The Peter Attia Drive - #46 - Chris Masterjohn, Ph.D.: Navigating the many pathways to health and disease - NAD and sirtuins, methylation, MTHFR and COMT, choline deficiency and NAFLD, TMAO, creatine, and more

Episode Date: March 25, 2019

In this episode, Chris Masterjohn, entrepreneur, independent researcher, and doctorate in nutrition, elucidates the latest research on the risk and benefits of NAD supplements, and shares his personal intuition on the topic. We also dive deep into choline deficiency and its role in the rising prevalence of nonalcoholic fatty liver disease. From there, Chris enlightens us on the importance of methylation, a simple yet profoundly important biochemical process affecting our physical and mental health. He also describes the variations of the genes MTHFR and COMT, enzymes which play important roles in methylation and which have profound impacts on our well-being.   We discuss: Chris’s background, falling in love with biochemistry, and decision to pursue research over medicine [7:45]; Choline: what it is, why it is important, and how a deficiency can cause non-alcoholic fatty liver disease [11:45]; NAFLD: increasing prevalence and potential causes [25:00]; TMAO: Should we be worried about the TMAO content in choline and our foods? [39:15]; Types of fatty acids: How they may predispose us to different types of illnesses [53:30]; Why don’t we see low VLDL in patients with NAFLD? [59:45]; Understanding flux, and how machine learning may affect medicine in the near future [1:03:15]; NAD: How it works, supplements, sirtuins, and the central role of the liver [1:09:30]; Intravenous NAD [1:33:00]; Oral NR: Is it the optimal way to get more NAD? [1:38:30]; What is the possible harm of taking an NAD precursor? [1:47:15]; The MTHFR gene [1:49:45]; The methylation pathway [1:58:15]; The COMT gene [2:04:30]; Creatine: The uses and benefits and its important role in methylation [2:10:15]; Dietary strategies for MTHFR: choline, creatine, folate, and glycine [2:16:45]; How to mitigate the negative effects of NAD supplements [2:23:45]; A case study of a person with high homocysteine [2:28:00]; What is the level of evidence that you need to take action? [2:32:15]; Does Chris supplement with NAD precursors? And can it improve symptoms of rosacea? [2:35:45]; Decision making in the face of inconclusive data, and trying to disentangle the placebo effect [2:39:00]; What does Chris believe to be true that very few people would agree with him about? [2:43:15]; How to follow Chris’s work [2:48:45]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. 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 peteratia-md.com. [♪ OUTRO MUSIC PLAYING [♪ 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 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 could 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 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 guess 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 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 PhD 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 do we talk about? Well, we talk about a ton of stuff. We kick this episode off by going deep on co-ling. Co-ling 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, so two inactivators, 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 Chromodex's true niogen. 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. Hey Chris, thanks for trekking in, man.

Thanks for having me, Peter. It's good to be here. Yeah, so you said you've moved. You're no longer in Brooklyn, right? I moved to Astoria, so pretty close by. Yeah. It was probably a quicker trek here from Astoria than Brooklyn, I think. Yeah, it just has less cache, right?

Like Brooklyn is so cool. Well, yeah, maybe I would have wanted to spend more time in Brooklyn, but just geographically a story is more in the edge. Yeah, it's a heck of a lot of history. Closer to the river. Yeah, yeah. And where'd you grow up? So I was born in Queens, actually.

I kind of came full circle back, but when I was 10 months old, my family moved to 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 impressive. So not framing him? No, no. About an hour and a half west of framing him. And no accent. Yeah.

You can do it on demand. Wait, just too far away from Boston. Yeah. Got it. And what did you study in college? I know you're I will talk about your PhD because it's so interesting, but what did you study in college? I in my undergrad I studied history. Okay. I focused on completely irrelevant things to medicine nutrition like medieval church history and early American revolutionary history. I history and early American revolutionary history. I originally wanted to be a social studies teacher and so 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 at doing, but in order to go to medical school, I had to take years worth of undergrad science classes to get the basic pre-rex. 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 kind of combined to make me decide to go into research 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. Yeah, and it's funny, you know, I think I've said this before maybe on the podcast, but if I haven't, I've, I've, I've, I've said it elsewhere. I always think the worst thing you can do is do an undergrad what you're necessarily going to do in graduate school. So if you're going to 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 similarly, when you're doing your PhD, I mean, sometimes you don't have a choice. 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 is pretty interesting in that regard. And I suspect you're, when some ways better off for having done something totally different, if nothing else it gave you, I suspect kind of a fresh enthusiasm for what you were studying in graduate school. Yeah, I think for sure. And I also think to some degree, I actually bring my history

in mind with me. So I think one of the things 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 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 only look at what's been done over the last 10 or 20 years. You know, 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 realized 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 these notes are going to kind of keep me honest because they're going to at least remind me of major themes. I've used different fonts and highlighted things in a way. 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 Colleen.

And I think the context in which it came up was when a paper came out of Cleveland Clinic, I believe it was Stan Hayeson'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 going to get atherosclerosis and diets that are high in colon are predisposing to this. And I remember you, me, Stefan Guy and a Chris Cresser, we were talking a lot about this because certainly at the time something didn't make sense to.

We first encountered each other, right? Yeah, I don't know if it was the first time, but it was certainly early on. Yeah, the first really email discussion. 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 colon-laced sport strings. So let's go back in time to that whole thing. So let's start with what is colean? Colean, you could look at it from a health perspective or a chemical perspective. Yeah, let's start chemically. Let's just say, yeah, what? So, colean is a methyl donor. Colean

is an essential part of acetyl colean, which is a neurotransmitter. And colean is an essential part of phosphatidyl colean, which is a phospholipid that is in our cell membranes. 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 going to come back to these terms so often, what's methyl? What is a methyl group? Okay, so I think the easiest and simplest way to think of a methyl group 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 going to have to put together carbons or take them apart. And you can either put together carbons in two carbon units called the cedal 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 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. Right. So we use the term methylation as a verb to say to put on a methyl group, right? Right. And in fact, the methylation is also called the one carbon metabolism. So a methyl group and a one carbon is identical. Okay, so we've got this idea of Colleen plays an important role in regulating how that whole methylation thing works.

Colleen is relatively abundant in certain things that we eat, right? Yeah, if you look at the diet, you see enormous amounts of Colleen and liver and egg yolks, and then you see moderate amounts of colon in many other foods. Most of those foods that are pretty good sources of colon, but not awesome sources of colon are meats, nuts, and low carbohydrate low calorie vegetables, especially cruciferous vegetables. And in fact, we did not know for the longest time that colonn was an essential nutrient

in humans, and still they started feeding people on total parental nutrition. And they weren't putting colonn in because- And I'll explain to folks what that is. So total parental 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 going to go with this is, when you're feeding someone with total parental nutrition, you have 100% control over what they're consuming. And I know where the story is going. It's so interesting. It can really expose deficiencies that we take for granted. That 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. So what happened with the Colleen deficient TPN folks? Those folks developed fatty liver,

which is very counterintuitive, right? In the sense that they probably weren't being mainlined a lot of fat, right? Right, but it turns out that because Colleen is an essential part of the phospholipid, phosphatidyl Colleen, 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 colon, you can't make the VLVL 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. First and foremost. Right. So if colon 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

colean 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 where 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 triglystides out of the liver. So that's interesting. I mean, it'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 and talking about. I'm so sick of talking about the fact that I'm in the middle of 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 naffledy, Nash, insulin resistance, and type two 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 an Apple D 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. He's just mainlining Coke. This is back in the 50s. 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 person, let's just make it clinical, take a person who has non-alcoholic fatty liver disease, and we'll talk a little bit more about that in a second. But with enough co-lean, 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. that are predisposing to more fat accumulating in the liver than exiting the liver? 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 colon out of their diet, 9 out of 10 of them will develop fatty liver disease. 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? In those days you're looking at short-term development of statoosis, which is just 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 all that kindling would 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 statoidosis necessarily leads to stato hepatitis, but that you can't develop stato hepatitis without statoidosis, 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 out there who doesn't have fatty liver, they don't have fatty liver because of the colon and their diet. 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. Well, it's both. But what I'm saying is in the studies that were done,

I believe this was Steven Ziesel's group, who's one of the main Colleen guys, they just took people 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 Colleen out of 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-coling 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 coline or you put in things that can be precursors to coline and any of them at a high enough ratio with the other things that

are producing the fat and liver, we'll get rid of the fatty liver. So if we know in humans that you get fatty liver when you take the colon down and we know in animals that you get rid of fatty liver, if you put the colon up, then I would think that if you took the humans with the fatty liver and you put the colon up, you'd get rid of it.

But for some reason, that hasn't been tested the way you'd think it would be. Do you have a sense of how much colon 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 coline 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 coline, or would you actually need to supplement it? I can only give you a wild guess. And my wild guess would be about 1200 milligrams of coline. and you could get that by eating food, but it would be very difficult. So how many milligrams of Colleen in an egg? 130. You don't know how many eggs I eat.

How many eggs do you eat? No, well, I have chickens, so I have four this morning. Yeah, yeah, I could easily eat six eggs a day. You can do it, but it's hard, and you'd have to design the diet to do that, right? I'm basing on a couple of things. One is there are human studies where it has been shown that some people require 1200 milligrams of colon a day.

And those studies are not looking at liver fat, they're looking at other markers, but people who have a genetic pre-susposition to need what we know is the highest colon requirement that a human can have is about 1200 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 Stéato Hepatitis, they have information 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 colon is higher, I think the average colon intake is probably somewhere around 300 milligrams. What's the RDA for colon? It depends on men and women. 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. You know, the funny thing 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 underdiagnosed. In the book, I'm actually writing about sort of the first patient I saw that likely had it. And it was 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 fat and 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, talk, I don't drink anything. And I sort of forgot about the whole thing until 10 years later when I realized, oh my God, that was Nafoldi. What year was that? 2001. So in 1980, the myoclinic published a paper in which they coined the term Nash, which came before Nafoldi.

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. Right, 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 lot of alcohol. Now, Ron Bucetile, who 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, and this is probably about four years ago, you know, in the year 2000, something like 1% of liver transplants were being done for Nafoldi,

Nafoldi predisposed. Nobody needs a liver transplant if they have Nafoldi, but if you get Nafoldi, Nash, and Serosis, you do need a transplant. And that amounted to 1%. And I think about 13, 2014, he predicted that Nafoldi, Nash, he predicted that Natholde 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 Natholde, and of course, the success of treatment for both HEPI and HEPC. 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 are over diagnosing it today, or seeing it more than it was there before, it seems hard to deny that Natholdy is more prevalent now than 20 or 30 years ago. Would

you agree with that? 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. So do you believe that it is more driven by a fat accumulation in the liver problem or colon being less prevalent in our diets and therefore more of a clearance problem. It's hard to make an either or question about it because it comes down to fat in versus fat out and Collin 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 cooling intake over those years. And I think you probably could show that there was a fairly linear increase in naffledy 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 over the overwhelming reason for that is that the more obese you are, the more likely you are to have visceral 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, 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 the polices, 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. Now, one of the challenges of studying naffledy is, and I can say this with some experience because I used to be involved in an organization that was funding research in this is removing the biggest confounder of the reduction of naffledi, which is weight loss. So the biggest challenge is, so let's say you're hypothesis, and I think fructose is overwhelmingly on a molecule for a molecule basis, probably one of the greatest drivers of naffledi.

