cyclical ketogenic diet. And I'd love to get your thoughts on why...he said the reason they did it was because the mice were overeating, which I found to be interesting because I've always been satiated on a ketogenic diet. But anyways.

Dr. D'Agostino: A lot of nuance Eric [crosstalk 01:31:32].

Dr. Patrick: Yes. Let's get into that. But also the thing that was so striking, and you know much more about the details of these studies than I do, but the effects. I mean, their health span was improved. So their median lifespan was improved. They were dying less earlier, but maximum lifespan I guess wasn't affected. But the effects on the brain and cognition like he said, you know, that these...the older mice had better cognition than younger mice. And when he said that, I mean, I was, you know, like that's really.

Dr. D'Agostino: Things are magnified in rodents. So I'll say as far...and especially [crosstalk 01:32:10]

Dr. Patrick: Yes. So my question is, do you think this is going to translate to humans?

Dr. D'Agostino: Rodent model studies are in very, very informative, especially mechanistically, not always predictive. Some of the nuances is that there's different strains of rodents that will overeat ketogenic diets. Like early studies before, some colleagues were feeding it and said, "This is not gonna work. They're hoarding the food. They're eating. They're getting blown up." There's like this is obesogenic, you know. So the high fat... There's a lot of high-fat diet research that detractors of ketogenic diet will point to and say, "This diet is...you know, causes all these bad things." But that's a westernized obesogenic high-fat diet. So, what Dr. Verdin used and Ramsey...so they did actually the study that I really wanted to do, and they probably did it better than I could ever do. They have really great molecular tools and everything, and they did it in a very clever way. From my understanding, they did... And the results were to be expected. You know, I think the results are what I would expect.

So my understanding is that they did the cyclic ketogenic diet because, yeah, they didn't want them to gain weight, which could negate. So, I have to look to see what animal model they used, but the C57BL/6 mice will eat a ton of the ketogenic diet food, and they don't gain weight. Whereas other...depending upon the strain. And then we have the VMDk mice that we use for our cancer research, and they tend to... It corrects their eating behavior, meaning that if you give them a standard diet, ad libitum, they just gain weight like a couch potato. But a ketogenic diet, they will lose weight and everything improves. So they're like the other end. The C57BL/6 are kind of like athlete mice, I think, where the other models are more like sedentary mice. They are not as active. But what we found... I have to look exactly at the feeding protocol. But when we did a little bit of calorie restriction...our calorie restriction is just putting, you know, 5 or 6 grams of food into it every day, and then they eat it within an hour, and then they essentially fast for 23 hours.

Dr. Patrick: [crosstalk 01:34:30].

Dr. D'Agostino: So it's kind of more like... But you have to individually house the animals, and then, you know, sometimes if you house them together, they'll start, like, fighting and eating each other because they're kind of hungry. But one thing that we saw very consistently early on is that a mild amount of calorie restriction makes these mice like super mice. Like they become...you know, they're thinking faster. They are really thriving in the context of a calorie deficit, and I think that goes back to human evolution too. So, we survive today because we undoubtedly experience food scarcity and limited food availability, and in the context of being hungry, that enhanced our cognition and even exercise performance to be able to acquire resources, right? So the same thing I think is happening in their mice, and it could be...

I have to look at the weights of the mice, but a lot of it's kind of like weight dependent and producing that energy deficit. But you just get a whole plethora of things to happen in regards to suppressing age-related chronic diseases with just a little bit of dietary restriction seems to unmask this probably because, with a standard rodent chow-fed ad libitum, they overeat, and it just basically fuels metabolic derangement that contributes to early-onset age-related chronic diseases and also the formation of spontaneous tumors. And I think in their studies maybe with both or at least one...maybe both studies showed a suppression of spontaneous tumors too. So, this has major implications, I think.

We're very interested in actually taking animal models that have inducible tumors, for example, you know, various genes that will kick on at 200 days and then form spontaneous tumors or a melanoma model where you subject to UV radiation. And if they're fed a ketogenic diet, can you suppress that? People don't do these studies because the NIH doesn't really fund like cancer prevention research. I feel like these are the most important studies that need to be done. You put a variety of different rodent strains under different conditions that are known to like induce tumors, and you feed them, you know, a low carb diet or ketogenic diet that you could actually feasibly maintain and do. And you see if you could suppress these spontaneous tumors. But that's what they did in this experiment, and they showed, like you said, an enhancement of cognitive and learning ability relative. The older mice learned better than the younger mice [inaudible 01:37:09]. Yeah.

Dr. Patrick: I know in John Ramsey's publication. Dr. Verdin mentioned also in the podcast when we had him on a few years ago that they had a time-restricted feeding aspect to it because they were feeding the animals proportions of very specific proportions. They were only given their food, you know, when the people...the scientists were going there into the house and giving them the food. So they had this sort of dietary restriction component to it. Whereas Verdin's they were ad libitum. They were cyclic. They were going on the cyclic ketogenic diet. And Ramsey's data was more pronounced, like you mentioned, the combination of the dietary restriction plus ketogenic diet seems to be like secret sauce in a way. But, you know, to me, it was...

And again, like you said, you know, the animal rodent research isn't necessarily predictive of what's going to be, you know, occurring in humans, but it certainly is promising in my opinion. It got me very interested in it and, you know, I've got nerve degenerative diseases on both sides of my family, Parkinson's and Alzheimer's. So I'm very interested in, you know, any types of lifestyle... And I also have genetic factors there at play as well. I'm certainly very interested in any sort of lifestyle factors that can mitigate that genetic risk, which as we know there are many things that you can do in your lifestyle that can help. Doing some sort of modified ketogenic diet, cyclical maybe, you know, because it is for me hard to sustainably do it all the time, you know.

Dr. D'Agostino: That's where intermittent fasting kind of comes in too because people don't have to tinker around with their... I mean, the foods that we eat are super important just like eliminating processed sugar, carbs, things like that. That's going to move the needle, like, quite a bit. But there are some people that I know like family member and [inaudible 01:39:08] There are just some people who are not going to count carbs even to do that. You know, this is just not going to happen. But eating within a predetermined time window is pretty easy for...that's like a good introduction. Once you start doing that, then you start realizing how good you feel in this mild state of ketosis. And then you start maybe...that becomes the entry point to where you start manipulating your food and your macros and things like that.