216 - Metabolomics, NAD+, and cancer metabolism | Josh Rabinowitz, M.D., Ph.D.

1. 0:00 – 0:08

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. [upbeat music]

2. 0:08 – 9:11

   Josh’s background and unique path to becoming a research scientist at Princeton

   1. PAPeter Attia0:09

      Hey, Josh. Great to see you again. It's been, uh, I don't know. I was trying to think about this the other day. Has it-- It was about three years ago, I think was the last time we saw each other in person at that, uh, some sort of conference in New York. Um, a cancer metabolism conference, I think, right?

   2. JRJosh Rabinowitz0:23

      [lip smack] Oh, yeah. The, uh, New York Academy of Sciences, I think.

   3. PAPeter Attia0:28

      Yeah, yeah. It was great. Um, and we somehow wound up at some kind of mediocre bar in Brooklyn and-

   4. JRJosh Rabinowitz0:35

      [chuckles]

   5. PAPeter Attia0:36

      ... it might have been the dorkiest concentration of people talking about autophagy and metabolomics and [chuckles] all sorts of things. There was-

   6. JRJosh Rabinowitz0:45

      Oh, yeah, yeah. That was actually the AACR Brooklyn Conference. That's true. [chuckles]

   7. PAPeter Attia0:51

      [chuckles] Um, well, you know, it's really funny. Just recently, I've interviewed a few of our classmates from med school, Max Dean and Carl Desroche. Um, and I think Carl and I were reminiscing about how you, me, and Carl all started our surgical rotation together in the same day. And I, I, I-- It, it's almost 25 years ago, and I remember it like it was yesterday when we were all sitting in the room practicing sewing with our big, goofy knots and things like that before we all got divided up into our surgical rotations. Do you, do you remember that?

   8. JRJosh Rabinowitz1:20

      [chuckles] I, I definitely remember you. I really do not remember Carl from those days, but I certainly remember you practicing a lot while I looked and said, "Oh, I guess that's what you're supposed to be doing if you wanna become a surgeon." Uh, the thing I remember most clearly is being in surgery with you, and it was like the very end of surgery rotation and, uh, finally being given the Bovie-

   9. PAPeter Attia1:42

      [chuckles]

   10. JRJosh Rabinowitz1:43

       ... a-and immediately making a mistake. And, uh, you know, then I got the nice lecture. You know, "We're happy to pass you on this rotation as long as you promise never to use, you know, a knife or Bovie again," so. [chuckles]

   11. PAPeter Attia1:57

       So, um, remind me, whose lab did you do your PhD in?

   12. JRJosh Rabinowitz2:01

       Uh, I did my PhD with Harden McConnell, uh, one of the great physical chemists, uh, together with Mark Davis, the, uh, immunologist.

   13. PAPeter Attia2:09

       And so t-tell, tell me and tell the listeners a little bit about what project you worked on for your thesis.

   14. JRJosh Rabinowitz2:16

       Uh, my thesis was about the physical chemistry of T cell activation. And so a-a-at that point in time, people had discovered that different antigens could activate T cells differentially, and so I was really interested in how that happened. And so I studied the process of antigens turning into peptides that could bind to MHC, and then how the kinetics of the interaction between the peptide antigen and the major histocompatibility complex protein, MHC, um, and then the interaction of that complex with the T cell receptor determined whether people have productive or failed immune responses with the hopes you could then manipulate those processes to promote better vaccination or, um, disease clearance, and also to potentially treat autoimmunity.

   15. PAPeter Attia3:05

       And did you also have an interest at all in cancer? Because of course, this would be one of the hallmarks of how immunotherapy would be effective in, uh, eradicating cancer.

   16. JRJosh Rabinowitz3:14

       You know, uh, shows how bad a prognosticator I am. At that point, I really felt that, like, immunological approaches to cancer didn't hold that much promise, and so I was really more focused on, uh, infectious disease and autoimmunity. Uh, so shows you what I know. It's wonderful to see that the world has turned out to be a lot better than I, I dreamed it would be on that dimension.

   17. PAPeter Attia3:37

       No, but it, it's such an interesting topic. Um, I had Steve Rosenberg on the podcast last year, and it was just a, it was a beautiful and fun recap of how the immune system works i-in general, but we were talking about it obviously through the lens of cancer. And [lip smack] I think the part that will forever, um, humble anyone who tries to think about how amazing the system is, is that these things have to be at, you know, nine to 11 amino acids long. I mean, the peptides have to be just the right size to be presented and then to be recognized, and that just doesn't seem to leave a lot of margin for error. I mean, it is really a, a tuned system. Do you have a sense of why evolution ended up with such a narrow fragment of peptides that were recognizable, um, as opposed to a broader range, or as opposed to just a range that's different? Like, why wasn't it two to three or 150 to 160 amino acids? Like, is there a chemical reason? Because you're a-- Because of your background in chemistry, I feel like you'd be more equipped to offer a teleologic explanation for this.

   18. JRJosh Rabinowitz4:40

       Yeah. I mean, I do have a intuitive sense on this that, you know, uh, our bodies work on the scale of, you know, billions of immune cells and billions of immune receptors that are made through recombination, and that naturally pairs with billions of antigens. And so you just think about this number nine, and you think about the number of amino acids, right? There are 20 amino acids, so you're talking about 20 to the ninth power of presentable peptide antigens. And so these things are all tuned to be on the same scale, this kind of scale of billions-

   19. PAPeter Attia5:15

       Tens of billions in that case. Yeah.

   20. JRJosh Rabinowitz5:18

       Yeah. Exactly.

   21. PAPeter Attia5:18

       Yeah. So if you did it-- If it, if it was like a three peptide, it's, it's really a small number, actually.

   22. JRJosh Rabinowitz5:24

       There's not enough information there-

   23. PAPeter Attia5:26

       Yeah

   24. JRJosh Rabinowitz5:26

       ... to, you know, selectively respond to a virus, you know, uh, or a, a bacteria.

   25. PAPeter Attia5:32

       And if it was 25 peptides, it, it's too much. It's-- There's too much information there.

   26. JRJosh Rabinowitz5:40

       There's extra information anyway, and this system, I think, was built to work on minimal or, or just the right amount of information.

   27. PAPeter Attia5:50

       Yeah. That's super interesting. So at what point during either your PhD or the end of medical school, where we met up in the, in the clinical-

   28. JRJosh Rabinowitz6:01

       Mm-hmm

   29. PAPeter Attia6:01

       ... portion, did you make the decision that you wanted to be a full-time scientist as opposed to a physician scientist?

   30. JRJosh Rabinowitz6:09

       You know, I, uh, applied to do a internship knowing that I really loved research, but, um, I guess I decided as I did more and more medicine that medicine is such a noble profession, but it involves a lot of doing the same thing right over and over again, uh, a lot of following the standard of care, even for the most creative physicians, and that ultimately, like, my passion is to come in and try to do something different, uh, every day, to think differently than people ever have before. And so that's what really led me to research. I, I love the patient interaction part of medicine. It was the, uh, doing things right part that was challenging for me sometimes.
3. 9:11 – 14:59

   What sparked Josh’s early interest in metabolism

   1. PAPeter Attia9:12

      So this is kind of an unusual path, right? I, I'm guessing that most people who experience that type of success that you had would wanna keep doing it over and over again. I mean, hence the term serial entrepreneur. What made you decide to take this lateral step to go into academics, which would've made a lot more sense if you'd done it coming straight out of your PhD?

   2. JRJosh Rabinowitz9:35

      You know, I think I was lucky to get the chance to go straight from that job into a, you know, faculty position at Princeton. That's a rare opportunity to have.

   3. PAPeter Attia9:44

      Because you didn't do a postdoc in there un-unless they considered your industry as sort of a grandfathered postdoc.

   4. JRJosh Rabinowitz9:51

      Yeah, it was a very, very weird version of a postdoc and, um, it, it united me with my, uh, wonderful wife and, uh, at Princeton on the faculty here and, um, turned out well.

   5. PAPeter Attia10:05

      So you show up at Princeton and they put you on a tenure track position, which means they're giving you the types of resources to now start solving whatever problem you want. What was the first problem that you said, "I wanna build a lab around"?

   6. JRJosh Rabinowitz10:19

      You know, one thing that I learned actually doing Alexa was, uh, about drugs because we studied every medication in the pharmacopeia for whether it could be a candidate for rapid delivery. Could you make a, a benefit by delivering it rapidly? And one thing I noticed is that so many of the most important medications work via metabolism. And then starting out my lab, I realized that there were relatively few labs looking at metabolism broadly compared to other, you know, really important areas of science like immunology or, uh, cancer or neuroscience. And so I started my lab with a really simple question: Could we measure the classic metabolites that you read about in a biochemistry textbook in one shot quantitatively? And so that was, uh, the starting point for my lab. And I guess the second question that we always had in our mind is, can we measure the activities of those metabolic pathways? So how fast are those metabolites flowing? Where are they coming from, and where are they going?

   7. PAPeter Attia11:20

      I had lunch or dinner actually with one of our mutual friends, Navdeep Chandel, um, who's also a previous guest on the podcast three or four years ago, uh, maybe a week ago. And he was here in Austin for, uh, a talk and we were talking about how in the late '90s he said, and he was obviously studying metabolism, he said, "If you were to rank me," meaning Nav was ranking himself, right? If he said, "You were to rank me and my work," uh, just across the spectrum of the stuff scientists were doing, he said, "I'm bottom 10 percentile." You know, I mean, nobody found metabolism interesting. It was-- This was sort of the, uh, I forget the term he used, but, like, this was basically the corner where the, the s- the kids went that nobody wanted to play with. You know, if you weren't doing genomics, if you weren't doing this other sexy stuff, immunology, you were, you were really an uninteresting person But he just found it interesting. And of course, today, as we're gonna discover, this is where the action is. So, w- uh, you know, Nav was talking about that in the '90s. We're now in the early 2000s. Was it still a little bit of that stigma that Nav described that he was kind of under where he was like a totally underperforming, you know, loser in his own [chuckles] words? Or was that transition already starting to happen where people saw, "Wait a minute, there's something going on here"?

   8. JRJosh Rabinowitz12:48

      [chuckles] You know, Nav is so funny and, you know, I don't think anyone who's ever met Nav thinks he's a loser. I'll say that right [chuckles] off the bat first.

   9. PAPeter Attia12:56

      Of course not. Yeah.

   10. JRJosh Rabinowitz12:57

       Um, you know, but, uh, uh, uh, I will say that, you know, metabolism as an area was definitely o- out of favor. And i- it was a really strange thing because you had the academic current that metabolism was a solved problem, right? Krebs was, you know, the culmination, uh, of metabolism research. At the same time, that metabolic syndrome was becoming worse and worse and worse in the population. And I would say wh- when I started, it was still not a real popular topic, metabolism, but I think, um, two things were beginning to shift. One is the fact that people realized that, you know, genomics as a standalone was not gonna solve health problems, uh, that it was really gonna have to be, um, supplemented by other technologies that looked at biochemistry broadly. And metabolomics proved to be one of those that I think has been enduring and will be enduring. And the second is that, you know, the metabolic syndrome epidemic just kept becoming more and more obvious.

   11. PAPeter Attia14:02

       Yeah, so this is kind of where your training as a physician becomes relevant because perhaps more so than somebody who didn't spend four years also doing [chuckles] medical school, you saw the clinical problem that was sort of kicking you in the face, even if it wasn't top of mind to a scientist.

   12. JRJosh Rabinowitz14:22

       Yeah, I, I think it's really true. You know, I just benefited so much from the breadth of biology, uh, and medicine that you learn in medical school. And I mean, it allowed me to start my lab working on bacteria, which I had never worked on at all as a PhD student because, you know, you learn bacteriology as one of the things i, in medical school, and that was, like, the perfect starting point for building these technologies with a view all the way to metabolic syndrome and ischemia-reperfusion injury, right? These huge medical problems. But, uh, I really wanted to start somewhere tractable where we could get, you know, firm proof of concept.

4. 14:59 – 25:42

   Metabolomics 101: defining metabolites and how they are regulated

   1. PAPeter Attia14:59

      So for somebody listening to this, which let's assume that they have a greater attention span than somebody you're gonna walk into at a cocktail party, but obviously not necessarily the, the depth of understanding of everything we're about to go into, how would you explain metabolism to that person?

   2. JRJosh Rabinowitz15:17

      Uh, metabolism is the process that converts the food we eat into usable energy and the building blocks our body needs to grow or regenerate itself, a- as well as waste along the way.

   3. PAPeter Attia15:31

      And so now how do you layer on the omic piece of that, which is really what we're starting to talk about? When people hear the word genomics, they sort of understand what that means. But I think when people hear the term metabolomics, it becomes a little harder to understand. So how would you now layer in that in, in, in the context of everything that you're now beginning in your lab?

   4. JRJosh Rabinowitz15:55

      Y- Yeah. So, you know, the bulk of activity in metabolism that makes most of our usable energy, uh, involves something like, uh, a hundred metabolites. And so the first thing we really wanted to be able to do was measure those hundred metabolites really well.

   5. PAPeter Attia16:10

      So tell, tell people some examples of those, Josh, 'cause w- I mean, I think we take it for granted, but, like, glucose would be an example of a metabolite. What are some other metabolites that are important to understand if you're trying to study this system?

   6. JRJosh Rabinowitz16:23

      Yeah. So, um, all the amino acids are other fundamental inputs that we get from the diet, like glutamine i- is a great example. That's a very important circulating nutrient. Uh, other things that come in, you know, from the diet, if you have vinegar, you have acetate, or else your microbiome can, uh, make acetate that goes in the body. Fats are obviously important input metabolites. A- And then there's sets of intermediary, uh, metabolites. Uh, these are things that are, like, glycolytic intermediates that people may have heard about in biochemistry. Fructose bisphosphate is a famous one of those. Uh, pyruvate, uh, lactate that a lot of people hear about from, uh, exercise. Uh, members of the Krebs cycle like citrate, uh, is a famous one that exists in our circulation, obviously in citrus fruits. Uh, so these are classic examples of metabolites. And then there are the kind of more effector or energy-holding metabolites like ATP, NADH, NADPH.

   7. PAPeter Attia17:24

      Got it. So I kind of interrupted you there, but you were kind of explaining how first you begin with sort of this survey of all of these metabolites.

   8. JRJosh Rabinowitz17:32

      Yeah. So we, we wanna be able to measure all of these. These are kind of the core components of metabolomics. And part of the, the beauty of metabolism as a system is that, uh, with some modest variation, there's a- almost a singular solution on Earth to how metabolism works. And so when we learn to measure the metabolites in E. coli, at the same time, we were really learning how to measure, uh, metabolites all the way up to human. And so there are these basic components of protein and nucleic acids, basic intermediates like fructose bisphosphate that e- exist at all of these levels. And if you survey relatively comprehensively, there's on the order of 1,000 of them that have clear biological function. So it's a big problem, but it's a problem on the scale of, you know, knowing all the kids who go to your high school, n- not a problem of, you know, knowing everyone in the phone book in New York City, right? So it's a problem, uh, that's right at this interface between, uh, the human scale and the computational scale

   9. PAPeter Attia18:38

      So I wanted to ask you about that. You already kind of anticipated perhaps almost the question, which is, do we think we have the complete solution set here? I mean, we clearly know all of the amino acids. Uh, we clearly know all of the intermediate steps, uh, and intermediaries period of the Krebs cycle. Do we think that that means we actually know every single metabolomic element? Or is there a chance that there are others out there that we don't know because we haven't looked for them, or they're very short-lived, for example, and we haven't stopped and looked at reactions closely enough or studied the kinetics hard enough? I mean, uh, this is almost a naive question in a way, but I've never actually thought about it until now.