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 Nafolde 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, poofa, fructose, an output issue, coline, or the way you describe it is 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. 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 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 control 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 to

the foods in their diet, they're actually changing like 30 or 40 things in their diet and that 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'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 ideas that you reduced your carbs, but actually you probably increased your protein, you probably increased your colon, you probably increased your riboflavin, you probably increased your zinc, you probably increased 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? When we were 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 would really. Wait, 60% fructose or sucrose fructose. 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? They might have had a little bit less digestion because they were a little bit leaner. But that's not the point. The point is there are studies out there showing a 60% fructose diet causes fatty liver. And did you see it in yours? No. Because you had lots of colon, do you assume? Well, I wasn't trying to have lots of colon. But in my department, we never fed rats where mice on casing diets, which is what almost every rodent study out there is. And my case in being the dominant protein that you would see. Yeah. But every rodent diet is based on casing 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 casing. And later I talked to my department head about it and he said, well, I've seen studies showing that casing 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 casing diet that everyone else is using. And it's something like six times more methionine, which is a colon per cursor that

has been shown in animals to obliterate fatty liver. Something like six times more methionine in my diet. So all of a sudden, 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're talking about at the beginning about getting a historical perspective. I was writing a review on Fadi liver with my doctoral advisor and I was obsessive about needing to know the origins of the methion and colon deficient mouse model. So I went all the way back to the turn of the century. And what they found originally was you could produce fatty liver in rodents. If you fed them an 80%

sucrose diet, if the nutrients came from whole foods that they were using before, like yeast and caliver oil and things like that. Then when they started producing chemically defined diets, all the sudden 50% sucrose was causing fatty liver. And so then they said, oh, we need to reduce the sucrose, so they reduced it further. But then people who took those same high sucrose diets at that time showed that you could add colon, you could add methionine, which is a colon precursor, you could just up the protein. If you just up the protein, which has methionine, which is a colon precursor, right? If you provide any of those precursors, it just gets rid of the fatty liver.

So I take those things and I look at the human data and I say, well, that person reduced the fructose in their diet I believe that's a contributor because fructose compared to starch is more lipogenic and in fact one of the animal models that you use for fatty liver is called the methion and choline deficient mouse model. Well, it's not just deficient in the thining Yeah, they have to get it's also got yeah, it's also got a bunch of sugar in it and it's got a bunch of corn oil in it. And they have shown that you can reduce the fatty liver if you replace the sugar with starch.

So when I look at the human data, I'm going to say, I do believe that reducing the fructose is going to reduce the amount of fat that the liver is producing from sugar. But I also believe that if you did that and you replaced it with protein, then that was part of the results. Or if you replaced it with vegetables or you replaced it with egg yolks, those were part of the results. Right. And to your point, it's very difficult. So when you look at the study that just came out in JAMA two weeks ago, which actually

was the one that way at the beginning I was involved in the funding of, but I had no involvement in the study whatsoever. I mean, I had to read about it like everybody else when it came out in JAMA, but this is the one that Miriam Voss, Emory, was the first author on. This is the study that took 40 Hispanic boys with biopsy proven Nash, and for eight weeks put them on a virtually zero fructose diet. With no instruction to reduce carbohydrate, in fact, the idea was to replace fructose with glucose to your point.

Right? Glucose is not going to produce fatty liver in almost any quantity. They saw a 50% reduction on MRI in liver fat, but if you want to be technically rigorous, they lost three pounds on average. Now, I don't know that the three pounds matters that much, but I think your broader point is, they almost assuredly cleaned up the quality of their diet in ways that's difficult to measure,

even just looking at the macros. Because I think it's easy to report the macros in a study like that. Well, carbohydrate content was unchanged. You know, protein went down a. Protein went down a little fat, went up a little or vice versa. But at the micronutrient level, or at the amino acid level, I just don't think that stuff's being tracked. It would be interesting. Again, I don't know. It might even be worth you contacting Miriam Voss, who I've met twice. And

she seems very collaborative and interesting. And it might be worth understanding what other data they would have with respect to the nutrient, because I'd be curious to dig further into this point. Yeah, and if they have food data, if they were collecting, what are they eating for foods and then they're... Well, the food was provided. Oh, I'm sure they could go back if they have what the foods were. I'm sure they could go back and that's right.

Yeah, this was a very well controlled study, in that the food was provided not just to the children but to their entire families. The idea was make it so easy for the child to be compliant for the eight weeks that they were on this diet that the entire family is going to get fed the same food. Yeah, so they have to know what they were providing in order to estimate the macros so they must be able to estimate the micros.

That would be interesting. Yeah, I'd like to see that because I remember when I read it, I was really hoping that the results would come out independent like that there would be no change in weight, that the kids could maintain their body weight, and then you could ask the question, could this nutritional intervention alternate will be independent of out-apacity?

Okay, so now let's go back to where we started, right? So you've made this great case for colon and its importance, and I've always found the TPN and stuff to be one of the most compelling reasons, because you just don't get, you don't often get in life a chance to create a truly deficient model in humans. 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, Colleen became public enemy number one. 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 with those genetic disorders where, but they were feeding them absolutely massive amounts of coline. And so it was known before that that in those cases of enormous coline loading, some of that coline would be converted to trimethylamine by gut bacteria and that that trimethylamine, and actually the interest was largely in the trimethylamine because the trimethylamine is the more smelly compound So this would produce fish odour 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 and most but also in humans showing I think in first and most, but also in humans 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 the two different papers. The first one looked at colon 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 colon or carnitine, they will metabolize both of those to try methylamine 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. 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 TMA- I don't think they mentioned fish. Maybe I'm confusing it with a different paper, but I thought one One was too much fish. If you eat fish, you're getting the TMA direct. I don't think they mentioned fish. 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 sport drinks, is going to be converted and too much colon. So basically, any of those three that were too many were problematic. Maybe this was stretched across a couple of different papers too. So 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 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. So my point was always, how can you not bring fish into the discussion? And... Yeah, so now it's coming back to me. You wrote a piece on this that I think 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? 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, someone else, and I don't remember who it was, came up with the idea. Well, wait a minute. I mean, we got to 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, converting to TMAO, it just seems to fail on first

principles. 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. 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 or in 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 I roll and I just sort of

send them a link to what you wrote or what Chris Cresser would say. Go and read this and then come back to me and let's discuss why I am not particularly impressed by this thesis. On a skill of 1 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 they come up with there. But on a scale of 1 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 colon 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 when I'm looking at Colleen supplements, I overwhelmingly prefer that someone would get phosphatidyl Colleen, which is the overwhelming form of Colleen

that's found in food. For two reasons. One is it's the overwhelming form of Colleen found in food. And the second is that it's the form of Colleen that's least likely to generate TMAO in the gut, almost exclusively driven because its absorption is better. Do you dose it milligram from milligram? In other words, if you believe that 1200 milligrams of colon is necessary. No, and actually that's very confusing on supplements because most supplements of phosphatibol colon tell you the amount of phosphatibol colon in them and they don't tell you how much colon is needed. No, you do.

You can estimate that's about 15%. Just by molar weight, it's about 15%. Right. Okay. 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, but it's close enough, right? But directionally, then, you would want like nine or 10 grams to hit your 12.

Yeah, I mean, it's only practical if you're taking tablespoons of less than. Yeah. But you can get food, so you could eat eggs. So eating eggs and eating foods is the best way to get colon, in my opinion. But if I were to take someone in a particular situation where for some reason they had one or two dietary restrictions in this way that may then not be able to get colon, but they needed colon for these other reasons and you had to supplement, I would do it with less than for those reasons. And one of the reasons is that I don't know whether the increased TMAO that's generated when you take colon by tartrate is problematic. Your Bob, the show notes guy, he sent me a paper that was

just recently published where they fed people 500 milligrams of colon by tar trait over the course of two months And they're they did an in vitro assay on their blood and showed that it was more sensitive to clotting So it's the lawful that evidence isn't super strong But it's an indication that maybe having that level of TMAO in your blood is bad But you cannot get that level of TMAO in your blood by eating four eggs, which supplies the same amount of colon. How do I know? Because Steven Zisels group did a study looking at plasma TMAO response to eggs. And if you eat enough eggs, you get a plasma TMAO response, but it's three or four times lower than when you eat the

same amount of colon as colon by tartrate. And it's only anecdotal, but at the time that I was involved in this discussion around developing an assay for TMAO, it was during that three, three and a half year window when I was on a really strict ketogenic diet. I was so, I mean, relatively speaking, hyper-choloric because I was also really active at the time. I needed about 4,000 calories a day. Now, 4,000 calories a day on a ketogenic diet means you are really having to limit your protein and carbohydrate.

So I was about 2% to 3% carbohydrate, and about 8% to 10% protein in the rest was fat. So it was on a, you know, what we would now call a 4 to 1 ketogenic diet, although I didn't at the time think about that way. My point is, one of the ways that I would, I had to make eggs is I couldn't just take 12 eggs and make scrambled eggs. That was too much protein.

So I could only eat, I'd have maybe four whites, eight yolks, and then I'd have to fluff it with heavy cream. So the point is I was mainlining this stuff. And when the lab was sort of kicking around the idea of developing the assay, I said, I had already done some work with them where we had done like nine blood draws on nine consecutive days under various conditions and they already had the serum. I said, well, let's look at the TMAO levels in there.

That should be a pretty good positive control. And interestingly, I had virtually none. Yeah, well, in that study that I mentioned looking at the plasma TMAO response to eggs, there was enormous variability and some people didn't really get, I think everyone got some response to six eggs, but there was a lot of variation on the fore egg mark. So half the subjects didn't get any response at all until they ate fore eggs, but some of the people got a very significant response to the four eggs, which is what you'd expect based on what the Cleveland Clinic group is arguing, which is that the gut microbiome is a big determinants.

Well, and that was sort of my conclusion, which is, again, it was a very deep look into one individual, me, and that's irrelevant because any one individual is irrelevant. But the thinking was, I gotta be honest with you, I still don't know what gut health means, like the concept is so, you know, it's so difficult for me to in a morphist to describe. But my intuition was, something in my gut was really preventing this from becoming problematic. I didn't know what it was. I didn't know if it could be replicated. But the story seemed a lot deeper than it was

being presented. Yeah. I think one important point is that it's not about how many eggs you eat in a day. It's about how many eggs you eat at a sitting. So the only reason eggs generate TMAO is because there's some poorly characterized absorption cap to phosphatidylcholine. And even though it's better absorbed than the other cooling that's sold on the market, there's some cap to how much cooling you can absorb

and no one really knows where it is. So where is it absorbed, which transporter? Is it an enterocyte transporter? Off the top of my head, I don't know, but it's gotta be in the small intestine. Does it come as a single phospholipid or is it a sterified in some way? I mean, how does it actually come in from food?

You mean how it's absorbed or how you eat it? So if you're reading a food that's high in phosphatidylcholine, does it actually show up like the analogous free fatty acid, or does it show up more as the analogous triglyceride, where you get, you know, say two or three of these bound to a glycerol bound to other fatty acids. Like do these things actually show up as free phosphatidol molecules? So I believe that most of the phosphatidol calling in most of the foods is going to be as phosphatidol

calling that are in cell membranes. I see. Okay. No, you've answered that question. Okay. So that's what I was wondering if it came in a more whole state or if it ever actually showed up like, so first of all, does it come in through a chalamicron? I assume so. I haven't looked at the absorption pathway for a while. So I might not be remembering the details here, but my guess is that you're going to have partial hydrolysis of some of the fatty acids and then that the phosphatidyl colon is mostly going to wind up making its way into the mixed micelles and is going to become probably part of the membrane of a chylomicron would be my guess.

Right, but coming in the lumen of the gut, and I get, I probably not even that relevant at this moment, why. I guess I'm just trying to figure out what the, if the bottleneck is at the enterocyte transporter, and that's why you're limited and how many of these things you can get into the enterocyte, which then on the backside go into the chile of micron. Right, that makes sense. I mean, back when I was trying to figure this out, I asked Steven Ziesel about this, who, if anyone knows about colon absorption or anything else about colon attend and he wrote back and was like, you know, I really don't know. I assume that there's some absorption cap in the small intestine.

I have no idea what it is. Interesting. So, the colon story is interesting and I think if you look at it over at least simplistically you could say, well, it's a good guy and a bad guy, but it seems to be more of a good guy than a bad guy, huh? Yeah, I think so. I mean, certainly from the perspective of fatty liver, that's clear. Yeah.

