Episode 167: Dr. Nicholas Norwit‪z‬

Welcome to the Low Carb MD podcast. No one is beyond help. No one is beyond hope.

As we have always said, we are bringing you medical information and cutting-edge science, but none of this is medical advice. Please seek out input from your own doctor.

Hello and welcome to the Low Carb MD podcast. We got a smart kid here today, Tro. He's one of the geeks that like studies all this stuff and he writes papers all the time. He's like another Jason Fung type guy. What do you think, Tro?

What caught me was his story with his own personal health. You know, I mean, this guy is actually Uh, you know, where was it? Oxford, Harvard, all of the above. I don't know.

He's been everywhere. Yeah, it's ridiculous.

And his, uh, like a YouTube clip, you know, that I watched recently really moved me. Just somebody who was suffering, you know, who said maybe diet can help, and then all of a sudden diet helped, right? How often have we seen that, right?

And I told his story, everyone. We're going to release them at the same time. Life's Best Medicine. Go listen to Nick's story because I want you to hear his backstory, but I don't want to cut too much into our science time because he's a science geek and him and Troy are gonna have fun. I already know that this is like a matchmaking session for me, I think. But Nick, welcome, man. Tell people your background, what you're doing now, and, you know, why you're so interested in science and, you know, in a nutshell, your story.

Yeah, well, thanks for the generous intro, Brian and Troy. In a nutshell, my background is, you know, I've always been a dork, someone who loves science, but I also was always really into athletics and I never had any health issues until I turned about 18. And then things just started falling apart. I didn't really think much about nutrition. I was just very standard Western medicine. And, um, you know, CICO, calories in, calories out, marathon runner, pushup athlete. That's a whole random story, but anyway, I did the whole, you know, 6 meals a day, fuel your body with carbs, doing that, doing that. And then I ended up developing osteoporosis. That was a little bit of a complicated case. And then ulcerative colitis, which almost took my life. Just after I moved to Oxford, my heart rate went down to the 20s after a bad colitis flare. And that was kind of the straw that broke the camel's back and really got me starting to take responsibility for my own health. Probably should have happened earlier, but I was, a bit naive, still a bit naive, but a little bit less so now. So yeah, it was a, a kind of, I think like a lot of people, I was at that point of hopelessness, but also nothing to lose. And so I just started experimenting with diet and tried keto and things just went away. Starting with the colitis, just literally within a week, my inflammation disappeared and my symptoms disappeared. And then I came off my medications and everything just stayed away. And the, um, I still, I'm on some bone medications, but I reversed my osteoporosis and the diet actually appeared to synergize with that. So it wasn't like gaining any cortical bone. Um, like I wasn't getting any bone in my hip and my femur on the most powerful drugs out there, um, Forteo and Prolia. And then my first year of keto, I gained in both those regions and my spine also accelerated its increase. So now I don't have osteoporosis. Colitis is no longer any issue, and I'm just now, you know, I've directed my scientific energy towards this metabolic health space because I think it's the future. And what I say in my little documentary, I think the thing I mean the most above all is that the most remarkable thing about my story is that it's not unique at all. I thought it was unique right as it was happening, but after the fact, I've met so many people, as I know you guys have, who had the same experience. Like, you're in desperate straits, and so you kind of go searching on the internet. And for most people, it's hard to suss out, you know, what's snake oil and what's real. If you don't know anything, keto versus, I don't know, what would— like, Noom, vegan, whatever. You just, you just try whatever. And I did. And it just so happened that this is the one that worked for me. And so happened, after looking at the literature, having a scientific background, this is the one that actually has some scientific legitimacy. So now it's what I'm passionate about— educating people, teaching, researching, publishing. Um, my career is still forming, so I don't know what I'm going to do in the end. You were just asking me about this offline, but yeah, that's me in a nutshell.

I think I said it accurately. You're like the Robin Williams of science because you're all over the place, man. You have your hands in brilliance in all these different areas. I'm like, oh my gosh, I can't even like keep up on the studies you're writing. I can't even read them as fast as you're writing them, you know, and joining in with good people like Chris Palmer, who's doing great things. And, you know, tell people like some of the— like give them a little nutshell of the projects that you're working on now.

Well, yeah, like you said, I've just— I'm really privileged to be in a position where I can just kind of do whatever. So secret about a PhD at Oxford, I can say this now because I've completed it. It's actually not that hard. Compared to a PhD in the States. So I finished mine, I submitted 1 year and 11 months after matriculation, and probably still only spent about 20% of my time doing the PhD. I know that if I were to do it here, like I've seen people do it here, it's a little more work. Go to classroom, do didactics, rotate through labs. Like I just chose a lab, asked the person, you know, if I get funding, can I, can I work with you? Made a clinical project and then did it. But while doing it, I got to do like everything under the sun and start exploring different things. So my first paper was actually on bone health. My first paper ever was a case report on my own scenario of osteoporosis, which was a weird case. I won't delve into it now, but then I went to do some like gut microbiome stuff, some mental health stuff. My main focus is neuroscience, so that's what my thesis was in, was in neurometabolism, neurodegenerative disease, and ketogenics. And what else have I done? Some lipidology stuff, cardiology stuff. It's really been just exciting. And so whatever project I get asked to get involved in, I'm writing a case report now or consulting on one about COPD. I just, it's an amazing learning opportunity for me right now before, actually I have a little break now before med school. So the story was I was finishing up college, I went to Dartmouth, and then as I was graduating, I got a scholarship to go to Oxford and got admitted to Harvard Med. And so Harvard Med let me defer to do my PhD at Oxford. So now I'm in this little window between my PhD and med school because of how the semesters lined up. So for the next several months, it's just like me doing what I love, getting up, reading papers, nerding out with people, and writing blogs, doing lectures, whatever. It's just a ton of fun. That's what I live for.

You know, I—

Oh, go ahead, throw.

No, no, go ahead.

I saw you drinking, I thought I was gonna have to ask a question 'cause I didn't want you to have an awkward silence of drinking. So go for it, man.

I wanna like step back because, you know, I, you know, and look, this isn't a medical podcast, but I certainly wanna, you know, we're all doctors here and scientists and clinicians. You know, I look back at your pictures of somebody with colitis, Probably very, very low appetite. You probably never had a weight issue in your entire life. In fact, you probably had an underweight issue if I'm not wrong, right? I know people who suffer from colitis that basically are anorexic. And when you can't take in food, can't absorb food, right? The direct result of that would be, you know, when I say anorexia, I should really say severe, severely malnourished.

Yeah, sarcopenia, right?

You know, sarcopenia, obviously, but osteopenia and osteoporosis are a direct result of that, right? So, so walk me through how you got to a diagnosis of osteoporosis at the age of under 20, right?

So the weird thing about— I, I know what you're probably hypothesizing is that maybe the colitis contributed to the osteoporosis. Given the timeline, the colitis and any food issues not happening for a couple years after the osteoporosis, um, probably we don't think it was that. I actually have a weird genetic mutation in a gene called LRP5 that controls Wnt signaling. We could really go down the nerd hole with that one, but it's a little bit, uh, esoteric. Basically though, the timeline was this: I had no problems until age 17, no problems whatsoever. No health problems. Like, I just didn't have to go to the doctor.

I—

healthy guy, happy, high school, high school nerd like the rest of us.

Yeah, no, I mean, I was not me, bro.

I was not me.

Oh yeah, you were the quarterback, right? You got the star cheerleader, right?

I got the cheerleader, I got the Miss Pound Valley.

But that's besides the point, guys. Healthy into—

I liked you kind of guys anyways.

Um, I did like my, my, uh, trademark was push-up-a-thons. When I was a freshman in high school, I wanted to— we had a fitness test every year, so I wanted to break the school record for push-ups. It was 72. So I tried to break it and I did 240. And then each year I just did more and more. And then I ended doing like 427 and then I was running marathons. Like everything was superb. And, and I just, you know, on the surface, I was one of those people, you look at me and you're like, oh, skinny, healthy kid can eat whatever he wants because it just doesn't matter.

When you say skinny, how skinny?

My BMI was like 21.

Okay. So very, very, very low BMI. Now body composition. I've seen pictures of you. You're basically ripped, you know, I'm guessing as a young athlete, probably same, right?

Yeah. I was always, um, I mean, I probably had more, uh, sub-q and visceral adiposity when I was eating like carbohydrates, but my BMI was higher than it is now, quite honestly, but I never had a weight problem. You're right. Despite eating a load of crap, like I'd come back from runs. And basically drink a bottle of Nutella. Like, I go run 20 miles, right? And just like that, you know, I, I was putting down food. And in college it was the same. It was just the culture there. Um, you know, you, you went to the all-you-can-eat dining hall and ate all you can. Like, it's the food culture we have, especially among athletic guys. You'll finish a workout and it's just like, who's going to eat more kind of deal.

And you did athletics in college? Did you do athletics in college?

I tried. Um, restart that thought.

With osteoporosis, or I started developing it.

Restart that thought.

We lost you for a second. Restart that thought after you asked the question about college, uh, college athletics. Hey Jack, cut out this part.

