#87—Rick Johnson, MD: Fructose—the common link in hypertension, insulin resistance, T2D, & obesity?

1. 0:00 – 0:11

   Intro

   1. PAPeter Attia0:01

      [upbeat music]

2. 0:11 – 5:58

   Intro and Rick Johnson's Path from Kidney Disease to Fructose

   1. PAPeter Attia0:11

      Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn more now, head over to peterattiamd.com/subscribe. Now, without further delay, here's today's episode. [upbeat music] My guest this week is Dr. Rick Johnson. Rick is a professor of medicine in the Department of Nephrology at the University of Colorado, where he's been since 2008. He's basically spent the last 17 years being a division chief across three very prestigious medical schools. He's unbelievably prolific as an author. He has well over 700, approaching 800 publications seemingly every week in JAMA, New England Journal of Medicine, Science, et cetera. He's lectured across 40 countries, authored two books, one of which we discuss in great detail in this podcast called "The Fat Switch," which he wrote about, uh, seven or eight years ago. He's been funded extensively by NIH and, in fact, has received the most prestigious grants that NIH has to offer. His primary focus in research has been on the mechanisms causing kidney disease, but it was doing this that he became really interested in obesity, diabetes, heart disease. And what connected me to Rick, I guess about seven years ago now, maybe, maybe a bit longer, was his work on fructose and fructose metabolism. And that's really what we talk a lot about in this podcast. So we start by talking about high blood pressure, the relationship between salt and high blood pressure, which is something that is incredibly controversial, and I actually learned a lot in this podcast. I'm really glad we had this discussion because I kind of thought I had this thing figured out, and I clearly don't. We talk about one of the most interesting bifurcations in evolution with respect to an enzyme that allowed us to use fructose in a certain way that was obviously advantageous millions of years ago. Today, not so much. We talk a lot about ur- uric acid, which you've probably heard me talk about on other podcasts. This will then be the master's class in it. We talk about artificial sweeteners, and we sort of touch on some of the most promising ideas around pharmacotherapy that are being developed in response to the epidemics of metabolic disease, especially in response to sugar. So this episode gets a little bit deep on some of the biochem. We're gonna have... Obviously, the show notes will, as usual, provide a great background and a list of references, and I hope you enjoy my discussion with Dr. Rick Johnson. [upbeat music] Hey, Rick. Thanks so much for opening up your office today and making time.

   2. RJDr. Rick Johnson3:03

      It's great. I'm very happy to have you here.

   3. PAPeter Attia3:06

      I've wanted to sit down with you for about a year in this format because I guess we've probably known each other for maybe about six years now, and every discussion has been one of those discussions where at the end of the discussion, I think, "Man, how am I ever gonna remember all of this stuff, and how will I be able to sort of synthesize this to translate it into sort of what I'm doing?" And I've said this sort of many times before, but that is the whole kind of reason that I started a podcast, was I just found myself every week having a discussion with someone, usually scientists, where I thought, "This, something's got to be shared." So you would certainly be one of the three or four people in- indirectly that was a real catalyst for the podcast because of the frequency with which we would either have these dinner discussions or discussions over the phone. And so anyway, for that, I want to thank you, and hopefully the listeners do as well. But in the introduction, I've set this up a little bit as to why this is such an important discussion. And because there's so much to talk about, I just kind of want to jump right into the meat of things. It would be not an exaggeration to say you are one of the world's experts on fructose. And I guess I would just start with the why. Where did that interest come from? You've obviously been doing this for a long time, and that passion has been sustained. So what brought you to this point?