   10. JRJosh Rabinowitz19:23

       Yeah, it, it's a great question, and we keep discovering, uh, new metabolites. So, um, you know, groups around the world keep discovering new metabolites. Uh, I would say it's a interesting yin and yang because there's this steady accumulation of new metabolites, but I don't really think there's been a completely new and obviously important metabolite yet this century.

   11. PAPeter Attia19:49

       Wow.

   12. JRJosh Rabinowitz19:49

       So I, I think at some level, in terms of the metabolite finding part of the problem, things were wrapping up around the time of Krebs, uh, the most important part of the work anyway. Um, but i- in terms of understanding how the system really works and how we can choose the right diet to be healthy given our genotype, given the disease we're fighting, you know, we haven't scratched the surface yet.

   13. PAPeter Attia20:15

       How many of these metabolites are really tightly regulated, uh, a la glucose, versus not that regulated at all? They can kind of fall to zero, and they can... Meaning how many of these things can change by log orders all over the place?

   14. JRJosh Rabinowitz20:31

       Mm-hmm.

   15. PAPeter Attia20:31

       And how many are regulated so tightly that if you just fall a little bit out of that range, I mean, you're dead? I mean, one of the things I try to explain to people when I explain regulation and homeostasis is I love using pH as an example because, you know, the pH spectrum runs from, you know, basically zero to 14, neutral being seven, but anybody who's taken care of a patient in the hospital knows that se- you know, 7.4 is where we live as an organism, almost unsurvivable to have an acidosis that goes below seven or an alkalosis that exceeds about 7.7. I mean, you know, so for a system that runs basically, you know, zero to 14, the fact that we can't as a species survive from m- outside of seven to 7.6 or 7.7 talks about something that is so tightly regulated. So in that field of metabolomics, which ones behave like pH and which ones don't?

   16. JRJosh Rabinowitz21:31

       Well, you know, pH is such a great example, right? And you have this giant logarithmic scale from zero to 14, right? And so e- even when you talk about, you know, 7.1 to 7.4, you're talking about something, you know, of a, you know, two, threefold change, right?

   17. PAPeter Attia21:46

       It's about a three, two to threefold change in, in acid concentration. That's right.

   18. JRJosh Rabinowitz21:51

       A- and I think a, a lot of metabolites that are the important ones live typically in that two to threefold range as being the preferred range. Uh, some of them, there's a lot more active regulation, like glucose. Some of them, uh, there's kind of relatively passive processes that tend to keep them in that range. Then, of course, there are all sorts of other metabolites that may be some cool secondary metabolite that's made by a plant, and some of us eat it, some of us don't eat that plant, and so some of us may have a lot, some of us may have none. But for, for the big ones, the biochemistry textbook ones, I think, you know, this kind of, uh, fewfold range in the bloodstream is, is a common healthy place to be.

   19. PAPeter Attia22:37

       Are there common and consistent tools that the body uses to regulate? Are there principles that the body just adopts over and over and over again in the form of this regulation?

   20. JRJosh Rabinowitz22:48

       Yeah. I, I think there's one most important principle, and that's when it's there, use it up. Uh, and so, you know, in a, a physics speak, you could say this is a, a, um, linear consumption of circulating metabolites, or in chemistry speak, uh, people call this mass action, just whatever mass is there, you tend to take it in. And so, um, you eat. Uh, a lot of what you eat after a little bit of processing enters the bloodstream, and then it's the job of tissues that need these ingredients to use them and use them, uh, at first blush in proportion to their availability in the blood.

   21. PAPeter Attia23:30

       Are there examples where that regulatory mechanism is not the preferred way to manage them?

   22. JRJosh Rabinowitz23:37

       Well, there's a lot of regulation layered over top of that in order to make the body work. And, you know, the most important regulatory hormone in, in mammals I, I'm pretty convinced is insulin, right? And, you know, there are two ways, uh, to look at insulin, I think, and there's the-- probably the way that comes to mind first to you, which is insulin is a hormone that acts to control elevations in blood sugar. Right? And it does that at the highest level by promoting uptake of glucose and preventing production of glucose. But there's an alternative way to look at insulin, and that's that w- we've evolved mainly to be able to survive lack of nutrients, okay? That this was the strong selective pressure on animals and mammals, and that storing fat is very precious, and that insulin is a hormone that says you don't have to use fat right now Okay? And so it senses that there's enough carbohydrate around, and therefore it's safe to not release, uh, free fat from your adipose tissue.

   23. PAPeter Attia24:57

       Does that mean that you think that an equally important role of insulin is not just the disposal of glucose into muscle and the cessation of glucose production in the liver, but you're saying it's equally important as a signal to stop lipolysis to keep your fat in its fat stores, meaning save this for a rainier day because you actually have the glucose here that I'm gonna deal with?

   24. JRJosh Rabinowitz25:24

       Yeah. That's, that's certainly, uh, how I look at insulin right now. And I, I think there's little doubt that, you know, biochemically a- and medically, the suppression of lipolysis is a primary... perhaps the primary, you know, function of insulin.

5. 25:42 – 34:43

   Fluxomics: Metabolism as a system in action

   1. PAPeter Attia25:42

      So kind of going back to the broad strokes of metabolomics, you alluded to it briefly without, I think, using the term, but w- what do we know about the flux of these things? Because when I think back to my-- even my biochemistry 25 years ago, you know, Stryer's textbook, which is, you know, the classic textbook, at least it was then, I imagine it's one of them still today. We really studied it in a static way. Um, and I'm guessing that that's one of the first questions you went after, right? Which is what's, what's the movement? What are the, what are the derivatives with respect to time of all of these things? So, um, m- maybe expand a little bit on this idea of the-- of fluxomics.

   2. JRJosh Rabinowitz26:30

      Yeah. I, I mean, metabolism is a, a system in action. And I think this kind of static view of metabolism, which is probably never a view that Stryer ever had in his mind, but that got codified in the textbooks, is one that kind of killed metabolism i, in a way as a, a topic of excitement. And so, you know, metabolites are intermediates in the process of converting what we eat into usable energy and protein biomass and these things. And so they're really, you know, relatively low in abundance, and they're flowing very, very fast. So they're completely different than parts of our body like neurons that are gonna sit there maybe for our entire lifetime, okay? [chuckles] Here, the metabolites are meant to be made and used somewhere on the timescale, depending on the metabolite of roughly a second to, you know, roughly an hour maybe for metabolites in the bloodstream. And so, uh, all the action is in the flow. And so, um, it's really understanding where things are coming from, where they're going, uh, where we can learn about how metabolism works.

   3. PAPeter Attia27:44

      Let's again just use glucose because one, it's ubiquitous. Everybody gets it. It's essential for life. But it also offers, I think, a beautiful portrait in velocity. So, um, I just had my blood drawn yesterday. I draw my blood about every two months. And, um, so, you know, tube of blood comes out and, um, l- let's say my glucose on that... 'cause that's a snapshot, right? That's literally-

   4. JRJosh Rabinowitz28:08

      Mm-hmm. Yep

   5. PAPeter Attia28:09

      ... in that moment, out comes five tubes of blood, and it's gonna look for a whole bunch of things, but one of them is glucose. And my glucose, 'cause I did a finger prick at the same time, my glucose was 89 milligrams per deciliter. Can you explain to people what that actually means? What does it mean that my glucose at that moment in time was 89 milligrams per deciliter?

   6. JRJosh Rabinowitz28:30

      Well, I'm sure you were smiling about it. That is like it's a, a super healthy blood glucose in terms of a level. But when, when you think of that absolute amount of glucose, right? If you took all the glucose in your bloodstream at that level, that's a few minutes of, of glucose or energy for the body, right? So-

   7. PAPeter Attia28:48

      Yeah. It's probably-

   8. JRJosh Rabinowitz28:48

      ... that has to-

   9. PAPeter Attia28:49

      ... what, four or five grams of total glucose.

   10. JRJosh Rabinowitz28:52

       Exactly.

   11. PAPeter Attia28:53

       Yeah. 20 calories worth.

   12. JRJosh Rabinowitz28:55

       Exactly. So that has to be constantly replenished in order to feed your brain and the other tissues like activated immune cells that depend on glucose.

   13. PAPeter Attia29:06

       Now, this is what to me is remarkable. If I had done that same test, Josh, and I had come back... and let's make the math easy and say it was 90. We'd still say, "Great. You're healthy. Your fasting glucose is 90." Now let's say I had come back and it was 180 milligrams per deciliter, my fasting glucose. There's a disease that I would immediately now know that I have. That disease is called type 2 diabetes. What's the absolute difference in the amount of glucose in my bloodstream? It went from being 5 grams to 10 grams?

   14. JRJosh Rabinowitz29:40

       Mm-hmm.

   15. PAPeter Attia29:42

       Seems like a really trivial amount. Why is it that the body in the person without diabetes seems to be able to keep it at, you know, 80 to 100 milligrams per deciliter overnight while you're fasting? But in a disease that's gonna more than double your risk of mortality and increase your risk of cancer, Alzheimer's disease, cardiovascular disease, I mean, it's, it's, it's, it's really a problem for your health. It's only doubling the amount of glucose in there, and it's still a relatively trivial amount that needs a constant, constant update.

   16. JRJosh Rabinowitz30:17

       Yep.

   17. PAPeter Attia30:17

       How can we explain this delta of... that seems so trivial in the absolute amount that could be consumed in just an extra couple of minutes, but yet the steady state is still off by this factor? What's going on and why?

   18. JRJosh Rabinowitz30:33

       Yeah. I mean, when you think about why is that a disease problem with only a twofold excursion, then you think that, right, the system has been built to have a- about the most circulating glucose that you can have safely, right? And I think a lot of the really important metabolites have been kind of pushed to the edge this way, right? And so we know that there are deleterious, you know, protein modification reactions, glycosylation reactions that occur when glucose gets above this point. So we, we kind of in evolution pushed right up to the highest non-problematic glucose. We didn't do that for a lot of other metabolites, and that's why there's not a lot of, you know, part of why there's not a lot of other diseases like diabetes. So, so that's part of the answer is that, you know, you know, evolution didn't build a lot of wiggle room for your glucose to safely rise because having that, you know, good amount of glucose circulating is really valuable, right? You know, every time your heart pumps, it's sending that amount of glucose to tissues, and that's productive. Um, o-on the flip side, obviously there's a broader set of derangements in the body to produce this twofold excursion i-in glucose, right? And so, you know, this has to do with, you know, things going wrong in fat and fat handling. And so that, that's part of this whole metabolic syndrome that leads to the full set of downstream health consequences.

   19. PAPeter Attia32:06

       It's so interesting that the body doesn't just... Again, I think this speaks to why the flux problem is the more interesting problem than the static problem. Because if you just think about this example in the static context, you would say, "Okay, well, at seven oh four and three seconds AM, your blood sugar is a hundred and ninety, but three minutes later, if nothing changes, meaning if your liver doesn't put too much glucose back into circulation, you'll be fine." So-

   20. JRJosh Rabinowitz32:41

       Yep

   21. PAPeter Attia32:41

       ... the problem is not that your blood sugar is too high in that moment. The problem is the liver assumes, I, I mean, in part, that that's the right level, and it continues to do it because at that moment when you're not eating, that is the only source by which glucose is getting into the bloodstream. So we're maintaining this elevated cycle, right? It's, it's everything from gluconeogenesis, hepatic glucose output. I mean, all of these things continue to stay unregulated, and I think that's only really appreciated when you think of time and the passage of time.

   22. JRJosh Rabinowitz33:11

       Yeah. I, I think one thing that's really interesting is that you can have, um, depending on the details of how processes are tuned, the, the same amount of production and the same amount of consumption, and these have to be balanced for your glucose to stay, you know, anywhere close to steady, okay? So in a diabetic, production and consumption are balanced. In a healthy person, production and consumption are balanced. And they can even be the same amount of production and consumption.

   23. PAPeter Attia33:39

       That's right.

   24. JRJosh Rabinowitz33:39

       But it can just be that you need a higher amount of glucose to achieve that same balance of production and consumption in the diabetic. A-and that reflects, uh, often in, in my opinion at least, you know, underlying issues with how fat is handled, that you either need more glucose to induce more insulin in order to suppress lipolysis in the diabetic, right? Or more glucose to out-compete fat to get burnt in tissues. And so ultimately, I think a, a lot of what's setting blood glucose is competition between glucose and fat. This is a very old, uh, idea called the Randle hypothesis, but, but I think there's a lot of truth to it. We have a lot of new data that's consistent with it. And so I think a, a lot of these issues come back to making room for glucose to be burned by controlling the amount of fat that's being used by

6. 34:43 – 37:44

   The Randle Hypothesis: glucose and fatty acids compete as substrates for oxidation

   1. JRJosh Rabinowitz34:43

      tissues.

   2. PAPeter Attia34:43

      So can you state for folks the Randle hypothesis? I'd, I'd love to actually talk a little bit about the, the more recent data, because as you said, I mean, this is, I mean, this is over fifty years old, isn't it?

   3. JRJosh Rabinowitz34:54

      Uh, you know, I'm a terrible historian-

   4. PAPeter Attia34:56

      Yeah, yeah

   5. JRJosh Rabinowitz34:56

      ... so I'm gonna trust you on that one. But, you know, I, I think the e-essence of the hypothesis is that fat is somewhere between a preferred and the preferred, uh, fuel for tissues, and there's competition between carbohydrates, uh, classically glucose and fat for burning. And so when fat is available, then glucose tends not to be burned effectively, and that's a possible cause of diabetes.

   6. PAPeter Attia35:25

      Now, of course, when you say fat, you don't mean fat within adipose tissue. You mean fat within-

   7. JRJosh Rabinowitz35:33

      I mean-

   8. PAPeter Attia35:33

      You, you mean fat that's available for use.

   9. JRJosh Rabinowitz35:36

      Fat that's available for use, and so that can come in multiple forms. The simplest way to think about it is free fatty acids that are floating in the bloodstream, and that may be the most important form of it. But there's, you know, also, uh, adipose stores within tissues, not, um, subcutaneous white adipose, which is typically a healthy place to store fat molecules. But you can end up with what people call ectopic fat, for example, droplets of fat building up in muscle, and when those are there, they can compete with carbohydrate for being burned. Or you can have, uh, breakdown, uh, of lipoproteins from the bloodstream, things like VLDL, okay, that we, we desperately need to have broken down in order to have a good HDL and a, you know, a low, um, LDL cholesterol.

   10. PAPeter Attia36:26

       Tell me about some of the more recent, um, evidence around why that hypothesis may be more compelling, even so than when it was proposed.

   11. JRJosh Rabinowitz36:36

       Yeah. I mean, I, I think we've been doing e-experiments that look at, you know, what are things that can suppress, uh, glucose use i-in tissues. A-and one thing we see is it's just very clear that fat does this. We're certainly not the o- only people To do this, I think there's a long history of this, but it maybe hasn't been adequately appreciated just how fundamental that result is. And if you turn off, uh, lipolysis different ways, then you rapidly induce glucose consumption. And if you provide other alternative fuels, and, and we've learned that lactate is a very important circulating fuel, and so it also will compete with glucose to suppress glucose use. So, uh, the fact that you can have multiple different types of fuels, either fat or lactate, and any of them will suppress glucose use m- really makes me believe in this kinda competitive nutrient environment, and that that plays a central role in determining whether you clear or don't clear glucose, and how high your glucose has to go basically in order to be cleared.