Yeah, no, I, um, I really tried to engage with athletics in college, but that was when my metabolic health problems were starting to come to the fore, so At the beginning of college, I had already gotten my first fracture, and so my running career really was done. When I got to college, I still signed up for the endurance racing team, um, you know, did triathlon team, tried to do all these things, but it just didn't work. During my first triathlon race, um, my best friend was the captain, so I was really excited to be on that team. Right at the beginning of the race, I broke my foot, um, and it was a 5K. It was a sprint triathlon, not like a long one. Like, somehow I broke this bone in my foot called the, um, uh, cuneiform or cuneiform. And I couldn't, I actually didn't feel it during the race. I couldn't figure out why during the transition to the bike, I couldn't get the damn shoe on. And the reason I came in third in the race, but, um, if you look at my, my, um, transition times, like everybody was having transitions of like 1 minute and I had like a 4-minute transition because I couldn't get the shoe on. Anyway, after that, I went to the, the, um, orthopedic surgeon, he's like, I've never seen anybody break this bone, um, in this way, and I've been doing this for 40 years. So that's when I finally got the bone scan and got the diagnosis of osteoporosis. And, um, after seeing my video, I just want to— I want to mention, um, I talked to some people, and Dr. David Ludwig, we talked, and he asked me, you know, was any of that exaggerated? Because if you see the little YouTube, it seems exaggerated. I'm like, not at all. When my heart rate was in the 20s, it was in the 20s. When I got osteoporosis, it was T-score -3.3. Like it was legitimate. And I had fractures all over my femur and my spine everywhere. And I just couldn't figure out what was going on. And the funny thing is, um, after describing, you know, kind of what I ate, when I went to, um, the endocrinologist to figure out what was wrong, why I had osteoporosis, they did a bunch of workups. And the diagnosis of exclusion that we came to after like over a year was relative energy deprivation syndrome. And that I wasn't eating enough. So the prescription was eat more. And I got hooked up with a Harvard nutritionist who would actually call me at school and ask me if I've had 5 servings of carbs that day, tell me to eat pasta. When I was in Oxford, I was being told to have fudge. So maybe it's no wonder the ulcerative colitis kind of like cropped up given my diathesis to IBD. I was—

You know, that's funny that the endocrinologist, because the first thing when I heard your story and I see your body composition and I, you know, you mentioned osteoporosis, you know, uh, and then the athletics, the young athletics, you know. I've, I've had a bad of anorexia myself as a young kid, and I was like, this guy's suffering from an energy deprivation, right? That's, that was my first thought, right? And then he's got colitis, he's probably not eating. That was my first thought. So I'm just, you know, it's funny that, that, that they, that this endocrinologist thought the same. That was his first instinct, you know.

Yeah. Um, well, to their credit, and they're actually two women Um, there, you know, it, it was— if I was in their position, they deal with a lot of anorexia patients, given their background and given how much time they have to see me, I probably would have come to the same conclusion. It's like, can you always believe a patient, especially a kid? So it was frustrating for me knowing I was telling the truth to be what I felt was like patient blamed. And then you want to overcompensate and be compliant. Well, then I want to—

then you want to eat a whole bunch of junk.

Right?

Exactly. And we heard it from the—

our patients have heard it from the other perspective, meaning like they're overweight and they're out there, okay, because you're lying to us, right? Because everyone assumes everyone's lying. And so in your case, like, I would do the same thing. I'd be doing drug tests to make sure there's nothing else going on. And I've been tricked before, actually. Someone was on meth and it took me a long time to figure it out.

Yeah.

Because they lied about it. And I was like, they were lying and they were on meth and I'm trying to figure all these metabolic problems and the waste of money.

No, you know, I almost think like You know, anyway, it's like when you— I've had both sides, the food addiction and the anorexia. So I kind of have a sense of, you know, that was my gut feeling having not talked to you ever. So, you know, sorry to put this on you, you know.

I understand.

Hello, I respect you, I love your work. Are you anorexic? It's not like that, you know. So, okay, so what happens next? So now they're like, okay, we think you're anorexic and she's trying to feed you a whole bunch of crap. Yeah.

I mean, what happened then? I complied because I have no, I have no idea what else to do. It's like at this point when I started getting fractures, I was, I was finishing up high school. I was 18. It was 6 weeks before the Boston Marathon, which is a race I was looking forward to my whole life. Um, like I grew up on the course and I, you have to be 18 to run a major marathon. So I qualified when I was 17 and I was just pumped to run the race. And then I got my first fracture, my tibia. And from then it was just downhill. But at that point I was literally in high school.

Yeah.

And it just didn't get a diagnosis for a couple of years because they wouldn't give me a bone scan. But even when the diagnosis came, I'm like, I'm an undergraduate. I'm like a 19, 20-year-old kid, like trying to balance all my pre-med courses. Like I'm not going to have time or I'm not going to even have the will at that point to, to go and do all my own research because I still have tremendous confidence in my doctors. They're really brilliant people, they've done all this schooling beyond what I have, so I have faith in them. And, and so I just was a compliant patient. I thought that was the most sensible thing. Um, and to—

but then they told you to—

they basically said eat a whole bunch of crap, you ate a whole bunch of crap. I'm wondering what happens next.

Oh, uh, well, the colitis happened next. I mean, that wasn't all their fault, that was also just the food environment that we had at at Dartmouth. I was joking with Brian because, I mean, even as I was graduating and I hadn't gone into this nutrition stuff, I was telling him that at my graduation speech, so I was the commencement speaker, and one of the things I had in my speech was giving my buddy Brant props for eating 26 cookies in a sitting, which was like a record at our dining hall. And it was like this really gooey, soft-baked chocolate chip cookies. But that was just the culture. We would go there, like we would steal gallon tubs of ice cream, eat junk out. And that was just reinforced weirdly in my particular scenario by my osteoporosis and my relatively lean physique. I mean, you know, you said earlier that you talked to a lot of people with the opposite perspective that they're told to feel, you know, shame about what they eat. You had a good quote. I just tweeted it. I was listening to the Ali podcast before about, you know, we give people addictive food and then shame them for having an appetite. I thought that was really, really clever. But the central theme here is a messed up relationship with food. For me, it was, you know, trying to eat crap to prove that I wasn't anorexic. So like, you know, when I'm around with my parents, like I'll eat crap just and make sure they see just to like prove it. Not because I want it, not because it gives me pleasure, The pleasure comes from showing off that I am not mentally ill in that way.

I got a quick question. Your whole family's lean?

Yeah.

Whole family's lean?

My dad's side of the family is quite rotund. My mom's side of the family is quite lean.

So— And you see a stark difference in the appetites from one side to the other?

Yeah. Yeah, definitely.

And you, do you think you're cut from the appetite-wise? You think you're cut from the same cloth as mom's side?

I'd say more because I don't have a drive to be hungry. Although my mom doesn't like restrict. I mean, we eat pretty well, but I'm the kind of person that I, you know, I was never really insulin resistant. I was never, never really had a physiological problem with saying avoiding snacking. Or having any sort of food addiction. It was just more habitual.

Yet, right? Yet. Yeah, I mean, yet, right? You know, so the answer— like, I didn't have— you didn't have that yet, you know? So it's like an inevitability for, for our population.

Well, what was happening, if I understood right, Nick, you, I— you had your visceral fat checked, right? My—

that's the interesting thing. Well, we're going to talk I know we're going to talk about that later.

I know we have another thing we're going to talk about, but, but just for curiosity's sake, when you were very thin, when was the first time you had your visceral fat checked?

The first time I ever had my visceral fat checked wasn't until well after the diagnosis, um, of colitis. Of, of colitis. Yeah, right. This was when they were doing like full body DEXAs.

And do you know how many liters you had at that time?

Nope. Um, What was it? It's relatively low, but here's the thing. It's like, um, it's, it's really high proportional to my sub-q. I have a genetic predisposition for holding visceral fat. Uh, it's probably the same LRP5 gene that I talked about with respect to my bones. In fact, yeah, uh, to plug what we're going to talk about later with Ben Bickman and Ben Bowe, um, I've talked to Ben Bowe about this LRP5 gene And to simplify it down, I think we both hypothesize that it directs growth of probably muscle tissue, fat tissue, and bone tissue, and different, um, compartmentalization of potentially fat tissue. In fact, there's, I think, a paper in Nature from 2015 saying that LRP5 does lead to gain in, um, uh, central adiposity. As opposed to like, you know, hip and thighs. So we can nerd out about that later, but yeah.

Yeah, like a TOFI, like a TOFI pattern, what we all call like a TOFI kind of pattern. Yeah. It's funny, I've seen the, and the women with TOFI, a more predilection to that osteopenia and osteoporosis, just 'cause we screen them more frequently. That's the only reason why I would've made that association.

Yeah.

You know?

That's exactly what I've seen clinically. And that's why this is really important 'cause I'm seeing TOFI that are getting diabetes, osteoporosis, and, Right. They look great and they're a disaster on the inside. And that's why you can't just look at someone and say, well, this person was metabolically healthy and they died of COVID Nope. You can't say that until you have the numbers and look at it. That is false. And I see, I have another lady just to make the point. She's 246 pounds. We worked with her, got her diabetes under control. Her, her visceral fat is 0.8 liters. That's nothing. And she weighs 246 pounds. All of her fat is going subcutaneous. She's lucky. Right. Or she can only store so much subcutaneous. Sub— uh, I'm sorry, visceral fat. So anyways, it's where the fat is makes a difference.