Now, we don't see, I'm assuming, although I've never looked at this, in people who you would expect to have huge choline deficiencies, which would be, you know, someone who's eating a very strict vegan diet, right? So by definition, they're not eating any liver, they're not eating any eggs. They could certainly be eating lots of nuts. Nuts and cruciferous vegetables, like eating. Now, but let's assume they're on like the college vegan diet, which is like, you know,

they're eating as much crap as possible that has no animal matter in it. Is there data that would suggest we would see a higher incidence of fatty liver in that population? I have no idea if that data's out there. My guess is you probably wouldn't because probably those vegans aren't too fat, but I don't know. This comes back to your point, which is there's just something about adiposity if it's accompanied

by visceral fat that is really stoking the fire. Yeah, I mean, if you take out all the fat in parts of the equation, then the colonel is not going to matter that much. It's just that it becomes the bottleneck to getting fat out when you have a buildup of fat in. 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, mono unsaturated 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 we're so quick to demonize one versus the other. But as you said, outside, it's really just a bunch of really fun biochemistry. A saturated fatty acid is specified by the number of hydrocarbons. 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 fat has. One double bond, a polyunsaturated fat has two or more double bonds that introduces a couple things. So 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 it's 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 mono and saturated and poly and saturated fat tend to be more liquid So olive oil is more liquid than butter because it's mostly mono and saturated 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 is going to harden and the sunflower and sunflower oil wouldn't. And that's because the sunflower oil is more polyensaturated 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 a polyensaturated

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. You alluded to these earlier, we'll come back to them, which is the omega-3. Right, well, I the omega-3. Right. Well, I know omega-6.

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 used 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 of 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 statoosis to stato hepatitis because you have more oxidative targets.

Right. Yeah. So if you look at the animal data, it depends on the model. Generally, you get more statoetosis with longer chain length and more saturation. And you get less statoetosis, the shorter chain length or with less saturation. But if you have the statoosis, you have a dramatic increase in the risk of progressing to stato hepatitis. However, in the alcoholic model, there are studies showing that you get less statoosis with saturated fats and with polyunsaturated fats. I think the reason for this is that oxidative stress does not just cause you to go from naffledeta nash, it also can cause stiotosis because you get oxidative destruction of the abob particle.

And so it's not just colon 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 all ready that's provided by the alcohol because the alcohol isn't just a way to get fat in the liver, the alcohol, 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 in oxidative flame. So you actually wind up causing stetosis by causing oxidative damage to the ape will be particles so that they can't leave the liver in that model. So poofas, I think, 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 going to be better if you look at a two week study, and we have the data and human showing that. But I think in the long term, if you're talking about the progression from state-tosis 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's like 55. But in this two-week study you're talking about, presumably the subjects were fed disproportionately high amounts of poofa versus SFA. Yeah. Do you recall like the magnitudes that they had to be fed to produce this phenotype? I don't recall the magnitudes, but they weren't ridiculously out of proportion. They weren't super physiologic.

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 in their diet, but in that case, it was atypical. But they weren't feeding them 80 or 90% fat diets. You know, it's interesting. You mentioned the APOB issue.

APOB is used, obviously, in two ways in the liver. The first way we've talked about, which is VLDL export, which is our main way to get triglycerides out. But also, we make the NOvo LDL in the liver. And so in those patients, do we see a reduction in LDL as well? I don't remember. That's interesting. I feel like I want to start paying a little closer attention to this.

I certainly haven't. I can't even remember if they measured that. I just haven't clinically seen that because I do see nafflede 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 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 in 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, we'll still have very low VLDL on triglycerides. A Hispanic patient with diabetes will generally have a high triglyceride and a high VLDL, and actually they're far more susceptible to an african American and Caucasian is in the middle. Are you familiar with any of the data on some of those differences? Is it pertains to the lipidology of these folks? I know, I'm not.

I'm not. Can we rewind a minute? What have you observed with BLDL? You said you haven't observed the association between a lot of levels of BLDL and... And that's what we're talking about. And that's what we're talking about. What would you expect to see that you didn't?

I would have expected based on what we're saying to see a reduction in BLDL. The more that they have, the less BLDL based on this idea. Well, I think the problem with that is that... I mean, I have an explanation for why that might not exist, and here's the explanation. And in ideal world, that might make sense, but there's another thing that's going on. If you have Nafoldy, you are very likely insulin-resistant. If you are insulin-resistant, you are are up regulating APOC3. If you are up regulating 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 down-regulated,

but if APOC3 is up-regulated, and it's hard to measure this, although Sam Temeckis 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 arthrogenic. 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. Right. And when you also expect that from lower rate of uptake of triglycerides from peripheral tissues. Yeah, that's a great point. You have a lower peripheral disposal of triglycerides. So the whole thing could be confirmed. 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 Because you can't understand flux with a snapshot. No, 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 Well, it's in what's out where it's being disposed of I love this point and one of the analogies that I like to use is although you can't know the flux. What's in, what's out, where it's being disposed of? 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. Now imagine that you have a picture of a car accident. Well, if you zoom in to the tire, you might not, 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, 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 in 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 diabetic and you're like, really? My insulin is unmeasurable. My glucose is 60 milligrams per desoliter.

Yes, my FFA is 2 millimolar, but my BHB is, you know, seven or, you know, 5 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 FFA's who's got diabetes, which is a much more stagnant form 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. And would you rather drink water out of a stream or out of a sitting pool with mosquitoes all over it?

Exactly. So no, it's a good point. And I like your point, which is, look, the picture can be helpful, but it has to be taken from a distance, right? So if you just look at one tread of the tire in a photo, you're probably going to have no clue what caused the accident. If you look at a huge picture, you could at least see where the skid marks are of both vehicles. Ultimately, there's no substitute for having a video of the accident. And those turn out to be the hardest things to do biochemically, is to generate tests that can actually show you the movement. Well, biochemically, what you do know, though, is that we've mapped out elsewhere biochemical

pathways. If you know all the possible sequences, and you can measure all the metabolites, you can often reconstruct what a video would have shown with fairly good precision. I think it's just that we're only on the horizon of being able to do things like that. But even still, if you measure 20 things in someone's blood, you can have a much better idea of what's going on, what probably happened, then if you measure one thing in that blood. I should say 20 things in the pathway, right? Yeah, yeah.

And what you can get by measuring serially, even a few serial measurements, can be quite helpful. I mean, even just looking at something as simple, I hate to say that, but as simple as an oral glucose tolerance test, you look at somebody's fasting glucose and fasting insulin. You have some idea of what's going on, especially in extremes, right? So a person who's fasting glucose is 70 milligrams per desolate or in their fasting insulin is one, the probability that they're going to have post-prandial hyperinsulinemia is low, but it's not zero. Similarly, you look at somebody who's fasting glucose is 130 and their fasting insulin is 30. The likelihood that there's not a train wreck there is also virtually nil.

But if you're willing to sample 30, 60, 90, and 120 minutes after a glucose challenge, you can develop a very interesting kinetic pathway using just two or three measurements. You know, I often get asked, where will machine learning wreak the most havoc in medicine? Intuition is most likely radiology,

is the most obvious place for machine learning to, I mean, wreak havoc's the wrong word, but displace human ability. I've often thought the ICU would be the second most valuable place just based on the reams of data that are coming out. But I've never thought of this particular question, right? Which is something as seemingly straightforward that are coming out. But I've never thought of this particular question, right, which is something as seemingly straightforward as looking at a bunch of biochemical metabolites

and precursors and intermediaries. There may be a very interesting opportunity here for machine learning to also start to differentiate, but you know, this question of flux. I'm always asking myself that question when I look at a blood test, which is this is a static test, can I infer the movement, the velocity or the derivative, the time derivative of this molecule or that molecule? So maybe that is an interesting place for machine learning to start to play a role because I do suspect it will do a better job than me. Yeah. And what we do have, taking it back to the fatty liver, what we do have is not, you'll never see this in your day to day clinical life, but what we do have is studies where we look

at labeled tracers. And that's what shows that in a random sample in Ash people, you have a 75% decrease in able BC accretion. It doesn't matter what the ape will be in the blood. You'd like to know why it's higher, but you know that it's not because it's coming out of the liver. It's not secretive. At a higher rate. It's a great point, right? It can be longer residents time of the VLDL, the LDL, the LLDL. That's such a great point. Okay, so speaking of tracers, which just prompted me to think of another thing I wanted to talk with you about. Let's talk about the most sought after discussed, asked about supplement on the market today,

which are NAD precursors. I know you've got some feelings on this. I have pretty strong feelings on this topic too. I'm trying to think how we can frame this. Let's take a step back. Well, let me do this. For the listener who is contemplating whether or not they should turn the podcast off now or not, because you've barely hung on to the biochemistry

of co-leaning fatty liver disease. Most people have heard of NR, the ketenomide riboside, NAD, as the sort of fountain of youth. And if you've listened to other podcasts I've done, specifically when I spoke with David Sinclair We talked a lot about certuans and the necessity of NAD as a substrate to certuans 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 a lesium. They make a supplement called basis the other is called chroma decks They make a a supplement I think it's called true niogen if I'm right on that. Yeah. I believe that basis takes nicotinamide

riboside combines it with terastil bean which is a Cirtuan activator and that is their product and my recollection is that the true niogen folks are just giving nicotine in my riboside. I don't know if they have a sir-2 in activator in there, but I could be wrong in it. It's probably not relevant unless you know the answer. 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 NAD H, and, apparently, NAD H to NAD. So as the race, as we age, it has been postulated and maybe even observed, 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 sertuins, which do many things, but primarily repair DNA damage, it would seem that we would want more NAD being an important substrate for certuins, which do many things, but primarily repair DNA damage, it would seem that we would want more NAD. Okay. You also have NAD depletion because the certuins and the parts, which is the other class of enzymes that are using NAD for the purpose of protecting DNA and telomeres and all the things that are postulated to be important to aging and longevity, they consume the NAD. They're consuming the NAD.

That's right. Absolutely. Which I think are two totally different things. 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 performance? Well, so 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 parts and certuents that are consuming it for the purpose of repairing damage. 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. And why can't you just eat NAD in my other words? I wouldn't say it doesn't exist, but it's questionable how powerful of a wand this is. So there's Naisen, these are all forms that, collectively we call all this stuff Naisen in the diet, it's vitamin B3.

And in the foods that 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 going to be in the form of NAD or NADPH that is in those cells. But 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 entire site, 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 robocide supplement, you got some nicotinamide robocide 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 try to convert as much of those forms into NAD as possible, not even just for itself, but because it's going to 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 there are 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. But the first pass effect is pretty significant, right? So let's talk about- First, the pass effect is basically complete.

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

Yes. So, do we have a sense of how much NAD actually makes its way into even the cytoplasm of a cell that is non-habhatic in that situation? NAD that came from where? That is derived ultimately from the NR that you ingested. From the liver? Yes. Oh, we know exactly what happens.

The liver turns that into nicotinamide and secretes it for the rest of the cells. How much? Like a meaningful amount of... As a portion? Yeah. Well, or just... Well, I don't know off the top of my head the amount, but what I can tell you is that for all intents and purposes, all of the NAD that is in any of your cells that are not the liver, well actually I should say maybe 5% the kidney synthesized from protein.

But aside from that 5% in the kidney, pretty much every molecule of NAD is ultimately derived from circulating nicotinamide that the liver put up. So in other words, it's not the case that NR needs to be brought into a cell to be turned into NAD. It's that nicotinamide gets into a cell to be turned into NAD. It's not even needs to, it's Ken, right? Because NAD, to my knowledge, does not go

from plasma into cell, but it's hard to know if- It does, it's Ken, right? Because NAD, to my knowledge, does not go from plasma into cell, but it's hard to know if- It does, it does. It just might be that you don't have enough in the plasma to justify the- Well, you do if you're injecting it. Oh, so this is interesting. Okay, I want to come back.

I'm going to park that because I want to let you finish, but I'm going to come back to that. So nicotinamide is the physiological circulating form of niacin that all cells will use to make nicotinamide. I mean, excuse me, that all cells will use to make an ADM. Minor exceptions are about five. We can make some niacin from triptophan, and about 95% of that happens in the liver. In the liver, 5% happens in the kidney.

So there is some, some tiny bit of this that the kidney is making its own, but overwhelmingly with that tiny exception, a tissue is getting NAD because it took nicotinamide out of the blood that the liver made from its store of NAD. Now, let me expose my ignorance in biochemistry and my forgetfulness. Nicotinamide is charged or not? I know NAD is, but... No, nicotinamide is charged or not. I know NAD is, but... No, nicotinamide is not charged. Okay, so nicotinamide makes its way into a cell through an active or passive transporter.