7. 37:44 – 50:09

   The important role of lactate as an alternate fuel

   1. PAPeter Attia37:44

      So let's talk a little bit about lactate, because this is one of those things where I, you know, now given how much I think about lactate, read about lactate, and w- had a number of podcasts where we get into some detail, either I was asleep through part of medical school or it just really wasn't presented in anything other than the following: when your demand for ATP gets high enough and quick enough, you're gonna basically take glucose, and when you turn it into pyruvate, rather than take the efficient path of shuttling pyruvate into acetyl-CoA through the Krebs cycle, where you can generate lots of ATP requiring oxygen, you're gonna take a quicker path that's less efficient but doesn't require the same cellular oxygen, and you'll turn pyruvate into lactate. You won't get nearly as much ATP, and you'll also tend to generate a lot of lactate, which tends to gravitate with hydrogen ions, which tends to kinda poison the muscle a little bit, and that's, you know, why it becomes rate limiting in terms of how long you can sustain that level of output. Maybe explain today why that's [clears throat] at, you know, the tip of the iceberg in a generous sense of the term.

   2. JRJosh Rabinowitz38:55

      Well, I, I think it's all actually really i- important stuff. Uh, uh, it's just only, as you say, part of the picture. And I think the other part of the picture is that m- mammals have been wired to use lactate as a major circulating nutrient. Um, it's a super, super fast turnover nutrient. So when you think about that glucose and you're having, you know, a few minutes supply, uh, circulating in your blood, lactate you have, uh, even short- shorter supply than y- that. It's constantly being, uh, made, released into the bloodstream, and consumed. And, and serves as an almost universal nutrient. There are transporters that'll carry it into, uh, virtually any cell i- in your body.

   3. PAPeter Attia39:43

      These are the a, a, MCH or is it the, uh, the MCT transporters?

   4. JRJosh Rabinowitz39:48

      These... Yeah, these are called MCT transporters, or so it stands for monocarboxylate because lactate has one carboxylic acid, if you think of it as a chemistry perspective. And so those transporters are ubiquitously expressed, and they allow lactate basically to go everywhere. And so it's the universally-

   5. PAPeter Attia40:09

      Wh- which by the way, Josh, that already differs from kind of how we learned it in biochemistry class, which was all that lactate goes back to the liver, and the Cori cycle turns lactate back into glucose, and then just exports it down the, the glucose pathway via hepatic glucose output. And you're saying, l- I'd like to understand when that happens versus when each other tissue says, "Oh, great. More fuel. Let me take in this lactate."

   6. JRJosh Rabinowitz40:35

      Yeah. I, I think the really important thing about lactate is that glucose penetration into tissues is actually heavily regulated. It has to be heavily regulated so that if we go through a period of having low carb intake, there's still glucose preserved for the brain and for other cells, uh, that particularly need it. And lactate is the universally available form of carbohydrate. And so, um... and I give an example like, you know, in healthy heart, uh, at least in the fasted state, it basically will not touch glucose. Uh, but it will use lactate as fuel.

   7. PAPeter Attia41:16

      So its preferred fuel is free fatty acid? Would that be the-

   8. JRJosh Rabinowitz41:17

      Its preferred fuel is free fatty acids. Uh, it probably also gets some fatty acids from lipoproteins, and it definitely uses lactate and also things like ketone bodies. But th- this is like a, a very clear example of a tissue other than liver that net consumes lactate, just using it as a fuel to have, you know, access to carbohydrate energy.

   9. PAPeter Attia41:40

      Now, lactate is a, is a, is, uh, uh, another metabolite that I pay a lot of attention to, Josh. So as regularly as I'm checking my glucose, I'm checking my lactate. And unlike glucose, the range is much greater, right? Like the lowest glucose I've ever measured in myself is probably 50 milligrams per deciliter, and the highest, not including the time Jerry Reaven had me do an insulin suppression test at Stanford, and I, and I almost died actually. This is actually a ridiculous story, um, because one of the IVs got blown, and we didn't know that they were pushing glucose, 'cause I was just getting so hypoglycemic, and, um, I could feel it. You know, you learn in medical school what hypoglycemia feels like and when you start sweating really profusely, and this was like nothing I've ever experienced. It felt like a bucket of water got dumped on me. So I knew, "Oh my God, I'm really... " I'm, I, I... and I was like, "They gotta push glucose," and I could feel the IV was blown. Anyway, to make a long story short, when they finally corrected it, my glucose got up to 240 milligrams per deciliter. So like there's... call it 250, right?

   10. JRJosh Rabinowitz42:55

       [laughs]

   11. PAPeter Attia42:56

       That's a, you know, a 5X range But with lactate, I mean, I've measured it as low as .3 millimole and as high-

   12. JRJosh Rabinowitz43:04

       Mm-hmm

   13. PAPeter Attia43:04

       ... as 20 millimole, right? So that's a 60-fold difference.

   14. JRJosh Rabinowitz43:09

       Yeah, that's, that's a big, big range, but it probably depends a lot on your physiological state.

   15. PAPeter Attia43:14

       Well, of course. The .3 would be, you know, at rest and fasted.

   16. JRJosh Rabinowitz43:20

       Mm-hmm.

   17. PAPeter Attia43:21

       The 20 is, you know, kind of an all-out two-minute effort.

   18. JRJosh Rabinowitz43:25

       [laughs]

   19. PAPeter Attia43:26

       But the point here is that's a much bigger range and, and is this regulated? Is there an upper limit to how high lactate can go, or is it simply how much pain you can tolerate? In, in terms of what is necessary-

   20. JRJosh Rabinowitz43:38

       Yeah

   21. PAPeter Attia43:38

       ... to generate lactate, like is there thr- truly an upper limit?

   22. JRJosh Rabinowitz43:41

       I'm honestly not sure. I mean, you, you may be r- [laughs] you may be right on the pain side of the scale, right? And, um, you know, this, this has to do with how fast i- its production and consumption are, right? So you can have that excursion to 20 and, you know, that can be clean-

   23. PAPeter Attia43:59

       But it goes down very quickly

   24. JRJosh Rabinowitz44:00

       ... cleaned up in a few minutes, you know, if you're actually, you know, completely resting. So, um, yeah, this is a very flexible metabolite this way.

   25. PAPeter Attia44:11

       When did people start to realize this, that, that lactate was a fuel? 'Cause I, I remember first reading about this in about 2011, where people were starting to say, "Hey, neurons might like lactate besides glucose." 'Cause at that point in time, there were really only two fuels that a neuron would ingest, right? So under normal circumstances, it was exclusively glucose, and then George Cahill showed in the '60s, yeah, but if you starve somebody, you can turn up to 60% of that fuel stock into beta-hydroxybutyrate. I think it was BHB. Maybe it was acetoacetate, but it was, it was a ketone, right?

   26. JRJosh Rabinowitz44:46

       Yeah.

   27. PAPeter Attia44:46

       So you'd be maybe 60/40 in favor of a ketone to glucose. But that was really it, and then there were these kinda whisperings in these, you know, animal studies that suggested, "No, actually neurons will consume lactate." Where are we today on that front?

   28. JRJosh Rabinowitz44:59

       Yeah, I think it's still very unclear which cell types in the brain are the lactate consumers versus lactate producers. Certainly, there's lactate u- use in the brain.

   29. PAPeter Attia45:10

       And is it more astrocytes, neurons? Do we know?

   30. JRJosh Rabinowitz45:13

       I, I think it's really an active area of investigation.
8. 50:09 – 57:17

   Fasting lactate levels as a potential early indicator of metabolic dysfunction

   1. JRJosh Rabinowitz50:09

      we distribute that problem across the body through this concentrating lactate in and out of cells and letting whatever cells that need, uh, carbohydrate energy use the lactate. The system would be way, way less flexible if, you know, only the liver could clean this up. And it would be also way less commensurate with effective burst exercise, right? Uh, you know, the heart is super well perfused, and if muscle is making, uh, l- if less well perfused muscle that's far from the heart, okay, so it's hard to get oxygen there, is making a lot of lactate, of course it's very advantageous at that moment for the heart, which is sitting on more oxygen than it needs, to use lactate rather than fatty acids, which are better long-term things to store for the future anyway. So it's way, way better to have the system designed this way.

   2. PAPeter Attia50:58

      And is that regulated then locally? Is that regulated at each cell? Like, how is that decision made? 'Cause how does that myocyte in the heart know the energy of the entire system so that it can make the decision that is, uh, in the short run counterintuitive?

   3. JRJosh Rabinowitz51:17

      You know, it's... seems medically or maybe textbook, uh, med school counterintuitive, but it's physical chemistry, uh, pure intuition.

   4. PAPeter Attia51:26

      Well, no, no. Yeah, yeah.

   5. JRJosh Rabinowitz51:27

      Okay? Right? It's, it's, lactate goes up and so it gets burned.

   6. PAPeter Attia51:31

      But regardless, how... but how is the decision made? Are you saying it's just made on mass balance and availability of substrate?

   7. JRJosh Rabinowitz51:37

      Yeah, it's m- it's, it's made on ma- it's made on mass action and availability of substrate.

   8. PAPeter Attia51:40

      Yeah, okay.

   9. JRJosh Rabinowitz51:40

      So there's no decision, okay? Th- that, this, it's, it's pure physics, basically.

   10. PAPeter Attia51:45

       Yeah, okay. No, I see what you're saying. So, um, it's basically a gradient problem across the board.

   11. JRJosh Rabinowitz51:51

       Mm-hmm. If you have too much lactate, it flows out. If you are short on energy, it flows in.

   12. PAPeter Attia51:58

       So tell me more about lactate. I'll tell you, uh, one thing that has... I've become very interested in clinically is the implication of fasting lactate levels in the population. So, um, if you, you know, measure a person's lactate level first thing in the morning, you're going to see quite a bit of variability.

   13. JRJosh Rabinowitz52:20

       Mm-hmm.

   14. PAPeter Attia52:20

       And it seems to be proportional to their metabolic health. The higher that number, the less metabolically healthy they are. Um, it's not uncommon in someone who's insulin resistant to see fasting lactate levels approaching two millimole with no activity. Whereas in a healthy individual it'll be below .5 millimole. What do you think that tells us about fuel partitioning and this problem of metabolomics?

   15. JRJosh Rabinowitz52:49

       Yeah, well, I, I think there's a correlation between fasting glucose and fasting lactate, but lactate is the kind of maybe harder to measure but perhaps even more intimately tied to the essence of metabolic dysfunction molecule. Uh, and I think, you know, very much, uh, the, the way you said it, that, you know, it, it, it reads out, uh, a few things. You know, it, it... when lactate is high, it reflects the fact that during these times of fasting when glucose is not really supposed to be being used much, okay, you're still using too much glucose, converting too much of it to lactate. And at the same time that your lactate clearance system isn't working very well, and typically that's because you're having competition between lactate and fat to be burned, and, you know, so th- this all feeds into the syndrome of diabetes.

   16. PAPeter Attia53:48

       Now, there's another interesting push observation that I've made, which is I wake up in the morning, check a lactate, it's .4 millimole. I eat the biggest carbohydrate meal I can ingest, don't lift a finger other than to feed myself. I recheck my lactate in an hour, it's one millimole.

   17. JRJosh Rabinowitz54:11

       Mm-hmm.

   18. PAPeter Attia54:11

       Why did that happen? I mean, we can understand the biochemistry, right? Which is I have more glucose to metabolize. But this get, kinda gets back to your point of med school biochemistry would suggest my lactate should not have gone up. I'm taking glucose, I'm making pyruvate, I have endless cellular oxygen. I should be running that pyruvate through the Krebs cycle and I shouldn't see any uptick in lactate. But that's exactly what I don't see.

   19. JRJosh Rabinowitz54:41

       Yeah. I mean, circulating lactate is an intermediary in glucose catabolism. And, uh, that's just the way the body works. It's not what we were taught in med school.

   20. PAPeter Attia54:51

       Yeah. Yeah. And I wonder... I mean, do you have a sense of, uh, of how it's being taught today? Do you, do you get the sense that, that biochemistry students at Princeton and Stanford today are being taught what we were taught with respect to this sort of, um- more rigid model of, of lactate and it's as a, as a, as a metabolite?

   21. JRJosh Rabinowitz55:11

       Well, I'm probably chipping away at it at Princeton, but, uh, you know, I, I don't know, uh, how much it's shifting at the medical education level yet. Uh, probably thank God I haven't sat through those classes at Stanford again. [chuckles] But, um, it, it... I think it's something that we should see shift and, and I hope we see the next generation of biochemistry textbooks talk about circulating lactate as an intermediary in glucose catabolism. I think that's a really fundamental thing for people who wanna just think about metabolism accurately to know. A-and as you say, it, it... You can do the s- the self-experiment very simply and see it.

   22. PAPeter Attia55:47

       And I think it's a very interesting thing to consider from a prognostic standpoint. You know, when you go back and look at Jerry Reaven's five criteria for what was then Syndrome X and what is now metabolic syndrome, fasting glucose is still one of them. You could make a case that fasting lactate would be more telling.

   23. JRJosh Rabinowitz56:07

       Yeah, I, I wouldn't be surprised. I mean, I think the challenge with lactate is that i- it is a metabolite that can get up and down faster, and one response to stress is to rapidly convert glucose into lactate. A-and so that's just part of your body activating, but of course, there are people who have stress at a blood draw, and because, you know, lactate is a little bit more fluctuating this way, th- there are gonna be pros and cons medically in terms of using it as a, a biomarker. You know, I, I, I don't think our problem with metabolic syndrome anyway is diagnosing it, right?

   24. PAPeter Attia56:39

       [chuckles]

   25. JRJosh Rabinowitz56:40

       Our, our, our problem is preventing it.

   26. PAPeter Attia56:43

       Yeah, although what I would argue is I think we treat metabolic syndrome too discreetly, and I think we come to it too late, right?

   27. JRJosh Rabinowitz56:50

       Mm-hmm.

   28. PAPeter Attia56:50

       I think we should be looking for things far before you actually have hypertension and truncal obesity and dyslipidemia and hyperglycemia. And I do wonder, with nothing other than just intuition, if, um, [lips smack] lactate dysregulation, for lack of a better word, might be one of the earlier canaries in the coal mine.

   29. JRJosh Rabinowitz57:14

       I, I totally agree with that.

9. 57:17 – 1:10:46

   The beauty of the Krebs cycle and the role of NAD in energy production

   1. PAPeter Attia57:17

      I wanna go back to something that we've talked about a couple of times. You've mentioned it in passing. You and I know what it's about, but I think it's such an important part of where we're gonna go in a discussion that I almost need you to go into full prof mode and really explain two things, which are obviously highly related in a moment, you'll see. The first is how the electron transport chain works. So what is, what is the Krebs cycle doing, and how is that feeding into this massive generation of energy currency? And specifically, can you talk about it with special attention to the concept of redox? And I-

   2. JRJosh Rabinowitz58:02

      Sure

   3. PAPeter Attia58:02

      ... I would encourage you, Josh, to take as much time as you need because the more the listeners understand this, the more they'll be able to understand NAD, NADP, NADPH, NR, NMN, all of these other things-

   4. JRJosh Rabinowitz58:17

      Mm

   5. PAPeter Attia58:17

      ... that people really care about. But I think unfortunately, they've been conditioned into very glib understandings of these things, which I think are serving no one any benefit without actually going back to understanding the root of this problem.