Yeah, no, completely. The thing is though, um, like you said, you just see it more frequently in women, bro, because you're screening them. Like, I was begging for a bone scan or a DEXA scan for years, and they were like, no, you're a healthy young male, like, there's no way. And you can tell me better how much a DEXA scan costs, but it's not that much. And if you're getting it for like $50 or less—

for— you could probably get it for $50.

They would not give me a DEXA scan. It took me 2 years and multiple broken bones to get a DEXA scan.

This is called the stupidity of modern, you know, insurance medicine.

Oh, you're a zebra. That's a— you're a zebra because they've never seen it.

Well, not really. Honestly, not really, you know. I don't think so, you know. I don't think it's a zebra, right? I think like some of this is like playing Monday Night Quarterback. You could, you know—

oh yeah, yeah, no, it's not a zebra, but I mean, it's fit. It's very unusual to have an 18-year-old kid that has this stuff.

It is.

But my whole thing with zebras— sorry, sorry to interrupt. I'm passionate about this.

Since he went to Oxford, it's probably a zebra. He doesn't say zebra.

I drift in and out, and my dad's South African, so sometimes I say like yaa or something. I don't know. It depends who I'm with. But I'm pretty passionate about the whole— you know, they say in medicine, if you hear hoofbeats, think horse, not zebra. Think the standard thing rather than the esoteric thing. I really disagree with that, maybe being a zebra. My thing is if you hear hoofbeats, look around for the damn horse or zebra and put some thought into figuring out like who, you know, what the case is, because yes, we can treat the population, but then we're like, we're throwing the baby out with the bathwater. Yes. I totally think that. I mean, this data show that on a population level, for example, statins, they reduce events, but that's a population level. That doesn't tell you anything about, you know, like, Look at somebody who has isolated high LDL versus the lipid triad. Like, think about it in a particular case and what the pros and cons are.

Diet's no different. Diet's no different because you're going to look at that person, go, okay, here's the best plan for that person, and here's the plan for a different person. The same plan is not going to work for two different people. I can't eat what you eat. I can't even— so you figure out what works for that person. That's why these tribalisms are, are, you know, it's hard. And plus plus patient preference and lifestyle and mom's side of the family versus dad's side of the family.

Well, that makes it even harder because food just intersects with everything.

So now here you are, you're like, you're truly a zebra and, or at least something that the doctors you've seen don't quite recognize. And I mean, now you get hit with colitis.

Yeah.

And this has gotta like ravage your life. I've seen people with terrible colitis. I mean, they're in the hospital, Every month or 2 months, depending on how, if their flares are acting up, they get put on steroids, which worsen osteoporosis, by the way. Yeah. So I'm like wondering what happens next here. I'm like, it's like an awesome—

I feel like, okay, we went over a lot of this, I think, in the Life's Best Medicine podcast. So I'm not sure if we want to, I can continue the story. It would be a little bit redundant and I'd love to nerd out with you. I've been looking forward to that.

Yeah, let's nerd out, bro. Listen, Life's Best Medicine, there's a plug for my other podcast, Nick's Great Life. And we go into detail on this stuff, right?

I'm much better about nerding out about science than I am about telling my own story. That's why I have—

I knew when I said that at the beginning, Troy would take you down that path. So man, let's talk science. This is science too, by the way. Let me step back, 'cause I think this is an important thing. There's one thing I just, from a psychosocial point of view, and I have permission from my daughter to talk about this. My daughter went to a university on a swimming scholarship. While there, she experienced exactly what you did. All these thin swimmers could eat whatever they want. So culturally, she felt like she had to eat like they did, but she was gaining weight and they weren't, right? So then that developed into an eating disorder where ultimately we decided to bring her home and try to work on her because her times were getting worse. She was, she just wasn't, and it put too much pressure on herself to keep her scholarship and all this stuff, the stress and all this. So we brought her home, you know, got her some counseling, nutritional advice, things like that. She's crushing it now. She's swimming all the time and loves every second of it. But what I'm getting at is there's a time when that peer pressure can be so difficult because everyone else is doing it, but you can't, right? And if you don't eat like everyone else, you get peer pressure. Like, why aren't you eating like them, right? Because they're 6-foot-5 skinny guys that, you know, that can get away with it. And I think that's a huge, very important topic.

Yeah, I think that's what pushes people to the breaking point. Um, you know, I, I say that I don't think low carb is hard in and of itself, but it's hard because of social pressure. Um, and I felt that, and I think a lot of people have to get pushed to the breaking point where they have to put their health as the primary priority and just accept that there might be awkward situations before they can really adopt the lifestyle.

Um, so how do you find keto? How do you find it? Like, what happens now? It all goes away and, and you get better? You know, like, what happened?

I got Brian's podcast. All right, short— come on, listen to my podcast, dude.

Yeah, I'm just trying to interview somebody, man.

Yeah, I know, I know, Troy, you don't have the back—

you're putting me in a hard spot, you know.

I'm gonna leave—

I was the same way.

I'm gonna leave the cliffhanger. Check out the YouTube, check out Brian's podcast, and we'll leave it at that. I just— I, I, I, I'm, I get— I'm getting, uh, branded as the young guy with an interesting story, and every podcast we just talk about it, and then I don't get to talk about any nerdy stuff.

Oh, we'll come to the nerdy friend. I promise you.

We still got an hour to go.

Yeah, we're good. But yeah, yeah, but well, all right, so I'll tell you, Troy, what he did.

Everything comes out better.

In a nutshell, I'll tell you because I can tell it quickly. What he did is he relied on his own intellect and knowledge to say, let me look to see what's the solution to my problem. He took it in his own hands, not the doctors, not the nurses, all that stuff. And he took it in and said, let me educate myself. And if more of us do that, then we realize, oh, okay, there's science here.

Right?

And so, he just kept turning over rocks until he started feeling better, right? And so, I think that's what a lot of us had. That's what I had to do. That's what you had to do. No one was guiding us. I mean, I had Jason Fung to teach me a lot. I was lucky. But there's a lot of stuff where you have to ultimately say, "Look, this sucks bad enough or I'm going to make changes." I had a guy yesterday, he goes, "I'm not willing to give up my bread with peanut butter and jelly." And I'm like, "Well then, go to this other place where you can get a lot of meds to take care of you. Yeah, that's your options right now. You're, you're fully diabetic and you're a disaster. You keep eating that way and you're going to die of your disease process. That's your choice. It's okay.

Let's, let's talk about the science then. Can maybe we could talk about, um, you know, intestinal permeability and, and how low carb could potentially help colitis. I think that's a big, you know, area of, uh You know, that's a big unexplored area, both the microbiome, intestinal permeability, you know, all of these things are, you know, the modern medicine has ignored them, you know, and there's a lot of data and interesting disparate data that if you put it together, I feel like it may, you know, it starts to make sense.

It does. The tricky thing with the microbiome is it's just so bioindividual that it's really, really difficult to do these studies. And so you can see a clinical effect, um, like you did in me. That was very stark. And I think a lot of people with IBD, IBS, you see it, but it doesn't get published much because one, these trials are hard to conduct, but two, there's so much bioindividuality. Um, and so I know people that have gone keto that haven't had as stronger response with respect to their IBD. And yeah, it's—

I mean, I've seen data showing in animals that fructose can really disrupt those tight junctions in between the cells in the intestines. I've seen some data showing, you know, it's interesting if you look in, you know, the possible mechanisms that ketosis actually prevents seizures. You know, they, they've done some elegant studies in mice that show that it's probably mediated by the microbiome.

Yeah, I think a lot of these things are mediated by the microbiome. I mean, even things like DHA, like omega-3 supplementation, the studies they do, for example, for cognition and omega-3 supplementation, they're all relatively short-term, and yet the half-life of DHA in the brain is 2.5 years. So now there's a lot of speculation that even that is microbiome-mediated. And you're right, there are certainly mechanisms by which ketosis can help with intestinal permeability. In fact, there was a paper showing that even, like, that colonocytes use ketones to sustain stem cell renewal, and that even systemic ketones can support that process. Other ones showing bile acids are also really important for intestinal stem cell health. So if you're eating a ketogenic diet and you're having, you know, high fat, you'd be secreting more bile acids. The diversity with respect to the microbiome among people and how you might react to different things is just phenomenal. I mean, another totally random thing is you hear a lot on Twitter now about, like polyunsaturated fats being obesogenic. There's a paper showing that some people have bacteria that convert linoleic acid to this molecule HYA, and that protects them against N6-mediated obesity or induced obesity, at least in mice. So it's complicated. There's stuff there, but it's too complicated to apply at the individual level because the microbiome's just way too dynamic.

Yeah, definitely the other way around is true. It's probably difficult to take these things and make population-wide, you know, like, oh, everybody should get rid of, you know, omega-6 oils or omega-6 fats. Well, yes and no, you know, it's like there's disparate data, it's not very clear, you know. So where are your scientific interests? I'd imagine your scientific interests are in colitis because you suffered from it, but Maybe what other interests do you have? So, you know, what are your scientific pursuits?