Active transport, I believe. I would need to check that out. That's okay, we'll figure all that out. Once nicotinamide is in the cell, how does it combine with adenosine, et cetera, to become NAD? It goes through two steps that are ATP dependent. It gets converted to nicotinamide mononucleotide, and then it gets converted into NAD,

a portion of the NNN, nicotinamide mononucleotide, a portion of that becomes NR, and then gets, comes back to NN. And I don't know exactly why, but I think it's like a pressure release valve. So if you're trying to hold on to the nicotin of the and get it to NAD, more than the rate at which you can make the NAD, you might convert some to NR to kind of hold on to it.

And then it comes back and went to NR or to NMN. No, to NR, to NR. So you have nicotine of the NMN, you go up to NAD. You can go from NMN over to NR, but you have to go back over from NR to NM go up to NAD. You can go from NAMN over to NR, but you have to go back over from NR to NAMN to get NAD. Yep, and I think of it as a cycle. Way easier to look at this in a picture. Yeah, the picture that I have in my mind

is NAD going to NAM to NAMN as a cycle with NR being a pop-off of NAMN. Okay, yeah. So what you're talking about is in the case of NAD consuming enzymes enzymes like certuents and parts that are using NAD for DNA repair and all those things we were talking about before, what they do when they consume the NAD is they release nicotinamide. So imagine you're a muscle cell.

You took originally to get every molecule of NAD you have, originally you took some nicotinimide in from the blood, but then you did things with it. Some of those things were what you were talking about with oxidative phosphorylation. You don't consume NAD in that process. You just cycle it back and forth. You use it over and over and over and over and over again. But some of the things that you did were with the sirtunes and parts that are engaging in protection. And those enzymes will consume the NAD to generate nicotinamide.

The big problem here is that nicotinamide is an inhibitor of all those enzymes through negative feedback loop. So you have to have to have to have to have to have to do something with the nicotinamide, very fast, or you need to methylate it, bring it back to the earlier discussion and pee it out. So, nicotinamide is circulating as the circulating form in the blood, but intracellularly, you don't let it hang out there, you do something with it, right? So, you take in the nicotinamide and you either make NAD or you get rid of it.

Yeah, actually I didn't even realize one could have free nicotinamide inside a cell, which I guess you're basically saying that that's, but only momentarily. Momentarily, yeah. Yeah, yeah, but it doesn't hang out there in that form. No, it doesn't. Okay, so now let's go back to the question that I'm still trying to wrap my mind around, which is if I give you a gram of nicotinamide riboside, you're saying none of that NR is basically going to leave the liver. Instead, just nicotinamide is leaving the liver. It is found in the blood. So there's clearly there is some nicotinamide riboside in the blood. And we don't have the data in humans, but we do have the data in

mice. Isn't this what Josh Rebenerwitz did in that research? Right, so this is exactly what I'm referring to. So in his paper, what he showed was that there is a little bit of nicotinamide riboside that gets into the blood, that there's a little bit that gets into some of the cells, not others. So for example, it can't cross the brain at all. It's fairly decent at getting into muscle if it's there. There's not a lot there, but what is there can get into the

muscle. And there is a little bit that gets turned into NAD. But the nice thing about his study was he was the way that he designed the tracers was they could see. Yeah, you want to be able to separate the nicotinamide from the nicotinamide riboside, right? Well, they could see even at the level of detail as what was the history of this molecule before it became NAD. So they could differentiate inside the muscle so they could differentiate the pool of NAD

that the muscle made from nicotinamide riboside. They could, from the pool that it made from nicotinamide, even from the pool that it went through the cycle and then back. So they had extremely fine detail. And what they showed was that there's a little bit in the tinamide riboside that makes it into the muscle intact, it pulled up the graph to try to see the amount, and they have to blow up that part of the bar graph to show you what that tiny trace looks like.

It's basically practically meaningless. Now, what they also showed in their papers, and also in the same group published one in 2016, what they also showed was that you do increase NAD in the muscle a lot when you supplement with the nicotinamide riboside, but it all comes from nicotinamide that the liver had made and circulated in the blood. And let's just make them atheasy. You take one mole of NR orally. We've already acknowledged that the amount of NR that escapes the blood is so small, you need a magnifying glass to see it. So it's a peak of mole or something.

How many moles of nicotinamide make their way into the cell? Again, I'm sort of directionally speaking. But order of magnitude is it more of it or like the majority of it does or how much loss is their outside of the first pass effect? Is there an inefficiency? What are you calling loss? Are you calling increasing hepatic NAD loss or are you calling? I'll call loss anything that prevents the actual nicotinamide from making it into the cell. I don't know off the top of my head what those numbers would be, but I can come back, I'll come back to the human data that the chromidex people have published on that point. What I can say about the physiology is that

there's a lot that doesn't get into any particular cell that isn't actually lost. And I think this is a really important point because in the Rebinoids group, in 2016, they had another paper where they actually, when you're listening to this, I mean, what's your thought right now would NR be more effective than nicotinamide eating it?

That's a good question. My intuition would have been NMN would have been the best precursor if you could get it around the liver. So as a thought experiment, like SL, like, you know, sublingual or intravenous NMN would have been my intuition is the best way to increase into intercellular NAD. If you didn't have that choice, if nicotinamide is the

circulating form that's getting into the muscle, would you think that an NR is just generating nicotinamide that gets into the muscle? Yeah, I think based on what you're saying, I would now say nicotinamide per se would be a better substrate. Right, but it's not. And in the two, that's what I would think too. I love how you walked me down that path. Well, well, no, because as I'm saying this, it sounds like why on earth would you take anything other than a nicotine of mine? Right. It's just going to make nicotine of mine anyway.

And I think this gets back to your waist point too. In the 2016 paper that the Rubinoids group put out, they showed that, and this was a minor portion of their studies. They didn't have anywhere near as much data as they had on the NR, but they showed that they got a much less NAD response in the muscle with oral nicotinamide than they did with NR, even though they also showed with very elegant tracers that it all got there as nicotinamide. Let me make sure I understood what you said. You give oral nicotinamide, and you are now asking the question,

how much of it goes to the liver, how much of it leaves the liver, also as nicotinamide and makes it to the muscle. They didn't have all that debt on the oral. Okay, so they skipped that step, but they're great. They're asking the question, in the muscle, our goal is to increase an AD in the muscle. Yep. Is it more effective to give oral NR or is it more effective to give oral nicotinamide?

And a minute ago, I would have said oral nicotinamide made more sense. But they showed that. They showed the opposite. Yeah. Here's the rationale that now this is kind of my synthesis of what. But the 2018 paper shed light on that now because now they had a tracer. They had tracers in the 2016 paper too. But they couldn't see how much tyrosine in the liver was being.

Yeah, there was much more kinetic flux data in the 2018 paper. That clarified, you know, if you had them on to talk about it, I'm sure you'd have a better answer. Believe me. And by the way, I've tried to get Josh on 100 times, and Josh and I are friends, because we went to medical school together, and I just can't get him to hop on a train and come up here.

You know, Josh, if you're listening to this, just please just come up so we can talk about this. Yeah, I'll just say what I learned about this paper, right? Cause I read the paper, I took notes, I synthesized them, I did my own podcast about this, so I think I have a pretty decent understanding of that paper, but I'm sure there's details that I forgot. So what I learned from that paper is a bunch of things.

Like for example, I know now that the average NAD molecule turns over every eight hours, you consume an NAD molecule. And most tissues, but it's every two hours in the liver, things like that. I know that the spleen and the small intestine consume 40 times more NAD than the muscle and the fat does. I know, so there's a the small intestine consume 40 times more NAD than the muscle and the fat does. So there's a bunch of data in that paper, but there's not infinite data about the proportion

that went in each compartment everywhere. Back to the point about why is it more effective to take the NR? And this is what I think is going on when I think is the most sensible rationality makes sense of this. So in the liver, you imagine that the NR, the nicotinamide, nicotinic acid, whatever was you ate, gets into the liver. Think about that cycle that we talked about before. So we go from nicotinamide and we go up to NMN, we go up to NAD.

If we consume the NAD with certuans and parps, we come back to nicotinamide. And having that nicotinamide around is a liability because it's going to inhibit all of the repair enzymes. So we either want to make NAD out of it or we want to get rid of it. If you eat oral nicotinamide and you absorb oral nicotinamide into the liver and the liver gets it, that oral nicotinamide is immediately a liability before it ever becomes NAD, because it can inhibit all those enzymes, the sertoins and the parts. So the liver has a bifurcation of what can it do with this. It can methylate it

to get rid of it and pee it into the urine, or it can make NAD. If you take NR, then you go into NMN, you have to make NAD before you ever generate nicotinamide and expose it to the detoxification process. What I believe is happening, and I think this is backed up by the animal data, is nicotinamide riboside is a superior way to increase hepatic NAD because when it gets to the liver it can't be immediately detoxified. It's not immediately a threat to the ser twins and parps and it can only make NAD before it does anything

else. And again, this is a flux thing, right? It's not like the liver says, okay, cells, tell me what are balance of NAD and NNN is on Friday and on Saturday, I'll make a decision about how much to empty into the urine. This is an immediate thing that's happening right now. The liver says, oh, got two choices. I either to talk to this or I do something useful with it. And so if you're presenting it with that thing that's a threat and it has to make that decision, it can only make so much NAD at once at one time, then you're gonna have much more waste

in the detoxification pathway than if you put the thing in that has to make NAD, that is not a threat when it makes NAD, and that has to actually generate NAD to ever be exposed to the detoxification pathway. So you have to appreciate the central role of the liver in controlling the flux throughout the entire body. The liver is not just making NAD for itself. It's making NAD because it carries all of the reserves for the rest of the body as NAD.

So the liver doesn't just have NAD that's immediately being used in respiration and is immediately being used in ser twins and parps. It has a reserve pool of NAD that it holds on to for the specific purpose of a slow release of nicotinamide to the rest of the tissues that they will take up. And then they will have the immediate decision to either detoxify it or make NAD. But if the liver can hold on safely to the NAD and have a better ability to release nicotinimide on an as needed basis and a continuous basis at a rate that the other tissues can take up and do something useful with, then because you got a superior way of increasing hepatic NAD, you got a better continuous flux that was optimized of nicotinema

to reach the other tissues so they can make NAD. Yeah, so in that sense, it's actually sort of parallels glucose, right? In the sense that we have to maintain about five grams of glucose in our bloodstream at all times. So if you have 10 grams of glucose in your bloodstream, you have diabetes. You've got huge problems. You're going to go blind and get your toes cut off. Not if you have 100 grams in your liver. Exactly.

But five grams is perfect. And if, by the way, if you have two grams, you die. You know, it's just, it's an amazing problem where the liver is constantly titrating. So you're basically drawing a parallel that says it's probably doing the same thing holding onto NAD. In this analogy, NAD is to glycogen. What glucose is to nicotinamide? Yeah.

Is that a fair analogy? It's a fair analogy, except there's a probably much larger percentage of the hepatic any deep pool that's actually being proportionally, they're different, but yeah, in principle, I think that's a good analogy. So let's see if we can go deeper on that analogy. There are a lot of people out there who, in fact, I have a friend who came to me a year ago and he said, I've got the greatest idea I'm going to open up an IV, NAD, clinic, and we're going to do NAD and ketamine.

So I'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 because 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 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.

Oh, I know it's the worst feeling in the world. Say why? We need to come back and say, what is the role of free NAD that's found extracellularly? I can guess what the role is. What I can tell you is that one of the things it does is it activates granular sites to cause vasodilation and a massively ramped up influence. Not unlike niacin. No, it's very different from niacin.

But niacin has a very similar response, doesn't it, at very high levels? Well, yeah, but biochemically what's happening is totally different. Oh, it is, okay. So, why is niacin causing a flush? But it's not the same as NAD's flush. 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. Not necessarily granulocytes.

Yeah, so NAD is acting on, it's a different receptor and, you know, I don't know, maybe it's more, it might be more similar than I was leading on. It's a different receptor, but maybe the results are some, 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 mechanism. So, if you do inject this NAD, what is it now you've bypassed the liver and it's sitting there in the plasma? What's clearly happening based on the anecdotal reports of the immediate response to that is that they are causing an inflammatory response. What is not clear is the kinetics of where that NAD is going.