   6. JRJosh Rabinowitz58:33

      No, that's a great framing. So i- you know, you can think of it this way. Fundamentally, you know, you eat three macronutrients: carbs and protein and fat. And in a healthy adult, um, first approximation, every carbon atom that you eat in any of those three forms needs to exit your body as exhaled carbon dioxide. Okay? And all of that exhaled carbon dioxide, to first approximation, is made in the TCA cycle. And, uh, the main way that nutrients flow into the TCA cycle to become carbon dioxide is first turning into pieces that are two carbon units, uh, in size. All right? And so from carbohydrate, the basic flow is glucose to lactate, and then lactate to pyruvate to a two carbon piece that goes into the TCA cycle. Fat is basically composed of preassembled two carbon pieces, so they just get chopped up two carbon pieces at a time, and the protein part is a little more complicated. We can probably skip it, okay? So you end up with these two carbon unit-

   7. PAPeter Attia59:56

      But worth, worth just sort of noting, Josh, that protein really... the primary role of protein is actually the nitrogen side, which we're kind of putting into these amino acids that are building blocks. It's really less of an energy substrate, but it does have that carboxylic acid on it that still has to go through this cycle and be exhaled. But that, that's, in other words, well, that's why we'll skip it for now 'cause it's really not a significant energetic component, right?

   8. JRJosh Rabinowitz1:00:23

      Yeah. I mean, I, I think it really depends on the kind of diet you eat, right? If you... So there's a very dif-

   9. PAPeter Attia1:00:30

      So if you're on a carnivore diet, that, uh, then it's probably a different situation, yeah.

   10. JRJosh Rabinowitz1:00:34

       I- it's a very interesting side discussion. But ultimately, you know, unless you're gaining protein mass, which of course, wonderful for us guys anyway when that happens, typically at least societally smiles on it. Um, you know, but other than that, you know, whatever amino acid carbon you take in, in the form of protein has to be balanced with also amino acid catabolism. So, uh, at that level, it's not that different than, than carbs and fat. It's just a little different in that it can enter the TCA cycle sometimes also as four carbon pieces. Uh, but a lot of amino acids are broken down into these same two carbon pieces. There are just 20 of them, so it's, uh, you know, n- no one wants to hear a discussion of how-

   11. PAPeter Attia1:01:15

       [chuckles]

   12. JRJosh Rabinowitz1:01:15

       ... all, all 20 of them get chopped up. Um, so ultimately, you end up with these two carbon ... pieces, and then, uh, they congeal with a four-carbon piece, and that makes citrate. And a lot of the-- One of the problems with the Krebs cycle is that it has three names, okay? The Krebs cycle in honor of the amazing biochemist who, uh, played a key role in, in figuring it out, uh, the citric acid cycle, and that's named for this condensation molecule of the four-carbon and the two-carbon piece citrate, um, or the TCA cycle, and TCA is tricarboxylic acid, and that's because citrate has three carboxylic acids. Okay? So you have this, uh, cycle that unfortunately has three names, but that, um, uh, it's probably three times as important as anything else in metabolism, so may-maybe it's fair.

   13. PAPeter Attia1:02:08

       [chuckles]

   14. JRJosh Rabinowitz1:02:10

       Um, so, uh, ultimately, a-as this cycle turns, it's gonna spit off the two carbon pieces that, uh, came in as carbon dioxide, and in so doing, it's gonna take the electrons that were part of those two carbon pieces and pass them to this, uh, famous cofactor NAD to make NADH. Okay? And, um, that H stands for hydrogen. All right? And that hydrogen is really, uh, one proton and two electrons. And so this is another confusing nomenclature thing that you just can think of that H, even though it may sound to those who've taken f-freshman chemistry like H+, like acid, this is an H with two electrons stuck to it, so it's really what we call hydride or, uh, electrical form of chemical energy. And so then, uh, the NADH that's made from NAD there is what feeds into the electron transport chain, and those electrons then flow through a series of proteins that sit in the inner mitochondrial membrane. Uh, the mitochondria have two membranes. The outer one is kinda leaky and, you know, kinda not so important. The inner one is super tight and has a ton of regulation in it, and most importantly, uh, can be used to pump protons to one side or the other. And ultimately, it's the pumping of protons out of the mitochondria that's the function of the electron transport chain. And in this kind of metabolic flux way that we talked about earlier, the protons that get pumped out just flow right back in. But as they flow back in, they turn a turnstile, and as that turnstile turns, it squeezes ADP and inorganic phosphate, physically squeezes them together to make ATP, the master energy currency that we use to power our neurons for thinking, our muscles for moving, and so on.

   15. PAPeter Attia1:04:24

       So o-one of the things about this system that is just so beautiful [clears throat] is the transition from chemical energy to electrical energy back to chemical energy. And I, you know, I've tried to explain this to my daughter. She's thirteen. She's not fully in love with it yet, but I know at some point it'll be a more fun discussion. But it really is a miracle, right? Like, [clears throat] so much of biology just seems like it's hard to believe it all worked out. But if you were gonna rank all the things that I can't believe it worked out, this has got to be in the top five, right? It's... Like, let's go back to the basics again. You, you eat a piece of bread, right? You're eating glucose. It has these carbon-to-carbon bonds and carbon-to-hydrogen bonds and some carbon-to-oxygen bonds. Now, refresh my memory, but carbon to oxygen is not a very energetic bond, right?

   16. JRJosh Rabinowitz1:05:20

       You know, this is a-an-another thing where you have to be careful with the nomenclature. So, like, CO double bonds are spectacular bonds. They're super high energy, but that's where life... Or I shouldn't say life. That's where, uh, physics and chemistry want to flow to. They want to make these high energy bonds. And in making high energy bonds, you can release a lot of energy. And so, uh, those are bonds that are, are very energetically favorable. Uh, so they're the end state. It's the CH bonds, as you're alluding to, that start out energetically loaded, okay? They're less energetically good in and of themselves, so they have the potential to become something better.

   17. PAPeter Attia1:06:02

       Yeah, it's the, it's the potential that I really... Yeah. It-- Uh, I'm glad you're, I'm glad you're adding this level of, of sort of chemical rigor to this. So yeah, the point I want to make is the-these, these carbon-carbon, carbon-hydrogen bonds have this potential that this entire cycle with three names that's so wonderful basically liberates. It basically says, "We're gonna take that chemical energy, and we're gonna liberate it through electron transferring apparati." And then at the last second, using that-- I love the turnstile analogy, right? We're basically gonna quickly shunt it right back into a chemical bond, which is the P binding to the ADP to make the ATP, and now we have this energy currency that is gonna go and do its own thing, and it has lots of different ways that it unleashes itself. So explain to people the difference between oxidation and reduction in chemical terms, because I think people have to at least hear once what's an oxidation reaction, what's a reduction reaction, and then why we use the term redox synonymously with these two.

   18. JRJosh Rabinowitz1:07:11

       Right. So, um, oxidation and reduction are always coupled, okay? And they refer to the movement of electrons. And so when electrons go from, uh, substance A to substance B, okay, the one that gives up the electrons is oxidized. It's subject to oxidation. The one that receives the electrons is reduced, okay? It's the subject of reduction.

   19. PAPeter Attia1:07:36

       Let's talk about redox pairing. So you've already brought up NAD and NADH. So talk about how oxidation-reduction pairing works with those two to facilitate the electron transfer down this lovely chain of the inner mitochondrial membrane.

   20. JRJosh Rabinowitz1:07:51

       Right. So this is a, a pair where NAD is the oxidized form, NADH is the electron holding or reduced form, and it normally exists in a quite, uh, biased ratio towards a lot of NAD and a small amount of NADH. Uh, and the way nature works is that whenever, um, any pair of chemicals is, uh, skewed in one direction, it's favorable to turn the one that's abundant into the one that's less abundant. And so this makes NAD a, a, a decent electron acceptor. And so it's sitting there prepared to pick up electrons from these, uh, intermediates, carbon intermediates of the TCA cycle that are coming from carbohydrate and fat, and take the electrons, make NADH, which then can feed into electron transport chain, and that back end has to happen fast in order to keep this ratio, uh, skewed so you have mainly NAD and not too much NADH. Uh, and that's really important because when that NADH starts creeping up, all sorts of things start going wrong.

   21. PAPeter Attia1:09:03

       Such as?

   22. JRJosh Rabinowitz1:09:05

       Well, uh, N-NADH going up will, uh, drive too many electrons into the electron transport chain, and going back to, uh, Nav, you know, he's done a spectacular job showing how that leads to production of free radicals. And so when you... You need a, the right amount of this, but this is a, a clear way to get toxic amounts of free radicals if you have NADH buildup. Secondly, it just gums up metabolism if you have, uh, too much NADH relative to NAD. And so then you can get into problems not having enough ATP, and so, a-and then it can also make signaling things go awry.

   23. PAPeter Attia1:09:45

       Now, are there clinical scenarios in which we see that happen, or are these more typically they're things that result from toxicities where... You know, for, like, you know, the, the classic thing you learn in medical school to explain the significance of this whole system is cyanide, right? You know?

   24. JRJosh Rabinowitz1:09:59

       Mm-hmm.

   25. PAPeter Attia1:10:00

       Maybe tell folks how cyanide works, and I don't know if that's too extreme an example of how this system can be hijacked, but, but let's see.

   26. JRJosh Rabinowitz1:10:08

       Yeah, no, I mean, uh, obviously, you know, cyanide is electron transport chain i-inhibitor, and so that leads to the whole system just backing up a bit by bit. And so you can't then transfer electrons from NADH into the electron transport chain, and so NADH goes way up, NAD falls to the floor, and then you have no way to make ATP, and that unfortunately leads to rapid mortality, right? Um-

   27. PAPeter Attia1:10:32

       Yeah, and that's, that's, that's an interesting point because it speaks to-- this again comes back to the kinetics and the flux, which is it, it's not like cyanide kills you in an hour. I mean, it kills you in seconds. It, it's really a sobering thought.

10. 1:10:46 – 1:15:30

    How the drug metformin acts on complex I of the electron transport chain

    1. JRJosh Rabinowitz1:10:46

       Yeah, ATP turnover via this system is on the timescale of a, a second, um, and so same for NADH. And so these are things that are just whizzing through, uh, our bodies all the time and that we're constantly dependent on.

    2. PAPeter Attia1:11:02

       Are there, are there less extreme examples, Josh, of things that will put that balance in the wrong direction kind of chronically?

    3. JRJosh Rabinowitz1:11:11

       I think it's a really interesting question. I, I mean... A-and I don't want to give the misimpression that, you know, the right thing is to have as much NAD and as little NADH as possible, right? This is a-- First of all, it's designed to be a dynamic system. You know, if you undergo intense exercise, you're gonna drive NADH up, and this is a very healthy context for doing this transiently. Um, metformin, of course, is a super interesting medication and-

    4. PAPeter Attia1:11:45

       I was going to bring it up, yeah

    5. JRJosh Rabinowitz1:11:46

       ... probably works, you know, mainly by slowing the conversion of NADH back to NAD by impairing the complex one of the electron transport chain, the one that does this initial electron offloading from NADH to make NAD.

    6. PAPeter Attia1:12:03

       How, how well is that understood? I mean, this is-- You'll talk to five people who study metformin, and they'll tell you five different things, which I think just tells you how much we don't know. But what, what is your view of the... I, I, I don't think it's really disputed that metformin inhibits complex one, is it? I think the broader question is how much is that the main attraction versus kind of a sideshow, right?

    7. JRJosh Rabinowitz1:12:26

       Yeah. I, I'll say, you know, there are many people who know more about this than me, but one thing that we tend to do in our lab sometimes is take these kind of, um, famous metabolic effects like metformin inhibiting complex one and just do a quick test of it. And I say when we do that, about half the time they look to be true and half the time they look to be dubious, a-and metformin was a shining star in our hands in inhibiting complex one. It was one of the cases where I really felt like, you know, it may do other things, but it certainly does what it's supposed to do there. It does that strongly, and I think it's probably the fact that it does it in a relatively liver-specific way due to the way that metformin enters cells of the body that leads to it, first of all, being safe, okay? There are many things that make it safer than cyanide, but it is really crazy that, well, you know, it's the, maybe the world's most widely used medication is at some level a-

    8. PAPeter Attia1:13:19

       Inhibits the electron transport chain. Yeah.

    9. JRJosh Rabinowitz1:13:21

       Yeah, and it's a mechanistic analog of cyanide, right? And so you have, like, one of the most acutely lethal substances a-and the most widely used drug working in a remarkably similar way. And so I think the fact that there's a strong liver specificity is probably what makes it, you know- net beneficial for at least a subset of people.

    10. PAPeter Attia1:13:43

        And, and what's the, what's the, what's the change that you saw in your lab, Josh, between-- So if you were off metformin, what's your NADH to NAD ratio, and then on metformin, how much did it change that?

    11. JRJosh Rabinowitz1:13:55

        Uh, it depends how much metformin y- you use.

    12. PAPeter Attia1:13:58

        But if you tried to approximate like a, a... You do your best to approximate a, an actual clinical dose of, you know, say a couple grams a day.

    13. JRJosh Rabinowitz1:14:06

        Yeah. I, I'm not sure we did this in a way that I would consider-

    14. PAPeter Attia1:14:08

        Mm

    15. JRJosh Rabinowitz1:14:08

        ... clinically applicable, so, uh, but, but I'll, I'll say that i-it, it's certainly crystal clear that it, it goes in the right direction.

    16. PAPeter Attia1:14:17

        And so it doesn't surprise you that metformin would raise fasting lactate levels, correct?

    17. JRJosh Rabinowitz1:14:23

        No. I mean, it certainly is a-aligned to do that, right?

    18. PAPeter Attia1:14:27

        And that's just backing up further. It's, it's just basically creating more of a roadblock into the TCA is going to give you more lactate.

    19. JRJosh Rabinowitz1:14:36

        Yep. More of a roadblock in electron disposal, basically.

    20. PAPeter Attia1:14:40

        Do you think that that's a neutral effect, or do you think that that's a potentially deleterious effect of metformin that is probably offset in a patient with diabetes by the benefits that it has on hepatic glucose output?

    21. JRJosh Rabinowitz1:14:53

        That's a great question. I don't think I know. I mean, I think having more circulating lactate can be, uh, you know, a bit of a challenge for clearing fat, right? 'Cause they have some sort of competition. So from that perspective, I think, you know, being in a, a lower state might have some benefits, but then, you know, lactate is a valuable fuel as long as it's not getting to h- too high levels. So I, I, I'm not sure how that all plays out in terms of long-term health.

    22. PAPeter Attia1:15:29

        Interesting. Yeah.

11. 1:15:30 – 1:17:45

    The difference between NADH and NADPH

    1. PAPeter Attia1:15:30

       Um, anything you want to say about NADP and NADPH just to round it out so people know the full story?

