#46–Chris Masterjohn, Ph.D.: Pathways to health and disease (NAD, sirtuins, methylation, choline...

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [intro music]

2. 0:04 – 11:59

   Chris's Background and Why History Shapes His Science

   1. PAPeter Attia0:04

      Hey everyone, welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [intro music] Hey everybody, welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I, I, I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will get back more than you give. So for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone. But instead, what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all, but my hope is that many of you will find enough value in, one, the podcast itself, and two, the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Chris Masterjohn. I've known Chris for probably about six or seven years. He's an incredibly bright guy, and we've been going back and forth over the past several months just trying to figure out a date when we could get together, and I, I knew this was going to be an exciting episode. I also want to preface this by saying this may rank among one of the more technical episodes that we've done, and that's probably saying a lot given our podcast. So this is definitely one where the show notes are going to be helpful. So Chris earned his Ph.D. about 10 years ago in nutrition science, and after a brief stint as an academic, he has largely devoted himself to creating just a vast wealth of information for people to help them understand so many aspects of nutrition. I have learned so much from Chris over the years, and I must say I probably learned more on this podcast than I learn on many of the podcasts that I host, although I do like to learn something on every podcast and think that I do. What did we talk about? Well, we talk about a ton of stuff. We kick this episode off by going deep on choline. Choline deficiency is something that, as Chris explains, predisposes us to a whole bunch of bad stuff, not the least of which is non-alcoholic fatty liver disease, which if you've heard me rant on this before, you realize is an enormous epidemic and is in fact on pace to become the leading cause of liver transplant in the United States. Of course, that leads us into a lengthy discussion of non-alcoholic fatty liver disease and also a detailed discussion about the different types of fats and how they may predispose us to different types of illnesses. We also get into a topic that I get asked about all the time, and I have purposely not gone into this in detail because I've known that I want to have Chris on and I want to discuss this with Chris. And those are the enzymes MTHFR and COMT. I get asked tons of questions about these, and many of you ask questions about methylation. They're great questions, and I think it's safe to say virtually every question you have on the topic of MTHFR methylation will be addressed here. We save the best for last. And again, Many of you have asked this question: Peter, what is your view on nicotinamide riboside, or NMN, or NAD, sirtuin activators, all of these things? Now, we talked about this stuff in pretty good detail with David Sinclair on one of the previous episodes. We go a little deeper here, and in particular, that's because since the episode with David Sinclair, there has been a little bit more research that's been published, and we go really deep on some of those papers. So I would say that by the time you're done with this episode, you will have as much information as one could say is available on the use of supplemental products that contain NR or NMN. So obviously, the two of these that are most commercially known are Elysium's Basis or ChromaDex's Tru Niagen. Again, I want to just say this episode is a little more technical than most of our episodes, and again, I acknowledge the irony of that statement. That means it's really technical. The show notes will be helpful. There may be parts of this that are more interesting to you than others, although personally, I found every minute of this to be like drinking from a fire hose and truly learning this stuff. You can certainly find out more about Chris and his work on his site, which is chrismasterjohnphd.com, and that's basically spelt as you would expect it to be. John is J-O-H-N. Chris is very active on social media, loves to interact with people. So if you haven't heard about Chris prior to this episode, I suspect you'll become a fan of his going forward. So I hope you'll enjoy my interview with Chris Masterjohn. [upbeat music] Hey, Chris. Thanks for trekking in, man.

   2. CMChris Masterjohn7:51

      Thanks for having me, Peter. It's good to be here.

   3. PAPeter Attia7:53

      Yeah. So you said you've moved. You're no longer in Brooklyn, right?

   4. CMChris Masterjohn7:56

      I moved to Astoria, so pretty close by.

   5. PAPeter Attia7:59

      Yeah.

   6. CMChris Masterjohn7:59

      It was probably a quicker trek here from Astoria than Brooklyn, I think.

   7. PAPeter Attia8:03

      Yeah, it just has less cachet, right? Like, Brooklyn is so cool.

   8. CMChris Masterjohn8:06

      Well [laughs] yeah, maybe I, I would've, uh, wanted to spend more time in, in Brooklyn, but like, no, just geographically, Astoria is-

   9. PAPeter Attia8:13

      Yeah

   10. CMChris Masterjohn8:13

       ... more on the edge, so.

   11. PAPeter Attia8:14

       Yeah, it's a heck of a lot easier.

   12. CMChris Masterjohn8:15

       Closer to the river.

   13. PAPeter Attia8:16

       Yeah, yeah. And where'd you grow up?

   14. CMChris Masterjohn8:18

       So I was born in Queens, actually. I kinda came full circle back, but when I was 10 months old, my family moved to Mussa- Massachusetts. So I grew up in a small town that almost no one has ever heard of, that wasn't big enough to have its own high school, and, uh-

   15. PAPeter Attia8:32

       Impressive. So, so not Framingham.

   16. CMChris Masterjohn8:34

       No, no. About an hour and a half west of Framingham.

   17. PAPeter Attia8:38

       And no accent.

   18. CMChris Masterjohn8:40

       Yeah.

   19. PAPeter Attia8:40

       You can do it on demand?

   20. CMChris Masterjohn8:41

       Too-- Way just too-- No, just too far away from Boston.

   21. PAPeter Attia8:43

       Yeah.

   22. CMChris Masterjohn8:43

       So.

   23. PAPeter Attia8:44

       Got it. And what did you study in college? I know you're-- I-- We'll talk about your PhD 'cause it's so interesting, but what, what did you study in college?

   24. CMChris Masterjohn8:50

       I-- In my undergrad, I studied history.

   25. PAPeter Attia8:53

       Okay.

   26. CMChris Masterjohn8:53

       I focused on [laughs] completely irrelevant, uh, things to medicine, nutrition, like medieval church history and early American revolutionary history. I originally wanted to be a social studies teacher, and so in my, in my vision, I was majoring in whatever was the most efficient way to get an undergrad that would be relevant to being a social studies teacher. I just had such profound experiences with health in my last year or two that I-- by the time that I was in my last year, I completely changed my mind, decided I wanted to go to medical school, but I had to finish my degree, and then in order to go to medical school, which I didn't wind up doing, but in order to go to medical school, I had to take years' worth of undergrad science classes to get the basic prereqs. And while I was doing that, a combination of my colleagues, my teachers, me falling in love with biochemistry and molecular biology and all the little invisible things that we couldn't see, and also me starting to come up with my own scientific hypotheses that I knew no one would ever research them unless I did. All of that just kinda combined to make me decide to go into research instead of, instead of medicine. So I think what I really wanted to do is take my own experiences and pay them forward in some way, and I think the best way that I can do that is by using the creative part of my brain to really immerse myself in the research and come up with new ideas.

   27. PAPeter Attia10:21

       Yeah, and it's funny, you know, I think I've said this before, maybe on the podcast, but if I haven't, I, I've, I, I know I've said it elsewhere. I always think the worst thing you can do is do in undergrad what you're necessarily going to do in graduate school. So if you're gonna go to medical school, I've never really understood the logic of studying pre-med. I mean, I, I understand the logic, but I think if you can stomach it, it's better to do something completely different. And then, and, and similarly, when you're doing your PhD, I mean, sometimes you don't have a choice. You know, if you want to do your PhD in aerospace engineering, you have to do something that approximates engineering as an undergrad. But yeah, your story's pretty interesting in that regard, and, and I s- I suspect you're, in some ways, better off for having done something totally different. If nothing else, it gave you, I suspect, kind of a, a fresh enthusiasm for what you were studying in graduate school.

   28. CMChris Masterjohn11:09

       Yeah, I think for sure, and I also think to some degree, I, I actually bring my history mind with me. So I think one of the things that we, that we often neglect in science is we get so caught up in the latest research that we forget to study the foundations of where things came from. And so my instinct is always to say, "Well, where did this idea come from? What was the origin of this?" And that inevitably leads to finding a fresh way to look at something, because you realize that the path that led you there, that there were details that got left behind because no one knew what to do with those details at that time. But then 70 years later, oh, now that, that little detail that we forgot actually makes sense now, and you can start to just get a fresher perspective than you would have if you, if you only look at what's been done over the last 10 or 20 years.

   29. PAPeter Attia11:58

       You know,

3. 11:59 – 17:00

   What Choline and Methyl Groups Are

   1. PAPeter Attia11:59

      when I was thinking about us sitting down together, I was having a hard time figuring out where I wanted to start because I also-- I realize we run the risk of once we start on a topic, it's possible we will never get out of said topic. But there really are several distinct things I want to get into with you. So I actually did something I don't often do, which is I made a bunch of notes, and, and these notes are gonna kinda keep me honest 'cause they're gonna at least remind me of major themes. I've used different fonts and highlighted things in different ways.

   2. CMChris Masterjohn12:27

      [laughs]

   3. PAPeter Attia12:27

      I've really nerded out on this. Why don't we start with something that you and I have spoken about- Probably six, seven years ago, which is choline. And, and I think the context in which it came up was when a paper came out of Cleveland Clinic, I believe it was Stan Hazen's paper, that looked at TMAO, and it got a ton of attention. And the thesis was this TMAO thing is the arch enemy of your arteries and you're gonna get atherosclerosis, and diets that are high in choline are predisposing to this. And I, I remember you, me, Stefan Guyenet, Chris Kresser, we ta- we were talking a lot about this because certainly at the time something didn't make sense to me.

   4. CMChris Masterjohn13:09

      This is how we, we first encountered each other, right?

   5. PAPeter Attia13:12

      Yeah, I don't know if it was the first time, but it was certainly early on.

   6. CMChris Masterjohn13:14

      Yeah, the, the first real email discussion.

   7. PAPeter Attia13:15

      That's right, yeah. We had this huge email thread, and I couldn't wrap my mind around how could this be true if the epidemiology, which I'm not a fan of epidemiology, but in the contrapositive it can be quite helpful, which is every epidemiologic assessment of people who consume high amounts of fish would suggest the exact opposite, and yet this paper would suggest that there's nothing you could do worse than eating fish outside of choline-laced sports drinks. So let's go back in time to that whole thing. So, so let's start with what is choline?

   8. CMChris Masterjohn13:46

      Choline, you could look at it from a health perspective or a chemical perspective.

   9. PAPeter Attia13:50

      Yeah, let's talk chemically.

   10. CMChris Masterjohn13:51

       Choline-

   11. PAPeter Attia13:51

       Let's just say, yeah, what is-

   12. CMChris Masterjohn13:52

       So choline is a methyl donor. Choline is an essential part of acetylcholine, which is a neurotransmitter, and choline is an essential part of phosphatidylcholine, which is a phospholipid that is in our cell membranes.

   13. PAPeter Attia14:06

       And I'm just going to, because I know there's half of our listeners will know exactly what you just said, and half of them won't, but because we're gonna come back to these terms so often, what's methyl? What is a methyl group?