Right. But there is definitely papers that I was able to find showing that there are a variety 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 really want to know what can happen. First I want to know what's supposed to happen. 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 this 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. You mean as a signal? As a signal. Interesting. Oh, yeah. I think it's very clear. You think it can be a signaling molecule as yeah, I think it's very clear. You think it can be a signaling molecule as well? I think it's very clear that 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 extra cellularly. There's a whole class of extra cellular NAD consuming enzymes. So if NAD is 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 got to have, it has to be the case, that extra cellular 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 going to 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. Right. Because you're amplifying Potentially a signal that's that's negative Yeah, and you know maybe that has good consequences because maybe it's some kind of rescue signal Maybe that maybe a stress cell puts an AD out and says come help me or come get rid of me because I I suck

Yeah, but if that's the case gosh when you took a mother load of NAD in the plasma, what are you supposed to go after every cell? I mean, how would you even differentiate where that signal, where that alarm is to my cell? Well, that's why I would never do that. But I think if I'm trying to, if I'm trying to explain why are people experiencing benefit, reporting benefits from it, either it's placebo or it's doing something. And if it's not just placebo, my guess is that it's probably it's probably having some signaling effect that is by virtue of luck

doing something that the person is reporting is beneficial. But I'm not going to do that because I have no idea exactly what that signal means. So what's your take then kind of going back to where we were a moment ago, which is doing what seems to be much more commonly done, which is taking oral NMN. Okay, so oral NMN, I would bet money that it's not observed intact.

That's because NMN has a charged phosphate group on it. And generally, charged phosphates cannot cross cells, and so they're hydrolyzed. And even if it were to be true that there were transporters in the intestines that could take NMN up intact, it probably still would not be absorbed intact because the phosphatases in the small intestine that cleave the phosphates off of everything that all the molecules in the food you eat,

do so non-specifically to all of the molecules in the food you eat. So for example, riboflavin, when you consume riboflavin five phosphate, I'm quite certain that none of it is absorbed intact. Were that because there were a specific riboflavin 5-phosphate phosphatase that just cleaved that phosphate, then I would say, well, I don't know about niacin, I need to look for the phosphatase.

But that's not the case. What is the case? Is that an anomaly functioning, small intestine? You have this overabundance of non-specific phosphatases that just cleave the phosphates off of everything that you're eating. And that's because even though there might be some exceptions to the rule perhaps, the overwhelming rule is that it's really difficult to carry charged phosphates across the intestines or across cell membranes in general.

So I doubt that the NMN gets in there intact. And I think that if anything, maybe it gets cleaved to NR and the NR does. I believe the NR gets intact because that's what the Rebenowitz group's paper showed that it was getting into the liver as NR. And because it makes sense because NR doesn't have a charged phosphate on it.

Okay, so we can simplify it and say, let's just limit our discussion to NR. And let's just say, now we're taking super-physi logic doses of NR, which would be what's prescribed in these supplements, sort of 500 to a thousand milligrams daily. We, you know, using our glycogen somewhat oversimplified analogy, we're now increasing our hepatic reservoir of nicotinamide that we can slow drip out when it's demanded, because that's going to be the better way to do it.

Right, so there's promise based on the animal experiments, although there are in the human trials that they've done, they haven't showed any benefit of doing this at all. Now, what you mentioned Brenner, I mean, you didn't mention him by name, but you mentioned Chromadex. Tell me a little bit about their work. I've looked at a couple of their human studies,

and they've done a couple of studies where they've characterized the metabolites that are produced when you take oral NR and they've done a couple studies where they tried to look for some benefits and didn't really find any. So there's no benefits on glucose metabolism, there's no benefits on lipid metabolism. Now, were they doing these as kinetic studies or were they actually trying to look for phenotypic improvement? In the first study, they just took one person and they extensively characterized all the metabolites that were produced in three different compartments. But then there were two, and I don't know if this is comprehensive, but in the studies

that I looked at, there were two other studies where they were measuring in different populations, they were measuring things that you would relate to health like glucose and triglycerides. And you're saying those things did not improve? Yeah, in fact, there's in one of the papers, I believe it was the triglycerides went up a little bit and the potassium, the serum potassium went down a little bit. I mean, nothing that was, that you wouldn't conclude anything from it, but it didn't, it didn't look like it was doing anything good. Now, I want to make a couple caveats here because these have been pretty short studies and my suspicion is for them,

they're not even measuring what we really care about, right? I also don't think they're measuring like what you would necessarily expect to see, which I think is harder to measure. So if you think about it, think about the Rebenowitz paper, which showed that the turnover of NAD is, and this is in mice, but it's all we have for right now. The turnover of NAD and the small intestine is 40 times what it is in muscle. Explain that to me. I mean, that is so counterintuitive. Think about it from the opposite perspective. So we're thinking about life extension or health span extension with super physiological doses of NR. Think about the opposite case of Pallagra, which is nice and deficiency. Where do you see that? You see the, if you're an

optimist, you say the three D's of dermatitis, diarrhea, and dementia. If you're a pessimist, you say the four D's and you include death. And in the brain, what's going on is, NAD is actually generating molecules that are directly involved in immediate neurotransmitter production. So I think that's why you see brain effects in Pallagra. But overwhelmingly, if you exclude the brain, the two tissues where you are seeing the most dramatic effect

are the two tissues that are outside of the body. Okay, so I was going to say, is it because they're outside the body or is it because of the rapid turnover? I think part of the rapid turnover is because they're outside the body. Think about the quality control inside your body, compare it outside your body. Think about once we cross the intestinal barrier, ideally, we have incredible control over what passes that barrier. But we have no control of what it encounters.

Think about what goes into the toilet. Like, would we want that inside our body in the number two, right? So I think part of the reason that NAD is so, and I'm guessing in their paper, if they had characterized it in the skin, that it would be high, but they didn't. So what do we know about what causes pelagor? Well, when you're out in the sun, you're always experiencing DNA damage from that sunlight, you're always repairing it. So in the skin, you have this very incredibly high NAD turnover in the skin because even things that you

normally think are benign, like just going outdoors, is actually causing damage that you are repairing always. And so when you have the skin having a very high need to constantly repair itself, and then you take away its ability to do that, then suddenly you see this manifestation in the skin. In the gut, what's happening is, I think part of it is that it's so energy intensive to maintain the cell turnover in the game. But it's also the case that just like the skin, the gut is exposed to so many insults

of just total lack of quality control over the things that come inside it. And my suspicion is that where you would be likely to see benefits of increasing tissue NAD over the short time frame is going to be in those tissues with the highest turnover. Like you're going to look at skin quality and small intestinal health, both of which are very hard to wrap my mind around how you would design the ideal study compared to measuring

glucose and insulin and triglycerides and lipoproteins, right? Like, you know exactly what you would measure for metabolic syndrome. I would have to sit down and really think about how I'm going to measure someone's skin quality or their small intestinal health. Over the long term what you would expect is increased genomic stability, decreased accumulation of DNA damage, and increased telomere length, none of which have been measured. But also why, I mean, I could certainly think of ways that those things could not be preserved, even in the absence of gut and skin dysfunction.

In other words, you could still see epigenetic damage in the presence of perfect gut and skin barrier, right? You're just saying you expect to see less of it if you created a better barrier. You were saying that over the long haul you would expect to see less epigenetic change. Oh, okay, let me clarify. The point that I'm trying to make is that if you're talking about a 12 week or 16 week time period, I don't think you're going to see any results unless you're looking for for specific things. Oh, you're saying based on the non-external benefits. In other words, to understand what it's doing inside all of the other cells in the body, you're going to need a much longer time. Exactly. Okay, I got it, I. Exactly. Exactly. And so we basically don't have much data because we have these week, several week long

studies in humans. And if we're going to look at things going on inside the body, besides those tissues with super high turnover, I think we're going to have to look at longer studies that have more relevant endpoints. So let's talk about it from the standpoint of harm. Because the other way we can think about this is if your cost insensitive, what's the downside in spending a hundred bucks a month, which is about what you're going to spend to take the party dose of these compounds. So I think the potential risk is that you're sapping your methyl group supply. And the reason is that like we said before,

part of this cycle is when you do generate nicotinamide, you face the possibility that you have to methylate it and you have to pee out the methylated metabolite. And then the question is, well, if you're taking a thousand milligrams or two thousand milligrams of NRA day, which for the sake of putting some numbers on it, the RDA for niastin is around 15 milligrams. So we're talking a ton of time.

You are losing a lot of methyl groups. And we know this in humans because the two papers that I found where they did measure methylated metabolites of the nicotine myriboside. And what you see is that in urine and in blood cells, you see incredible increase in the methylated metabolites of nicotinamide. But wait, so wouldn't a quick and dirty test be homocysteine should go up, for example, in a patient taking NR, if they're losing methyl donors. No, I don't think so.

I don't think that would be the most sensitive thing. And I think we will eventually see a paper showing that that's not true because I've heard Brenner on a podcast say that he measured home assisting and he measured S-A-Denizial methining levels in the blood and showed that it doesn't have any effect. So I didn't see that paper. So you're saying, but I think it will come out. You're saying that you're always able to methylate, folate even, like we just prioritize the methylation

of folate high enough, that even if we're losing methylation capacity to NR, we're still gonna preserve it at the folate level. Like I said. Yeah, I don't know if we, we might need to back up and talk about the methylation cycle to make this clear, but you tell me. The most sensitive thing that changes when you have a change in the methyl group supplies

your creatine synthesis. Interesting. I want to come back to that. If we jump to methylation, can we remember to come back to finish this? We do need to talk about MTHFR and COMT and all of our other friends. If we're going to do, I think it would be much easier to talk about the methylation of NR and what you would want to measure in a study to test that I think would be way

easier to do after. All right, so now we're going to, hopefully, I'm going to write this down. We're going to come back to this. 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? All right, so as we had said before, a methyl group is a one-carbon unit, and the methylation cycle uses the amino acid methanine to Donate that one carbon to dozens of different things So what we do there is we activate Methionine to acid denysyl methanine using ATP and acid denysyl methanine is the universal methyl donor so no matter what we're talking about synthesizing what we're talking about

regulating it is always acedentazolemethynein 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 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 home assisting. Home assisting regenerates methionine. Or,

colon can be oxidized to betaine, which can be then the methyl donor to recycle home assisting to methionine. Those two pathways are equivalent. In the average person, they're probably 50-50, but it's going to 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 full-ate molecule. And that's how full-ate passed the methyl group on to be 12 and then on to homocysteine to recycle

methionine. There's a lot of people going around saying, I have MTHFR. Well, we all have MTHFR. We all have MTHFR. I have ATP. Exactly. It's not just misleading because we all have MTHFR. It's also misleading because there's actually, if you look at the two common polymorphisms,

which are gene variants in the MTHFR gene, they are 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 2020, 2020, 2020, 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 coline, and you do that because you suck at using folate and you have no problem using coline.

So you basically say, I'm not that good at using this pathway, I'm going to use the alternative. And that nutritionally, that makes the coline requirement go up. At the very beginning of this podcast, I said that I'd seen some studies where some people need 1200 milligrams of coline. 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 colon metabolism was different in each population, but the commonality was... And the worst function is remind me, it's ACCC, which, or TTCCC, which SNPs would be the quote-unquote worst.

The worst case for MTHFR is the C677T homozygous. Homozygous A or... Homozygous for T instead of C. Yeah, yeah, yeah. So it's the TT and then on the A1298C, it's like the... For the A1298C, that one is less significant than the C677T, but you can have both of them. So 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 little hit is to have- You're basically a CA or a CT, and you're functionally pretty close to normal. I like the way you describe it, actually, which is think of it in quintiles. Yeah. 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%. No, exactly what it is.

It would be surprised if it's 10%. No, it's not exactly quintiles. But it depends what population you look at too. It's going to vary. But it's, you know, it's basically there's, there's a little bit in each category. Yeah, yeah, yeah. There's not a category that has, and it even has a large minority of the people.

That's right. It's not, it's not even like APOE where you can say, well, the two twos are basically unheard of in the three threes, the wild type. There's no one that's unheard of. Yeah, yeah. And I don't, it's almost like I don't really know what the wild type really is. Yeah. I think it's misleading to call it even wild type and to say you have the mutation.