    2. JRJosh Rabinowitz1:15:38

       Uh, yeah. These are, you know, super, uh, important cofactors that, um, personally I'm very obsessed with, [chuckles] um, that are kinda-- they live just on the edge of what people who take biochemistry, either in, uh, undergraduate or med school, learn about or don't learn about. And, um, they're fascinating cofactors because in terms of their intrinsic chemistry, all their intrinsic chemistry from the energy point of view is exactly the same as NAD, NADH. But they have a different handle on them, uh, chemically that allows biology to use them in a different way, and the, the ratio is maintained, uh, quite different level from NAD, NADH. So NAD, NADH is super biased towards NAD. This is much more of an even pairing, which means that, uh, there's much more driving force to dump the electrons off, okay? Rather than to absorb them up. And so NADPH is really, to me, second only to ATP, a, a master, uh, energetic, um, building material. And it's the building material that's used, for example, to assemble fat. I mean, it's the most important one. So as you take, uh, pieces, two carbon pieces from carbohydrate and want to put them together to make fat, you keep dumping in electrical energy in the form of NADPH. Um, and then NADPH is used in all sorts of other really interesting ways to fight reactive oxygen species. It's also used if you're trying to kill bacteria to intentionally make reactive oxygen species. [clears throat] So th-this is where biology is freaking confusing and complicated, and, and there's definitely the yin and yang that you have this, um, awesome cofactor that's so important for fighting oxidative stress and also can be used to create boatloads of oxidative stress intentionally, uh, when it's needed.

12. 1:17:45 – 1:31:44

    NAD levels with age, and the efficacy of supplementing with intravenous NAD

    1. PAPeter Attia1:17:45

       First of all, that was a fantastic overview of how the Krebs cycle works and specifically with, uh, attention to how electrons move through it and move through these, um, redox factors. Which then brings us to, I think, a part of the discussion where a lot of people have an enormous interest, which is, I don't know, go back seven, eight years, it started to become fashionable, and it's only become more fashionable to talk about supplementing with NAD. I say that quote unquote, and we're gonna talk about why you don't actually supplement with NAD. But is it safe to say that at least part of the impetus for this was the observation that as we age, cellular NAD levels decline? And you've already made a very compelling case for why NAD is important. I mean, I don't... I, I, I, I almost want to avoid the whole sirtuin side of this because I think that story keeps changing, so maybe we can just-- unless you feel strongly or compelled to get into sirtuins, we can put those aside for the moment.

    2. JRJosh Rabinowitz1:18:51

       Yeah. I love putting sirtuins aside. Um-

    3. PAPeter Attia1:18:53

       [laughs]

    4. JRJosh Rabinowitz1:18:54

       Let's, let's just get to real metabolism. Um, and, um, yeah, I, you know, I think the first, um, principles in this field are great, right? That, you know, NAD plays this super central role in energy generation, that we all want to feel more energetic, whether, you know, you want to be a more extremely successful athlete at age twenty-one or whether you want to feel at age, uh, fifty like I am or later, you know, like you're twenty-one. Um, a-and so you think, you know, if we could just, you know, turn up the, the burner capacity, right? Th-this would be absolutely fantastic. Um, and then we have this data that NAD is depleted with aging. Although I have to say when we do those measurements, we agree that NAD is depleted with aging, but it is a lot more subtle than, you know, you would think, uh, looking at the literature. And so these are really quite subtle N-NAD depletions. You know, we were talking about these ranges earlier and, you know, the kinda threefold, uh, range where a lot of metabolites live on a daily basis. Some of them glucose, that's their worst day, right?

    5. PAPeter Attia1:20:15

       Yep.

    6. JRJosh Rabinowitz1:20:15

       And as you pointed out, some of them like lactate, you know, they may do the threefold all the time and then the 60-fold when you stress them. Uh, the NAD changes we see with aging are like, you know, 10%, 20%.

    7. PAPeter Attia1:20:29

       Oh, wow.

    8. JRJosh Rabinowitz1:20:29

       They're-

    9. PAPeter Attia1:20:29

       I didn't realize it was that little, Josh.

    10. JRJosh Rabinowitz1:20:32

        Yeah. So I, I think, um... A-and I'm not saying that in some tissue of, you know, an aged human there might not be bigger effects, but I, I think this is the first caution I would give to people thinking that they're gonna fix everything through, uh, NAD. And, um, so, y-y-you know, on one hand it's a robust finding that this is something that changes with aging, that with a central metabolic role. On the other hand, it's something that happens with a, a fair amount of subtlety.

    11. PAPeter Attia1:21:04

        Can you explain to folks how this is done? Because, again, w- I mean, you know, we talk about measurement sometimes a little too glibly, right? So pretty easy to explain how we can measure glucose and hemoglobin and lactate. At the other end of the spectrum, we've talked a lot about ATP, but, but I, but I think most people don't understand is it's very difficult to measure ATP. It comes back to what you said a moment ago. This ain't sticking around a very long time, right? You're using MRS and super complicated physics to be able to measure these things. Where does NAD fit on that spectrum, and how do you actually measure it?

    12. JRJosh Rabinowitz1:21:41

        Yeah. I mean, I think the good news is that N-NAD, um, unlike NADH, is not like one of these, you know, super transient metabolites. And so NADH measurement is wickedly difficult, but, you know, most of this NADH, NAD pair sits as NAD and it tends to sit around for, you know, um, hour-ish timescale.

    13. PAPeter Attia1:22:03

        Oh, so you don't even have to f-- you don't necessarily have to flash freeze tissue or things like that.

    14. JRJosh Rabinowitz1:22:07

        That's right. You have, you have some, uh, more flexibility in making those, uh, measurements as long as you're not irritating the tissue in a way that leads to, you know, massive NAD degradation, which, you know, people may do, uh, sometimes by accident. But I, I think generally it, it's not that hard of a measurement, um, NAD. Obviously like ATP, it's a tissue metabolite, not a circulating metabolite, so you need biopsy specimens to measure it. Uh, I'm not a master of the literature of, you know, NAD, uh, levels in human tissues, but my, um, not fully informed perspective is that there probably isn't as much as we should have, okay? And that's 'cause it's hard to get biopsies-

    15. PAPeter Attia1:22:50

        Yeah

    16. JRJosh Rabinowitz1:22:50

        ... from, from people.

    17. PAPeter Attia1:22:53

        A- and if you, if you took... if you take blood, if you take a whole blood-

    18. JRJosh Rabinowitz1:22:56

        Mm-hmm

    19. PAPeter Attia1:22:56

        ... and you look at PBMC, can you look at NAD levels in there with relative ease? Or is it too complicated because by the time you separate the PBMC you've kinda lost your window?

    20. JRJosh Rabinowitz1:23:07

        I think it's a really good question, um, because there is quite active NAD metabolism in, i-in immune cells. So yeah, I, I'm not an expert in this. Uh, uh, but I, I bet there's a way you could develop a good protocol. I, I haven't followed, you know, how good the measurements up to now have been.

    21. PAPeter Attia1:23:28

        So most of what you've measured has been in tissue?

    22. JRJosh Rabinowitz1:23:32

        Yeah, typically, you know, we work a lot in mouse. Sometimes we measure human, but more typically on the cancer side. And, um, yeah, there we just take tissues and freeze them and, you know, extract metabolites, do mass spec.

    23. PAPeter Attia1:23:47

        You're seeing a consistent, clear decline in NAD with the aging animal or human, but it's, I mean, it's not a fold reduction, it's a percent reduction, 10%, 20% reduction.

    24. JRJosh Rabinowitz1:24:01

        And that's, that's the most common thing, yeah.

    25. PAPeter Attia1:24:03

        Okay. So this p- this generates a hypothesis. The hypothesis is if you restore NAD levels in the old organism to the level that they were in the young organism, the old organism will feel and perform like the young organism. That's one hypothesis. Another hypothesis would be if you induce supernormal levels of NAD in any organism, they will feel supernormal. So y- let's assume that both of those hypotheses are simultaneously testable. What happened five, seven, eight years ago, NAD clinics started popping up all over the place, and they started saying, "If you come here, we'll put IVs in you and we'll give you NAD." So let's first explain why did they do this intravenously? Why couldn't they make an NAD pill?

    26. JRJosh Rabinowitz1:24:51

        Yeah. So, um, N-NAD and its precursors are broken down in the gastrointestinal tract and so, um, you know, if you take, you know, NR for example, so nicotinamide riboside orally, it mainly will enter the body in the form of nicotinic acid or niacin, right, which is a healthy substance, so there... and nothing wrong with it. But, you know, e-e-except for maybe the epithelium or your gastrointestinal tract, you know, the body is not seeing nicotinamide riboside.

    27. PAPeter Attia1:25:29

        A- and NAD, just to be clear, 'cause, uh, b- we're gonna talk about NR and NMN in a moment, but NAD, there's no way to orally take it, right? It has to be...

    28. JRJosh Rabinowitz1:25:37

        Yeah. There, there's no known absorption route for NAD, and I, I think it'll get broken down probably all the way to nicotinic acid, although I'm not 100% sure anyone has proven that. But, uh, I, I certainly don't think it would enter the body any other way than either nicotinamide, which is like, you know, little bit closer to remaking NAD or, or nicotinic acid.

    29. PAPeter Attia1:26:00

        So what happens when a person receives intravenous NAD? What's the fate of that NAD? 'Cause, uh, you know, one of the things in, uh, metabolism and biology is anytime you put something in a vein, you bypass the liver with something called-

    30. JRJosh Rabinowitz1:26:17

        Mm-hmm
13. 1:31:44 – 1:43:59

    The usefulness of restoring NAD levels and efficacy of oral supplementation with NAD precursors NR and NMN

    1. PAPeter Attia1:31:44

       Today, I think the majority of efforts to increase intracellular NAD are done through oral, uh, precursors, and the two are NR and NMN, which as you said, are pretty similar and- Are you aware of a more convincing argument for why one might be a more preferred substrate? I haven't particularly seen arguments that one is superior than the other. Uh, I've seen some unpublished data that suggests one can be made more temperature and moisture stable than the other. But, um, let's put that aside for the moment. Would you consider these two a first approximation equivalent approaches?

    2. JRJosh Rabinowitz1:32:28

       Yeah.

    3. PAPeter Attia1:32:29

       Okay. So now talk about something else that you said that it also kind of news to me, which is what is the effect of the gastrointestinal tract on, um, these agents?

    4. JRJosh Rabinowitz1:32:41

       Yeah, I mean, they get broken down and they get broken down, um, all the way to the level of nicotinic acid or niacin, basically. And, um, this is the main way they enter the body. It doesn't mean that, you know, there can't be a trickle of them entering some other way that has a physiological effect, or that there's some local effect or some effect on the microbiome of taking them. So they're... You know, biology is super complicated. There are ways that these could be doing interesting health supporting things, but I don't really think they're fundamentally different than taking a physician-prescribed niacin pill from the perspective of providing NAD precursors.

    5. PAPeter Attia1:33:23

       Now, a physician-prescribed niacin pill, when people used to take niacin for hyperbetalipoproteinemia, right? Which is really obviously no-- I mean, there's probably still some patients out there who take niacin, unfortunately. But it wasn't uncommon to get a real flush from the medication. Now, I don't remember what doses people were taking, but I feel like it was on the order of grams-

    6. JRJosh Rabinowitz1:33:47

       Mm-hmm. Yep

    7. PAPeter Attia1:33:48

       ... not milligrams.

    8. JRJosh Rabinowitz1:33:49

       Yep.

    9. PAPeter Attia1:33:49

       Do, do you recall how much niacin you would need to give somebody for them to experience an actual flush?

    10. JRJosh Rabinowitz1:33:55

        I think it was a few grams. I think that that's where my recollection is too.

    11. PAPeter Attia1:33:59

        Okay. So, so is that the reason people don't experience a flush with NR and NMN because they're typically taking, you know, five hundred milligrams to one gram, and that's simply not gonna produce enough niacin to reach that threshold?

    12. JRJosh Rabinowitz1:34:13

        Yeah. They're also kind of niacin prodrugs, so they probably are delayed absorption forms of niacin, so that may smooth things out enough. So they may be better tolerated, but I think this is how I'd fundamentally think about them, is that they're niacin prodrugs.

    13. PAPeter Attia1:34:30

        Your lab has done some, some of the flux work on this, correct? What, what are some of the most interesting things you've learned about how NR and how NMN, when given orally, end up in different tissues and what the effect is in the liver versus the muscle versus the plasma?

    14. JRJosh Rabinowitz1:34:49

        Yeah, I think the main thing you see is that, you know, these are converted to niacin. They will raise niacin, particularly niacin heading to the liver out of the, uh, gastrointestinal tract, so in the, what we call the portal circulation that connects, you know, your intestine to the liver, uh, very effectively. And that, you know, other than that, their effect on like boo- boosting their own circulating levels is, um, somewhere between subtle and vanishing. Uh, I'm still not sure which of those two it is, but I, I, I think they certainly remain in the bloodstream much less abundant than nicotinamide, which is the thing the liver is normally producing to feed NAD precursor to the tissues of the body. And so there, there's, from what we have seen, no clear route for oral NR or oral NMN to produce circulating levels of NR or NMN that are high enough to compete, at least at a standard concentration level with nicotinamide, the physiological precursor, as a way of feeding NAD precursors to tissue. So basically, at some level, they don't change what's happening and what most of your tissues are seeing that much if our measurements are correct.

    15. PAPeter Attia1:36:12

        Where do you think you could be fooled on this? I mean, I know that's a question every scientist a-- or every good scientist asks themselves that question, right? How can we be fooled by our measurements? Uh, I'm sure you've thought about this. Where, where do you see this, the opportunities in this particular case to be misled?

    16. JRJosh Rabinowitz1:36:31

        Yeah, I mean, it could be that, you know, there are local effects of NR or NMN on like the intestine that are really important. It could be that, uh, their availability impacts the microbiome in important ways. The microbiome can have big effects on health. Uh, it could be that even though the amounts of like NR that may reach the liver or even lower amounts that may reach, you know, the heart or something are really small, that there's a subset of cells there that are really NR preferring because maybe they're really deficient in using nicotinamide and maybe getting even small amounts of NR to those cells, uh, is meaningful. So I, I think these are all possibilities that we're sh- you know, very much open to. Um, but, you know, my base assumption is that often the obvious is true, and here the obvious would be, you know, the physiological system just isn't that impacted by this particular type of s- oral supplement.

    17. PAPeter Attia1:37:34

        Do you think there's any chance that with chronic administration you'd see something different? Because I'm assuming in these experiments you're not seeing the effect of these chemicals being ingested chronically, or are you?

    18. JRJosh Rabinowitz1:37:50

        No, I, I think it could be... I mean, human can be different than mouse, okay? First of all, it's another important thing that I say.

    19. PAPeter Attia1:37:55

        Yeah.

    20. JRJosh Rabinowitz1:37:56

        Uh, we haven't done these experiments in human. Uh, I think someone, if they aren't already, should do these experiments in human. Uh, and um, Yeah, chronic versus acute. So, so there's a bunch of variables that could alter things

    21. PAPeter Attia1:38:11

        Based on what you know now, if, if the hypothesis is true, if giving... Well, not, let's not talk about the route. If restoring intracellular NAD levels at 50 to the level they were at when you were 20 would improve some measure of performance, based on what you know today, what do you hypothesize would be the most efficient way to restore NAD levels?