Actually, my primary interest is in brain health, first of all, because it's actually easier to study than the microbiome, weird as that sounds, the brain. But yeah, I really did not hit the genetic lottery with respect to brain health. I am an APOE4 homozygote. So for people who don't know, APOE4 is the leading genetic risk factor for Alzheimer's disease. And being someone who kind of likes nerding out, I, I'm really scared of Alzheimer's disease. And so 20 to 25% of the population has one copy of APOE4, which will increase your risk like threefold. And only 2% of the population has two copies, and that can increase your risk up to 12-fold. And considering the number of people who have Alzheimer's disease and the rate at which it's progressing. So right now there are about 5 million people in America with Alzheimer's. By 2050, it's projected to have 13.8 million. It's like diabetes. It's just going up. Um, my chances will be, if you just did the multiplication, like over 100%, which obviously is mathematically incorrect, but point being, I should get Alzheimer's disease if I live the standard lifestyle. I prefer for that not to happen. So in addition to this just happening to be my PhD topic and my research interest— so I didn't find out I was ApoE4 until after I was doing neurodegenerative disease research at Oxford. I guess it just, it was a coincidence. Um, it's, you know, given me a real personal passion for this and really motivated me. So that's why I spend all day reading papers. It just like I know I can help people with it. I think I can help people with it. And, um, you know, it has personal relevance to me because any kind of intervention I develop, um, you know, lifestyle or otherwise, I can apply to myself. So everything I'm reading—

where do we stand now? Like, based on what you've seen so far in research, what do you say is our best— if, if we are at significant risk, um, what do you think is the best bet right now if for for you? What are you personally saying? Okay, look, here's what I'm avoiding, here's what I'm doing. Because I don't think there's a scarier diagnosis than Alzheimer's disease.

I agree.

It's horrible. It's horrible to think about. So, so, so give people hope now in prevention rather than treatment.

I agree. I think you need prevention. I don't think that once the disease is manifesting, there's that much you can do to stop it. It's like a boulder rolling downhill, but I do think it's preventable. But before I answer that question, or I, I think actually to answer that question, we need to talk about what the limitations of the literature are. Like, what do we have to point to in terms of what's the best lifestyle for Alzheimer's, for prevention of Alzheimer's? And so the place we typically start is epidemiology because, you know, that's the easiest, is where we generate hypotheses. Um, one thing people often point to is a Nigerian example. So Nigerians and West Africans, they tend to have the, uh, like a high prevalence of APOE4. However, it's not associated with an increased prevalence of Alzheimer's disease. So there was one study done that looked at, you know, a population of Nigerians, and then they had people with like cognitive decline and age-matched people that were healthy, and the APOE4 prevalence was the same. It was 17% in the people that were cognitively declined and 20% in the cognitively healthy, which was not statistically different. So that's interesting. And they've actually done analyses of people in Indianapolis versus Nigeria. So African Americans in Indianapolis and then Nigerians with some similar ancestry. And the incidence rate of Alzheimer's disease is twice as high in America, in America, in in African Americans versus the Nigerians, suggesting that there is a lifestyle factor. And then you have epidemiology looking at the whole Mediterranean lifestyle and ApoE4s. There was an extreme longevity study done. This is one I found very interesting. It was looking at, you know, if people live, like what proportion of people live beyond 95 for men and 99 for women. So into the top 1%. And what they found is that Southern Italians living in, um, Southern Italy, there was no difference between APOE4 carriers and non-carriers versus Southern Italians living in the States. There was an odds ratio of living into the extreme old age, 95 for men, 99 for women, of 0.29. So 29% is likely more or less. Living into, you know, extreme old age. So again, there's a lifestyle factor. It doesn't necessarily say diet, but it does say lifestyle. And that is relevant to Alzheimer's because the median longevity past diagnosis is like 3.1 to 5.9 years. So it's short. So these people probably didn't have Alzheimer's disease when they died.

So that's where we—

I mean, the epidemiology is just epidemiology. It doesn't tell you much. And then There are some, you know, there are some— there's a couple randomized control trials. The only one to the best of my knowledge that did a sub-analysis on ApoE4s was the, um, uh, I forget what it stood for, is FINGER trial, is Finnish something something geriatrics elderly something like that. But it was, I think, I forgot what the follow-up was, if it was 2 or 5 years, but they, um, follow— they, they had 2 groups of people and they put one on a lifestyle intervention consisting of, um, exercise, both aerobic and resistance. They had cognitive training, uh, you know, a, a, a certified training app. They had, um, like professional nutritional consulting. And then there was like a social aspect versus general health advice. So those are the comparisons. And then they did a sub-analysis for ApoE4, and actually the ApoE4s did benefit. Just, you know, after the fact, they, they, um, they actually benefited more than the non-carriers. The reason they benefited more is because in the control group they got worse if they didn't have the intervention. So what that told us also was that lifestyle intervention works. Even a little bit later on, lifestyle intervention still works. And I think that's what we need at the clinical level, but it doesn't tell us anything about the nutrition. So, you know, everybody that is afraid of Alzheimer's disease should get good sleep. They should exercise, they should practice stress reduction, but what do you eat? That's a big open question that I don't think we have much insight to from human studies. Because everything else involves lifestyle. Like, even with these RCTs, what I would say is it's like, okay, you have this complex lifestyle intervention versus standard nutrition advice. You could have the worst diet, but if that is, say, minus 2 points, but then the exercise and the sleep and everything else is like plus 1, plus 1, plus 1, you still come out at a net positive. And so people need to be very careful interpreting the literature, because what I hear people say is— and I've heard this— it's like the diet for Alzheimer's disease is the diet that we should, you know, we're extrapolating from these studies, like the Finnish study. And I'm like, you can't do that because you just don't know. I mean, in that study they had seed oils, I think, involved. I think they had like whole grain cereals and up to 50 grams of sucrose on top of that. And I'm like, you know, taking 50 grams of sucrose is definitely not helpful, but that was permitted. So where we are with respect to Alzheimer's prevention, in my opinion, is based on speculation from in vitro models and animal models. But I would argue that's better than nothing. So that's what I've been working on recently, was a paper. That's what I was working on last week, is about what new research has come out in Alzheimer's prevention with respect to this vulnerable fifth or quarter of the population. So a lot of people are gonna be walking around with ApoE4 and don't know they have it. That would inform best speculation about what you should do when you have ApoE4. I've been blathering on a little bit. I'm gonna pause and go ahead and think.

No, I love it, man. No, I love it. 'Cause we're gonna be thinking, we're gonna have questions. In my mind, I'm saying, okay, people are calling Alzheimer's disease type 3 diabetes. Is that inaccurate? Do you think that is an accurate statement based on what you've seen so far, or is that a stretch?

I think that is a component of it, and it's actually quite interesting. Um, so diabetes does massively increase your rate— risk of Alzheimer's disease, and that is independent of APOE4. You know, Alzheimer's brain—

Nick, can you say that again? Sorry, you cut out just for a second. I'm gonna buy you internet at your house. I'll pay for it, man.

Sorry, I don't know where we cut off, but—

You said, you said, I asked if—

If Alzheimer's disease is type 3 diabetes, is that accurate? I'd say that's a part of the picture. So in Alzheimer's disease, there is cerebral insulin resistance and typically hyperinsulinemia and inflammation. So basically everybody with Alzheimer's disease is gonna have insulin resistance and inflammation that is irrespective of APOE4 status, and it can contribute to the pathology of Alzheimer's disease in many ways. So the, um, for example, so when you have insulin resistance, right, and hyperinsulinemia, they go hand in hand, um, you have high insulin, say, in the brain. Insulin gets broken down by insulin-degrading enzyme, which also breaks down amyloid. So you have competitive inhibition of an enzyme that would otherwise be breaking down the amyloid that's going to lead to amyloid you know, oligomers leading to tau tangles, etc., etc. Um, also insulin just regulates, you know, neuronal growth and function. So if you don't have healthy insulin function, your, your neurons aren't going to be maintained and growing well. Also, insulin resistance, one of the downstream, um, uh, targets in the insulin pathway is GSK3 beta. It was pretty poorly named. It was named glycogen synthase kinase 3 beta because it's a kinase that phosphorylates glycogen synthase. That's how it was discovered. But it has another name that most people don't know, and that is tau kinase 1. So in the standard amyloid cascade hypothesis, it's like amyloid leads to something something leads to tau, and that really contributes, you know, that's associated with inflammation and Alzheimer's disease. It's obviously more complicated than that, but that's a standard model. Amyloid to tau. Um, but amyloid and insulin resistance both, they can stimulate glycogen synthase kinase 3 beta, GSK3 beta, which then phosphorylates tau. It is the primary tau kinase. Like I said, it's also called tau kinase 1. Breathe, Nick. Um, I get excited about these things. So yeah, insulin resistance is a common feature. And Alzheimer's disease, and ApoE4 might even contribute to it in the brain. Um, the cerebral effects of ApoE4 are a little bit different, but there was a paper by Zhao et al. in Cell in 2017 which showed that ApoE4, what it actually does, it decreases insulin receptor numbers on the surfaces of cells, and it does that by trapping insulin receptors in the endosome. Inside cells. So it prevents recycling of these insulin receptors, so you have less insulin receptors on cells because you have APOE4. APOE4 also leads to a downregulation of this gateway protein to glycolysis, hexokinase. So in APOE4, you do have a decrease— this is, I know I've been spewing a lot of nerd stuff, but you have a decrease in cerebral glucose metabolism. That is present way preclinically, even in healthy people with APOE4.

Um, so the question begs now, what do ketones fit into this model?