Yes. It's really like there's a spectrum that's more can even work in vincing than gender, right? In this case, it's like a very even literal even spread. Like no one could make a case for binarism in MTH of our. So's, for the sake of being overly simplistic, which is not necessarily a good thing, but to illustrate this point, let's compare the best methodulators to the worst methodulators, meaning let's take the top and bottom quintiles of MTHFR function to now illustrate the point

you were making a moment ago before I interrupted. Right, and that's, I mean, that's really where we have most of our data from. So if you compare the best, and I don't even wanna call in the test... I know, I ago before I interrupted. Right. And that's really where we have most of our data from. So if you compare the best, and I don't even want to call in the test. I know, I know, I know. Because they're not bad method leaders. They're pretty good because they're using up

their co-lead to do it. So if you compare the people with the best methylfolate status compared to the people with the worst methylfolate status, the people of bad methylfolate status are the people who are doubling up the amount of colon that they're blowing through for the cycle. Now, if that said, Chris, it's hard to deny. I'm getting to the point where one of my favorite games to play, because I just love to play

games with myself when I'm reviewing a patient's labs. I like to predict a homocysteine based on an MTHFR. And there's an undeniable correlation, which is not to say I can always predict it, but when I look at your MTHFR status, the lower you are in your capacity to efficiently do so, the higher your homocysteine is, all things equal. Now, wouldn't we expect that if they're truly as efficient at methylation even using colean, shouldn't they be able to compensate for that? Okay, so right, I think I probably misspoke when I said they're just as good methylaters because they're using colean. Yeah, it's a compensatory response, but the thing is what you see in the literature at least is that studies that can show a statistically significant rise in

homocysteine is generally limited to the the people who are in the worst case scenario. What's interesting that I think no one is talking about, not even even realize this until last week, is that if you subdivide those people by their riboflavin status, all the people who have the MTHFR genotype that look bad, that have high homocysteine, have bad riboflavin status, and the thing that lowers MTHFR activity with those polymorphisms is that MTHFR

is a riboflavin dependent enzyme, which is vitamin B2, and it has a lower affinity for the riboflavin as a cofactor. And so you need better riboflavin status to optimize your MTHFR. This is so counterintuitive, because the thing that we find clinically that is the best hammer is B6. Because you're not thinking about optimizing the MTHFR activity, you're thinking about getting rid of the homocysteine. That's right? And do you think that's the wrong way to think about it clinically? Yeah, I think it's the wrong way to think about it. I think it's too simplistic Uh-huh But if someone has high home assisting goes away would be six

Applementation that person probably needed to hide B6 we should talk a little bit more about how this pathway is regulated So I have a feeling this is gonna be a set of show notes that's going to have some really awesome diet. I actually sent Bob 30 slides on this. Awesome. Thank you. Okay, so let's say that you eat a steak. There are some good things and bad things about that. One thing is that you have a bunch of methion in there. And you can use that methion in for methylation. One of the negative aspects of that is that if you have this boatload of methyne that

comes in, you're going to generate a boatload of homocysteine. And you also don't have the problem of needing to recycle that homocysteine because you've got a boatload of methyne in coming in. In fact, it's probably dripping into the liver and you can probably predict that if you have a lot right now, you're going to have even more coming in 10 minutes from now and even more coming in 10 minutes from now. even more coming in 10 minutes from now. So what do you do? You totally shut down NTHFR.

You totally shut down the enzyme that uses coline, so you're not recycling it anymore. And then you flip on this other enzyme that's not usually active, that gets rid of the homocysteine by just breaking it down. And then on top of that, you want to get rid of the extra methyl groups. And you turn on this other enzyme that is going to use the amino acid glycine as a buffer. And then that glycine is going to, if it can, hold on to the methyl group for later use. But if you methylate too much of that glycine, you wind up peeing it out. So in this context, what the B6 is doing is it's activating the enzyme that kicked on when you ate the steak that helped you break down the homocysteine.

So if a person has high homocysteine, it goes down. The part of the point that I want to make here is that they're not different parallel ways to do the same thing. Your MTHFR shuts down in the fed state if you ate protein. The unsigned that uses P6. And when you say protein, do you mean specifically methionine or other amino acids? Well, there's methionine in every protein. There's more methionine in eggs. There's more methionine in meat compared to plant foods, but there's enough

methionine that if you just eat a meal that has a reasonable amount of protein, you're going in this direction. So, take the opposite situation, which is the amino acid that falls most quickly when you fast is methionine. We don't preserve methionine the way, for example, we preserve branch chain amino acids in a non-fed state. So three days into a fast, you should have very high MTHFR activity. Yes. How this ties back to the patients with the B6 is that it's proof of concept that the B6 worked,

that the problem you addressed was not MTHFR. That means that part of their high homocysteine, it was a result of fed state homocysteine that should have been broken down using the vitamin B6. That wasn't broken down because they didn't have enough B6. The B6 is working because people need more B6. So this is actually very interesting, Chris. It's almost like we should define how much methylfolate and how much methyl B121 needs, even in the presence of MTHFR mutations that are, quote unquote, bad.

And if they're still not lowering humocysteine, flogging them with more of that is not the answer. You have to move to TMG or B6 or something like that. So, you know, I think the typical supplement we would give a patient would have 400 micrograms of methyl folate and maybe 800 micrograms of methyl B12. Does that seem like even overkill, reasonable, more than sufficient? I think it's reasonable. Yeah.

And if that's not fixing the problem, you've got to look elsewhere. Well, you're not going to fix MTHFR with methylfolate. No, no, sorry. If that's not fixing the homocysteine, you haven't identified what the deficit is. Yes. But we went down this direction because we were talking about is homocysteine a good indicator whether you're messing up your methylation. So I think homocysteine, yes, there's data saying maybe

the homocysteine is a problem in and of itself because it causes oxidative stress and might contribute to cardiovascular disease. But mostly it's also just a marker that things aren't working right in that cycle. But it's not the only thing that goes wrong in that cycle. You have other alterations. So, for example, what I had said at the very beginning of this about some people need 900 to 1200 milligrams of colon.

That's because people with, and you're not going to fix this by fixing home assisting, people who have low MTHFR activity are doubling the amount of colon that they blow through and they have problems that are a result of not having enough colon that have nothing to do with home assisting whatsoever that need to be fixed by putting more colon into the system. So I'm not telling you that their home assisting

is gonna go down when you put the colon in. Maybe it will. There's colon's a methyl donor, but what I'm telling you is that the data indicate that those people have a higher colonine requirement and the way that you address that is by consuming enough colon. Is there then a relationship between MTHFR and propensity to fatty liver disease given that a subset of patients are going to be burning through colon quicker and therefore have less colon to do its job in the liver. I would expect that that could be the case off the top

of my head, I don't know if data on that, what I do- Hopefully there's a graduate student listening to this who's going to pick, because that'd be a really interesting and elegant experiment that that's right there. What I do know there's that on is showing that 912 milligrams of colean will do two things. One, it will minimize markers of oxidative DNA damage.

I'm not even sure what that mechanism is. And the second thing that it does is it just, it brings colean utilization markers back down to what you would find in someone who didn't have the MTHFR Paulin morphism. And it comes back to everything that we said before about the relative fluxes, right? So if someone's using up their Colean morph of that process, I wouldn't necessarily expect them to have fatty liver, but I would expect them to have a higher probability of developing

it if you put the other conditions in. And again, just going back to what you said earlier, you would generally recommend people supplement with phosphatidylcholine versus choline. I would prefer food, and if you're gonna do a supplement, I would prefer phosphatidylcholine over a choline salt. So where does COMT fit into all of this? Because it's another enzyme, it's involved in the catabolism of catacolamines.

Talk a little bit about that. Part of moving beyond homocysteine, one whole side of this equation is, what are you methylating? Because homocysteins are 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 groups of prey and a 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 warrior phenotype. So the person who's the warrior, W-A-R, is the person who has a higher rate of methlating dopamine. It's 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 warrior gets stuck on things that they're worrying about. But you look at just like MTHFR activity, you look at CONT 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 in 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 warrior, warrior phenotypes is a bad way to talk about it because actually the people with the so-called warriors, the so-called people who worry. W-O. W-O, yeah, it's hard to pronounce that exactly right. So the people who have a low rate of methylation, they're also better at doing a lot of things that require sustained focus. So better 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 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 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 depression and you think 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 might be better at that because you've put the right thing in your mind and you had a better ability to make it stick there. Is the other group, the warrior group, more susceptible to addiction? 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 the low methylation phenotype, whereas substance abuse and ADHD are associated with the 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. But just taking the extremes, how strong are those hazard ratios? Off the top of my head, I don't know.

Directionally, are they meaningful? Are we talking about hazard ratios of four and five? Or are we talking about like 1.17?, I don't know. Directionally, are they meaningful? Are we talking about hazard ratios of four and five? Or are we talking about like 1.17? I genuinely don't remember. I can put a meta-analysis of this in the show notes that I have. Okay, that would be great. I mean, because this is one of those things that 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. 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 data is so noisy about like, let's say,

things in the middle, like depression and anxiety, which they do correlate. And there are studies that show it 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.

Of which there's like 73, right? I mean, there's virtually none. It's not the norm, right? When you're talking about this, it's like CMT is not a gene for a mental state. Right. It's a gene that has a partial influence on the stickiness of your mind.

And the way that CMT methylated dopamine is with all the methyl donors. So nutrition is gonna play directly into that. And so your CMT genotype isn't even going to tell you the rate at which you're methylating dopamine. It's going to tell you the rate at which you could methylate dopamine, given a certain supply of methyl donors. You've put a lot of time into this, Chris, 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. 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. Sure. So MTHFR, I think what you want to do is number one, you want to get between 900 and 1200 milligrams of colon a day. That is the. And your preference clear, you started on the right. But get it from your food. Like if you can eat enough eggs and, you

know, 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. 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 supplement. Creatine monohydrate. 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 meat head phase. But the most recent literature, I... No, I did that. You... It could. The tradition lived on. It's still on the label.

Is it really? Although the most recent literature I've seen said just monohydrate 5 grams a day is plenty. But again, for most people, we think of that as creatine as a phosphate donor, and in certain types of exercise, I eat the most high intensity. So weight training, for example, 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 coline in synthesizing creatine. It's a role of methylation in synthesizing creatine.

So that whole cycle, whether you're taking the methyl groups from coline, 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 groups supply. So you ate that steak, you synthesized creatine. Five hours later, you're synthesizing nowhere near as much creatine. And the whole system is...

So creatine tracks much more closely to say methyonine than lucine? 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 stake 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. Yeah, log cold.

That's a lot of trouble, right? Yeah, log cold. 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 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 for 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 can do all your creatine synthesis when you had enough methyl groups. Then five hours later, you're in the fasted state and you don't synthesize creatine anymore. It doesn't matter because 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. What determines the phosphorylation status of creatine? About 120 grams. How much of it has an an organic phosphate? 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,

creating phosphate in when you're, so instead of, kind of, but do we have an enzyme? So the way that, you know, for example, like AMPK is a great surrogate for ATP, ADP AMP, right? It really gives you a sense of the energetics. Do we have similar enzymes that give us a sense of CP versus C, creatine phosphate versus creatine?

I don't think there's an analogous enzyme, but there's a completely analogous energy state. So when you're exercising, for example, your ATP levels go down, your AMP levels go up, your creatine phosphate levels go down, your creatine levels go up, when you recover everything reverses. So this is most studied in muscle, but in an exercising muscle, if you do weight lifting to failure, you're going to see the creatine phosphate go from about 100% down to about 40% at the point of failure, and then you rest for five minutes and you're gonna see most of it recovered. So by that logic, I mean, the reason athletes like to use creatine is for increasing that

maximal performance or the duration of short maximal performance, right? It's not gonna have an impact on your ability to run a marathon, but it certainly could have an impact. I think it will have an impact on your ability to run a marathon. You do. Yeah. Interesting. Because creatine does things in muscle that are independent of that. Independent of its phosphate donation.

Yeah. So the another thing that creatine does in muscle is that it hydrates the muscle more. And so you literally have. That's for sure. Yeah. I mean, that's a given just based on the amount of water that travels. That is a direct factor in strength in a way that has nothing to do with the duration of the exercise.