    22. JRJosh Rabinowitz1:38:41

        Yeah. I mean, I, I guess, you know, IV is the promising way to do the restoration. Um, I'm, I'm not very convinced about the first hypothesis, and, you know, I think the, the big history of medicine, you, you and I can debate it, is that things are way more complicated than people can envision, right? That, you know, hormone replacement therapy is, like, one of the great examples, right? It d- didn't turn out to-

    23. PAPeter Attia1:39:11

        Although it's being overturned. Well, but I think... You know, I think HRT is one that I, I think if you go back and look at the Women's Health Initiative, um, I think it got it wrong, right? I mean, I think it was the randomized experiment, but it was really misinterpreted, so-

    24. JRJosh Rabinowitz1:39:26

        All right. So, so, so, wait, what, uh, tell, say a bit more about that?

    25. PAPeter Attia1:39:30

        Maybe I picked up on the wrong thread of where you were going, but I assumed what you were going to say was, look, the epidemiology in the '80s and '90s was that giving women hormones post-menopause was a good thing, and then the Women's Health Initiative came along and said, "No, it's a bad thing." I assume that's what you were going to say.

    26. JRJosh Rabinowitz1:39:49

        Yeah.

    27. PAPeter Attia1:39:49

        And, and what I was going to say was, actually, no, I think that's actually misleading. I think if you actually go back and look at the Women's Health, Health Initiative, um, it was just an awful example of how to misinterpret a study. Um, I think there was no increase in the risk of breast cancer, and if there was any risk, increase in the risk of breast cancer, it probably had nothing to do with the estrogen that the women were given. Um, when you actually look, for example, at the relative risk and absolute risk different in those cohorts... So remember, the Women's Health Initiative had three cohorts. You had your f- full placebos. Well, technically it was two parallels, right? So you had the placebo versus, uh, estrogen only in women who did not have a uterus, and then you had, um, placebo versus estrogen plus, um, MPA, the synthetic progesterone. So in the estrogen only versus the placebo, there was a non-statistical significant reduction in the risk of breast cancer. So there was a hazard ratio of about .8 or .79 or .81, something like that, but it didn't quite reach statistical significance, but trending towards estrogen actually reduced the risk of breast cancer. In the estrogen plus MPA group, there was a barely statistical significant increase in the risk of breast cancer. I think the hazard ratio was... I wanna say it was about 1.24, 1.25, um, and the P value was exactly .05 or .049 or something like that. So at the surface you'd say, "Gosh, this is increasing the risk of breast cancer," and what was talked about was it was, it was a 25% increase in the risk of breast cancer. But the, you know, to talk about the relative risk increase without talking about the absolute risk is obviously irresponsible. If you look at the absolute risk change, it was a .1%. It was one in 1,000. And that says nothing about a, a lot of other methodologic issues with the study, in- including the fact that pr- in my opinion, a more plausible hypothesis was that the MPA was more the issue than the estrogen. But the estrogen gets all the attention, right? So estrogen causes breast cancer gets the attention. And, you know, if you look at subsequent studies, I don't think we see that to be the case. So, so I'm gonna hypothesize or predict that in 10 years, I think that we'll look back at what happened to a generation of women, which I think is really unfair, in that a, you know, basically an entire generation of women got deprived of hormones, um, because of, I think, a really poorly interpreted study. But your point notwithstanding, sometimes the obvious is not obvious. [chuckles] Sorry for the digression.

    28. JRJosh Rabinowitz1:42:29

        Well, I, I mean, uh, uh, yeah, but, like, no, I mean, that, that was super interesting and, and, and I, I thought there was some cardiovascular risk data in that study that was surprising, but I, I... It's... You know it much better than me.

    29. PAPeter Attia1:42:40

        Yeah, I think on the cardiovascular front, there probably is a, a slight increase in risk with oral estrogen because of the hypercoagulability. Um, I also think it speaks to understanding the use case. Um, today, very few women on hormone replacement therapy are given oral estrogen. The preferred route of administration is, is, uh, is a, is a patch, you know, something like a Vivelle Dot where you're given topical estradiol, and you get all of the benefits of a reduction of vasomotor symptoms, the incredible benefits that you see on bone health, um, without any of the hypercoagulability and cardiovascular. So now we actually see the reverse. Now there's a very clear trend, uh, not just trend, it's statistically significant. There's a very clear reduction in cardiovascular mortality.

    30. JRJosh Rabinowitz1:43:24

        Yeah, so that's a great example where you had to give by the right route of administration, right, in, in order to get, uh, the net positive health benefit, right? And, uh, I mean, I, I think, you know, right, NSAIDs, Advil, an- another one, right? People knew they had a lot of side effects, but everybody assumed that they were kind of counterbalanced by the fact they were reducing coagulability and that this was gonna be cardioprotective, right? And I, I don't know if you're gonna tell me that y- you, you still believe that, but-
14. 1:43:59 – 1:51:25

    Exploring the hypothesis that boosting NAD levels is beneficial

    1. JRJosh Rabinowitz1:43:59

       so you're-

    2. PAPeter Attia1:43:59

       Anyway, so, so really where you were going, I think, is you were saying, look, you might even just reject the outright hypothesis. Like, this idea that, yeah, we do observe a 20%, 10% to 20% reduction in NAD levels as we age, you haven't even bought the first hypothesis, which is even if I could magically deliver 20% more NAD to a 50 year old, y- you're not, you're not sounding very convinced that that's going to improve quality or length of life

    3. JRJosh Rabinowitz1:44:26

       Yeah, not at this point in time, right? I mean, these, these things involve such complicated interplay of different organ systems, and it may turn out that, you know, NAD supplementation is super valuable medically. I am completely open to that, and I would love that to be the case. Um, but I think if so, it's gonna be because there are select cell types that are genuinely severely NAD depleted and that we will need to figure out how to restore NAD in those cell types, and then we may see big health benefits. So I think that would be fantastic, and it's completely possible, and it's possible, um, that the general intravenous supplementation is hitting those cells and doing that. But I think it's equally possible that it's having some adverse effect that's gonna be net negative for people, and they-- we, we don't know the science well enough, and we certainly haven't done the clinical experiment well enough to give good health guidance yet.

    4. PAPeter Attia1:45:23

       So two things. Uh, first, a statement. I, I th-- I mean, this is really interesting for me because I, I really stand corrected, and I just want to apologize to all the people over the years that I've said intravenous NAD is not getting in your cell. Uh, I stand corrected. It indirectly, based on everything you're saying, may actually be getting into at least some cells. The second is a question, right? Which is, how would you even begin to tackle that question, which is, are there certain cell subtypes that may indeed benefit from NAD boosting? Um, I haven't really seen a single convincing clinical study in humans using either NR or NMN that has made me excited about this. And I'm not a stranger to putting things in my body without absolute perfect information, right? I mean, I take rapamycin. I've been taking rapamycin for four or five years. I will be the first to admit, I think we have very good evidence for that. It's not perfect. It's far from perfect. Um, we're, we're never going to have a definitive human clinical trial. But if I'm willing to take rapamycin, why am I not taking NR, and why am I not taking NMN? And the reason is I just can't find a shred of compelling evidence to tell me to do so, and I'm in the same boat you're in. I'd love it if there was 'cause it's a pretty easy, safe thing to take. So what study needs to be done to help a, a... someone like me, a, a reluctant NADer get on the NAD train?

    5. JRJosh Rabinowitz1:47:00

       You know, I, I think we need to, first of all, map better the basic pharmacology o-of NAD, uh, in animals and human. I mean, that, that's quite doable, and this is something that we as a field, uh, are, are doing, and there are a lot of s- great people doing this and, and... but we can do more, uh, and, and better. Then we need to have the technologies to look at this at cellular resolution rather than bulk resolution. So this is something we're pushing very hard to develop, the ability to take a slice of tissue and say, "What's the heterogeneity across cells in NAD levels?" And I think that'll be very helpful, 'cause if we see that that's really scattershot in aging and homogeneous in young, then you have your answer that, you know... All that we need is for one in ten cells at any time to be really NAD depleted, and we view that ten percent reduction not as some tiny wiggle down but as one in ten cells being on the road to a catastrophic outcome. Okay? And so, um, I think this is gonna be a really important measurement. Uh, and I, I think the field will get there over the next, you know, few years, uh, not instantly. And then ultimately we need successful clinical experiments, right? And I, I think there, there have been some really persuasive experiments in animals, you know, with, uh... for example, I think there are experiments on reversing, you know, bad outcomes after renal ischemia. Um, and so it'd be good if we could find niche experiments where there's a very strong effect in animals, a very quick clinical readout, right? You have a ischemic renal event, and you do the supplementation, and you get a benefit or you don't. So I don't think the right way to go about it-

    6. PAPeter Attia1:48:50

       How was, how was it administered in that experiment? I don't think I remember that one.

    7. JRJosh Rabinowitz1:48:54

       You know, I, I, I may not get the details, uh, of that right. So, um, but I, I think I would just say conceptually, we need to find the strongest-

    8. PAPeter Attia1:49:04

       Yeah

    9. JRJosh Rabinowitz1:49:04

       ... animal proof of concept that can be translated into a small but definitive clinical trial and prove that this really can do something beneficial in the right context. And then from there you can think about kind of, you know, expanding the indication to general health betterment.

    10. PAPeter Attia1:49:23

        Who, who's the natural owner, uh, funding wise of this, uh, investigation? I mean, is, is NIH... Is this a question NIH is interested in? I mean, indirectly through the ITP, Rich Miller, Randy Strong, et al., have, have already done an NR test, uh, in, in their very rigorous tried and true model. As you know, that failed, right? So NR did not extend life. Um, is NIH still interested in this question enough to continue funding it? Do you... You know, where, where is your funding for this level of, uh, investigation coming from?

    11. JRJosh Rabinowitz1:49:59

        You know, we mainly try to help the real, uh, NAD expert labs by, you know, doing the flux studies, uh, facilitating measurements. But y-you know, it's not the bread and butter of my life. I'm probably about a observer at the same level as you of this, this field, broadly speaking. Um, I think, you know, there's, there's money in NIH for interesting science, and so, uh- This is too central to metabolism and too much public health interest for, you know-

    12. PAPeter Attia1:50:33

        So you're not worried that-

    13. JRJosh Rabinowitz1:50:34

        ... the waters to run dry

    14. PAPeter Attia1:50:34

        ... you're not worried this is not gonna run up against a-

    15. JRJosh Rabinowitz1:50:36

        No, and I think biotech is interested in this and, you know, there's very interesting ways to do this pharmacologically and so we may see those mature faster, you know? C- CD38 inhibitors, uh, obviously there's a whole different financial structure there, right? If you can make a patent-approved, you know, medicine and all that economic incentive is, is great for driving, um, first, you know, science answers and then clinical answers.

    16. PAPeter Attia1:51:02

        What are the top labs right now in your mind in, in studying NAD and its, and its precursors or ways to increase it?

    17. JRJosh Rabinowitz1:51:10

        Oh gosh. I, I think I'm too much of an outsider to get into naming names on that. I'm gonna only get myself in trouble other than-

    18. PAPeter Attia1:51:17

        [laughs] Okay

    19. JRJosh Rabinowitz1:51:17

        ... to cr- credit, other than to credit, you know-

    20. PAPeter Attia1:51:20

        In a, in a... You're, you're

    21. JRJosh Rabinowitz1:51:20

        ... Joe Bauer for being a fantastic collaborator on this.

    22. PAPeter Attia1:51:22

        Yeah, yeah. You'll, you'll, you'll fail to mention somebody. Fair enough.

15. 1:51:25 – 2:00:17

    Cancer metabolism and the intersection with immunotherapy

    1. PAPeter Attia1:51:25

       Fair enough. Okay. Let's pivot to the final thing I want to really get into, Josh, which is cancer metabolism. It kind of ties in so, so much of what we've talked about and that's how you and I reconnected five or six years ago-

    2. JRJosh Rabinowitz1:51:35

       Mm-hmm

    3. PAPeter Attia1:51:35

       ... at a conference and then obviously a number of times since then. So, um, you know, the irony of it is, right, you do your PhD in the inner workings of how the immune system works, but you're not particularly interested in cancer at the time. You, you, you, you come back to academia as a metabolomics experiment-- uh, as a, as a metabolomics expert and now you've kind of wound your way back to oncology in a way. So, um, tell me a little bit about that journey, right? How did you go from this profound interest in metabolism, metabolomics and fluxomics to realizing a beautiful application for this is in the field of oncology?

    4. JRJosh Rabinowitz1:52:18

       Yeah. I think, um, you know, part of it is really the human connection and, uh, I was so fortunate to be at Princeton, which is this kind of academic bubble where I could do my experiments on E. coli and yeast and really, um, set up these good metabolic measurements unmolested. But then, uh, you know, also we're close to Penn and, uh, at some point I got a call from the head of the Penn Cancer Center at that point in time, Craig Thompson, saying he wanted to visit and it just-- of course I just say yes, you know? It's a, it's a simple one and, uh, that was kind of a life-changing call for me because it brought me into the world of biomedicine, you know, again basically i- in the context of working on cancer metabolism. And, um, it was very natural because if you look at the history of cancer therapy, right, you know, the first great rational triumph in treating cancer was, uh, antifolates and Sidney Farber and you, you know, his name memorialized on the Dana-Farber Cancer Center, right? And so, um, this is really the origins of how cancer was rationally treated [clears throat] by targeting metabolism and it just got, um, understudied for so many years and it, it was a, a very natural re-entry point for me because cancer you can study as isolated cells, uh, in a culture dish much as we were studying E. coli and yeast and so that was much more comfortable to me, uh, in, you know, the, uh, 2008 or whatever timeframe than, you know, starting to work on mice. So I'm delighted that we got back to mice a few years after that.

    5. PAPeter Attia1:54:03

       What year did Craig leave Penn to go to Memorial Sloan Kettering? Must have been shortly after he invited you over, right?

    6. JRJosh Rabinowitz1:54:10

       Yeah. A, a few years after I, I think. So yeah. And...

    7. PAPeter Attia1:54:15

       So, so people like Craig, who I have not had on the podcast but I'd love to, but Lou, who I have, um, y- you know, when you think about cancer metabolism today, I mean, it's just a booming field, right? I mean, I, I, I would argue and no disrespect to people in different fields but that cancer metabolism and, and immunotherapy are really two of the most promising and exciting areas in the field today, which were two things we didn't have a single word about in medical school, right?

    8. JRJosh Rabinowitz1:54:42

       Yeah. That's, uh, absolutely true except, yeah, may- maybe some anti-metabolites for cancer hidden somewhere-

    9. PAPeter Attia1:54:48

       Yes. Yeah, yeah, yeah

    10. JRJosh Rabinowitz1:54:48

        ... in the pharmacology book, you know? [laughs]

    11. PAPeter Attia1:54:50

        Yeah. Yeah.

    12. JRJosh Rabinowitz1:54:50

        Uh, but, but um, yeah, I think, you know, one of the most exciting things is gonna be the interface of those two fields also and, and we see this with, you know, microbiome composition being predictive of whether immunotherapy works, uh, amazing work from Jennifer Wargo, uh, showing that, you know, fiber can promote the effectiveness of immunotherapy and so we're seeing that connection also being made.

    13. PAPeter Attia1:55:14

        Soluble or insoluble?

    14. JRJosh Rabinowitz1:55:15

        [laughs] Yeah. TBD, okay? So we're very excited to work on that answer and then, you know, um, there are different flavors of soluble fiber and so I have my pet dreams for how this may work mechanistically but, uh, I, I think it, it's gonna be an incredibly important interface.