Well, I'm also going to throw out one other wrench there because, you know, my, my hypothesis is that, you know, brain running on fat is probably better, but there's also data Show— this is really recent. This was, um, Q et al., 2021, I think. Um, I think I have the right paper, but what they showed is that there's impaired lipid metabolism. So astrocytes are the main cells in the brain involved in lipid metabolism, and APOE4 impairs lipid metabolism too in the brain. So, you know, if, if you have an impairment in lipid metabolism in the brain and you have an impairment in glucose metabolism, it's actually— okay, I'll say in the Zhao paper, you'd want ketones, right?

You'd want a high amount of ketones.

So how do you get through that, that rock and a hard place? How do you get around the metabolic blockade? Ketones would be one way. So in ApoE4, one thing it can do is it can inhibit pyruvate dehydrogenase, can inhibit hexokinase, and, um, well, it can do a lot of things, but yes. Ketones, beta-hydroxybutyrate, would serve as an alternative source of acetyl-CoA to fuel neurons. Um, it also would do things to help reduce the impaired lipid metabolism. Weirdly enough, I know it sounds paradoxical since it's a high-fat diet, but like what they showed in the Q et al. paper was that, um, neurons, they package extra fatty acids into these things that they're supposed to, called lipid droplets. And then what lipid droplets need to do is get shuttled over to astrocytes for metabolism, because neurons are not good at actually metabolizing fatty acids. But ApoE4 is a transport protein. That's what it does, you know, like, you know, ApoB in the periphery— ApoE is actually also in the periphery, but it's important in transporting lipids and cholesterol. And it— that process is impaired in the brain with ApoE. So what happens is neurons aren't as good at trafficking their lipid droplets to, uh, astrocytes. And so there's possible lipotoxicity where the lipids actually damage mitochondrial function, and that actually just exacerbates the problem. But they showed in that paper that you can actually get rid of the lipid droplets in neurons by lipophagy, so autophagy of lipids. So in theory, intermittent fasting or having a high glucagon to, you know, insulin ratio, being on a ketogenic diet could actually help clear out these lipid droplets in neurons, helping to therefore also further reduce, um, this metabolic crisis. And, and yeah, well, there's also other interesting— there might be hacks. And I actually, you know what I'll do is I can list at the end of this podcast, but we can drop in the show notes. I'm putting together a little table of like you know, my top tips and supplements that people might want. But one thing they showed— I forget what paper it was— but, um, that this impairment in glucose metabolism in ApoE4 can be recovered by, um, increasing— I think it was PGC-1α, the master regulator of mitochondrial biogenesis. Um, and, and there are supplements that might be able to boost that, like resveratrol. So high, high dose resveratrol, like 2 to more grams a day, might be able to boost that, might be able to circumvent. It's a little speculative, it's very speculative actually. But if you have a combination approach, and I'm trying to formulate my own right now, that's what I'm doing with this little, my own little paper, is, um, you know, do what you can because, and you know, to me, to me, when I have patients who come to me and say you know, I'm APOE4, what should I do?

I think my first response is, well, know kind of where this is going. Like, I personally know my own genetics is going to lead me to obesity, right? I know that, right? You can look at my family, look at my family's family, and look at my extended family, and, you know, I know which way this is going. Now, I certainly don't have any of the genetic markers, interestingly enough, that we've recognized, you know, POMC and MRC4 and all these other obesity-related genetic, uh, uh, kind of, uh, markers. But I know, so, but I know what I have to do to prevent the disease I know I'm going to get, right? And when I have a patient who knows they're going to get Alzheimer's, everybody in their family's had Alzheimer's, they're ApoE4, and, you know, um, my advice is generally, look, you know, make sure your diet is real food, Avoid processed food at all costs. You'd want to keep your insulin levels low as possible, exercise, right? And this is, if it was me personally, I have no, besides this kind of amalgam of different disparate information, I mean, I would be on a ketogenic diet, but would I know specifically that that's gonna be better in the long term? I wouldn't. But theoretically speaking, I'd want to use BHB for fuel.

So, right, let me, let me now make a little bit of a stronger case for a ketogenic diet because that's what I practice. And, you know, I had like mentioned things like resveratrol there. I do think certain supplements might be helpful as medicines. And wait, just total aside, I'm not endorsing having red wine for a source of resveratrol. I've done the numbers out, and to get the doses I'm recommending from red wine, you need to drink 8.4 barrels every single day, 119-liter barrels, just FYI.

So how many barrels, man? I'm, I'm like 3 off, I think.

8.4. I did a tweet about that and I knew that the main, the major response would be challenge accepted. And there were like 50 responses like that, like challenge accepted. So, okay. Don't be drinking 8.4 barrels of that. That amount of alcohol might not be great for your visceral fat.

Yeah. It may not be good for your liver. Maybe a problem.

But, um, So I think the big thing with respect to ketogenic diets or just clean diets in general is inflammation. A brain without inflammation is a brain that's not going to get Alzheimer's disease. If you want it, man, you want it simply. And, and we can talk about— there's two things I want to talk about with respect to inflammation: disease-associated microglia, which are the resident immune cells in the brain, and then the blood-brain barrier. In fact, my favorite paper that I've read thus far for the APOE4 paper I'm writing is one about the blood-brain barrier and specifically APOE4, and it's really interesting. I'll leave that for the end, so, or next. I want to talk about microglia first.

Let me jump on something really quick just because it's exactly fitting in with what you're saying. Rob Zivis, who you probably know through our networks, is, he has data on, you know, these endothelial cells in the setting of high sugar, high insulin breaking down the basement membrane pulls apart.

Oh, we're going to get that. I got to get to the best study. You're going to love this study.

It's—

anyway, but another aside on your aside about Rob Sibees, um, he trained with my dad at the University of Cape Town. My dad grew up in South Africa. They were both, I think, uh, under Tim Noakes. So wow, there's a small world, man. And in fact Rob's just put me in touch with the sister a few days ago because his sister's living in the Boston area doing microbiome Alzheimer's research. So super small world. Wow. But Rob's great. Yeah. And anyway, so microglia. So microglia are the immune cells in the brain. And several lines of evidence actually suggest that these disease-associated microglia, these activated inflammatory microglia, could be another bridge between early amyloid and tau pathologies. So studies have shown that these reactive microglia, they, they are necessary to drive tau pathology in animal models, and that in humans are associated with, with tau pathology. And in mice, just little injections of small little bits of amyloid are enough to induce microglia inflammation But the interesting thing is that a key component of activating microglia is turning on this NLRP3 inflammasome. And because you guys are fellow nerds, I think you might know where I'm going with this. Um, it's well known that the NLRP3 inflammasome is inhibited by ketones, which would lead to the speculation that ketones could prevent disease-associated microglia and, um, this inflammation in the brain, reducing tauopathy, which is a distinct possibility. In fact, there's a paper, the famous paper is like the Yom 2015 showing that ketones inhibit NLRP3, but I think there's a 2020 paper as well. In fact, let me Google it. Let's just say NLRP3, NLRP3, Um, hydroxybutyrate.

While you're Googling that, I'm just enjoying watching Tro's face while you're talking with science geek stuff, man. Um, his eyes are like happy.

Okay, shippy, shippy. Uh, it's in Journal of Neuroinflammation. Beta-hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer's disease pathology. Doesn't that title just say it all? Um, and, and so Simply put, and hopefully this paper will— I'm going to be doing it with Dr. Richard Isaacson at the Alzheimer's Prevention Clinic over at Cornell. But hopefully this one I'm conceptualizing now will get published and we can share it with people. But the simple takeaway from this, without getting too deep into the weeds, is that inhibiting disease-associated microglia should help with Alzheimer's disease. And one more thing on that note, actually. ApoE4 has immunomodulatory properties, and there is a human study. I think this one's Freiberg. I think it's in Nature. Again, really recently, 2020. And what they showed was that a marker of activated microglia, IBA-1, is associated with tau pathology specifically in ApoE4s. Which is a little bit weird. And when they dig into it, what they find is the protective effects of certain anti-inflammatory cytokines that should balance out the inflammatory cytokines is absent in APOE4. So in non-carriers, like IL-13 will protect against microglia-mediated, maybe tau pathology, but in APOE4, that— there is no association. So I think it's especially important in ApoE4s to really reduce your inflammatory state because systemic inflammation can activate cerebral inflammation. That is pretty—

And with ulcerative colitis, that plays a role, depression, anxiety, stress, all these things with pro-inflammatory of the brain. We're talking about Parkinson's disease. Yeah. All these things that we say, well, you're talking about this magic pill thing. And it's like, well, I'm seeing it. And I think, you know, and, and, and full disclosure, we're both on an advisory panel for KetoKind, right? Which is a, a drink that is, It's really gonna help see that what I see personally looking at the science and what I know now, and the reason I, I believe in the product, I'm not paid by the way, is that it is going to help seniors who can't change their lifestyle. They're eating terrible stuff right now. That's gonna make their dementia worse. Why not give them something that gives them a fighting chance?

100%. And just on the, the topic of KetoCon, I only joined the board, board last week in part because Brian was on it. And anything that's good enough for Brian is good enough for me, but The founders are Harvard undergraduates and really spectacular kids. I just did an interview with the one, Andreas, and we can post that. But it's like the most— this kid's younger than me, he's like 21, 22.