   14. CMChris Masterjohn14:16

       Okay. So I think the easiest and simplest way to think of a methyl group is, is to come back and look at the fact that we are biological organisms. All biological organisms are made of hydrocarbons. And if you look at any molecule in our body, it's mostly a string of carbons. And if you want to synthesize one of those molecules or you want to change one of those molecules, you're gonna have to put together carbons or take them apart. And you can either put together carbons in two carbon units called acetyl groups, or you can put together carbons in one carbon units, and that one carbon unit is a methyl group. And if you just think about it very simply, if you had a molecule with an odd number of carbons, you'd have to put a methyl group in there sometime because y- two plus two plus two plus two never makes an odd number. Or you might have a molecule that has something else in it, like a nitrogen, and it's got three carbons attached to it. Well, the only way you can do that is methylate that nitrogen three times.

   15. PAPeter Attia15:12

       Right. So we use the term methylation as a verb to, say, to put on a methyl group, right?

   16. CMChris Masterjohn15:17

       Right.

   17. PAPeter Attia15:17

       And we'll talk about that so much.

   18. CMChris Masterjohn15:18

       And, and in fact, the meth- methylation is also called the one carbon metabolism, so a methyl group and a one carbon is, is identical.

   19. PAPeter Attia15:26

       Okay. So we've got this idea of choline plays an important role in regulating how that whole methylation thing works. Choline is relatively abundant in certain things that we eat, right?

   20. CMChris Masterjohn15:37

       Yeah. If you look at the diet, you see enormous amounts of choline in liver and egg yolks, and then you see moderate amounts of choline in many other foods. Most of those foods that are pretty good sources of choline, but not awesome sources of choline, are meats, nuts, and low carbohydrate, low calorie vegetables, especially cruciferous vegetables. And in fact, we did not know for the longest time that choline was an essential nutrient in humans, and still they started feeding people on total parenteral nutrition, and they weren't putting choline in because no one-

   21. PAPeter Attia16:14

       And I'll explain to folks what that is. So total parenteral nutrition, or TPN, is something that is completely given intravenously, but into large central veins, and it's for people who have such severe pathology in their gut that nothing that you trickle into their gut could ever give them nutrition, and so you're feeding them through these large veins. And I guess where you're gonna go with this is when you're feeding someone with total parenteral nutrition, you have 100% control over what they're consuming, and I know where this story's going. It's so interesting. It can really expose deficiencies that we take for granted.

   22. CMChris Masterjohn16:50

       The same thing is true of omega-3 fatty acids or a number of nutrients that we just assumed no one needed until we fed them on TPN without that thing, and then all of a sudden something really, really bad happened.

4. 17:00 – 25:10

   Choline Deficiency and Fatty Liver

   1. PAPeter Attia17:00

      So what happened with the choline deficient TPN folks?

   2. CMChris Masterjohn17:04

      Those folks developed fatty liver.

   3. PAPeter Attia17:06

      Which is very counterintuitive, right? In the sense that they probably weren't being mainlined a lot of fat, right?

   4. CMChris Masterjohn17:12

      Right. But w- it turns out that because choline is an essential part of the phospholipid phosphatidylcholine, and because that phospholipid is not just in our cell membranes, but it's also in the membranes of the lipoproteins that carry fat out of the liver, then if you don't have enough choline, you can't make the VLDL particle to get triglycerides out of the liver. And we think a lot about we want triglycerides out of the blood, but we want triglycerides out of the liver too.

   5. PAPeter Attia17:39

      First and foremost.

   6. CMChris Masterjohn17:40

      Right.

   7. PAPeter Attia17:40

      Yeah.

   8. CMChris Masterjohn17:41

      So if choline is not there, you get fatty liver. That's not surprising in hindsight if you just look at the animal research because you go back almost a century, and they had basically done the same thing to animals. So when they started purifying animal diets, it was almost the same story. They didn't realize these things were necessary, a bunch of problems happened, they realized the nutrients that were necessary. And going back to the beginning of the 20th century, what we have is rodents developing fatty liver on the diets until they were able to either put choline in or reduce the sugar content. But in those animal experiments, what ultimately was shown was that it doesn't really matter what the cause of the fatty liver is, as long as you have enough choline in the diet or you have some precursor to make choline, whether it's sugar, alcohol, fat, as long as you have enough choline in the diet, you can clear those triglycerides out of the liver.

   9. PAPeter Attia18:36

      So that's interesting, and that's something I actually wanted to explore with you because, you know, I'm in the midst of writing this book, which I'm so sick in talking about. I'm so sick of talking about the fact that I'm in the middle of [laughs] writing this book. I can't wait to just be done with the thing. But one of the chapters is on kind of this spectrum of NAFLD, NASH, insulin resistance, and type 2 diabetes. So in doing that, you know, I went back and had to look a lot more at the history of who was the first person to describe it. What was that index patient who first had NAFLD? And it's this sort of funny story of this character who was drinking something to the tune of, like, 20 bottles of Coca-Cola a day. You know, he's just mainlining Coke. This is back in the '50s.

   10. CMChris Masterjohn19:14

       Right.

   11. PAPeter Attia19:14

       So you alluded to this a second ago, which is, you know, sucrose plays an important role in this. Ethanol plays an important role in this. So the question is, if I understood you correctly, is it safe to say that you take a, a person -- Let's just make it clinical. You take a person who has non-alcoholic fatty liver disease, and we'll, we'll talk a little bit more about that in a second. But with enough choline, you don't have to necessarily restrict any of the substrates that are predisposing to more fat accumulating in the liver than exiting the liver?

   12. CMChris Masterjohn19:45

       That's what I would believe based on all of the animal experiments that were done. It baffles me that we don't have human studies addressing exactly that. I mean, we have human studies that if you put people on a... If you take what the average person is eating right now, and then you put them in a controlled lab environment and you take the choline out of their diet, nine out of 10 of them will develop fatty liver disease.

   13. PAPeter Attia20:08

       And by the way, does it progress from fatty liver to the NASH variant where you actually start to see the inflammation, or is that not necessarily a place that they progress to? Is it just the accumulation of fat?

   14. CMChris Masterjohn20:21

       In those studies, you're looking at short-term development of steatosis and which is j- the simple fat accumulation. Based on how I understand the physiology of fatty liver disease, what you would expect is that putting a bunch of fat in the liver is kind of like building the kindling for a fire. So you build the fire, and you don't light it. Then that person, at some point, they might not ever light that fire, but all it takes after the, all that kindling wood is put into place is some hit of inflammation or oxidative stress that suddenly lights that up on fire. And in the literature, that's called the two-hit hypothesis of fatty liver. So what you presume is not that steatosis necessarily leads to steatohepatitis, but that you can't develop steatohepatitis without steatosis, right? So it just puts you now into this new category where there's a fairly high probability that that will happen. But the point I want to make with these acute studies is we know that the average person walking around that, out there who doesn't have fatty liver, they don't have fatty liver because of the choline in their diet.

   15. PAPeter Attia21:30

       Not because they're consuming a paucity of the things that are uniquely fattening to the liver, the two most obvious being fructose, ethanol, or highly abundant polyunsaturated fatty acids, things like that.

   16. CMChris Masterjohn21:43

       Well, it's both. But what I'm saying is in these studies that were done, I, I believe this was Stephen Gesell's group, who's, who's one of the main choline guys. They just took people eat, randomly eating whatever they were eating, and they didn't have any fat in their liver, and then they put them on this experimental diet where they took the choline out of the, what they were already eating. So they probably were eating some sugar. They were probably drinking some alcohol. I don't know exactly how much, but the point is if you're out there walking around without fatty liver... And you can see this in the TPN, too. Like, those people at some point in their history didn't have fatty liver. They went on the TPN. They got fatty liver. But you don't have to put them on TPN. You can just put them on a low choline diet. And if you look at all the animal experiments, what they show is you can cause fatty liver with sucrose. You can cause fatty liver with alcohol. You can cause fatty liver with fat. And no matter how you cause it, you just put in choline or you put in things that can be precursors to choline in any of them at a high enough ratio with the other things that are producing the fat in the liver will get rid of the fatty liver. So if we know in humans that you get fatty liver when you take the choline down and we know in animals that you get rid of fatty liver if you put the choline up, then I would think that if you took the humans with the fatty liver and you put the choline up, you'd get rid of it. But for some reason, that hasn't been tested the way you'd think it would be.

   17. PAPeter Attia23:03

       Do you have a sense of how much choline is required in that situation? So if you took a patient who unequivocally had fatty liver disease by, say, MRI. So we take the gold standard, and we could actually measure, you know, they, 20% of their liver was now made up of fat. And they were on... Let's say they were not on an especially restrictive diet, so they weren't someone who was avoiding eggs or anything like that, but presumably they weren't having enough. How much choline would you guess you'd have to put in the diet, and would you be able to achieve that through eating more foods rich in choline, or would you actually need to supplement it?

   18. CMChris Masterjohn23:37

       I can only give you a wild guess, and my wild guess would be about 1,200 milligrams of choline. And you could get that by eating food, but it would be very difficult.

   19. PAPeter Attia23:46

       So how many milligrams of choline in an, in an egg?

   20. CMChris Masterjohn23:48

       130.

   21. PAPeter Attia23:49

       You don't know how many eggs I eat. [laughs]

   22. CMChris Masterjohn23:51

       How many eggs do you eat?

   23. PAPeter Attia23:52

       No. Well, I have chickens, so I, I-

   24. CMChris Masterjohn23:53

       I had four this morning.

   25. PAPeter Attia23:54

       Yeah, yeah, yeah. I could, I could, I could easily eat six eggs a day.

   26. CMChris Masterjohn23:57

       You can do it, but it's, it's hard, and you'd have to design the diet to do that, right? I'm basing that on a couple things. One is there are human studies where it has been shown that some people require 1,200 milligrams of choline a day. And those studies are not looking at liver fat. They're looking at other markers. But people who have a genetic predisposition to need what we know is the highest choline requirement that a human can have is about 1,200 milligrams. The other way I base that is that it's been shown with labeling studies that in, if you take a random sample of people with NASH, which is the steatohepatitis, they have inflammation too. If you take those people and you look at their triglyceride export, it's reduced by 75%. So if it's 25% of normal, then I look at that and I say, "Well, you probably want to quadruple the ability to export triglycerides from the liver." And it's my guess that although the adequate intake, which is the replacement for an RDA when you don't have enough evidence, for choline is higher, I think the average choline intake is probably somewhere around 300 milligrams or something like that.

   27. PAPeter Attia24:59

       What's the RDA for choline?

   28. CMChris Masterjohn25:01

       It depends on men and women. I, I might be wrong on this, but I think it's around 500, but it's a little bit higher for men, it's a little bit lower for women. I don't remember the exact numbers.