   4. RJDr. Rick Johnson4:18

      Well, I'm a kidney doctor, so normally we wouldn't be studying sugar. So it was kind of a circuitous way that I got there. I was very interested in the cause of high blood pressure, and it'd been known for a long time that high blood pressure is linked with kidney. And in fact, the going theory is, for years, was that the kidney in high blood pressure has a, a defect in its ability to excrete salt, and so that you end up retaining salt, and that leads to elevated blood pressure. And when we were studying, trying to understand how the kidney handles salt in high blood pressure and so forth, we were trying to understand potential pathways, and we stumbled on the fact that hyperuricemia or elevated uric acid could be a very significant risk factor for high blood pressure. And when we started studying uric acid, we realized that when you raised uric acid in animals, they developed high blood pressure. From there, we started to try to understand what made the uric acid go up, and we knew from the literature that sugar and particularly fructose raised uric acid. So we started studying fructose, and pretty soon we were so excited about what we were finding that we just kind of changed our research direction to focus more on how fructose has all of its metabolic effects.

   5. PAPeter Attia5:40

      Well, there's a lot to unpack there, so let me kind of go back to bits of it. You sort of gloss over the fact that the conventional approach to high blood pressure is that sodium is the culprit. And isn't it still safe to say that most advice around reducing blood pressure comes down to reducing sodium intake?

3. 5:58 – 11:37

   Salt, Serum Sodium Concentration and Blood Pressure Thresholds

   1. RJDr. Rick Johnson5:58

      Well, we've actually been studying this pretty extensively. There's a lot of pearls I can teach you Or I can talk about related to salt. And when I was in training, I was taught that you restrict a certain amount of salt. You should be on a low salt diet as a mechanism to prevent high blood pressure. It was always about the amount of salt. In fact, we were teaching that for a long time, that if you want to have a low blood pressure, you should restrict your salt intake, or if you want to try to treat your high blood pressure, you should restrict your salt intake. What's happened in the last couple decades has been the increasing knowledge that it isn't really the salt amount that makes a difference, but the salt concentration. So when you eat salt, like if you eat a salty soup, the salt concentration goes up in your blood first, and it translates into a thing called osmolality and so your serum osmolality goes up.

   2. PAPeter Attia7:02

      So osmolality is sort of like the ionic pressure buildup in a fluid? Is that a way to...

   3. RJDr. Rick Johnson7:08

      It's sort of like the number of molecules in a set of volume. So literally when you eat salt, if it's really salty, let's say you have a serum sodium concentration of one forty millimoles per liter. If you eat a really salty soup, your serum sodium may go up to one forty-two or one forty-three. What looks like pretty insignificant, but that actually is what triggers a rise in blood pressure. And so we've actually done the study where we took people and gave them soup with or without salt. When they drink the salty soup, their serum sodium goes up and their blood pressure shoots up.

   4. PAPeter Attia7:44

      How much would a person's blood pressure go up if their sodium went from one forty to one forty-two?

   5. RJDr. Rick Johnson7:49

      It's about six millimeters.

   6. PAPeter Attia7:51

      Okay. So they'd go from one twenty to one twenty-six.

   7. RJDr. Rick Johnson7:53

      Yeah. And that happens acutely.

   8. PAPeter Attia7:55

      And how long does it take to resolve?

   9. RJDr. Rick Johnson7:56

      Maybe a couple hours. So if we give... And we did this study, we published it last year. If you give salty soup with water so that the serum sodium doesn't go up, they got the same amount of salt, guess what? The blood pressure doesn't go up.

   10. PAPeter Attia8:11

       And the serum sodium does so not go up or does go up?

   11. RJDr. Rick Johnson8:14

       Right. Right. Does not go up. So if you block the serum sodium from going up-

   12. PAPeter Attia8:18

       So basically the closer you can bring the total accumulated concentration of what you ingest down, the more likely you are to prevent this transient rise in serum osmolality and blood pressure.

   13. RJDr. Rick Johnson8:31

       Yeah. Well, it turns out that serum osmolality has a real major role not only in blood pressure, but also in, in obesity, and we're going to talk about that in a second. But when you take a high salt diet and your serum sodium goes up, it triggers a rise in blood pressure, and it's working through the brain and actually through the liver and other sites too.

   14. PAPeter Attia8:52

       Pause for a moment. Tell the listeners why it would be better to have a blood pressure of one twenty over eighty than one forty over a hundred.