And, uh, these kids calling people kids, bro, you know how old we are now, man? It's getting ridiculous, dude.

But, but, um, he's one of these people that's just— he's the right person coming in with a fresh perspective who is completely, you know, you know, he hasn't been— I'm trying to come up with a better word.

Tainted yet.

Tainted. That's a better word. I was going to say brainwashed. Actually, tainted is not that much better. But anyway, he's very genuine, like generated this product because he wanted to do good. And he was just looking at the research. He came in and he's one of these kids just like, wait, Warburg effect. Why are we giving patients that are having, you know, that have cancer sugar? This doesn't make sense. I want a better product than Ensure to give to oncology clinics. I think that's—

and diabetics predispose all these disease processes. You go, look, we have to have a better alternative. And the reason I was on the board is I sat with these guys for hours and hammered them because I don't want my reputation to get messed up to help someone out, right?

Because it's—

what are you trying to accomplish? What are you doing? And I felt very comfortable with the science, with the, with the goal of helping people. That's what we're here for.

Yeah, this kid's gonna be like a— he's like a likable keto Mark Zuckerberg. I think this is gonna be big. I, his product seems pretty cool and I have ideas about how to further the formulation. So me and him have been nerding out about that. But on the topic of Alzheimer's, so yeah, I think one takeaway is ApoE4s really do have less wiggle room. Like, you know, we hear this number thrown around a lot about the 88% that are metabolically unhealthy in America. Some people can get away with being in that 88% and not get Alzheimer's. If you have APOE4, and especially if you're me and you have 4/4, you cannot get away with that. You're in that 88%, I'm pretty confident if you're 4/4, you're gonna get Alzheimer's disease.

Well, plus you have ulcerative colitis on top of it, right? You have an inflammatory condition.

Do I though?

Or do you? I don't know.

That's a, that's an interesting topic. I talked about it. This, this, this bit of wisdom is from Alicia Dr. Sonny Sarno, who's the microbiome zanyoling guy, really sweet guy, kind of reminds me of like a very sweet Dustin Hoffman, although nobody else sees it. But what he explained to me about the gut and inflammation is that, you know, it wouldn't make sense evolutionarily to have our immune systems just break and just be in this cycle of being inflamed, inflamed, inflamed. So if you have a chronic inflammatory disease, there's some sort of insults. There are some exceptions, maybe like certain cases of lupus, but there's some sort of like thing that's poking your immune system. And if you remove that insult, the disease goes away. And that's what happened with me. I think, I think I removed the dietary insult and all the manifestations of disease went away. So I reversed the disease. Maybe I have a, like a real susceptibility. In fact, I know I have a real susceptibility based on things in my past, but, um, If I remove the insult and the disease goes away, do I still have the disease? People, this, the standard lingo is to say, oh, you're in like remission, just because of the way medicine is practiced. The same with diabetes. But it's like with diabetes, if you remove the sugar and all the markers go away, do you still have diabetes? I would say no. I think you're susceptible to getting it again, but I don't think you have it. And I'm, I feel the same way. I don't think I have ulcerative colitis. I think if I ate like crap, it would, I would come back. But currently I don't think I have an inflammatory disorder like that.

And we're seeing that a lot in patients.

Hold on, let's just be super, super clear. So I don't think you can reverse your body ever knowing— making an autoantibody, right? Like, I, I don't— you know, once your body knows how to make a certain antibody, I don't— you know, that I don't believe that it can just forget that.

So what autoantibodies am I making? We talk about ulcerative colitis as an autoimmune disease, but what are the actual autoantibodies?

So if that's the— if the idea is that it's autoimmune disease, I'm not— not that you can't be in remission, but, you know, we've had people with, uh, autoimmune, you know, Type 1 diabetes being in honeymoon for a long time. But at some point, and certainly if they get their act together, I think— I suppose, and I— every part of me believes they can prolong the honeymoon. Right? They can prolong it. Same thing with like Hashimoto's. You know, we had somebody talking about autoimmune disease very recently on the podcast. And the idea is that you'd want to do everything you can. And even with Alzheimer's, you'd want to do every risk factor. You'd want to address every risk factor. But when it comes to autoimmune disease, like, I don't— I've never met somebody who reversed celiac, let's say. I just haven't met that person. Do I believe it's possible? I think probably not. Like, mechanistically, I don't, you know.

Well, true. What is if you go to a lectin— like, if you look at a lectin model of autoimmune disease and you take that lectin away and your body doesn't respond to it anymore?

I think now we're just— I've gone down this rabbit hole before with the semantics. I, I get where you're coming from, Tro, and I don't even think it's a, you know, a worthwhile thing to hash out now because it's, it's just not important. What we're agreeing on is if you remove the insult It's gonna get better. It's gonna get better. And that's the best thing you can do. That's what you should focus on.

Like, if you're not, you know, if you have allergic, uh, I have patients with allergic asthma. Yeah, right. If their weight is down, their diet is low inflammatory, they're low carb, their visceral fat is down, they're exercising, they have no symptoms. No symptoms. Yeah, right. None, none whatsoever.

Well, yeah, and, um, uh, you know, I want to give a hat tip to Dr. Sean O'Meara too. I've had some discussions with him offline and Another wrinkle to this thing that we're talking about is the reason we're hammering lifestyle so importantly is he has data on erectile function coming back. I think people might be interested in that and mental functioning improving with lifestyle change, decreased inflammation, and increased nitric oxide to the brain and to the penis, right? So if you make those lifestyle changes, some of this function we've lost can come back. We just got to really focus on lifestyle.

Yeah, I'm laughing because— go ahead, go ahead.

Yeah, no, I mean, so I think it's, it's like funny, I was on a, um, so I mean, do you think like if we— if they found an autoantibody or some precise mechanism for, you know, I think Crohn's is a little bit more of a better, you know, example, but do you think that, that, you know, autoimmune disease can be reversed? Maybe that's the question to say. Do you think it could be ameliorated, reversed, both? You know, I guess that's—

I think that let's say the immune system can be diffused. If we're talking about antibodies and cytokines as like the arsenal or the, you know, artillery of the immune system army, then let's just like de-amo them. You know, if you're not shooting out cytokines and antibodies, then it's not a problem. I think, you know, you can make a semantic argument either way, and I, you know, that's That's not the thing I even want to try to defend and argue because I think, you know, it's just an opinion statement almost, but I agree with you.

I think when we step back again, the other topic we're going to talk about later at, on another podcast is visceral fat, pro-inflammatory, you know, cytokine storm, all these things we're seeing right now. This is, I think it's our Achilles heel that we're seeing now. This, this, the vast importance of metabolic health in all these disease processes. Like Ben Bikman has been talking about this. Ben Bikicchio has been talking about it from a muscle standpoint is, is The more muscle you have, less visceral fat generally you're going to have, right? It's a partitioning of energy and all these things that are so, um, it's hard for people to understand that you could— what I'm getting at is it's hard for people to understand that you can go be a carnivore, decrease your visceral fat, and maybe be metabolically healthier than someone who just eats a vegetarian diet, maybe, right? It depends on muscle mass, partitioning of energy. There's— it's such a complicated thing, but inflammation, like you're saying, Ties all these things together.

Yeah.

And so the other paper I wanted to talk about with respect to inflammation, you were talking about it a little bit with respect to the basement membrane and blood-brain barrier, was— I don't know how to pronounce the guy's name— Montagné et al. I think it was. Let me actually pull it up so I can just skim over the data. Um, yeah, it's like Montagné 2020. It was, um, Nature again. I've read a lot of Nature papers. And what they were showing was that blood-brain barrier breakdown was independent of the standard amyloid and tau pathologies in Alzheimer's disease and specific to ApoE4. So only in ApoE4s was blood-brain barrier breakdown predictive of cognitive decline. And it was again independent of the standard pathology. So showing a whole new way by which ApoE4 can contribute to Alzheimer's disease. You're breaking down this blood-brain barrier. And that is just— that was fascinating. And what they discovered was, at least in this paper, this is the 2020 paper, they found a correlation between an increase in this blood-brain barrier breakdown marker. It was like PDGF, platelet-derived growth factor beta, I think. And this pathway called the CYP-A-NF-kappa-B-MMP9 pathway, so cyclophilin A, NF-kappa-B, and then matrix metalloproteinase 9, the last component of that is this gelatinase enzyme that breaks down the blood-brain barrier. And so that pathway is controlled by this receptor LRP-1. Which you guys might know about, but, um, ApoE3 can bind and activate LRP1. ApoE4 can't, and LRP1 inhibits this pathway. So basically the idea goes like this: you have ApoE4, you can't bind LRP1, therefore this pathway— CYP-A, NF-kappa-B, MMP-9— gets activated. That breaks down the blood-brain barrier, and that predicts and contributes to inflammation and cognitive decline. This is an inflammatory pathway. So that correlation was actually backed by transgenic mice data where they took mice— this is another Nature paper back in 2012 by Bell— and they took APOE3 knock-in mice and APOE4 knock-in mice and observed that yes, indeed, this pathway is causal: CYP-A, NF-kappaB, MMP-9. And if you block any component of that pathway, you inhibited CYP1A, you inhibited NF-kappaB, you inhibited MMP-9, then it protected the blood-brain barrier function and cognitive decline of the mice. I think that was the report. And the interesting thing about that is that there are actually a lot of things in the diet that can inhibit that pathway. So, um, beta-hydroxybutyrate can protect against NF-kappaB and MMP-9. So it inhibits NF-kappaB and can reduce MMP-9 levels. And blood-brain barrier parasites. So protectively— protect— potentially protecting the blood-brain barrier, which appears to be very important from inflammation-mediated damage and, and breakdown in ApoE4s. Again, resveratrol has similar effects. Vitamin D and K2, B vitamins 6, folate, and 12, quercetin at high doses, um, probably a little more than you can get through food. High some, some data on sulforaphane even from cruciferous vegetables, and then quite a bit of data on hydroxytyrosol and oleocanthal from olive oil. And so it's just interesting to take these sorts of data that are mechanistic and put them into the context of epidemiology. I don't make much of epidemiology on itself, but if you consider the fact that ApoE4, though only being 20%, of the population contribute to 65% of the, you know, population of Alzheimer's disease. And that things like the Mediterranean diet, which are rich in some of these components like sulforaphane, olive oil, which has components that at diet levels could reduce blood-brain barrier breakdown via inhibiting the CYP NFFB MMP9 pathway, putting those things together. And it's just like, it's interesting. So maybe if you're keto, when you have that food forage, you should have a I think we can safely say, Nick, that it's the Mediterranean lifestyle. Yes, I agree.