Yeah, so for the listener, they should know that for, you know, anyone who's taking creatine knows this, you're going to put on about four or five pounds, and it looks sort of like muscle. I mean, it shows up in the right places, but a lot of it's just water moving to the muscle, right? That's water that directly increases your muscular strength. Interesting. So it's not just, you know, because a lot of guys will say, well, that's great because I look bigger, but the reality is it's actually functional. And they're stronger. Yeah. You know, you could get that amount of creatine if you just ate a few pounds of meat every day. And apparently there's a diet going around these days with people doing just

that, but I'm not willing to commit to it. Yeah, yeah. The extent to which is important to kind of modify your diet around MTHFR really depends on what problems are you facing and what goals do you have and to what degree do you want to be anal about doing things that have theoretical payoff, right? So I think that for someone who has either high homocysteine or they have psychiatric difficulties, what you would expect from the low methylation state is for someone to be overly ruminating on things. And so if you feel like that's a problem for you

and you feel like what you would typically do to be psychologically healthy is an uphill battle because of your physiology, it might be. And so in that case, I think you would stick do to be psychologically healthy as an uphill battle because of your physiology, it might be. And so in that case, I think you would stick more to that protocol. So obviously taking creatine, increasing your colon amount is the most data back thing. But taking creatine makes a lot of sense

because if you cut your methyl demand in half, then it's probably gonna matter half as much that you're not that good at methylating. So you increase colon because that's the alternative methyl donor. You put creatine into the system because that's decreasing the demand. But there's another overlooked thing here, which is that methyl folate is, I don't know if you want to go into the reasons why,

but let me just state as a fact for faith acceptance, methyl folate is the thing that controls whether you pee out glycine as a methyl buffer. If your methyl folate level is low, I'm closing my eyes because I'm now trying to figure out how tri-methyl glycine will fit into this because I have an anecdote to share with you. So, tri-methyl glycine is beta-ing, which is a thing that you make from calling. Finish your story. I'm going to come back to this interesting anecdote because I'm looking anecdote to share with you. Well, try methyl glycine is beta-image, which is a thing that you make from calling. Finish your story. I'm going to come back to this interesting anecdote because I'm looking forward to you explaining

to me why I observed this case, but keep going into this. When your methylfolate level is low, your body thinks that you are in a state of methyl abundance and that you need to methylate glycine and pee out the methyl groups and the glycine into the urine. And so you probably need more glycine as well.

No one's quantified it. No one's actually shown that that's the case, but what we know is very, very data backed in terms of how does the system work. And everything that we know about the system, how the system works, says, if you have low methylfolate levels, you'll lose glycine in the urine as methylated metabolites. And so that means that you do want to put methyl folate in there because you want to try to have some there to stop that, but you probably need more glycine. And what we know is that we can synthesize glycine, but the average person probably falls

short of their ability to synthesize glycine by 10 to 60 grams a day in terms of optimizing collagen turnover in the skin and et cetera, et cetera, et cetera. We also know that there are studies showing that people get better sleep if they take three to six grams of glycine before bed at night. People have better blood sugar if they take three to five grams of glycine with a meal. So it's entirely reasonable that the average person could use more glycine. And so I think it's entirely reasonable to say maybe throw some bone broth in here or throw some collagen in here or some gelatin or some glycine.

Do you think it matters whether you're getting it in bone marrow bone broth versus a supplement. It would be in the bone broth, and I think the big differences are between getting collagen in versus getting glycine powder. So for collagen, and collagen is what you would get in bone broth, it's been shown to be better at increasing collagen synthesis. Is that, see, I've never understood why that's the case. I've always kind of thought that that makes no sense because you eat a bunch of collagen, what basically emerges from your gut is free amino acids.

No, there's some collagen peptides, there's some dipeptides in there. I mean, how robust are the data on that? I don't know how robust they are. I've actually told patients on a couple of occasions that have insisted that they take their collagen that I just don't think it's helping them. Well, I can believe that. For the benefit of replacing their own collagen, I've always been like, I just don't see how that works.

I mean, there's not. But there's not. Right, there's no good data showing that you will have less wrinkles if you take collagen. I've never heard of any doubt on bone health. The other stuff's more interesting, frankly. If you tell me that five grams of glycine in the form of collagen will produce better glycemic control and better sleep, that's more interesting. I'm pretty sure all of the blood sugar studies were done with glycine powder.

I might be wrong about that. I know the sleep studies were done with glycine powder. All I can think of off the top, my head for a study that was done, and this wasn't even with collagen, it was with a gelatin, which I would assume would be the same. His last name is bar, I forget his first name, but there was a study that showed that before you exercise, if you take 15 grams of gelatin, but not 5 grams, with a little vitamin C, you will increase collagen synthesis in the tendons. And the rationale for the study, and actually I didn't even look at this paper, I just listened to an interview that he did about it.

The rationale was that in your muscle, your muscles very metabolically active, very good at taking things up when it wants to. But the connective tissues in your joints are very dependent on you just pushing more blood supply there. And so when you exercise, you have the amino acids coming in before you exercise, and then when you're exercising, there's an increased blood flow that gets the collagen peptides into those tissues. So part of my ideas here are speculation based on why this works. And so I'm I'm using the reasoning that we would expect those like probably if you were measuring plasma glycine levels and those people you'd find lower levels of plasma glycine and you'd find higher

levels of the methylated metabolites of glycine. Probably if you looked in the year and you'd find those things. And so it makes logical sense to say that you may need more glycine, and so you can put into your diet in these ways. But ultimately, this is like- What foods would be high enough in glycine if someone was sort of opposed to- Skin in bones. Yeah. But- Including like chicken skin and things like that. So bones are the highest, and skin is intermediate. And bones to your point, it's not the marrow, it's the broth you make from the bone. Yeah, it's not the marrow, it's the broth, and it's dependent on the protein content. So if you're making it homemade, you don't know exactly what the protein content is, I would use the metric of whether it's well-geld.

If you assume you can trust the label, there are several bone broth products on the market where they say they have 10 grams per cup. And if they have 10... That's 10 grams of protein or 10 grams of glycine. 10 grams of protein, which should be about 3 grams of glycine. Oh my God. So you got to drink quite a bit of this stuff. Well, a cup is 3 grams of glycine.

Yeah, but if you want to, you know, that's... That's the bottom of your 3 to 5. Yeah, you're going to drink that before bed every night and it might help you sleep, right? In theory. Okay, so now that we've walked through the methylation stuff, I still wanna go back to this NR women, because this is what got us down this path. Right, 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. I don't know exactly what the up and down fluxes 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. But in theory, I mean that means that you're on from 120 to 116 instead of 118, right? In a day. You're talking about whole body

creatine stores. I'm talking about day. You're talking about whole body creatine stores. I'm talking about the cellular level too. First of all, no one's taking this for a day. They're taking it every day, if you're taking it, right? And you don't need your creatine to go to zero before you have problems, right? Like the body builders 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 increase creatine because they're hoping to maybe increase their body's 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 5 grams of creatine a day improves depression and 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 acid into your stomach. So creatine is important in all kinds of areas that you would not expect

to think about it in. So if one was going to take creatine, which I've probably haven't taken since NAM, you wouldn't just take it during exercise. If you wouldn't just take it on the days that you were lifting weights, 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? 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 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 third. Yeah, you'll hit that steady state. 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 want to do in an NR study to show that you're not impacting methylation? So I expect that sometime rather soon, we're going to see a paper coming out showing that it doesn't elevate homocysteine and showing that it doesn't affect the esodena zylmathinine in plasma. And 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 we're-sying in their energy levels

and were really sea-sying 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 is being sent.

And would that person be better off supplementing with coline or creatine if they were going to pick? I would say take a lower dose of this stuff and match it with a methyl donor. 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, I said, I said match at milligram for milligram with TMG tri-methyl glycine. 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 methylfolic 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. Homocysteine falls by 50%. What was going on in this guy? 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 colon to remethyl state homocysteine issue, right? So the way these things work is you're trying to use MTHFR We're calling 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 getting 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 a bunch of snapshots of the sky signal assisting. My guess is that unlike the guy whose home assistant went down with the B6,

this guy, he had a recycling issue. He did not have a problem of disposing of the home assistant 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 tri-methglycine, which is the choline pathway.

So when you use choline from ethylation, what you do is you convert it into trimethylglycine and that becomes the methyl donor that's the alternative. I mean, it makes me wonder now if we just supplemented more choline if we could have got the same result. Yeah, I'm sure you could have gotten the same result. The only possibility that would prevent that would be if he had a problem with the enzyme that oxidizes Colleen to trimethylglycine. I like that it all comes back to Colleen. We have four chickens at home and my kids named them,

so they have the funniest names that two of them have pretty normal names. There's Sarah is one of them and Bang Bang and a go-go. you can almost tell which of my kids named them. I feel like Sarah would feel left up. Yeah, yeah exactly. So little bang bang and go go and Sarah and I can't even I'm embarrassed to admit on the spot I forgot the name of the fourth chicken, but it's a totally normal name that's not funny because my daughter named the Sarah and the normal one on my other guy. But now I feel like even more indebted to these little guys. I mean, I've always loved eggs. And of course, once you eat eggs that are like,

coming from the chickens that you're feeding, the leftover vegetables on your table, like the yolks are so yellow, the eggs taste so good. It's very interesting to see this connection between Colleen Cri creatine methylation. I mean, this is complicated stuff. And of course, the skeptic will take a step back and say, well, Chris, what if you're just fixing a bunch of numbers?

Like, yeah, you can make homocysteine go down. And yeah, you can do this and you can do that. Outside of the naffledee, which there's no disputing if you fix naffledee, you've improved a person's life. Does it matter if homocysteine goes down? Does it matter if you're at six instead of 14 because you've optimized these things? I don't think we can change it. Oh, ginger, by the way.

Ginger is evident. It's Sarah ginger, bang bang gogo, or archick. Yeah, I would still feel left out of those, Sarah. Yeah, yeah, no. Okay, so to the skeptic, no, I don't think the argument is super super strong that by fixing a homocysteine You're reducing cardiovascular risk. That's definitely not a narrow tight argument. I look at homocysteine and I say well look young healthy people have a homocysteine on average between seven and nine That's probably a sweet spot. But yeah, I mean if I were looking at that from the perspective of

what is the least stuff I can do unless I am very compelled by the data to do it, then I would throw out at least everything that I just said except the Colleen, and depending on how hard of a skeptic I am, I'd probably throw out the Colleen too. And that's because this comes down to a philosophical question of what is the level of evidence that you need to take in action? Versus the level of evidence to not take in action, which people always forget that they have to ask

that question just as well. Well, also versus the level of evidence to state that you have a certain degree of certainty or confidence in something. So the thing is, I think that we can be fairly, we will debate it, but I think we can be fairly rational and within a fairly narrow window on what do we believe are the principles that we need to secure to say we have a certain degree of confidence that something is true. But we can never create that window

for saying, what is the level of evidence that I need in order to take an action? Because that comes back to your subjective values. A lot of this is assumption as well. Even if you're coming to the question of what is the probability that we should assess that something is true, for me, I would take as a background assumption that things that have a proven track record and human history over a long period of time should be assumed as a default. Someone else may take the assumption

that nothing is the default or that the status quo is the default. So if you're basically saying that we have to have meta analyses of large randomized controlled trials on clinical endpoints in order to have something, you are assuming that in the absence of that evidence, we will follow the status quo. So even in the case of us debating how confident we are that something is true, we have reasons like that to have a spectrum of agreement or disagreement. But when it comes down to, should I take this supplement, that comes to subjective value

over what kind of risks do you want to take? So, there are some people that want to optimize their metabolism to make their body run like a well-oiled machine, the best way that they know how, and they're willing to spend some money or design their diet around doing so. And I think most of what I said mostly applies to those people, I think for people

who are looking for hard clinical endpoints. And in fact, this is why there's Twitter words over MTHFR sometimes, which is that they're really... Oh, thank God I missed those. Oh, okay. So, yeah, so I mean, so I've gotten into some tussles on the internet with some people who look at this from the perspective of, look, there's no hard clinical

endpoints for which MTHFR is diagnostic. There's no hard clinical endpoints for which MTHFR is diagnostic. There's no hard clinical endpoints for which people with MTHFR, for whom that population has some specific dietary or supplemental regimen that alters that clinical endpoint. And I think that's true, where I come from. If I were in that situation, I would want to bring my homocysteine down to what by all probability appears to be the healthy level. If I were that person, I would want to reason, well, I feel like my mind is too sticky and I want to loosen it up a little bit. If I were that person, I would want to have good energy and I would want to use a rational

assessment of why my energy might be low and what I can do to bring it up to normal. And I'm probably never going to convince anyone that if I feel better, that there's a hard testable endpoint to that. Let's come back to the NR. I did a... I was just about to say, the one thing I really want to ask you about is in all of this stuff, whether it's the increased colon, the glycine, the creatine, I think I get the sense where you, on your own personal spectrum of risk fall on those.