   29. PAPeter Attia25:10

       You know,

5. 25:10 – 39:37

   NAFLD Epidemic, Visceral Fat and Confounded Diet Studies

   1. PAPeter Attia25:10

      the funny thing with, with non-alcoholic fatty liver disease is it's hard to know the rate at which it is increasing because like many things, it was so likely under-diagnosed. In the book, I'm actually writing about sort of the first patient I saw that likely had it, and it was, you know, during a case when I was a resident and we were operating on this guy, and prior to surgery, I had done all the usual things and tried to figure out how much alcohol he drank, which you do with every patient because you need to understand what their requirement for benzodiazepines is going to be and if they're going to have withdrawal in the perioperative period. And this patient claimed he didn't drink any alcohol, and I believed him, and then we got in there and operated, and his liver looked like a fattened duck liver. And I remember thinking, "I can't believe this guy lied to me." But after the fact that, you know, I went back to him and we-- I said, "Just look, I'm not here to judge you. You got to tell me how much you drink." And he's like, "Doc, I don't drink anything." Then I sort of forgot about the whole thing until 10 years later when I realized, oh my God, that was NAFLD.

   2. CMChris Masterjohn26:07

      What, what year was that?

   3. PAPeter Attia26:08

      2001.

   4. CMChris Masterjohn26:10

      So in 1980, the Mayo Clinic published a paper in which they coined the term NASH, which came before NAFLD.

   5. PAPeter Attia26:16

      Mm-hmm.

   6. CMChris Masterjohn26:17

      And they coined it because of that. If you read their paper, their rationale is, we have doctors that are seeing fatty liver. They assume that fatty liver happens because of alcohol. The patients are telling them they don't drink alcohol, and they're saying, "You're lying to me." And the best thing that can come from that is an argument, and there could be worse. Part of it was that it facilitated the growth of a whole body of research, but the other part of it was it allowed doctors to have a way of thinking and talking about the person who says that they don't drink alcohol and yet they have fatty liver.

   7. PAPeter Attia26:50

      Right. They have, they have a liver that for all intents and purposes, looks grossly just like that of someone who is about to kill themselves through a, a, a lot of alcohol. Now, Ron Busuttil, who is certainly one of the preeminent liver transplant surgeons in the world, said, and this is probably about four years ago, you know, in the year 2000, something like 1% of liver transplants were being done for NAFLD, NAFLD predisposed. Nobody needs a liver transplant if they have NAFLD, but if you get NAFLD, NASH, and cirrhosis, you do need a transplant. And that amounted to 1%. And in, I think about 2013, 2014, he predicted that NAFLD, NASH, cirrhosis was going to be the leading cause of liver transplant by the year 2030 in the United States as a result of two things. One, the sort of undeniable increase we were seeing in NAFLD, and of course, the success of treatment for both hep B and hep C. So it's both those things coming down and the other one going up. So my question to you, which I apologize for how long-winded it is, even if we're over-diagnosing it today or seeing it more than it was there before, it seems hard to deny that NAFLD is more prevalent now than 20 or 30 years ago. Would you agree with that?

   8. CMChris Masterjohn28:01

      Yeah. I think even though you can't track the prevalence over time, you can assume that the prevalence has increased over time matched to obesity because that's the overwhelmingly predisposing risk factor.

   9. PAPeter Attia28:11

      So do you believe that it is more driven by a fat accumulation in the liver problem or choline being less prevalent in our diets and therefore more of a clearance problem?

   10. CMChris Masterjohn28:26

       It's hard to make an either/or question about it because it comes down to fat in versus fat out-

   11. PAPeter Attia28:32

       Mm-hmm

   12. CMChris Masterjohn28:32

       ... and choline is such an overwhelming factor in the fat out part of the equation. But I think the reason that it's increasing over time, if you had the data, I really doubt that you could show that there's been a linear decrease in choline intake over those years, and I think you probably could show that there was a fairly linear increase in NAFLD over those years that tracked with obesity. And I think, you know, you can look at it like what's the percentage of people with obesity who have fatty liver, or what's the percentage of people with fatty liver who have obesity? And I might have these numbers backwards, but I think it's 67% of people who have obesity have fatty liver, and 76% of people who have fatty liver have obesity, something like that. And I think the overwhelming reason for that, and I don't think it's the only reason, but I think the ov- the overwhelming reason for that is that the more obese you are, the more likely you are to have visceral a- adiposity, and the visceral fat pad directly empties into the portal vein and so is a huge factor in fat in compared to the subcutaneous fat pad. And I think that that's probably a huge factor in why, again, not the only factor, but I think that's probably a huge factor in why the metabolic health of someone who has relatively more visceral fat is so much worse than the person who has relatively more subcutaneous fat, is because you're basically pounding the liver with fat all the time. You don't even have to eat anything. It's just you're always engaging in lipolysis. You're always freeing some free fatty acids, and if you have this gigantic tube going right into the liver just feeding fatty acids in all the time, then I think that's the major thing.

   13. PAPeter Attia30:15

       Now, one of the challenges of studying NAFLD is, and I can say this with some experience because I used to, you know, be involved in an organization that was funding research in this, is removing the biggest confounder of the reduction of NAFLD, which is weight loss. So the biggest challenge is, so let's say your hypothesis, and, and I think fructose is overwhelmingly on a molecule for molecule basis, probably one of the greatest drivers of NAFLD. When you take fructose out of the diet Very often a person is going to lose weight, either through some reduction, you know, spontaneous reduction in intake or some other thing. So it's hard to then say, well, with fructose elimination, you're ridding yourself of NAFLD or dramatically reducing it, and how much of that was due to the fructose reduction and how much of that was due to the weight loss? Are you aware of any data that have done a great job at trying to disentangle those two? And it doesn't necessarily have to be fructose, but it could be an input issue, so ethanol, PUFA, fructose, an output issue, choline, or the way you describe it as sort of this in-between visceral thing, which is visceral fat tends to decrease when adiposity decreases. So it's almost like there's a third variable, and it is challenging in humans to figure out how to isolate each of those.

   14. CMChris Masterjohn31:34

       I don't think you can do it in humans. Well, I think you could do it in humans. I don't think anyone will do it in humans, and I don't think that there's any data out there that do do it in humans, and I don't think every- anyone will ever bother to try to figure that out because what that would require would be putting people in a metabolic ward and feeding them precisely controlled diets. And I think this is a huge point that you're making that applies so much broader than this discussion because whenever people make one change in their diet and that changes, changes to the foods in their diet, they're actually changing like 30 or 40 things in their diet and they have a high-- Their driving idea of what they're doing is only one tiny part of what they're doing. And so if you look at, say, taking the fructose out of the diet, well, what, you know, what's the fructose in most cases? It's a bunch of junk food. What did they eat instead? Well, either they ate nothing instead or they ate something different than that, which was probably better. So the average person who takes fructose out or who takes carbs out, even if you just go on a low-carb diet, well, your idea is that you reduced your carbs, but actually you probably increased your protein. You probably increased your choline. You probably increased your riboflavin. You probably increased a bun- You probably increased your zinc. You probably increased a, a bunch of different things. And I think that the only way to make sense out of the human data is to take all of the animal data that does have precise controls on it and say, you know, not assume that the animal data always matches the human data. But if you can take all the animal data and you can say, "Wow, everything that is in the human data makes perfect sense according to what the theory we get out of the animal data is," then that's what you do, right? So when we're talking about fructose, when I was in graduate school, I fed rats a 60% fructose diet, and I was hoping that they would get fatty liver. And I was hoping that I would... Actually, what I, what I was really-

   15. PAPeter Attia33:25

       Wait, 60% fructose or sucrose?

   16. CMChris Masterjohn33:27

       Fructose.

   17. PAPeter Attia33:28

       How can they even digest that? I mean, how do they, how do they not just get such severe dumping syndrome with so much fructose?

   18. CMChris Masterjohn33:34

       They might have had a little bit less digestion because they were a little bit leaner.

   19. PAPeter Attia33:38

       [laughs] I was gonna say, I mean-

   20. CMChris Masterjohn33:40

       But that, but, but that's not the point.

   21. PAPeter Attia33:40

       Okay.

   22. CMChris Masterjohn33:41

       The o- the point is there are studies out there showing a 60% fructose diet causes fatty liver.

   23. PAPeter Attia33:45

       And did you see it in yours?

   24. CMChris Masterjohn33:46

       No.

   25. PAPeter Attia33:47

       Because you had lots of choline, do you assume?

   26. CMChris Masterjohn33:48

       Well, I wasn't trying to have lots of choline, but in my department, we never fed rats or mice on casein diets, which is what almost every rodent study out there is. And my depart-

   27. PAPeter Attia33:59

       Casein being the dominant protein that you would see.

   28. CMChris Masterjohn34:02

       In milk.

   29. PAPeter Attia34:02

       Yeah.

   30. CMChris Masterjohn34:02

       Yeah. But every rodent diet is based on casein almost. I didn't even know why we did this. It was just tradition in our lab and in our whole department that we never used casein. And I, and later I talked to my department head about it and he said, "Well, I've seen studies showing that casein is inflammatory in rats and it causes copper deficiency, so we just prefer to avoid it." So then I look into the amino acid composition of my diet versus the casein diets that everyone else is using, and it's someti- something like six times more methionine, which is a choline precursor that has been shown in animals to obliterate fatty liver. Something like six times more methionine in my diet. So all the sudden my, my negative finding makes perfect sense with everything else that I'm looking at. And, you know, part of the reason that I have a unique perspective on this goes back to what we were talking about at the beginning about getting a historical perspective.
6. 39:37 – 53:36

   TMAO, Fish, and Choline Forms

   1. PAPeter Attia39:37

      So now let's talk about this thing called TMAO. What is it and how did it rear its head into this discussion, and all of a sudden choline became public enemy number one?

   2. CMChris Masterjohn39:46

      Before these studies came out from the Cleveland Clinic, TMAO was mostly known in being found naturally in fish and in being produced in the gut in very rare cases where there were people with genetic disorders, and I don't even remember off the top of my head what those genetic disorders were, but they were feeding them absolutely massive amounts of choline. And so it was known before that that in those cases of enormous choline loading, some of that choline would be converted to trimethylamine by gut bacteria, and that that trimethylamine... And actually, the, the interest was largely in the trimethylamine because the trimethylamine is the more smelly compound.

   3. PAPeter Attia40:26

      Mm-hmm.