They're not stressed and hating the world and bitter and all these things play a role. So we try to just say it's about what you're eating. Okay, look, they're not stressed out. They wake up and go, yeah, I don't feel like fishing today, I'll do it tomorrow. You want help? I can help you fix your roof. And you have community. This is why what we're seeing at a global level right now— yes, I think that's depression, bad food, all this stuff sets us up for all of these disease processes.

100% agree. And I think that was a great point of— I don't want to bash, like, the FINGER trial we talked about earlier, that RCT. What it showed was lifestyle works. And at the clinical level, lifestyle, complete lifestyle, is what we need. Nutrition is one piece of the puzzle. However, if you want to optimize complete lifestyle, you need to know what optimal nutrition is. And so that's kind of what I'm questioning right now. And again, this is speculation. I could be dead wrong. But for me personally, I'll talk personally now, I'm going to do the best I can with speculation because that's all I have right now. And I don't really want to wait for 40, 50 years for data to come out because at that point it might be too late. Intervention early really, really matters. In fact, just this morning I was reading a paper by Yassin Hassib, I think it was, a 2018 paper about DHA. So DHA is one of the— it's the main omega-3 in the brain. Of the, I think, unsaturated fats in the brain, it's like 40%, and it's like 8% of the brain dry weight, and just incredibly important to brain function throughout life. And one of the things it showed was that although there's a decreased amount of DHA in the brains of people with Alzheimer's disease or cognitive decline, because usually we do these studies in people who are kind of like at least 60 or older that are kind of approaching cognitive decline, if not already there, but But they looked at a young population. Mean age was, um, 35. I think there were 23 participants and 21 of them are at least under 50. And what they showed is that in ApoE4, there was a 16% increase in DHA incorporation into the brain. There's also greater DHA loss, but there's a 16% increase in DHA incorporation into the brain. And it was hypothesized that this is the brain of the APOE4 person trying to compensate for one, increased metabolic need. And, um, and two, just like maybe, you know, what is now for us a maladaptive, uh, DHA type metabolism. So people with APOE4 also metabolize DHA more quickly. They're more likely to burn it as fuel, which is not what you want. Because you want it to get into the brain and be incorporated, um, as a, you know, a structural component. So that would suggest one, okay, you want early, you know, intervention, at least with this, you know, fish oil. It's not about like giving fish oil to people who are like 70. It's not going to hurt them, but it's about doing this your whole life, um, and, you know, and doing it at the right doses. For somebody who's, you know, ApoE4, I would probably be eating fatty fish more than 2 times a week, which is what people talk about. There's not data to show that that would help you, but that's because the data really haven't been collected over the life course.

Hey Nick, one question.

Like the very concrete things we've mentioned so far is, you know, a higher dose, uh, um, what was it, reserve, uh, reserve, right? And then you've mentioned, uh, some of the compounds in olive oil. Obviously we've talked about fatty fish. Uh, um, is it any exercise keeping insulin low? You know, can we— is there anything else that I missed in there?

I mean, I can list off some things, I think, um, in addition to those things. So what I'm going to be doing, I'm still formulating my, my strategy, but I, I have a ketogenic diet. I stay in ketosis, and I do tend to do a higher monounsaturated fat Keto. I've always just kind of preferred that. I'm definitely not like, I mean, I still love beef and liver and I eat a lot of liver and a lot of eggs and, you know, pork, but I do eat fatty fish every day. In particular salmon, sockeye salmon. I have this whole thing about wild Alaskan sockeye because it's the highest in a compound called astaxanthin. It's the pigment that makes salmon pink. They actually— the reason they express it and the reason you get it in wild salmon, not farmed— they're farmed ones, if they're dark red, they're pseudocolored— is because this is an amphipathic animal-based antioxidant. They get it from the microalgae and krill they eat, but they express it during their upwater trek to spawn. So people might know that salmon, at the end of their lives, they spawn once and they will go from the ocean back upstream. And that is a crazy marathon trek that takes a lot of energy and reduces— produces a lot of oxidative stress. And so what they do during this trek is they increase astaxanthin levels, which protects their vulnerable DHA fat. DHA is like 6 double bonds. It's super vulnerable to oxidation. So having higher levels of this antioxidant that's both water and fat soluble will actually protect them. And presumably when you eat it, it can protect the DHA in you too. So that's why I always go for like the wild Alaskan sockeye, and I eat basically that every day. I love sardines and then mackerels, like the fattiest fish. Supplementation with DHA, I do as well. I do a combination of two forms. One, phospholipid DHA, which you get from krill oil. So I take krill oil, and reason for that is I know Rhonda Patrick has talked about that phospholipid-bound DHA gets privileged access into the brain via something called the MSFD2A transporter, especially when the blood-brain barrier starts to break down a little bit. And so in people with ApoE4, that might be particularly beneficial. But, um, if you want bang for your buck, consider a triglyceride molecule has 3 fatty acids attached, and most of the time when you take fish oils, you only have 2 DHA, or even 1 in the case of phospholipid DHA. So Nordic Naturals has a triglyceride DHA formula, so I take that as well. So fatty fish, DHA, I haven't added these yet, but if I were to say quercetin, which acts on some of the pathways that I've mentioned and, you know, inhibiting NLRP3 inflammasome, inhibiting this COIP, NF-kappaB, MMP9 pathway at 1 to 2 grams a day based on the literature I've looked at, resveratrol maybe at 2 grams a day, not via red wine, You can combine that with people like nicotinamide riboside as an NAD source. Um, so DHA, quercetin, resveratrol, maybe some NR, um, vitamin D3. I do recommend higher doses. Like I take 4,000, 5,000 IU. K2 MK-7 at 180 micrograms, uh, full spectrum B vitamin complex, including at least folate, B6, and B12, 'cause those support methylation cycle. And you guys probably know that basically half the people are walking around with loss of function in the MTHFR gene. And so those people, this is half of people, really need extra B, might need extra B vitamin support. And B vitamins actually synergize really well with DHA. They help it get uptaken and incorporated into the brain. So having, you know, adequate B vitamin supplementation is really important with respect to omega-3. And then weirdly enough, lithium at 5 milligrams. This is something I can't believe I haven't talked about already with respect to the brain. Um, but, uh, I mentioned GSK-3 beta as tau kinase 1. Lithium's a GSK-3 beta inhibitor. That's one of the ways it works. And not at like bipolar doses that would, you know, both doses for bipolar disorder, which is like, you know, 1,000 grams or something, or maybe 1,000 milligrams. But I'm talking like 5 milligrams lithium. And low-dose lithium, there was one trial, Núñez, I think it was 2013, showed that microdose lithium could stall cognitive decline. In people with mild cognitive impairment over 15 months. So the control group had cognitive decline. The lithium group had no cognitive decline. They were using like, I think it was 300 micrograms. And then there's interesting association data showing that trace lithium in the drinking water in Denmark and in Texas is associated with lower rates of Alzheimer's disease. So you can get lithium actually over the counter. Um, like at a drugstore. So, um, lithium as well. So DHA, quercetin, resveratrol, D3, K2, B vitamin complex, lithium, fatty fish, keto diet.

So we want to—

awesome.

I just want to just, uh, you know, uh, maybe reiterate this. None of this is medical advice, and this is all based on best available evidence mechanistically.

Yes.

Right. Nobody's ever taken these I think the next step for, for the good doctor will be to take all of these and, you know, uh, take at-risk people and give it to them and see what happens.

100%.

This is, this is speculation. I want to agree with you on that 100%. It's a matter of, for me as an athlete, for me personally, speculation is the best we have. And I'm not waiting for proper trials to be conducted. It's, I just don't want to wait. I'm impatient. You can't, you can't wait. You have to— I think caring clinicians and, and, and patients— I had somebody reach out to me today because I mentioned something about ApoE4 on Twitter, and he's like, my son has ApoE4, can you help me out? It's like, people just don't want to wait. Like, if you wait, it's too late. Like, maybe I'll wait for the data to come out and then I'll be 60 and I can't incorporate DH into my brain. Oops, too late. Maybe what I'm going to be doing is completely wrong and maybe it's going to make me worse. It could be, but you I'm gambling here. I'm just, you know, well, we're left, right?