I haven't actually got a sense of where you fall on the NR spectrum. Personally. Yeah. Oh, well, if it helps clarify, I took 75 micrograms of it with breakfast and 75 micrograms with lunch. Micrograms? Milligram, sorry. Which is still pretty low.

I mean, that's much lower than what's provided in those supplements. Right. I got 150 milligram capsules that I broke in half. Okay. So that's much less than what's being provided in basis and true niogen, right? Yeah. I might go up. I'm just playing around with it. It's just a tinkering thing. With or without a serotonin activator? Yeah. It's the true niogen. There's no, there's no tear still being in it. I was studying it a lot, so I figured, let me take it and see what happens.

Which by the way, to me is one of the most tried and true interesting ways to do science is to, you have to become a little bit of a self-experimenter on this stuff. Well, H. Pylori. Yeah, everybody loves to point to that example. I will say this anecdotally, for the patients of mine who do religiously take one of those

two products, basis or true niogen, the one thing that seems to across the board improve and it would be very difficult to attribute this to placebo is patients who have even an inkling of rosacea seem to have a monumental improvement. And again, I don't know if that has to do with the skin. We were talking about the skin again, but- Is it sun sensitive? Rosacea often is, but I don't know if I can say across the board of each of those patients has rosacea.

No, I wouldn't say it's exclusively sun sensitive, right? So some people, their rosacea gets amplified by certain things in their diet. I have some patients when they eat chocolate, it goes off the rails or alcohol or stress or sleep deprivation. So, no, I would say there could be multiple different triggers for it. And I remember once even looking it up and finding sort of an old esoteric paper about topical niacin, I believe.

I think it was in the form of niacin that could improve rosacea. I said before, I think that the skin is one of the areas where I would expect to see fast results. And so it's this question of how do you pick the right people and design the right study to see an effect like that. And so that's interesting. Maybe a rosacea endpoint in a clinical study would have good results to it. Yeah. But what I'm basically taking away from you is IVNAD is not a great idea.

Just on the principles we've described, that does not seem to be the way you want to administer it. It's much better to build up a haphatic reservoir of nicotinamide that's converted through the NR that you can then slow trickle into circulation as needed is probably a better bet. Yeah, I mean, I'd be, I would consider it fascinating to see studies of what is actually

happening physiologically when people inject it. But nothing about that. But outside of that granulocyte response, which some people take that to mean it's doing great things. Like, look at how shitty I feel. This must be doing something right. I've always taken that to mean I don't know. That's why Mercury was so successful back in the day. Yeah, I mean, it makes no physiological sense, but yeah, I mean, a study could prove me wrong, but there are no studies, and it makes no physiological sense.

But I want to come back to one little point on the decision-making thing. So the nicotine-mide riboside video that I made, it was took an anecdote of someone who posted on my Facebook on something else that I was doing and told like a four paragraph story about how she started taking the true niogen and she felt great for a couple weeks, but then she started feeling the energy sapping off and then dropping and then she felt like going through a mental rollercoaster. And I used this anecdote that obviously could have

other explanations and clearly has no clinical measurable endpoint. And I got people just came out of the woodwork. Meaning, custom. Yeah, trolling it like in the YouTube comments. YouTube comments should be never read. But no, but I think listen, this is, I think this is an interesting contrast anecdote

So here there are there are people Often pointing out that there's no hard data in that story Who are saying all kinds of great things about the way they feel when they take a lot of this stuff not realizing the already? So not yeah, so I think it's irony, but it also comes back to the point where, look, people are going to make a decision to take this or not, and there is no clear data on what it does. And so you either take the position that you are going to wait 10 or 20 years until we know something better or you take the position that you're going to tinker. And if you're going to tinker, you're going to tinker a lot more successfully if you have a working

model of what's going on than if you don't. Yeah, I mean, I think it comes down to, and it would be impossible for me to say I don't subscribe to that ethos because, I mean, look, I take Rapa Mison for heaven's sakes. And if you want to talk about a much bigger hammer, I mean, Rapa would probably be the single most out there thing that I do, but my model's robust. Now, I also think I have much more data to point to. So, even though people could say, oh my God, rap amaisin is so scary, I get the point to what happens in the yeast, the flies, the worms, the mice, the rats, the dogs, the kangaroos, the hew... So, I feel like I'm standing on the shoulder of much more evidence, even though

I'm interfering with a much more important sensor, right? I'm actually going after the God sensor, right? Like the single most important nutrient sensor in our body. But at the same time, you know, you don't feel anything, right? Like the, so what's interesting is if you're taking nicotinamide riboside for a way you feel, it's very confusing because I don't see how one can disentangle the placebo effect. I mean, I have, I think this has become something that has come to the public's consciousness

much more. I mean, even the New York Times wrote a piece on this several months ago, which is the power of the placebo effect. And I've even spoken with PIs who have run studies using psychoactive agents, and you'd think, how could you placebo your way out of that? And yet, they've told me that the placebo effect in terms of the post-depression you would get with certain psychoactive is actually greater in the placebo group than the treatment group.

So I just don't know that I trust myself to discriminate between something that works or doesn't work based on how I feel. I'd almost prefer to experiment with compounds where I'm just pointing to biochemistry and hopefully in times, and biochemical proxies. Of course with rapid mice, and we don't have a great biochemical proxy.

We can't measure autophagy, we can't count our senescent cells, you know, we can't look at inflammation within our muscles, things that we believe would be improving. But I just don't like the idea of having to rely on how I feel solely. I mean, yeah, look, if you feel like crap, that's, that's, that's reason, whether it's placebo or not, that's reason to stop. Yeah, or if you feel like crap, that's whether it's placebo or not, that's reason to stop. Yeah, or if you feel like crap and then you take something that makes you feel great, that's placebo, leverage it. Yeah, although, again, look, I mean, you could argue that taking heroin will transiently make you

feel pretty good too, and it's sort of a dumb example because it's so over the top. So Peter Tiel has this great question that he poses in, if he posed it in the book, you know, 0 to 1 or he certainly talked about this, which is, what's the important truth that very few people would agree with you on? So something that you think is definitively the case or probabilistically very likely to be certain that you would find very few people to agree with you on. And this doesn't have to be just limited to what we talked about today. This could be any...

Should it be limited to health and medicine? No. Okay, then I think that's easy. The thing that I believe strongly about that the largest number would people would think I was crazy for would probably be that I'm twice the libertarian of your libertarian uncle. I don't know. I think you'd find a lot of people that more and more now are losing faith in big government and would probably come to your aid on that. Maybe not.

I believe there would be a few hundred, yeah. You're that extreme in your libertarian views. All right. Well, then it's appropriate. I phrase this question through the lens of Peter. What about within the world of biochemistry, medicine, et cetera? So I think it's a very population-specific thing. So for me, I believe certain things in the alternative health sphere that I think I'm surrounded by people that disagree with me

on, and I spend a lot of time there, that other people in the conventional sphere might be, I think, I'm totally right for. I mean, by example. Okay. So as an example, in the alternative health sphere, it is almost useless. By the way, am I in the alternative health sphere or not?

I don't know where I live. Probably. Wow. So I think alternative medicine, it doesn't really have a clear definition. Like the NIH has an arm of alternative medicine. But alternative medicine is basically the stuff that's not standard practice, and then when it becomes standard practice, it's not alternative anymore.

Okay, fair enough. So by one definition, you could kind of encompass everyone who's doing something progressive or on the edge or whatever. I mean, to the extent we would disagree with that, I would probably just modify my definition here. So I find myself in the nutrition sphere, I find myself among many people who would throw out the RDAs, for example. So I would say people in nutrition that they're not RDAs, they're fairly progressive, they're

fairly alternative, they're into supplementation or whatever. Probably think that the RDAs are trash science. And I think that the RDAs are actually super good science. They're often outdated. probably think that the RDS are trash science, and I think that the RDS are actually super good science. They're often outdated. They're often limited by the fact that if you are a committee who's producing a report that someone else is going to simplify onto a four-inch square on the side of the boxes of the cereal, that everyone in, you know, that 300 million Americans are going to just

look at the number and make some assumptions about that you have to be able to a lot more careful about what you say. But I think that we really throw the baby out with bath water if we don't look at what's been done by the people who are hardcore conventionals. This is your history coming back to you, right? Your appreciation for the history of how this is going to happen. It's not just history. I mean, for right now, one of the first things that I did when I started researching Niasin was I read the DRI report for Niasin, which was in 1998.

There's a lot that you could say to criticize it, but I think that wherever you are in controversy that you really have to know the core of what constitutes the conventional belief. Just look at my Twitter feed over the last few days. I'm in an environment where many people are convinced about the carbohydrate hypothesis of obesity. And in fact, one of the interesting things about me is that I think I found myself very friendly with people in the low-carb community because of things that I think are crazy in the conventional community that we agree on. So, for example, I think the history of the dietary guidelines and the demonization of saturated fat and cholesterol in the diet is completely wrong. And I've done a lot on that to the point where I think probably both of us for the amount

of eggs that we consume, there is a very large number of colleagues of ours who might think that we're crazy. And let's take the example of the carbohydrate hypothesis of obesity. So I went into graduate school thinking that insulin was to cause obesity and that you couldn't store fats in adipose tissue unless you had glucose there available and kind of all these things. And also went in thinking that the chain of causality was from metabolic problems to obesity. I couldn't figure out why I don't have my professors seem to think that the causal chain was opposite and that obesity was causing metabolic dysfunction. I think I've come to really believe that the conventional view of obesity being a cause of metabolic dysfunction is true, and that puts me square in the middle of conventional

theory on a lot of metrics, and because of the environment that I've put myself in with the people that I'm friends with and colleagues with in that particular environment I think it's a truth that a lot of people find me crazy for Yeah, it's interesting. I mean Yeah, I've never really thought about where I said I mean, you know, so my view is that obesity is actually largely a compensatory response for something metabolic so that's the opposite view of you, I think, if I'm understanding you correctly. It's also hard to neatly fit these views into a box. Because you're always going to find a patient that's an exception to your rule.

That's a whole separate story. There's a lot more I'd like to go into, but we have been at this for about three hours. We might just have to do around two at some point. In the interim, what is the best place for people to find you? I know you're pretty active on social media, where how do you like to engage? So my website is chrismasterjohnphd.com. Everything I do is posted there.

I'm on Facebook, Twitter, Instagram, and YouTube are the main places to find me. Twitter is a good place. And your handle is. Chris at Chris Masterjohn on all of those. But not Chris Masterjohn PhD. That's only your website. Yeah.

I would have made it at ChrisMasterjohn.com, but when I decided to buy it, there was someone who bought it years ago and was selling the domain name for like $50,000. So they could have said, I'll just add the PhD. That's why mine has MD by the way. Yeah, yeah, yeah. I didn't want to pay for the regular one. A lot of the stuff we've talked about, this will be some pretty robust show notes because we've got to, there's so much stuff to link to as you pointed out, so many of these things

are not as difficult to, I don't want to say easy, but they're not as difficult to understand when you can see the diagrams. Yeah, for sure. You've done some really elegant videos on a number of these topics, which we'll link to. And I just wanna thank you for being here, man. Yeah, thank you for having me. It was great.

How was that Topo Chico, by the way? That was your first. It was great. It has a slight taste of beer to me. Interesting. I promise I didn't spike it, so I'm glad. Whenever I can give someone their first Topo Chico, it is such a feeling of gratification, so. I'm really glad. Whenever I can give someone their first Topo Chico, it is such a feeling of gratification.

I'm really glad. Thank you so much. You can find all of this information in more at pterotiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peteratiamd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email, where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc.

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