   4. CMChris Masterjohn40:26

      So this would produce fish odor syndrome. These people are smelling like fish. So that was what was known about it at that point. But then in 2011, I think, was the first paper, the Cleveland Clinic came out with experiments, I think in, first in mouse, but also in humans showing... well, showing different things. So in mice that were genetically engineered to have defects in their lipoprotein metabolism, they showed that TMAO was directly atherogenic. And in humans, they showed that in-- There were two different papers. The first one looked at choline, and the second one looked at meat. But what they were showing was that TMAO levels in humans correlate with heart disease risk, and when humans eat either choline or carnitine, they will metabolize both of those to trimethylamine in the gut, and the liver will convert it to TMAO. And so the argument is the TMAO in those humans will cause heart disease the way that it causes heart disease in the genetically engineered mice.

   5. PAPeter Attia41:34

      And if I recall, there were basically three ways that they were suggesting you could get too much of it. One was too much fish. If you eat fish, you're getting the TMAO directly.

   6. CMChris Masterjohn41:43

      I don't think they mentioned fish.

   7. PAPeter Attia41:45

      Maybe I'm confusing it with a different paper, but I thought one argument was too much fish is too much TMAO, too much carnitine, which is found in sports drinks, is gonna be converted, and too much choline. So basically, any of those three that were too many were problematic. Now, maybe I-- maybe this was stretched across a couple of different papers too.

   8. CMChris Masterjohn42:02

      So my, my recollection is that I brought the fish up because my argument was it's really easy to just look at this stuff and say, and repeat what we already believed about eggs and red meat being bad for you. And if you isolate it to that, it kind of makes a clean story, but it makes a really bad story if you bring fish into the equation, because fish have so much TMAO that you're probably literally getting hundreds of times more TMAO exposure when you eat fish than when you eat those foods.

   9. PAPeter Attia42:33

      Yeah.

   10. CMChris Masterjohn42:33

       So my point was always, how can you not bring fish into the discussion? And, um-

   11. PAPeter Attia42:40

       Yeah, you-- Yeah. So now it's coming back to me. You wrote a piece on this that I think we'll, we'll be, we'll be sure to link to. I think the reason I had seen this fish issue separately was I was actually at an advisory meeting for a company that had asked me and a dozen other people a question which was, should we be using TMAO as a new biomarker for cardiovascular disease?

   12. CMChris Masterjohn43:03

       Uh-huh.

   13. PAPeter Attia43:03

       And so it was part of this two-day meeting where we're sort of in this room looking at all of the data that somehow this-- so- someone else, and I, I don't remember who it was, came up with the idea of, "Well, wait a minute. I mean, we gotta take a step back here. I mean, if fish has more TMAO than you could ever get from all of the red meat and eggs in the world, it converting to TMAO, it just seems to fail on first principles."

   14. CMChris Masterjohn43:28

       Yeah, and there were later papers that happened after those first two where there was some observational data showing that people who eat more fish have more TMAO in their blood.

   15. PAPeter Attia43:36

       I still get asked about this, I don't know, twice a year. A patient will bring in a copy of that paper, I think it was in Nature, uh, or Nature Communications or something like that, and say, "Oh my God, Peter, like, what do you think about this TMAO thing?" And it's just always one of those things where I kind of eye roll and I just sort of send them a link to what you wrote or what Chris Kresser and say, "Go and read this and then come back to me and let's discuss why I am not particularly impressed by this thesis."

   16. CMChris Masterjohn44:02

       On a scale of one to 10, I wouldn't say that my opinion that TMAO has negative properties in humans is zero. I think it's maybe one or two or something like that, and I'm willing to see what, what they come up with there. But on a scale of one to 10, my view of the overall story that eating eggs and meat are bad for you because they alter the microbiome in a way that makes you take the choline and the carnitine in those foods and convert it into TMAO and make you as a red meat and egg eater uniquely vulnerable to heart disease, I'm very close to zero on the probability of that story being true. I'm totally open to seeing new studies on the ability of TMAO and plasma to be a biomarker and the potential for maybe eventually altering the gut microbiome in a way that generates more TMAO. And actually, I incorporate this on a practical level in some cases. So in-- when I'm looking at choline supplements, I overwhelmingly prefer that someone would get phosphatidylcholine, which is the overwhelming form of choline that's found in food, for two reasons. One is it's the overwhelming form of ch- choline found in food, and the second is that it's the form of choline that's least likely to generate TMAO in the gut, almost exclusively driven because its absorption is better.

   17. PAPeter Attia45:23

       Do you dose it milligram for milligram? In other words, if you believe that 1,200 milligrams of choline is necessary-

   18. CMChris Masterjohn45:29

       No, and actually that's very confusing on supplements because most supplements of phosphatidylcholine tell you the amount of phosphatidylcholine in them, and they don't tell you the to-

   19. PAPeter Attia45:36

       So you don't know how much choline is in it?

   20. CMChris Masterjohn45:37

       No, you do. You can es- estimate that it's about 15%.

   21. PAPeter Attia45:39

       Just by molar weight, it's about 15%?

   22. CMChris Masterjohn45:41

       Right.

   23. PAPeter Attia45:41

       Okay.

   24. CMChris Masterjohn45:41

       Yeah, I mean, it's probably an imperfect number because probably most of the time the fatty acids are different in each molecule, right? So it's just an average.

   25. PAPeter Attia45:51

       Yeah, yeah.

   26. CMChris Masterjohn45:51

       But it's close enough, right?

   27. PAPeter Attia45:52

       But directionally then you would want, like, nine or 10 grams to hit your 1,200 milligram.

   28. CMChris Masterjohn45:57

       Yeah, I mean, it's on- it's only practical if you're taking tablespoons of lecithin.

   29. PAPeter Attia46:01

       Yeah.

   30. CMChris Masterjohn46:02

       But you can get food, so you could eat eggs, right?
7. 53:36 – 59:48

   Fatty Acids, Oxidation and Liver Fat

   1. PAPeter Attia53:36

      So what do you think are the role of different fatty acids in this problem? And I guess we'll just define it for the listener, right? So we sort of loosely characterize fatty acids as either saturated, monounsaturated, or polyunsaturated. We can further divide the polyunsaturated into a number of constituents. I always think it's important that people sort of demystify this stuff, and it-- we're so quick to demonize one versus the other.

   2. CMChris Masterjohn53:58

      Yeah.

   3. PAPeter Attia53:58

      But it's, as you said at the outset, it's really just a bunch of really fun biochemistry. A saturated fatty acid is specified by the number of hydrocarbons, or the number of carbons it has. That's the chain. So a C8 versus a C12 would have 8 versus 12 carbons. But being saturated just means there are no double bonds. Every carbon is fully saturated with a hydrogen. And then, of course, you can finish the explanation for what a mono and polyunsaturated is.

   4. CMChris Masterjohn54:26

      Right. A monounsaturated fat has one double bond. A polyunsaturated fat has two or more double bonds. That introduces a couple things. So one, one thing is that whenever you introduce a double bond, you create a kink in the molecule. So saturated fats are really... You can imagine them as, as just being straight and linear, and you can pack them together very well. So saturated fats tend to be solid. Less saturated fats, fats that are higher in monounsaturated and polyunsaturated fat tend to be more liquid. So olive oil is more liquid than butter because it's mostly monounsaturated fat. If you take olive oil and you put it in the refrigerator, and you take corn oil or sunflower oil and put it in the refrigerator, eventually the olive oil's gonna harden, and the sunflower and sunflower oil wouldn't, and that's because the sunflower oil is more polyunsaturated, and that has even more resistance to packing together. The other thing is that In a fatty acid with two or more double bonds, so polyunsaturated fat, the carbon that's between two of those double bonds is very unstable, and it is uniquely vulnerable to being damaged, and we call that damage lipid peroxidation. So that fatty acid is not harmful in and of itself, and in fact, there are polyunsaturated fatty acids that are absolutely essential for us.

   5. PAPeter Attia55:41

      You alluded to these earlier, we'll come back to them, which is the omega-3.

   6. CMChris Masterjohn55:44

      Right. Well, and the omega-6. Ome- there are omega-3 and omega-6, both polyunsaturated. They're both essential to human physiology. But it's also the case that the more of these that you have in your cell membranes, the more of a liability it becomes because if you have oxidative stress, if you have inflammation, then all of a sudden those fats are more vulnerable to damage. And it's very, very tricky when you're talking about fatty liver because there was a human study that was about two weeks long that was published when I was in graduate school, so maybe 2010 or 2009 this was. They showed that over the course of a couple weeks, polyunsaturated fats compared to saturated fats lead to less liver fat, and it was very, you know... They, they used, uh, MRS, so it was, you know, highly reliable data that they had. And if you just take that at face value, you say, "Well, there's one study that looked at it in humans. There's a couple observational studies. Overall, PUFAs are what you want to eat for fatty liver." There's a problem with that, which is that if you have fatty liver and it's mostly PUFAs, you are way more vulnerable to progressing from steatosis to steatohepatitis because-

   7. PAPeter Attia57:03

      You have more oxidative targets.

   8. CMChris Masterjohn57:04

      Right. Yeah. So if you look at the animal data, it depends on the model. Generally, you get more steatosis with longer chain length and more saturation, and you get less steatosis with shorter chain length or with less saturation. But if you have the steatosis, you have a dramatic increase in the risk of progressing to steatohepatitis. However, in the alcoholic model, there are studies showing that you get less steatosis with saturated fats than with polyunsaturated fats. I think the reason for this is that oxidative stress does not just cause you to go from NAFLD to NASH. It also can cause steatosis because you get oxidative destruction of the ApoB particle. And so it's not just choline that allows you to export triglycerides from the liver. You also need sufficient antioxidant protection in the liver because if you damage that particle before it ever exports to triglycerides, then you prevent it from doing so. I think the way you reconcile these different animal models is you say, well, in the alcoholic model, there's so much oxidative stress already that's provided by the alcohol because the alcohol isn't just a way to get fat in the liver. The alcohol, uh, alcohol's metabolism generates oxidative stress. So you're taking a liver that doesn't yet have fat accumulation, you're putting a bunch of fat into it, and you're adding on top of that an oxidative flame. So you actually wind up causing steatosis by causing oxidative damage to the ApoB particles so that they can't leave the liver in that model. So PUFAs, I think, are, are very complicated to think about because in the short term, in someone who doesn't have a lot of stuff going on in their liver, they're probably gonna be better if you look at a two-week study, and we have the data in humans showing that. But I think in the long term, if you're talking about the progression from steatosis to NASH, they're a clear disadvantage. And I think if you're not talking about the healthy person who's got nothing wrong with them, then they're... Who knows? It, it's like 50/50.

   9. PAPeter Attia59:13

      But, but in this two-week study you're talking about, presumably the subjects were fed disproportionately high amounts of PUFA versus SFA?

   10. CMChris Masterjohn59:21

       Yeah.

   11. PAPeter Attia59:21

       Do you recall, like, the magnitudes that they had to be fed to produce this phenotype?

