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.

Dr. Patrick: So what happened with me totally in that very order. I mean, I'd practice a lot of time-restricted eating and started to notice in the mornings with stuff. It was like I'm just so much sharper and my anxiety was a little bit lower, you know, believe it or not, while I was not eating. So I decided to experiment with ketogenic diet, and while I did do it, as you mentioned earlier in this podcast, one of the most pronounced things I noticed, and this is totally subjective, was my anxiety level was so much lower. I mean, very noticeably. I'm somewhat of an...I mean, I've got some anxiety, you know, that can kind of kick in, and that was...

Dr. D'Agostino: High performers are like that though. So that's like pretty much [crosstalk 01:40:17] personality. Yeah, sure. And then you leverage that into productivity. Yeah, I think. Yeah.

Dr. Patrick: I felt like it was very noticeable for me with the anxiety. And then, you know, it's like that feeds into if it's affecting anxiety, what else in the brain is it affecting, you know, cognition wise? You know, if you're anxious, it does sort of limit cognition in a way. It can kind of like, you know, distract you and so...

Dr. D'Agostino: And you did this back like in grad school you started doing this? I started doing it. Like before big talks, I would chew on a propranolol and hold it to get like a beta-blocker. I like needed this when I was like in grad school I think in my early...And then I realized as I think I got into my postdoc and I started tinkering with intermittent fasting at first and then just carb, I was like, "Wow, this is how I feel," you know, especially when I kind of dieted and brought my weight down a little bit, it's like, "Wow, I just feel like super calm." It's like, "I can't even get anxious under certain conditions." So, it...

Dr. Patrick: Well, I didn't do a ketogenic diet.

Dr. D'Agostino: ...like a nootropic, it almost too.

Dr. Patrick: Yeah. Well, I didn't do the ketogenic diet until of recent. Like this was like last summer. But caloric restriction, I used to do a lot of that combined with exercise as well. So I was kind of like...I was getting in ketosis, you know, without having to do...

Dr. D'Agostino: Yeah. Exercising ketosis.

Dr. Patrick: Yeah. I mean, I was running...this was like even before grad school but like early in grad school. I was running like 10 miles a day, and I was doing that like four to five times a week. So I was running [inaudible 01:41:47]. I had gone almost to an extreme too where it was like I changed my menstrual cycle where I wasn't getting it, you know, because I was very active. I was doing a lot of caloric restriction. I felt great. I mean, I really did. That was actually a long time ago, and it wasn't until like sort of...my time-restricted eating when I had Sachin [SP] on the podcast back in 2015, I mean, that's when I really got hardcore about trying to like time my timing with my food intake and following that really, you know, obsessively for the last, you know... has it been like six or seven years? That's really helped. But the ketogenic diet was also unique. I do want to sort of incorporate that into my... I want to do some kind of cyclical version of it. I really want to and I want to, you know, measure my biomarkers and all that, which I...

Dr. D'Agostino: And do them together.

Dr. Patrick: And do them together.

Dr. D'Agostino: So you're still going to do intermittent fasting.

Dr. Patrick: Yeah. And do them together, you know, as well.

Dr. D'Agostino: That's the key. Like people think it's one or the other, whatever, but low carb intermittent fasting, so just a modified. Low carb intermittent fasting probably has more benefits than chronic ketosis, eating like throughout the day I think for a normal healthy person. And maybe even therapeutically for managing...because I'm communicating with adults that have epilepsy and they're following ketogenic diet. They breakthrough seizures. But then they take the same diet, same calories, and then do an intermittent... And this is not promoted in the world of epilepsy, but when they take their ketogenic diet where they're having breakthrough seizures and they implement time-restricted feeding, then they get seizure control again.

And I think the people in the trenches know this. Like the neurological teams and dietitians, they realize, "Hey, well, if you can do this." It's not part of the medical literature, but they know this intuitively just because of the information people are putting out, all the information on intermittent fasting. You know, Mark Mattson has been studying this stuff since the '90s, and I first stumbled upon his stuff in grad school. And I always kept his papers with me. I was like showing people. I was like, "Look at this. Why don't people looking at this research? It's like so important." I haven't read his book yet, but he has a new book out to it. [crosstalk 01:44:01].

Dr. Patrick: Yeah, he does. Yeah, we have...

Dr. D'Agostino: He inspired me. I think that's how I got inspired into the ketogenic diet, it was looking at the calorie restriction and then fasting, and then that led me to ketones. But it was Mattson actually that actually sparked my fire, and then that led me to some of the ketone researchers.

Dr. Patrick: I asked Mark this question when he was on the podcast, and I'll kind of ask it to you in reverse. And that is...you've already sort of touched on it, but like what do you think the overlap between being on a ketogenic diet...a modified ketogenic diet is with intermittent fasting, whether we're talking about these epigenetic changes with beta-hydroxybutyrate being an epigenetic modulator, a signaling molecule, autophagy's one that I'm very interested in as well?

Dr. D'Agostino: Yeah. Two things in my mind, insulin and insulin signaling like IGF-1, you know, activation of AMP kinase, IGF-1, mTOR, but also the ketones as a drug-like mediator on not only alternative energy substrate but also as a drug-like mediator for all these different things like suppression of inflammation, activating epigenetic effects, and things like BDNF, which I think I... You know, Mattson's work actually showed that many of the benefits of intermittent fasting were associated with beta-hydroxybutyrate-induced growth factor effects on like BDNF and things like that. So I see there's the hormonal effects of intermittent fasting are replicated with the ketogenic diet, and then the hyperketonemia that's associated with intermittent fasting in the ketogenic diet then have their own effects through beta-hydroxybutyrate and acetoacetate. So that's two main things, but there's a whole...it's pleiotropic, right? So the ketogenic diet.

I've given talks to pharmaceutical companies where I go there and they say, "Well, let's key in on the mechanisms that we can sort of drugify," right? But the end summary slide is like a dozen or more mechanisms, and there's probably many more that are all sort of working in synergy. And I think that becomes the reason why the ketogenic diet works when drugs fail because you have drugs work through a GABAergic mechanism, these drugs work through suppressing glutamate. You have a variety of anti-epileptic drugs that work through different pathways, but combinations of them used in high dose often work initially then they fail, and then patients are put on a ketogenic diet and it works. So the ketogenic diet is working through a mechanism independent of what we know these pharmaceutical drugs are working. And that becomes...you know, the complexity of metabolism is very...it's like daunting, right? And to key in on something that's really having... And it could be depending...

The etiology of epilepsy is largely unknown, and the ketogenic diet seems to work through all these different types of epilepsy, whether it's like tonic-clonic, there's Dravet syndrome, there's different metabolic disorders, absence seizures. And the ketogenic diet seems to work across all these different seizure types probably because working through all these different mechanisms.