Nobody benefits from taking these supplements and studying them, right? We can't, you know, market this. And even if you do market it, then somebody could just recreate Nick's formula because none of it's patented. So the bottom line is there's no economic incentive to do all this, and that has to do with how our system's set up. It's unfortunate that we don't have this, this data, but hopefully good scientists like you and Good doctors like you will, will push this data to where it needs to be.

Yeah, yeah.

Nick, I have one question that was just on my mind, and I have to— I have a hard out in a couple minutes, but okay. Is there— what is the survival benefit of APOE4? There has to be some reason where it's protective for something.

Um, yeah, so antagonistic pleiotropy, that's my answer. So people talk about, um, APOE4 is the ancestral allele. Because early humans only had APOE4, actually. And the reason is, APOE4, I think, is APOE4 is inflammatory variant, just in general. So it has a lot of functions in the periphery as well. But, you know, when we were evolving, evolution cared a lot more about the young person surviving to have kids than it did about the old person potentially getting dementia after they're, you know, they're in their post-reproductive reproductive years. So it made more sense to have an inflammatory state when you're young and then reproduce, have more offspring. Then you get dementia, who cares about you? There's a grandmother principle, but I think that's, that's a smaller deal. Also, you, you think, and this is the second reason, burn hot, die young. Um, ApoE4 youth tend to be, um, cognitively precocious tend to have slightly higher IQs. Um, it's, it's a matter of, I think sometimes there's just a lot of neural and metabolic activity and they burn hot and they die young, or, you know, it burns out their brain more quickly.

Well, same thing, you know, one of the data I saw on, on hemochromatosis very recently was they have a higher VO2 max, right? For the longest time we thought hemochromatosis, which is iron accumulation in the liver, is a genetic defect, right? But then, you know, all of a sudden life shows us that there was some advantage to it.

Yeah, so I think, I think the real question is why do we have ApoE3 and ApoE2? Why did those even arise? Because in evolutionary terms, we, you know, things haven't changed that much. Agriculture was, is more recent, and so Yeah, I mean, I don't know. It's interesting to also observe that in populations with high exposure to agriculture, early exposure to agriculture, there's a higher rate of ApoE3 and ApoE2, whereas people that are traditionally hunter-gatherers that eat, you know, fattier diets, they tend to have more ApoE4. So the Inuits, for example, have much higher ApoE4 rates than like the Greeks or the Turks or the Mayans. And I don't know how much you can make of that because you could kind of spin it either way. One way you could spin it would be that, all right, now people are living longer, so there's more of a— because of agriculture, you're, you know, you have more of a community, you don't have to run around chasing animals as much, you're maybe living longer. And so that has, you know, Apple E3, Apple E4, so you're not getting dementia, would be beneficial. Um, another spin you could do on it— hey Nick, I gotta—

hey, I'm gonna jump out. I'm hoping I don't mess you guys up. I'm gonna have to leave and join another podcast, but awesome Nick, great having you. Troy, you, you close out, man. You do, you do. I'm hoping when I leave I don't mess you guys up, but peace out guys.

Um, all right, I guess you're— then you're the who knew host. But another way you could spin it is that agriculture and eating more carbohydrates, like the Mayans have a lot of corn, created an evolutionary pressure to, you know, generate other variants of ApoE4 because ApoE4 has functions in the periphery as well. So it's associated with like, say, increased LDL levels. And so maybe it's only under a carbohydrate-rich context that ApoE4 is disadvantageous.

Yeah, it could be the environment basically bringing out the phenotype, I guess, you know.

Yeah, it's difficult.

Absolutely.

It is right now in the realm of speculation, as we said. But, you know, I know I listed a lot of things. I have like little tables. I don't know what your show notes look like, but I can blast you I can send you an email with like a list of the recommendations because there was a lot.

Send it, we'll put it in. I really appreciate you sharing all this stuff, you know, especially about yourself and your, you know, intellectual interests. It's tough, you know, it's a lonely world out there. People don't understand that when you've gone into these rabbit holes, really there's very few people to talk about, to talk about this with. You know, a lot of times, you know, we get excited about these and people need to understand at the end of the day, just live a great life. You know, lower your stress, get sleep, exercise, move, eat real food as best as you can. You know, some of these supplements you said seem to make sense. Hopefully one day you can test them and make sure they do.

Yeah, you know, I might be selling snake oil with respect to the supplements, but I agree, just live your own n=1 life. I always say, you know, in the hierarchy of, of types of studies, you know, I'd say maybe epidemiology at the bottom, you got RCT up there, but N equals 1, your N equals 1 is the top. So like, if it works for you, don't let anybody tell you different. And, you know, I'm not like say pro-vegan, but I've had people that are vegan come to me and say, you know, I went vegan and like, it's helped me keep my cancer in remission and then my eczema's gone away and blah, blah, blah. It's like, if it's working for you, don't let anybody tell you different. Um, but just, you know, I always encourage people to just get to the point where they adopt that mindset where, you know, food not only becomes a gustatory pleasure, but an experimental one. 'Cause it's really cool when you can take like food as a tool and start figuring out, oh, I can be observant and iterate on this to continually improve myself and improve my health rather than have health and age just be a decline, have it be an incline. Uh, when people can grasp that mindset, that just unlocks so many doors, supplements aside.

Absolutely.

Absolutely. So how do people contact you if they're interested in your work, what you're doing? You have a book coming out which we didn't even talk about. So you have a book, tell us about the book and then where they can get it and how people can find you and support you. Yeah.

No, thank you super, uh, much. Okay. Articulation ability's gone out the window with all the signs.

Yeah, it's been an hour.

Thank you super much, Joe, for, uh, the book. But, um, but yeah, so the book, it's called The New Mediterranean Diet Cookbook: A Keto-Friendly Something Something Something. Uh, I wanted to be focused on, on keto, but the way it spun out was I was doing my research at Oxford and really getting into this metabolic health space, and then The first person I quote treated as a client was the head chef at one of Oxford's restaurants, The Quad. And then he got really into it. He reversed his obesity, prediabetes. Keep in mind, this is a chef in the kitchen all day, exposed to, you know, nice food, but he just went low carb and everything got awesome. So, uh, he helped me host some dining events. A keto cookbook author, Martina Slereyova, came in from London and then we started a team. I had this idea that, you know, wouldn't it be really cool to have like a science-based cookbook where like, well, I'll write an opening chapter with fun analogies about inflammation, oxidative stress, insulin resistance, and then we'll build recipes with fat profiles, omega-6 to 3 indexes, but also like fun facts to engage people, tell 'em about why salmon is pink and why you should have sheep's milk cheese and not cow's milk cheese, whatever. So there's fun facts incorporated, but, and ended up being a really fun collaboration. Between us but also other people in the scientific communities that just contributed recipes, like Dr. Russell Swerdlow, who's the amyloid cascade hypo— sorry, the mitochondrial cascade hypothesis guy, David Diamond, who's like the anti-statin dude, Nina Teicholz, you know, these people. But so it's just a nice collaboration, and I think the actual book is kind of a a springboard for hopefully other things. I call it my little Trojan horse of keto because right now Mediterranean is still super accepted. So this isn't like pro-grain, anti-saturated fat Mediterranean. This is like real historic, but also, you know, somewhat adapted Mediterranean.

So, so what's the title again and where can people get it from?

Oh, I'll put, I'll plug the book's page. We can plug it in the show notes and people can get it on Amazon. It's available for pre-order. And we really appreciate pre-orders because it helps Amazon rank it and helps then bump down what I call the pseudo health cookbooks, including pseudo Mediterranean cookbooks.

So how do people find you?

They find me, uh, I'm most active on Twitter right now at, um, uh, Nick Norwitz, N-I-C-K-N-O-R-W-I-T-Z. And I recently started a YouTube I didn't intend to, this was a couple of weeks ago, but when I put my story up, people were like, oh, we're glad you started YouTube. So I've started doing little YouTube videos. And those, you know, right now I'm doing like what I call Nick's Noodles, where if I just got like a random idea, I noodle on it. I think about it. People have criticized the noodle thing because it's, I was trying to be ironic, but I guess the irony didn't land. So sometimes I just, you know, nerd out about different things like insulin resistance or inflammation, brain health, the paper I read, I'll do a paper digest and oral, maybe do an interview and talk with someone, but it's small now, but some people seem to like it. So mainly on Twitter, I'd say @NickNorwitz. I have a YouTube as well, and all patronage supported.

Cool, awesome. Well, thank you for coming on.

Thank you for sharing your story and your interests.

Yeah, no problem. Brian had to bail on you. He doesn't like you as much as I do.

Uh, we talked— we're gonna talk again though this afternoon with, uh, Ben Bikman and Ben Bowe about visceral fat. Perfect. I now have another— do you have 2 hours to actually go read on that topic so I don't feel like a total doof?

Good luck.

Yeah, yeah, I guess I'm gonna— it's inevitable, right, when talking to Ben Bikman that you're gonna look like a doof.

So he's brilliant. He's absolutely brilliant. We love him.

All right, all right.

Thank you again.

Thank you so much, Drew, uh, and Brian, absent. And, uh, yeah, this is great. I'm excited.