   12. CMChris Masterjohn59:26

       I don't recall the magnitudes, but they weren't ridiculously out of proportion to the-

   13. PAPeter Attia59:29

       They weren't, they weren't supraphysiologic.

   14. CMChris Masterjohn59:31

       No, no, no. They were basically the typical amount of fat that someone would eat, but they controlled the fat intake. So maybe people would prefer to mix the types of fats that are, that are in their diet, but in, in that case, it was atypical, but they w- they weren't feeding them 80% or 90% fat diets.

   15. PAPeter Attia59:48

       You know,

8. 59:48 – 1:09:40

   Flux Versus Snapshots in Biomarkers

   1. PAPeter Attia59:48

      it's interesting you mention the ApoB issue. ApoB is used obviously in two ways in the liver. You-- The first way we've talked about, which is VLDL export, which is our main way to get triglycerides out, but, but also we make de novo LDL in the liver. And so in those patients, do we see a reduction in LDL as well?

   2. CMChris Masterjohn1:00:11

      I don't remember.

   3. PAPeter Attia1:00:12

      That's interesting. I feel like I want to start paying a little closer attention to this. I, I certainly haven't-

   4. CMChris Masterjohn1:00:17

      I, I can't even remember if they measured that.

   5. PAPeter Attia1:00:19

      I just haven't clinically seen that, 'cause I do see NAFLD all the time in the practice. Usually, you suspect it with an elevated ALT disproportionate to AST, and then an ultrasound will confirm the diagnosis. Very, very f- rarely do you need an MRI and certainly never a biopsy. But I haven't seen the association with an alteration in VLDL, which we can estimate, and obviously we can measure triglycerides and LDL. It's also confounded, by the way, by different ethnicities. So, you know, when you look at African American patients, even with type 2 diabetes, will still have very low VLDL and triglycerides. A Hispanic patient with diabetes will generally have a high triglyceride and a high VLDL, and actually they're far more susceptible to NAFLD than African American, and Caucasian is in the middle. Are you familiar with any of, uh, of the data on some of those differences as it pertains to the lipidology of these folks? I g-- I just haven't paid attention to it myself

   6. CMChris Masterjohn1:01:23

      No, I'm not, I'm not. And can we re- rewind a minute? What haven't you observed with VLDL? You said you haven't observed the association between-

   7. PAPeter Attia1:01:31

      I-

   8. CMChris Masterjohn1:01:31

      ... blood levels of VLDL and-

   9. PAPeter Attia1:01:33

      And NA- and NAFLD

   10. CMChris Masterjohn1:01:34

       ... NAFLD?

   11. PAPeter Attia1:01:34

       Yeah.

   12. CMChris Masterjohn1:01:34

       What would you expect to see that you didn't?

   13. PAPeter Attia1:01:36

       I would have expected, based on what we're saying, to see l- a reduction in VLDL. The, the more NAFLD they have, the less VLDL based on this idea.

   14. CMChris Masterjohn1:01:44

       Oh. Well, I think the problem with that is that-

   15. PAPeter Attia1:01:47

       I mean, I have an explanation for why that might not exist, and here's the explanation. In an ideal world, that might make sense, but there's another thing that's going on. If you have NAFLD, you are very likely insulin resistant.

   16. CMChris Masterjohn1:02:00

       Right.

   17. PAPeter Attia1:02:00

       If you are insulin resistant, you are upregulating ApoC3. If you are upregulating ApoC3, your VLDL are going to stick around a hell of a lot longer than if you do not. And that's why we see these pathologic remnant VLDL particles that become atherogenic. So when you or I, presuming we're both insulin sensitive, our VLDL really don't pose much of an atherogenic risk because they stick around for such a short period of time. So we don't have many of them, they don't stick around long. Our ApoC3 is quite downregulated. But if ApoC3 is upregulated, and it's hard to measure this, although Sam Tomicus is working on an assay to do so, you have VLDL now start to act like LDL. They stick around long enough, they have a high enough residence time in the plasma that they become atherogenic. And so I do wonder if maybe why I don't... Not that this is scientific, but the reason even my gestalt is not to see that is maybe the less VLDL that's being exported in that patient because of the reasons you've described is offset by a longer residence time due to more ApoC3.

   18. CMChris Masterjohn1:03:08

       Right. And wouldn't you also expect that from lower rate of uptake of triglycerides from peripheral tissues?

   19. PAPeter Attia1:03:15

       Yeah, that's a great point. You have a lower peripheral disposal of triglycerides, so the whole thing could be confou- In other words, it's a great point you raise, actually. We should take a macro step back. This is a problem of flux, and people struggle to understand flux-

   20. CMChris Masterjohn1:03:30

       Mm

   21. PAPeter Attia1:03:30

       ... because you can't understand flux with a snapshot.

   22. CMChris Masterjohn1:03:34

       No.

   23. PAPeter Attia1:03:34

       You have to have the goddamn video, right? I mean, that's the analogy. You can't... You take a picture of something, you don't know the flux.

   24. CMChris Masterjohn1:03:41

       Well-

   25. PAPeter Attia1:03:41

       What's in, what's out, where it's being disposed of.

   26. CMChris Masterjohn1:03:44

       I love this point, and one of the analogies that I like to use is, although you can't use the picture, how much information you have in a snapshot can have a huge effect on your ability to know what's going on. You know, imagine that you have a picture of a car accident. Well, if you zoom in to the tire, you might not... And y- and you look at that, you don't know what happened. You might not have any idea what happened. The more you zoom out and the more different angles that you have, at some point you can start to build a story of what probably happened based on that snapshot. But if you're looking at one element in the snapshot, you can never even so much as build a story about what probably happened. And I think that, yeah, the idea that mistaking a concentration for flux is one of the overwhelming interpretive problems in science and in popular science. In both.

   27. PAPeter Attia1:04:37

       Yeah, one of my biggest pet peeves. So every quarter when I do one of these seven-day fasts, I get a lot of blood work done on myself throughout the process, and I get a real kick out of it because by the time you're five, six, seven days into water only, you start to look like there are things that if looked at in isolation look horrible. For example, your free fatty acids get into the diabetic range. So if you show that to somebody, they think, "Oh my God, you're, you're diabetic." And you're like, "Really? My insulin is unmeasurable. My glucose is 60 milligrams per deciliter. Yes, my FFA is two millimolar, but my BHB is, you know, seven or, you know, five millimolar." Isn't it possible that what you're seeing is an incredible turnover of lipolysis? And so, yeah, there's a lot of free fatty acid there, but it's in motion, it's in transit, versus what I think is probably happening in the person with high FFAs who's got diabetes, which is a much more stagnant form-

   28. CMChris Masterjohn1:05:34

       Right. Yeah

   29. PAPeter Attia1:05:35

       ... of elevated FFA. And so that's a muscle that's full of fat that's going nowhere versus the fasted person where that fat is being turned over very quickly.

   30. CMChris Masterjohn1:05:44

       And would you rather drink water out of a stream or out of a sitting pool with mosquitoes all over it?
9. 1:09:40 – 1:33:12

   NAD Precursors: How NR Is Handled by the Body

   1. PAPeter Attia1:09:40

      let's talk about the most sought-after, discussed, asked about supplement on the market today, which are NAD precursors.

   2. CMChris Masterjohn1:09:50

      Mm. [laughs]

   3. PAPeter Attia1:09:51

      I know, I know you've got some feelings on this. I have pretty, I have pretty strong feelings on this topic, too. I'm trying to think how we can frame this. So let's take a step back. Well, let's t- let me do this. For the listener who is contemplating whether or not they should turn the podcast off now or not, 'cause you've barely hung on to the biochemistry of choline and fatty liver disease, most people have heard of NR, nicotinamide riboside, NAD as the sort of fountain of youth. And if you've listened to other podcasts I've done, uh, specifically when I spoke with David Sinclair, we talked a lot about sirtuins and the necessity of NAD as a substrate to sirtuins. What many of you have also probably heard of is there are a couple of companies out there that are making a very popular supplement. One of them is called Elysium. They make a supplement called Basis. The other is called ChromaDex. They make a supplement, I think it's called Tru Niagen. If I... Am I right on that?

   4. CMChris Masterjohn1:10:47

      Yeah.

   5. PAPeter Attia1:10:48

      Yeah. I believe that Basis takes nicotinamide riboside, combines it with pterostilbene, which is a sirtuin activator, and that is their product. And my recollection is that the Tru Niagen folks are just giving nicotinamide riboside. I don't know if they have a sirtuin activator in there, but I could be wrong and it's probably not relevant-

   6. CMChris Masterjohn1:11:10

      They don't

   7. PAPeter Attia1:11:10

      ... unless you know the answer.

   8. CMChris Masterjohn1:11:11

      No.

   9. PAPeter Attia1:11:11

      Okay. All right. So the thinking goes as follows. We have this little thing in our cells called mitochondria and they have all these little complexes and these complexes are basically used to generate reducing agents that move electrons to one side of a double membrane and it builds up a gradient and then that gradient allows us to make a bunch of ATP and that whole process is called oxidative phosphorylation. The first of these complexes turns NAD into NADH and, uh-- or pardon me, NADH to NAD. So as the ra- as we age, it has been postulated and maybe even observed, although I don't know if it's been truly observed inside the mitochondria, maybe it has, that the ratio of NAD to NADH goes down. And if that's happening, then you have presumably less NAD. With NAD being an important substrate for sirtuins, which do many things, but primarily repair DNA damage, it would seem that we would want more NAD. Okay. That, is that-

   10. CMChris Masterjohn1:12:10

       You al- you also have NAD depletion because the sirtuins and the PARPs, which is the other class of enzymes that are using NAD for the purpose of protecting DNA and telomeres and, and all the things that are postulated to be important to aging and longevity, they consume the NAD molecule.

   11. PAPeter Attia1:12:25

       They're consuming the NAD. That's right. Yep, absolutely.

   12. CMChris Masterjohn1:12:28

       Which I think are two totally different things.

   13. PAPeter Attia1:12:30

       Correct. And there's another great example of it's hard to know why NAD levels might be low. Is it low because of high consumption and high demand or is it low because of low production?

   14. CMChris Masterjohn1:12:41

       Well, so if you have, if you're looking at the ratio of NAD to NADH, then I think that being in the overfed state is the thing that's the problem. If you're talking about NAD amount levels dropping, then you're looking at consumption by the PARPs and sirtuins that are consuming it for the purpose of repairing damage.

   15. PAPeter Attia1:13:01

       Of repair.

   16. CMChris Masterjohn1:13:01

       Yeah.

   17. PAPeter Attia1:13:01

       Yeah. So in an ideal world, if you could wave a magic wand, you would presumably want more NAD inside your mitochondria. Tell us why that magic wand doesn't exist.

   18. CMChris Masterjohn1:13:10

       It might-

   19. PAPeter Attia1:13:11

       Why can't you just eat NAD in layman words?