    15. PAPeter Attia1:55:35

        Wow. Um, so tell folks a little bit about, um, what it is about cancer cells that makes their metabolism distinct from their, uh, non-cancer counterparts but within the same tissue even. Like if you want to compare adenocarcinoma of the colon or breast or prostate and look at the perfectly normal non-cancer cell sitting right next to it. I mean, we, we typically talk about two hallmarks of cancer, right? We talk about the inability to respond to cell cycle signaling, so this is why these silly things-

    16. JRJosh Rabinowitz1:56:03

        Mm-hmm

    17. PAPeter Attia1:56:03

        ... just keep growing even when they're told "Stop growing," and then the capacity to metastasize to basically pick up, leave, go grow in a not- grow, grow in a new site. Um, but what is it about them metabolically that also, uh, is a piece of their signature?

    18. JRJosh Rabinowitz1:56:19

        Well, cancers tend to be glucose users and, you know, o- once you step back and think that, you know, in the fasted state in particular using glucose is a, a- a weird thing rather than a default thing, okay, and that the, the default thing is to use fat and lactate, then the fact that cancer uses glucose i-is very distinctive. Um, and they do this in large part because they're programmed internally to basically feel like they're always seeing insulin, and this is through mutations in something called the PI3 kinase pathway that Lou Cantley, who you mentioned, you know, pioneered. And this leads to the fact they're positive on this FDG PET scan, so they'll constantly take up and phosphorylate and trap glucose or glucose analogs, and this is actually the most sensitive way to detect most types of cancer. Uh, downstream from this, though, there's a, a ton of metabolic changes in the cancer cells. Um, and, you know, the most fundamental of these is the fact that i-in order to do the uncontrolled growth, they have to do uncontrolled nucleic acid synthesis. And this is the vulnerability that was targeted initially by Farber but has been targeted by a lot of very important medications that are, you know, widely used still today. You know, pemetrexed is first-line treatment for lung cancer, and if you get these medications right, you can induce mutations through, uh, you know, the metabolic stress on the nucleotide system, and this can make immunotherapy work better. And so th-that's a, a very exciting part, and I, I think that part has gone understudied as cancer metabolism has, you know, returned to the fore. There's been a lot of focus on fuel usage cutoff, which is tough because like most cells in the body, cancer cells can use a lot of different types of fuels depending on what's available.

    19. PAPeter Attia1:58:19

        Yeah, this is an important point, Josh, because a lot of people, I think, would hear the first part of what you're saying and their natural conclusion would be, "Well, wait a minute. If, you know, you do a PET scan on somebody and it lights up with glucose, that tells me cancer loves glucose, ergo, the way to treat cancer, don't eat glucose." The problem with that logic is no matter how little glucose you eat, you still have plenty of glucose in your circulation. I mean, even if you're in a complete state of starvation, again, going back to George Cahill, 40 days of starvation, they still had three millimole of glucose in their circulation 40 days out. So there is no way to eliminate glucose. Now, an argument could be, "But you're gonna minimize insulin." So I guess the question becomes is minimizing insulin actually more important than minimizing glucose? But s- the, the idea of starving cancer seems potentially overly simplistic, right, based on everything we've already talked about.

    20. JRJosh Rabinowitz1:59:18

        Yeah, I, I think starving cancer is very, very hard, and as you say, getting circulating glucose to go meaningfully down below, you know, the healthy eighty-nine where you last measured yourself is very, very difficult. And, um, e-even if you could do that, it's not gonna prevent the cancers from having access to internally stored fuel for a while in the form of glycogen and then ultimately to amino acid fuel and fat fuel and lactate fuel, uh, ketone body fuel, and, you know, we've shown very clearly that cancer can use all of those things, [chuckles] right? So they're, they're all valid inputs. They can't replace glucose in the test tube, um, but y-you know, it, it's not easy to cut off the cancer fuel supply, um, especially not without cutting off some other critical fuel supply, the immune cell fuel supply, right, which would be a disaster-

    21. PAPeter Attia2:00:13

        Yep. Mm-hmm

    22. JRJosh Rabinowitz2:00:13

        ... or the brain fuel supply, which would be an even more acute disaster.

16. 2:00:17 – 2:05:06

    Making cancer a chronic disease: exploiting the metabolic quirks of cancer, augmenting the immune system, and more

    1. PAPeter Attia2:00:17

       This idea that there's a way to exploit the metabolic, I don't want to say limitation, but I would just say quirk of cancer-

    2. JRJosh Rabinowitz2:00:28

       Mm-hmm

    3. PAPeter Attia2:00:28

       ... in a way that also augments the immune system, say a bit more about that because that's both fascinating intellectually but also elegant in that it's mechanistically in line with a bias I have, which is cancer's really gonna be hard to, you know, get under control. So, you know, hoping for a stalemate where you use multiple modes of action is probably a better strategy than hitting really hard on one lever. Again, it's a bias of mine, but y- you know, uh, at least I can acknowledge it. [chuckles]

    4. JRJosh Rabinowitz2:01:04

       Yeah, well, I think we're seeing a lot of moves to try to make cancer into a chronic disease where the therapies are not so, uh, terrible, and, you know, certainly hitting the nucleic acid side o-of cancer is something people are trying for, you know, maintenance therapy, and I think w-we need to think about that whole side of cancer metabolism fresh because I think there are targets, you know, waiting to be, uh, developed there. I think, you know, if they create nucleotide imbalances, which is a natural thing to do when you hit that system, then nucleotide imbalances are drivers of mutations and mutations in cancer cells are drivers of immune response to cancer. So, uh, that's one very appealing avenue.

    5. PAPeter Attia2:01:52

       So in other words, int-interrupt their ability to synthesize DNA, they will create more mutations. More mutations is more shots on goal for the immune system.

    6. JRJosh Rabinowitz2:02:02

       Exactly. So I, I think that's one really exciting avenue. Another exciting avenue is to apply a very strong stress to the cancer while putting pressure on their fuel supply. And so I think it's very hard to think that you're gonna put so much pressure on the fuel supply, okay, that that alone is gonna make the tumor, uh, slow or even more optimistically regress or something. But if you come in with chemotherapy, for example, that's already targeted, uh, preferentially, not perfectly, right, to the tumor, and then you pair that with something like ketogenic diet, which is lowering insulin, lowering glucose- Then we at least see in animal models that this can be a very powerful combination. We see that the tumors, uh, start to deplete glucose in response to the chemotherapy, whether that's because their vasculature is breaking down or whether that's because they have heightened glucose demand because they're having mitochondrial damage from the chemotherapy, I'm not sure. But we see that chemotherapy lowers glucose in the tumor intrinsically, and then if you come in with a diet that lowers glucose availability, this becomes stronger, right? And then you can get to really low tumor glucose, and we see pretty big improvements in outcome in mouse experiments. Hopefully, they'll translate to the clinic. We have a clinical trial open on this now.

    7. PAPeter Attia2:03:29

       And what's the best tool we have besides the conventional, and maybe it is simply the conventional, in terms of ways to inter- uh, i-interfere with their nucleic acid synthesis? Is it literally just going back to old school chemotherapeutics that do that?

    8. JRJosh Rabinowitz2:03:42

       Well, for the moment, right, yes. I mean, for the moment, pemetrexed is probably the most successful clinical agent, but, you know, uh, gemcitabine and, uh, you know, other things of this sort are, you know, all well used, uh, as part of the armamentarium. But I, I think we need to think fresh. I mean, I-I'll say on, on this front, it's really interesting to me that when we were in medical school, you know, I, I thought we would not see a cure in our lifetimes for hepatitis.

    9. PAPeter Attia2:04:15

       Yeah, and look at that now, huh?

    10. JRJosh Rabinowitz2:04:17

        Okay? And look at that, and that was m-mainly nucleoside analogs.

    11. PAPeter Attia2:04:20

        I mean, we were told that. I mean, I remember being told, like, there are two things that are absolutely-- 'Cause I remember talking about this as why can't there be a vaccine for hep C? And it's like you, you'll never be able to vaccinate a flavivirus. Okay, well, that still turns out to be true, but you'll never cure hep C. And yeah, lo and behold.

    12. JRJosh Rabinowitz2:04:40

        And this is just nucleoside analogs as the centerpiece of this, right? And so the fact that there's clearly untapped potential there... Now, maybe that potential was maxed out, you know, forty years ago, uh, you know, when people were doing this hardcore for cancer from the cancer but not hepatitis perspective. But, but my guess is that that's all chemistry that's evolved a lot-

    13. PAPeter Attia2:05:02

        Mm-hmm

    14. JRJosh Rabinowitz2:05:02

        ... and that this is a ripe area for, for rediscovery.

17. 2:05:06 – 2:12:07

    The challenge of treating pancreatic cancer

    1. PAPeter Attia2:05:06

       Well, it's interesting you mentioned gemcitabine because, of course, that's, you know, one of the first-line agents for pancreatic cancer. And if I, if I'm not mistaken, you have a particularly keen clinical interest in pancreatic adenocarcinoma. Is that correct?

    2. JRJosh Rabinowitz2:05:18

       Yeah. It's the cancer that I've worked on the most. Uh, it's obviously just a horrible disease. Um, you know.

    3. PAPeter Attia2:05:25

       It's definitely one of the cancers that gives cancer a bad name. It's, um, it's the fourth leading cause of cancer death in both men and women, and yet by incidence, it's a fraction of that, right? It's, it just speaks to how lethal it is. Um, you know, the last time I looked, Josh, I would say that adenocarcinoma of the pancreas is ninety-five percent lethal, and I've heard people argue that the five percent who don't die are misdiagnosed-

    4. JRJosh Rabinowitz2:05:51

       Yeah, that's right

    5. PAPeter Attia2:05:51

       ... almost suggesting that it's pretty much impossible to survive pancreatic adenocarcinoma, which is the worst thought in the world. Um, so you certainly picked a tough one to study.

    6. JRJosh Rabinowitz2:06:05

       Yeah. I mean, I, I, I feel a very strong commitment to it because of a bunch of reasons and, you know... But the, just the fact that it's so terrible is, uh, a motivation, and I think it's, you know, was a disease that for a long time people thought, "It's just so terrible, we just give up." And, you know, I, I don't think that's the right attitude for terrible diseases. And, you know, I think the, one of the hardest things in making biomedical progress is getting a clinical readout and, you know, um, the hidden positive in how terrible this disease is, is the clinical readout is just sitting there itching to be improved. And so, uh, there's the capacity to do really compelling clinical tests of any idea. And it's a terrible disease. Most of these, uh, you know, clinical efforts are gonna fail, but they can be done relatively fast, relatively cost effectively and, and we're seeing progress. I mean, that's what's so exciting that, you know, fulviranux is progress. A lot of patients' tumors respond. Even more will respond if you combine, uh, two agents that were approved, uh, gemcitabine and abraxane, um, which is a albumin-bound form of paclitaxel, uh, with a platinum agent. That triple combination, uh, produces, uh, regressions in most patients' tumors. Um, so-

    7. PAPeter Attia2:07:33

       But they're not durable. I mean, that's the thing that-

    8. JRJosh Rabinowitz2:07:34

       They're not durable. Okay. It's the-

    9. PAPeter Attia2:07:36

       ... that's the thing that's killing us

    10. JRJosh Rabinowitz2:07:36

        ... the, the duration of response is terrible right now, but the fact there's response is promise, okay? A-and I think i-in the-- Anyway, the, uh-- Normally, from my perspective, once you can start seeing response, you're on the road. We have to figure out how to make the response durable. I hope that's where the metabolic part becomes important. Uh, and it's gonna be some interface of the metabolic part or the immune part or, uh, a yet harder hit with, you know, chemo or radiotherapy, earlier diagnosis. These are the hopes for, for fixing this.

    11. PAPeter Attia2:08:14

        Is there something about pancreatic adenocarcinoma that you've observed metabolically that is distinct from other gastrointestinal adenocarcinomas?

    12. JRJosh Rabinowitz2:08:26

        I think, you know, colon is also a terrible disease. Liver is also a terrible disease. So all the gastrointestinal, you know, adenocarcinomas are unfortunately really bad diseases.

    13. PAPeter Attia2:08:37

        But at least with those, stage one can be-- I mean, certainly stage one colorectal cancer is survivable. Hepatocellular is a bit tougher, you know, you're-- but you're better than a coin toss. But, you know, again, coming back to pancreatic, stage one is 80 to 85% not survivable. Uh, I've always wondered what is it about pancreatic adenocarcinoma that is so difficult, and is it simply that its rate of early metastasis is so early that stage one is just sort of a, a misnomer term? It's not-- There's no such thing as stage one?

    14. JRJosh Rabinowitz2:09:13

        I, I think that is a, a big part of it. It's kind of a soft organ, the pancreas, and you get the-- It's a very, um, invasive cancer, and you can have s- local invasions so many places from that site in the body.

    15. PAPeter Attia2:09:26

        Plus immediate access to the portal system that's just seeding the liver constantly.

    16. JRJosh Rabinowitz2:09:30

        It's just seeding the liver, and so it's in an, anatomically a really, um, problematic location for keeping the cancer self-contained. So, um, and I think the other thing is that, you know, metabolically it's a very tricky cancer. It's almost solely driven by mutations of the Ras oncogene. Not saying there aren't other drivers-

    17. PAPeter Attia2:09:55

        Yeah

    18. JRJosh Rabinowitz2:09:55

        ... but almost every patient has this Ras driver. And this is an instruction manual for the cancer cells, um, n-not just to divide, but to do a bunch of metabolic things that involve scavenging nutrients from the environment and taking in nutrients in non-standard ways. And so it actually instructs the cancer cells to reach out arms, pull in nutrients, internalize them, uh, degrade macromolecule nutrients from the environment, and use this as kind of a, a garbage recycling form of nutrient access that, that makes them very, um, metabolically pernicious. The, the other thing that we see that's really interesting in new work in, uh, mouse models of pancreatic cancer is that they don't have to be very metabolically active in order to be horribly lethal. So the pancreas i-is a master protein-producing organ. And then you may think of insulin as the most famous protein to come out of the pancreas, right? But the bulk of the pancreas is not-

    19. PAPeter Attia2:11:03

        Yes

    20. JRJosh Rabinowitz2:11:03

        ... you know, beta cells that make insulin.

    21. PAPeter Attia2:11:05

        That's right. Yeah.

    22. JRJosh Rabinowitz2:11:05

        Exocrine pancreas.

    23. PAPeter Attia2:11:06

        It's only 5% of it. Yeah. That's right. The exocrine is the real gland.

    24. JRJosh Rabinowitz2:11:09

        And the exocrine pancreas is just making digestive enzymes like crazy. It does by far the fastest protein synthesis in the body.

    25. PAPeter Attia2:11:17

        Mm.

    26. JRJosh Rabinowitz2:11:17

        The cancer turns that protein synthesis way down, so it's not hypermetabolic. It's just that it has this huge capacity to make stuff that even when it turns it down, still has enough biosynthetic capacity to grow and divide and grow and divide. Because it's turned down its main energy-consuming normal function of protein synthesis, it can function with much reduced TCA activity, reduced ATP synthesis rates. And so i-it's amazing that it can be-

    27. PAPeter Attia2:11:49

        So it's very efficient then

    28. JRJosh Rabinowitz2:11:51

        ... very, very efficient. So it, it can turn down all these normal functions and it still has the capacity to reproduce the cells and make these horribly invasive and metastatic cells, which are ultimately lethal.