   20. CMChris Masterjohn1:13:13

       [laughs] I wouldn't say it doesn't exist, but it's questionable how powerful of a wand this is. So there's niacin in our d- these are all forms that, collectively, we call all this stuff niacin in the diet. It's vitamin B3. And in the foods that we eat, we primarily get niacin in the form of nicotinic acid from plant foods. We primarily get it in the form of nicotinamide from animal foods. Like, if we eat a steak, a lot of the niacin that's in the steak is gonna be in the form of NAD or NADPH that is in those cells, but, uh, all of that has to be digested, and what we're absorbing in the intestines is either nicotinic acid or nicotinamide. My guess is if you take a nicotinamide riboside supplement, you are absorbing the NR intact, and if you take a nicotinamide mononucleotide supplement, NMN, you are probably digesting that down to NR or nicotinamide and absorbing them. But we are definitely not absorbing NADH or NAD in the intestines. So when we're eating food, once we go into the enterocyte, we have nicotinic acid primarily being converted over to nicotinamide, and the intestinal cell tries to turn that into NAD. But whatever the intestinal cell doesn't turn into NAD itself, it passes on to the liver. So you're going through the portal vein. Now you have maybe some nicotinic acid left, depending on how much you ate. You have some nicotinamide in there. In theory, if you took a nicotinamide riboside supplement, you got some nicotinamide riboside in there. Then it goes into the liver, and the liver is the main site that's really metabolizing all these forms for the entire body. And what the liver is gonna do is it's gonna try to convert as much of those forms into NAD as possible, not even just for itself, but because it's gonna hold a reserve of NAD for the rest of the body. And then almost everything that comes out of the liver into the circulation is nicotinamide. So the overwhelming thing that gets niacin out of the liver to any other tissue is nicotinamide. That's the transport form. And then those tissues will convert that into NAD. So what we definitely don't see is we don't see NAD and NADH being transported in the blood. There's some there, but it's not a physiological transport way to get one-- something from one place to another. If you take a nicotinamide riboside supplement, you will get some nicotinamide riboside in the blood. Animal experiments suggest that there are trace amounts of that that will get into certain cells like muscle cells and be converted into NAD, but they're a physiologically meaningless amount of the NAD that wound up in that muscle cell from taking that supplement. Overwhelmingly, if you're talking about a tissue other than the liver, what's happening is that supplement gets converted into nicotinamide, reaches the other tissues as nicotinamide, and increases tissue AD, NAD by that tissue taking the nicotinamide and making the NAD.

   21. PAPeter Attia1:16:22

       But the first pass effect is pretty significant, right? So let's talk about-

   22. CMChris Masterjohn1:16:26

       First pass, the effect is basically complete.

   23. PAPeter Attia1:16:28

       We'll come back to NMN in a moment, but let's just talk about NR. NR becomes NMN, becomes NAD, I believe, in the cycle.

   24. CMChris Masterjohn1:16:37

       If you take it, NR, yeah.

   25. PAPeter Attia1:16:39

       Yeah. So if you take NR, which is the two most popular supplements on the market with respect to this, uh, particular pathway, the liver is basically, to your point, taking all of that NR and making NAD, correct?

   26. CMChris Masterjohn1:16:53

       Yes.

   27. PAPeter Attia1:16:55

       So do we have a sense of how much NAD actually makes its way into even the cytoplasm of a cell that is nonhepatic in that situation?

   28. CMChris Masterjohn1:17:05

       NAD that came from where?

   29. PAPeter Attia1:17:06

       That is derived ultimately from the NR that you ingested.

   30. CMChris Masterjohn1:17:09

       From the liver?
10. 1:33:12 – 1:50:00

    IV NAD, NMN, and Human NR Trials

    1. PAPeter Attia1:33:12

       So let's see if we can go deeper on that analogy. There are a lot of people out there who... I, in fact, I have a friend who came to me a year ago, and he said, "I've got the greatest idea. I'm gonna open up an IV NAD clinic, and we're gonna do NAD and ketamine." So we'll give you ketamine to get rid of your depression and NAD to make you live longer. And I said, "Well, I'm interested in the ketamine 'cause I do think that's a super interesting molecule for recalcitrant depression." At least a year ago, I said, "My understanding is giving intravenous NAD is not going to increase intracellular or certainly mitochondrial NAD, and I don't know that that makes sense." Though any-- I've, I've got many friends who have done IV NAD, and they all say the same thing. It's the worst feeling in the world.

    2. CMChris Masterjohn1:33:56

       Oh, I know why it's the worst feeling in the world.

    3. PAPeter Attia1:33:59

       Say why.

    4. CMChris Masterjohn1:34:00

       We need to come back and say, what is the role of free NAD that's found extracellularly?

    5. PAPeter Attia1:34:05

       Mm-hmm.

    6. CMChris Masterjohn1:34:06

       I can guess what the role is. What I can tell you is that one of the things it does is it activates granulocytes to cause vasodilation and a massively ramped up inflammatory response.

    7. PAPeter Attia1:34:17

       So not unlike niacin.

    8. CMChris Masterjohn1:34:19

       No, it's very different from niacin. So in-

    9. PAPeter Attia1:34:21

       But niacin has a very similar response, doesn't it, at very high levels?

    10. CMChris Masterjohn1:34:24

        Well, yeah, but biochemically, what's happening is totally different.

    11. PAPeter Attia1:34:26

        Oh, it is?

    12. CMChris Masterjohn1:34:27

        So-

    13. PAPeter Attia1:34:27

        Okay

    14. CMChris Masterjohn1:34:27

        ... yeah. So-

    15. PAPeter Attia1:34:27

        So why is niacin causing a flush? So it's not the same as NAD's flush.

    16. CMChris Masterjohn1:34:31

        So nicotinic acid is, specifically nicotinic acid activates the nicotinic acid receptor, and that is present on a bunch of immune cells that are responsible for the flushing response.

    17. PAPeter Attia1:34:46

        But not necessarily granulocytes.

    18. CMChris Masterjohn1:34:48

        It's... Yeah, the, so NAD is acting on-- It's a different receptor, and, uh, you know, I don't know. Maybe it's, maybe it's more s- it might be more similar than I was leading on. It's a different receptor, but maybe the results are sim- I've never injected-- I've never had the flushing response, and I've never injected NAD. It probably is fair to say that they're similar in their results and that there are some similarities biochemically, but it's not the same biochemical m- mechanism.

    19. PAPeter Attia1:35:14

        So if you do inject this NAD, what is it? Now you've bypassed the liver, and it's sitting there in the plasma.

    20. CMChris Masterjohn1:35:22

        What's clearly happening based on the anecdotal reports of the immediate response to that is that they're, that they are causing an inflammatory response. What is not clear is the kinetics of where that NAD is going.

    21. PAPeter Attia1:35:35

        Right.

    22. CMChris Masterjohn1:35:35

        But there's, there is definitely papers that I was able to find showing that there are a variety s- of mammalian cell types that do have the ability to take that NAD into the cells. But I look at this from the perspective of what is the normal physiology? I don't, I don't really wanna know what can happen. First, I wanna know what's supposed to happen.

    23. PAPeter Attia1:35:55

        Mm-hmm.

    24. CMChris Masterjohn1:35:55

        Then I'll build a theory about what I should do based on that, right? For people who are not injecting it, how does NAD get out of the cell in the first place? Well, the details aren't worked out, but it appears to be that NAD, extracellular NAD is from dead cells, from dying cells, and maybe from cells that are undergoing some sort of stress response and are secreting it to some degree to reflect their energy status.

    25. PAPeter Attia1:36:20

        You mean as a signal?

    26. CMChris Masterjohn1:36:22

        As a signal.

    27. PAPeter Attia1:36:22

        Interesting.

    28. CMChris Masterjohn1:36:23

        Oh, it, yeah, I think it's very clear-

    29. PAPeter Attia1:36:24

        You think it can be a signaling molecule as well?

    30. CMChris Masterjohn1:36:27

        I think it's very clear that there, if there is any role for extracellular NAD, it is as a signaling molecule, and I think it's almost certain that there is a role for extracellular NAD as a signaling molecule because there are fairly decently characterized enzymes that consume NAD that are found extracellularly. There's a whole class of extracellular NAD-consuming enzymes. So if NAD's not ever supposed to be outside of the cell, why would it be there? And it's like, well, what do those enzymes do? They break it down to use it as a signaling molecule. So it's gotta have a, it's, it has to be the case that extracellular NAD is primarily a signaling function. And so it's definitely not a normal way of transporting NAD from tissue to tissue. What the signal means, I think, will probably be debated if enough people care for a long time to come, so I have no idea exactly how to simplify and state what it means, but it's very clear that it's a signaling molecule. So when I look at NAD injection, I'm like, my idea is I'm gonna transport this thing, and that's definitely not the way you transport that thing. And my body's idea is that that's a signal that means something about what's happening that is definitely not happening when I-
11. 1:50:00 – 2:04:35

    MTHFR, Homocysteine and the Methylation Cycle

    1. PAPeter Attia1:50:00

       Let's talk about that five-letter acronym that pretty much everybody's heard of by now, but nobody really knows what the heck it is. What is an MTHFR gene and what is an MTHFR mutation, and should anyone care?

    2. CMChris Masterjohn1:50:14

       All right.

    3. PAPeter Attia1:50:15

       [laughs]

    4. CMChris Masterjohn1:50:15

       So as we had said before, a methyl group is a one-carbon unit, and the methylation cycle uses the amino acid methionine to donate that one carbon to dozens of different things. So what we do there is we activate methionine to S-adenosylmethionine using ATP, and S-adenosylmethionine is the universal methyl donor. So no matter what we're talking about synthesizing, what we're talking about regulating, it is always S-adenosylmethionine that donates that one carbon, that methyl group. It becomes ... Through two steps, it becomes homocysteine, which is the inevitable byproduct of using it. And once we have homocysteine, we have two choices. We can either get rid of the homocysteine if we have an abundance of methyl groups, or if we don't have enough methyl groups, we will recycle the homocysteine back to methionine. There's two ways to do that. One is that folate, which is vitamin B9, can take a methyl group from amino acid metabolism and can pass it on to B12. B12 passes it on to homocysteine. Homocysteine regenerates methionine. Or choline can be oxidized to betaine, which can be then the methyl donor to recycle homocysteine to methionine. Those two pathways are equivalent. In the average person, they're probably 50/50, but it's gonna depend on their dietary intake. To your question about MTHFR, the MTHFR enzyme is one of the enzymes that is involved in constructing the methyl group that came from amino acid metabolism that went onto the folate molecule, and that's how folate passed the methyl group on to B12 and then on to homocysteine to recycle methionine. There's a lot of people going around saying, "I have MTHFR." Well, we all have M-

    5. PAPeter Attia1:52:12

       [laughs]

    6. CMChris Masterjohn1:52:12

       We all have MTHFR.