18. 2:12:07 – 2:14:50

    Epithelial cancers that might respond to metabolic approaches to therapy

    1. PAPeter Attia2:12:08

       Of all the epithelial cancers today for which we don't have a cure, which is almost every one of them, right? Shy of like a GIST or something like that, or certain testicular cancers. Is there one that you're more optimistic about in terms of metabolic approaches to therapy?

    2. JRJosh Rabinowitz2:12:29

       It's a great question. Um, I mean, y-y-you see Pemetrexed being used effectively in lung cancer, right? And I think you see the cancers with mutational burdens, um, being the ones where you're getting the good, uh, immunotherapy responses. Um, whether they're ones that are particularly susceptible intrinsically to metabolic effects, I don't know. Um, I don't think that's gonna be the standalone heart of treating any of these cancers. I think it's more gonna be a key piece of a puzzle in getting enough either drug killing by preventing their metabolic escape mechanisms or enough immune activity, and those may be kind of, um, opposites. So you may need also kind of cyclic therapies where you go through rounds of metabolic suppression in order to, um, keep things calm while you can, and then periods of metabolic augmentation that are really directed at augmenting the immune system.

    3. PAPeter Attia2:13:36

       Mm.

    4. JRJosh Rabinowitz2:13:36

       Uh, a-and I'm a, I'm a big believer that, you know, there's metabolic limitations on immune response to cancer, and that if we can overcome them, we will, uh, have m-major therapeutic benefits.

    5. PAPeter Attia2:13:49

       You know, you mentioned Ras in the context of pancreatic carcinoma. Um, Ras is rarely immunogenic in the pancreas, right? It's, it's, it's a driver mutation, but the immune sys-- it doesn't produce back to the way we started our discussion. It doesn't give us a beautiful little nine to 11 amino acid peptide-

    6. JRJosh Rabinowitz2:14:06

       [chuckles]

    7. PAPeter Attia2:14:07

       ... that gets presented on an MHC class molecule, right?

    8. JRJosh Rabinowitz2:14:11

       Yeah, but-

    9. PAPeter Attia2:14:11

       It's the great irony of this whole thing.

    10. JRJosh Rabinowitz2:14:13

        Yeah. Y-you need more shots on goal. You need more antigens.

    11. PAPeter Attia2:14:19

        Do you have any sense of how many tumor-infiltrating lymphocytes are typically identified at all in resected pancreatic specimens?

    12. JRJosh Rabinowitz2:14:28

        I, I think it's typically quite the, um, lymphocyte desert.

    13. PAPeter Attia2:14:32

        Mm.

    14. JRJosh Rabinowitz2:14:32

        You know, there's a ton of macrophage activity in pancreatic cancer, and so I think macrophage rewiring is gonna be, you know, a, a big part of, um, allowing lymphocytes to enter a-and these are areas where I think metabolism can be quite impactful.

19. 2:14:50 – 2:16:39

    Josh’s hopeful outlook on the future of cancer treatment

    1. PAPeter Attia2:14:50

       Well, Josh, this is, uh, super interesting. I, I don't-- I hate that we're ending on somewhat a depressing note. Is there, [chuckles] is, is there anything more optimistic that we wanna talk about, uh, than pancreatic adenocarcinoma? Beyond, you know, the statement that, hey, look, you know, this is why we have the smartest people working on the hardest problems, but, um- Anything else within cancer metabolism specifically that you think, boy, 10 years from now, like I'm really optimistic that we're going to have a new way to, you know, hack into their, um, DNA synthesis pathway in a corrupt manner that just spits out mutations, um, using kind of novel systems, right? You know, I don't know if... Antisense oligonucleotides, like just something that totally disrupts them in a selective manner.

    2. JRJosh Rabinowitz2:15:40

       You know, I, I, I think my big hope on this front is that we're gonna be able to have some combination of, um, directed metabolic immune supplements and diet that really work with therapy to treat cancer. I mean, cancer is such a discrete disease. The clinical trials are so manageable, and the fact that things are metabolically messed up in the tumor is so incredibly clear, and they're so clearly messed up in a way that's favoring the wrong kind of immune cells. And so ultimately, uh, through either some sort of supplement or diet, we're gonna be able to reverse that, and we're gonna make immunotherapy work instead of for 10% of patients, for a majority of patients. So that's my uplifting thought for you, is that metabolism will be part a-along with, you know, you know, better pure immunological therapies of getting immune control of cancer over the coming decade.

20. 2:16:39 – 2:23:26

    Nutritional approaches to cancer attenuation

    1. PAPeter Attia2:16:39

       And besides reducing insulin, which is such an obvious strategy, are there other metabolic levers to pull with the diet? 'Cause really, between ketogenic diets and cyclic fasting, those are kind of the two ways that you do that. Do you see evidence of amino acid restriction or any other nutrient restriction that could potentially play a role?

    2. JRJosh Rabinowitz2:17:04

       [lips smack] Uh, I think amino acids are, you know, complicated, but they hold a, a lot of potential. I think the type of fat can be important. Um, you know, the, the saturated and unsaturated fat are, are really different, and in cancer they're gonna play, you know, different roles. So it's very nice work from Matt Vander Heiden's lab showing that, you know, a, a higher saturated fat ketogenic diet could be more tumor suppressive in some contexts because the tumors have trouble making unsaturated fat in the context of hypoxia.

    3. PAPeter Attia2:17:38

       Say, say more about that. I, I wasn't aware of that. So Matt-- I know Matt's work very well, of course. Is, uh, is he still at, uh, Dana-Farber?

    4. JRJosh Rabinowitz2:17:45

       Uh, he's at the Koch at MIT.

    5. PAPeter Attia2:17:47

       Okay.

    6. JRJosh Rabinowitz2:17:47

       So he's actually head of the, the Koch now, uh-

    7. PAPeter Attia2:17:50

       Okay

    8. JRJosh Rabinowitz2:17:50

       ... the MIT-

    9. PAPeter Attia2:17:50

       And, and was this in prostate cancer?

    10. JRJosh Rabinowitz2:17:51

        ... Cancer Institute. This was-- Oh, I forget what cancer background he did it in. I think it was in pancreatic, at least in part, but I'm not 100% sure.

    11. PAPeter Attia2:18:02

        Okay. So that's super interesting. So a ketogenic diet that was higher in saturated fat posed a greater problem for the cancer cells because they couldn't make presumably the essential unsaturated fats.

    12. JRJosh Rabinowitz2:18:18

        Exactly. So I, I think this is a, a interesting strategy. I mean, those effects were relatively subtle up to now, but, you know, it c-could be part of the picture. Um, [lips smack] you know, I, I think the really exciting part of the diet is also the parts that connect to the microbiome. So I think the fiber part-

    13. PAPeter Attia2:18:43

        Mm

    14. JRJosh Rabinowitz2:18:43

        ... really working that out, and maybe total protein matters in ways that we don't understand and needs to be, uh, much like, you know... M-maybe we need to not just think about cycling, fasting, and feeding, but cycling, you know, for example, there's a time maybe when you wanna come in with a lot of carbs in the absence of protein and that may achieve something that creates a particular immune milieu. Uh, and then, you know, you need protein and the right timing after that. So there's a lot of things we can do with timing of macronutrients that can be interesting.

    15. PAPeter Attia2:19:16

        And, and I mean, it seems like an eternity before we'd be ready to study this in a human clinical trial because the permutations are so many. So do you feel like we have high throughput animal models where we can test these hypotheses and say, you know, "Hey, this is one way to do this," and, um, you know-- or, "We, we've looked at 10 ways to do this in animals, but these are the three most promising, so we're gonna kinda go ahead and do these now"?

    16. JRJosh Rabinowitz2:19:42

        Yeah. I think, you know, the good animal models of cancer are still not that high throughput, and there's a lot of challenges converting animal diet-

    17. PAPeter Attia2:19:53

        Yeah

    18. JRJosh Rabinowitz2:19:53

        ... and human diet, [chuckles] right? And so, um, you know, we'll, we'll come out with some work showing that, you know, some of the most exciting dietary combinations, um, are absolutely effective in animals, but they're not effective through the mechanisms that people thought before. Um, a-and it's, you know, it's because the-- e-even in animals, trying to get the diets aligned so that you really isolate variables is tough. But I, I think the fact that we're asking these questions that haven't been asked before, uh, is gonna build momentum and, uh, we're gonna, we're gonna build this interface out over the next five-year period in animals. And, uh, we'll do clinical work, you know, as a field in parallel with that, that, um, has an impact and has an impact on patients' lives wi-within the five to 10 year timeline, I hope.

    19. PAPeter Attia2:20:48

        Do you worry that the challenges of even if you came up with the right diet... So let's just assume 10 years from now, the answer is a cyclic ketogenic diet that has this much saturated fat, this much monounsaturated fat, this much polyunsaturated fat, this much glucose on this day, this much protein on that day. Like you-- the, the formula exists, right? So this is almost an impossible thing. But that It's impossible to adhere to in the way that, you know, a pill or a drug or an infusion is much easier? Or do you think that in cancer, because the stakes are so high, adherence will be unlike it is in any other field of medicine?

    20. JRJosh Rabinowitz2:21:32

        No, we have to make it simple, right? I mean, this has to be clinically, um, actionable. And but, you know, uh, I would go much more back to the first question that we asked-- you asked maybe when I, I first mentioned the potential of immunotherapy and fiber, like is it soluble fiber? Is it insoluble fiber? And then there really are different flavors of soluble fiber. Now, maybe it's the gamish of them or maybe it's one in particular. Maybe it's one isolatable molecule that relates to that. And then we have one isolated molecule, tiny molecule, that will more than double the number of complete responses you get to immunotherapy in mice. One tiny molecule smaller than glucose, okay? [laughs]

    21. PAPeter Attia2:22:14

        You already have that.

    22. JRJosh Rabinowitz2:22:16

        As a-- We already have that as a, as a, as a metabolite, okay? And so I, I think we're gonna get, uh, to simple-

    23. PAPeter Attia2:22:22

        So it could almost be nutritional supplements as opposed to wholesale dietary changes.

    24. JRJosh Rabinowitz2:22:25

        They, they, they... W-w-well, these can be sup-supplements. The dietary changes may be in a very acute way, just the way the patient comes in the hospital for a, you know, tough bout of chemotherapy or a tough surgery. Maybe we're gonna go to a place where we, um, take people's glucose in the hospital almost down to zero for twelve hours, you know, with a, a deep ketosis and some pharmacotherapy at the time that we hit them really hard with chemo. And twenty-four hours of that, it's like light-- night and day in terms of the overall effect. But it, it can't be asking patients to give up eating and giving up the joy of food.

    25. PAPeter Attia2:23:03

        Yeah.

    26. JRJosh Rabinowitz2:23:03

        Or another trial that we're, we're starting now is a trial, uh, with SGLT2 inhibitor plus a low carbohydrate but not fully ketogenic diet to see if it can put people in ketosis. And then just looking forward to would this be a convenient way to get the benefits of ketosis in cancer patients while still allowing them to have a little bit of, you know, breaking bread with the family.

21. 2:23:26 – 2:27:09

    What makes Princeton University special

    1. PAPeter Attia2:23:26

       Last question for you is totally random. I don't know what made me just think of this. Princeton is the only Ivy League school that doesn't have a medical school, correct?

    2. JRJosh Rabinowitz2:23:33

       I think that's right.

    3. PAPeter Attia2:23:34

       Is, is, is there-- I mean, that-- there's gotta be a deliberate reason for that. It has-- It's-- Princeton is fantastic in everything. Do, do you know why it doesn't have a medical school and, um, is it just the proximity to Penn or that it was assumed that there-- that's where the collaborations would be?

    4. JRJosh Rabinowitz2:23:51

       I mean, Princeton doesn't have a medical school because at its heart, Princeton is a hybrid of a college and a university, and it, it is an institution that, you know, has the ultimate priority under undergraduate education. Uh, it's, um, committed to that. It's best in world in that. And, uh, so I think, um, in assessing how to be best in world at undergraduate education, the Princeton administration many times has asked the question: Is having medicine on campus part of that? And the answer has always been no. Let's have a somewhat more pure intellectual environment and keep our focus on doing the very best training for undergraduates. And so it's a very conscious decision.

    5. PAPeter Attia2:24:40

       It doesn't have, it doesn't have a business school either, and I guess it's the same argument, right?

    6. JRJosh Rabinowitz2:24:43

       There's no business school. There's no law school. So, uh, that's Princeton. Uh-

    7. PAPeter Attia2:24:47

       Yeah

    8. JRJosh Rabinowitz2:24:47

       ... it makes it very special. And it's good to have special places that are, you know, distinct. I, I think that's a wonderful thing.

    9. PAPeter Attia2:24:54

       Are, are you at all a fan of Richard Feynman's work?

    10. JRJosh Rabinowitz2:24:57

        [laughs] At a very, uh, light level, I guess I would say. That's the best way to put it.

    11. PAPeter Attia2:25:03

        But, but it doesn't... Th-there aren't places around Princeton that you go to see where, you know, he, you know, w-what eating club he was in or things like that. You don't, you don't, uh, you don't look for the old places?

    12. JRJosh Rabinowitz2:25:14

        No, I, I, I, I'm not, I'm not a, a f-fan that way. I guess there, um... I, I read a giant biography of Oppenheimer, and they're filming, uh, the film of that o-on campus. So Matt Damon was apparently on campus. Uh, I, I'm guessing he's playing Oppenheimer, but I haven't checked anyway, so... But I guess I've become a small Oppenheimer fan after reading, reading that intensive book. [laughs]

    13. PAPeter Attia2:25:39

        I have, uh, three of Feynman's books, uh, meaning like books that were actually his. So I have, uh, his table of integrals from when he was in high school-

    14. JRJosh Rabinowitz2:25:49

        Hmm

    15. PAPeter Attia2:25:49

        ... uh, and then two more advanced calculus books, one from when he was at Princeton and then one from when he was his first professorship, uh, professorship at Cornell. Um, and the-- it's just they're sacred to me, right? It's like his scribblings, like his notes all over these things signed Richard P. Feynman and like what, you know, what his address was-

    16. JRJosh Rabinowitz2:26:09

        [laughs]

    17. PAPeter Attia2:26:09

        ... and things like that. So, um, yeah, I've never, uh, I've never made the pilgrimage to, to look for his eating club and things like that. It probably doesn't even exist anymore. But th-- I just wondered if you'd been the-- been on the tour.

    18. JRJosh Rabinowitz2:26:21

        No, but y-you should come down. There definitely have been some, uh, you know, awesome Princetonians. Uh, you know, um, I, I guess my kids all went to nursery school in the building where Von Neumann built the first computer. So, you know, there's-- it, it is amazing-

    19. PAPeter Attia2:26:40

        Beautiful

    20. JRJosh Rabinowitz2:26:40

        ... the amount of stuff that happened around here.

    21. PAPeter Attia2:26:43

        Well, Josh, so great to see you again, and, uh, I hope it's not too long before I see you in person again. But, uh, really appreciate, uh, uh, first of all, the amazing work that you've done over the past twenty-plus years and, uh, and sitting down to, to share it with us today.

    22. JRJosh Rabinowitz2:26:56

        Uh, it's been fun. Uh, appreciate the opportunity. [outro music]

Episode duration: 2:27:09