    7. PAPeter Attia1:52:14

       I have ATP.

    8. CMChris Masterjohn1:52:15

       [laughs] Exactly. It's not just misleading because we all have MTHFR. It's also misleading because there's actually ... I- if you look at the two common polymorphisms, which are gene variants in the MTHFR gene, they are s- so spread out in the population that what you actually see is a gradient of MTHFR activity that's fairly even spread across the population. So you could basically divide the population into quintiles of MTHFR activity and you'd see it wouldn't be exactly 20/20/20/20/20, but it would be fairly close to that. So if you have limited ability to use folate for methylation, there are several things happen, that happen. The first is that you use up more choline, and y- you do that because you suck at using folate and you have no problem using choline. So you basically say, "I, I'm not that good at using this pathway. I'm gonna use the alternative." And that, nutritionally, that makes the choline requirement go up. At the very beginning of this podcast, I said that I'd seen some studies where some people need 1,200 milligrams of choline. That's the people with the worst MTHFR activity. What happens is there were two different populations that were studied, and exactly what happened to their choline metabolism was different in each population. But the commonality was-

    9. PAPeter Attia1:53:31

       And the worst function is, remind me, it's ACCC, which ... or TT- TTCC? Which SNPs would be the, quote-unquote, "worst"?

    10. CMChris Masterjohn1:53:39

        The worst case for MTHFR is the C677T homozygous.

    11. PAPeter Attia1:53:45

        Homozygous A or-

    12. CMChris Masterjohn1:53:47

        Homozygous for, for T instead of C.

    13. PAPeter Attia1:53:50

        Yeah, yeah, yeah.

    14. CMChris Masterjohn1:53:50

        Yeah.

    15. PAPeter Attia1:53:50

        So it's the TT and then on the A1298C, it's like the-

    16. CMChris Masterjohn1:53:56

        For the, yeah, for the A1298C, that one is less significant than the C- C677T, but you can have both of them. So in the, in the best case, you have neither of them. That's, like, 10% or 15% of the population. But the next step up to have a, a little hit is to have-

    17. PAPeter Attia1:54:13

        You're basically a CA or a CT and you're functionally pretty close to normal t- I, I like the way-

    18. CMChris Masterjohn1:54:19

        Yeah

    19. PAPeter Attia1:54:19

        ... you described it actually, which is think of it in quintiles.

    20. CMChris Masterjohn1:54:22

        Yeah.

    21. PAPeter Attia1:54:23

        And, and I would even say it's less than quintiles because to your point, in my experience, I only see maybe 10% of people that are wild type in both. That's pretty freaking rare. I mean, I would be surprised if it's 10.

    22. CMChris Masterjohn1:54:36

        No, that's exactly what it is. Yeah.

    23. PAPeter Attia1:54:36

        I would be surprised if it's 10%.

    24. CMChris Masterjohn1:54:38

        No, it's not ... Right, it's not exactly q- quintiles.

    25. PAPeter Attia1:54:40

        Yeah.

    26. CMChris Masterjohn1:54:40

        But it depends, it depends what population you look at, too. It's gonna vary, but it's, you know, it's basically there's, there's a little bit in each category-

    27. PAPeter Attia1:54:47

        Yeah, yeah, yeah

    28. CMChris Masterjohn1:54:47

        ... and there's not a category that has, that even has a large minority of the people in it.

    29. PAPeter Attia1:54:52

        That's right. It's not, it's not even like ApoE where you can say, well, the 2/2s are basically unheard of and the 3/3s are the wild type.

    30. CMChris Masterjohn1:54:58

        Yeah, there's no one that's unheard of. [laughs]
12. 2:04:35 – 2:10:31

    COMT, Dopamine and Warrior vs. Worrier

    1. PAPeter Attia2:04:35

       So where does COMT fit into all of this? Because it's another enzyme, it's involved in the catabolism of catecholamines. Talk a little bit about that.

    2. CMChris Masterjohn2:04:47

       So part of moving beyond homocysteine, one whole side of this equation is what are you methylating, right? Because homocysteine's a byproduct of the methylation cycle. What you're methylating is 90% of it is to synthesize creatine and to synthesize phosphatidylcholine, and then the other 10% is a gradient of a handful of things that are fairly sensitive to methyl group supply and a h- lot of things that aren't. If you look at the next most sensitive thing to creatine synthesis, it's dopamine, and COMT is the enzyme that methylates dopamine. Basically, what it does is it modifies dopamine metabolism in a way where if you methylate more dopamine, you are mentally more flexible, and if you methylate less dopamine, you are mentally more stable. And if you're in the middle of that, it could just be a variation of your personality, but as you start to get to the ends of that spectrum, you start to get into the possibility of psychiatric disorders that could be a result of being in the extremes. But in the middle of that spectrum, they talk about the warrior phenotype and the worrier phenotype. So the person who's the warrior, W-A-R, is the person who has a higher rate of methylating dopamine, is more mentally flexible, and that's the person that picks the battle, faces it, picks the battle, faces it, defeats, and just moves from one thing to the next. The worrier gets stuck on things that they're worrying about. But you look at just like MTHFR activity, you look at COMT activity, and it's a perfect spread. There aren't as many different types. It's basically like 50% of people are in the middle, 25% are on one end, 25% are on the other end. Why is it spread like that? Because there's a trade-off. And so I think the w- worrier/warrior phenotype is a bad way to talk about it because actually the people with the so-called worriers, the so-called people who worry, uh, they all-

    3. PAPeter Attia2:06:45

       W-O

    4. CMChris Masterjohn2:06:46

       W-O, yeah. It's [laughs] it's hard to pronounce that exactly right. So the people who have a low rate of, of methylation, they're also better at doing a lot of things that require sustained focus, so better a- academics. There was a recent study that came out that showed that competitive swimmers who are the low methylation phenotype get better results. They appear to do better competitively. And there was another study in elderly people that found that if you do a, an exercise intervention, the people with the low COMT phenotype are more likely to do more exercise because you told them to. So these are people where things get stuck in their mind, and things getting stuck in your mind is great if it's the right thing, you know? So you are predisposed to worry more because if you get an anxiety-producing thought or a depression-inducing thought in your mind, it gets stuck there more. But also, if you're gonna focus on work that needs to be done, if you're gonna focus on goals, you m- might be better at that because you've put the right thing in your mind and y- and you had a better ability to make it stick there.

    5. PAPeter Attia2:07:51

       Is the other group, the warrior group, more susceptible to addiction?

    6. CMChris Masterjohn2:07:56

       Yeah, so if you look at the associations of the genotypes with different psychiatric diseases The ones that are most clearly related to impulsivity or getting stuck on stuff are the ones that seem to be most consistently correlated. So obsessive compulsive disorder is associated with a low methylation phenotype, whereas substance abuse and ADHD are associated with a high methylation phenotype. Then when you start looking at other psychiatric disorders, you start to get into a lot of noisy data when you look at depression and anxiety and panic disorder and things like that.

    7. PAPeter Attia2:08:36

       But just taking the extremes, how strong are those hazard ratios?

    8. CMChris Masterjohn2:08:40

       Off the top of my head, I don't know.

    9. PAPeter Attia2:08:42

       Directionally, are they real-- are they meaningful? Are we talking about hazard ratios of four and five, or are we talking about, like, 1.17s?

    10. CMChris Masterjohn2:08:48

        I genuinely don't remember. I can put a meta-analysis of this in the show notes that I have.

    11. PAPeter Attia2:08:53

        Okay.

    12. CMChris Masterjohn2:08:53

        But I don't remember the data.

    13. PAPeter Attia2:08:53

        That would be great. I mean, 'cause this is one of those things that only, only once have I ever been asked about this, and I didn't know the answer, of course, but one of my patients asked me to go back and look through his genetic data to look at which SNPs he had for COMT specifically because of this question.

    14. CMChris Masterjohn2:09:12

        Oh, yeah, I don't think it has much diagnostic utility. I find it interesting from creating a theoretical model of how this stuff works. And I think part of the reason some of the data's so noisy about th- like, let's say things in the middle like depression and anxiety, which they do correlate, and there are studies that show it o- one way, but it's just very noisy data. I think part of the reason it's so noisy is that it's not really about the genetics. Like, you see really strong associations with genetics when you have a monogenic disease.

    15. PAPeter Attia2:09:42

        Of which there's like 73, right?

    16. CMChris Masterjohn2:09:44

        Right. There-- Like, yeah.

    17. PAPeter Attia2:09:44

        I mean, it's virtually none.

    18. CMChris Masterjohn2:09:45

        It's not the norm, right? When you're talking about this, it's like COMT is not a gene for a mental state.

    19. PAPeter Attia2:09:51

        Right.

    20. CMChris Masterjohn2:09:51

        It's a gene that has a partial influence on the stickiness of your mind. [chuckles] And the way that COMT methylates dopamine is with all the methyl donors, so nutrition is gonna play directly into that. And so s- your COMT genotype isn't even going to tell you the rate at which you're methylating dopamine. It's gonna tell you the rate at which you could methylate dopamine given a certain supply of methyl donors.

    21. PAPeter Attia2:10:15

        You've put a lot of time into this, Chris, and, and we'll make sure we link to this, but you've basically done probably a better job than anyone I know of at codifying the, if you have this mutation, this would be a great dietary strategy. It would take us another 12 hours to go through all of them.

    22. CMChris Masterjohn2:10:30

        [chuckles]

13. 2:10:31 – 2:23:55

    Dietary Strategies: Choline, Creatine and Glycine

    1. PAPeter Attia2:10:31

       Let's touch on three of them. You pick, but it seems to me that the COMT MTHFR would be an interesting one to at least start with.

    2. CMChris Masterjohn2:10:37

       Sure. So MTHFR, I think what you want to do is, number one, you want to get between 900 and 1200 milligrams of choline a day. That is the nutrient-

    3. PAPeter Attia2:10:46

       And your preference, clearly, sorry to interrupt-

    4. CMChris Masterjohn2:10:48

       Phosphatidylcholine

    5. PAPeter Attia2:10:48

       ... but get it from your food.

    6. CMChris Masterjohn2:10:49

       Get it from food.

    7. PAPeter Attia2:10:50

       Like, if you can eat enough eggs and-

    8. CMChris Masterjohn2:10:51

       Yep

    9. PAPeter Attia2:10:52

       ... you know. Okay.

    10. CMChris Masterjohn2:10:52

        Yeah. So there's that, and that is, that has the most data backing it out of everything else that I'm gonna say. But supplementation with creatine makes a lot of sense because 45% of your methyl demand is to synthesize creatine.

    11. PAPeter Attia2:11:07

        And just to put this in perspective for the listener, when people think creatine, these days we think about creatine monohydrate versus creatine phosphate, which used to be the sub- the supplement-

    12. CMChris Masterjohn2:11:17

        Creatine monohydrate.

    13. PAPeter Attia2:11:17

        Right. So creatine monohydrate is something that most people take for exercise. They take about five grams a day. Back when I was in high school, we used to load it. We would take 20 grams a day for five days, then five grams, and we'd cycle on and off. You're probably not old enough to have been in that meathead phase. But the most recent literature I s-

    14. CMChris Masterjohn2:11:36

        No, I did that.

    15. PAPeter Attia2:11:36

        You [laughs] ...

    16. CMChris Masterjohn2:11:38

        [laughs]

    17. PAPeter Attia2:11:39

        The tradition lived on.

    18. CMChris Masterjohn2:11:40

        It's still on the label.

    19. PAPeter Attia2:11:42

        Is it really?

    20. CMChris Masterjohn2:11:42

        Yeah.

    21. PAPeter Attia2:11:43

        Although the most recent literature I've seen said just monohydrate five grams a day is plenty. But again, for most people, we think of that as creatine is a phosphate donor, and in certain types of exercise, i.e. the most high intensity, so weight training, for example-

    22. CMChris Masterjohn2:12:00

        Yep

    23. PAPeter Attia2:12:00

        ... that burst is really a phosphate donation from creatine. It's not an ATP driven process. I actually wasn't really aware of the role of choline in synthesizing creatine.

    24. CMChris Masterjohn2:12:14

        It's a role of methylation in synthesizing creatine. And so that whole cycle, whether you're taking the methyl groups from choline or you're taking the methyl groups from folate, what you do when you synthesize creatine is you start with guanidinoacetate, which you make from the protein in your diet, and then you methylate it, and that makes creatine. So literally, creatine is the only thing that is super sensitive to the methyl group supply. So you ate that steak, you synthesized creatine. Five hours later, you're synthesizing nowhere near as much creatine, and the whole s- the whole system is designed-

    25. PAPeter Attia2:12:46

        So creatine tracks much more closely to, say, methionine than leucine.

    26. CMChris Masterjohn2:12:51

        Yeah, because the rationale is that some things are so essential to the body that you don't want them to ever change with the methyl group supply. So DNA methylation for gene expression, you don't want to regulate thousands of genes because you ate a steak and you had a bunch of extra methyl groups. You want to control that for totally different reasons. So that's designed to almost never change. Then there are other things that have to be fairly acutely stable, like your dopamine and other neurotransmitters. You don't want that to go up meth-

    27. PAPeter Attia2:13:27

        Yeah, log fold

    28. CMChris Masterjohn2:13:28

        ... twice as much because you ate, right? But your creatine, you-- average person has 120 grams of creatine in their body, and they lose two grams of creatine every day in the form of creatinine that, that they pee out in their urine. And so the whole point of creatine synthesis is to keep the accounts balanced. So if you synthesized no creatine in-- for a, an entire day, your creatine in your body is going from 120 grams to 118 grams. It's, like, barely a dent. So creatine is the ideal thing to vary with the methyl group supply because you can eat a steak, you can do all your creatine synthesis when you were, when you had enough methyl groups, then five hours later, you're in the fasted state And you, you don't synthesize creatine anymore. Doesn't matter 'cause it's not a neurotransmitter. It's not doing an acute thing. You just have to make sure that in 60 days from now, your creatine isn't zero. It's still 120 grams in your body

    29. PAPeter Attia2:14:20

        What determines the phosphorylation status of creatine? Of that 120 grams, how much of it has an inorganic phosphate-

    30. CMChris Masterjohn2:14:26

        Oh, that's completely unrelated from the synthesis. That's a matter of the energy state of the cell. So just like ATP gets used when you use energy, creatine phosphate in, when you're... So instead of kinase-
14. 2:23:55 – 2:43:20

    NR Methyl Drain, Personal Use and Evidence Standards

    1. CMChris Masterjohn2:23:55

       Right. So, so in the studies done by Brenner, what we do know is that an enormous amount of this NR is getting methylated as nicotinamide. I don't think it's possible to extract the data from those papers and say exactly how much, because they're in concentrations, and when they're in urine, they're not in a 24-hour collection, they're in spot urine.

    2. PAPeter Attia2:24:19

       Right.

    3. CMChris Masterjohn2:24:19

       I don't know exactly, like, what the up and down flux is over time. But what I can say is that just as a rough calculation to get a sense of how much impact you could have if the impact were maximal, for every thousand milligrams of nicotinamide that you detoxify, you are, in theory, decreasing your synthesis of creatine by 500 milligrams. So you're synthesizing two grams of creatine in a day. So if you're taking 2,000 milligrams of nicotinamide riboside, if all of it were detoxified, you'd be cutting your creatine synthesis in half. Or-

    4. PAPeter Attia2:24:57

       But in theory, I mean, that means that you're going from 120 to 116 instead of 118, right, in a day?

    5. CMChris Masterjohn2:25:03

       You're talking about whole body creatine stores. I'm talking about synthesis.

    6. PAPeter Attia2:25:06

       You're talking about at the cellular level, too.

    7. CMChris Masterjohn2:25:09

       First of all, no one's taking this for a day. They're taking it every day if they're taking it, right?

    8. PAPeter Attia2:25:13

       Yeah.

    9. CMChris Masterjohn2:25:13

       And you don't need your creatine to go to zero before you have problems.

    10. PAPeter Attia2:25:17

        Yeah. Yeah, exactly.

    11. CMChris Masterjohn2:25:17

        Right? Like, the bodybuilders and the athletes are taking creatine because they're hoping to maybe increase their body stores by about 30%. So just leveraging a little bit marginal increased creatine makes big results in your strength. We should clarify that although 90% of creatine is in your muscles, and although the most famous reason to take creatine is to support your exercise performance, it's also been shown that five grams of creatine a day improves depression in women with major depressive disorder. And if you just look at the physiology of creatine, for God's sake, you're using it to make your sperm swim, and you're using it to pump s- acid into your stomach. So creatine is important in all kinds of areas that you would not expect to think about it in.

    12. PAPeter Attia2:26:04

        So if one was gonna take creatine, which I probably haven't taken since 'Nam, you wouldn't just take it during exercise. Like, if you wouldn't just take it on the days that you were lifting weights, you, which let's say you were doing that three or four times a week. You would presumably want to take it daily, take that five grams daily, correct?

    13. CMChris Masterjohn2:26:20

        Yeah. I mean, I think on the whole, although you could say that it might be better if you take it after exercise with a carbohydrate bolus, it might be better if you split it up into two doses, on the whole, if you just take it every day and you take five grams a day and you just always do that, you're eventually going to get to the thir-

    14. PAPeter Attia2:26:37

        Yeah, you'll hit that steady state

    15. CMChris Masterjohn2:26:38

        ... you're gonna hit... Yeah, exactly. Yeah, it's something to take daily if you're doing that, but let's steer away from the person who doesn't care at all about creatine supplementation. They're not even thinking of that. What I'm thinking about is what would you wanna do in an NR study to show that you're not impacting methylation? So I expect that sometime rather soon we're gonna see a paper coming out showing that it doesn't elevate homocysteine and showing that it doesn't affect the S-adenosylmethionine in plasma. And, uh, it's not... My position is not that this stuff is really dangerous. That's not my position at all. However, I've been exposed to anecdotes of people who are taking this who experience things that were really seesawing in their energy levels and were really seesawing in their mental and emotional states that are anecdotes that could be explained by a thousand other things, but to me make it sound like, geez, this thing is really sapping the methyl group supply. It's exactly what I would expect to happen in someone whose methyl group supply was being sapped.

    16. PAPeter Attia2:27:43

        And would that person be better off supplementing with choline or creatine if they were going to pick?

    17. CMChris Masterjohn2:27:51

        I would say take a lower dose of this stuff and match it with a methyl donor. In th... Yeah, in theory you could do creatine. You'd have to test it, right? But my recommendation... I actually put out the recommendation, I made a video about this. I said-

    18. PAPeter Attia2:28:06

        We'll link to it

    19. CMChris Masterjohn2:28:06

        ... I said match it milligram for milligram with TMG, trimethylglycine.

    20. PAPeter Attia2:28:11

        Oh, that reminds me. I want to tell you about this anecdote. So we've got a patient who you just couldn't get his homocysteine to budge. So on our lab scale, below, like, nine or less is what would be normal. He's in the 13, 14, 15 region. On your standard dose of methylfolate, methyl B12, nothing. Even doubling it, which always makes me a little uncomfortable, nothing. Adding, you know, 50 milligrams of B6 three times a week, which strikes me as overkill, nothing. Going to B6 50 milligrams daily, nothing. Add TMG, boom.

    21. CMChris Masterjohn2:28:44

        Yeah. [laughs]

    22. PAPeter Attia2:28:45

        Homocysteine falls by 50%. What was going on in this guy?

    23. CMChris Masterjohn2:28:49

        Okay. So the fact that you added B6 and it did nothing indicates one of two things. Either that guy's enzyme for getting rid of the homocysteine didn't work that well, or more probably, this was not a fed state homocysteine issue, right? So the way these things work is you're trying to use MTHFR or choline to remethylate homocysteine when you're in the fasted state and you don't have a lot of methionine coming in. You stop doing that entirely, and you start trying to break down the homocysteine, get rid of it when you're in the fed state. So we don't know the flux. We didn't have the video. We just had the s- a bunch of snapshots of this-

    24. PAPeter Attia2:29:24

        Yeah

    25. CMChris Masterjohn2:29:24

        ... guy's homocysteine. My guess is that unlike the guy whose homocysteine went down with the B6, this guy, he had a recycling issue. He did not have a problem of disposing of the homocysteine in the fed state. He had a problem of recycling in the fasted state. He just couldn't do it, and he couldn't do it because his MTHFR just didn't work very well. And so only when you added the trimethylglycine, which is the choline pathway. So when you use choline for methylation, what you do is you convert it into trimethylglycine, and that becomes the methyl donor that's the alternative.

    26. PAPeter Attia2:29:56

        I mean, it makes me wonder now if we'd just supplemented more choline if we could've got the same result.

    27. CMChris Masterjohn2:30:00

        Yeah, I'm sure you could've gotten the same result. The only, the only possibility that would prevent that would be if he had a problem with the enzyme that oxidizes choline-

    28. PAPeter Attia2:30:09

        Mm-hmm

    29. CMChris Masterjohn2:30:09

        ... to trimethylglycine.

    30. PAPeter Attia2:30:10

        I like that it all comes back to choline. We, we have four chickens at home, and my kids named them, so they have the funniest names. The two of them have pretty normal names. There's, there's Sarah is one of them, and Bang Bang-

Episode duration: 2:51:59