   15. RJDr. Rick Johnson8:59

       Well, there's a pretty good epidemiologic data that shows that when your blood pressure is high, that you have an increased risk for heart failure and stroke. Those are the two major ones, but it also increases the risk for heart attacks and heart disease in general. Interestingly, there's a very significant inflection point, and what I mean by that is when the blood pressure gets around one sixty to one eighty, right in that range, the risk for stroke goes significantly up and the risk for mortality goes up. And that's because our body tries to autoregulate to blood pressure. So when the blood pressure goes up, for example, the kidney, the arterioles will constrict to reduce the pressure load to the kidney. But when it gets to about one seventy, it will overcome that restriction and the blood pressure will injure the kidney. Likewise, the brain kind of responds to flow more, so it tries to maintain blood flow. But if the pressure gets high, it tries to protect itself from the high pressure by constricting. But when the pressure's like one seventy, the risk, it can't constrict enough and you don't want it to constrict that much because it has to maintain flow, and so the pressure ends up increases to the brain and increases the risk for stroke.

   16. PAPeter Attia10:20

       Now, current guidelines seem even more aggressive. We would manage class one hypertension. We would consider something in the mid one thirties to be treatable.

   17. RJDr. Rick Johnson10:29

       Yeah. So let me get there. So originally when the studies came out, it was very, very clear that if your blood pressure was like one seventy or higher, that you had a dramatic increased risk for stroke, and that's because it would pass the autoregulatory point. But then what happened was epidemiologic studies showed that even a blood pressure of like one forty over ninety conferred increased risk. It just was much less than the one seventy. So at one seventy it just takes off. It's almost... The line goes up vertically. But between one forty and one sixty there is still a stepwise increased risk, but it's just a kind of a more gradual risk. In fact, for things like a stroke, you can start showing an increased risk from one twenty over eighty to one forty over ninety, uh, leading people to view one twenty over eighty as kind of the optimal blood pressure. As you get older, if the blood pressure's really low, you lose your autoregulation for low blood pressure, and so it, it increases the risk for kidney disease and, and problems as well. So you don't want to be extreme on either end, especially as you get older.

4. 11:37 – 17:39

   Kidney Inflammation, Autoimmunity and Primary Hypertension

   1. PAPeter Attia11:37

      This whole thing's kind of such a... It's a real clinical mystery in some ways still because in medical school we learn about this term called essential hypertension, which is kind of a wastebasket term for hypertension or high blood pressure for which we don't have an obvious cause. The problem is... And so having sort of that wastebasket term would be okay if it accounted for the minority of cases, but then you get to the clinic and you realize everybody walking around with high blood pressure basically is getting labeled as having, quote unquote, "essential hypertension." So it really is this epidemic without a clear description. Now we're going to come to a lot of reasons that... I mean, I think you have arguably one of the most compelling cases for what is at the root of essential hypertension. But for people listening to this, for doctors listening to this who treat hypertension- I feel like we just haven't made much progress in the twenty years since I've been out of medical school.

   2. RJDr. Rick Johnson12:27

      There have been some real breakthroughs in the understanding of primary hypertension just in the last five, ten years, and there's two major aspects I can talk about. The first one is that it does appear that salt really is important, and one of the key discoveries was that the kidneys are often normally handle salt fine, but they develop or acquire a change in the kidneys that lead them to hold onto sodium. And the mechanism has been identified just in the last few years. It's due to the fact that there's an inflammatory inflammation that occurs in the kidney, and that inflammation, which is driven by T cells and macrophages, causes a constriction of the blood vessels that leads to low-grade ischemia in the kidney. And that ischemia can translate into increased sodium absorption, which then leads to high serum sodium and the effects.

   3. PAPeter Attia13:31

      Is there a correlation between serum sodium and blood pressure across normal physiologic ranges of, say, one-thirty-five to one-forty-five milliequivalents per liter?

   4. RJDr. Rick Johnson13:40

      Yeah, I believe so. I'm not sure I can quote the paper, but yes, I think that's true.

   5. PAPeter Attia13:45

      So what you're saying is in people with high blood pressure that's otherwise viewed as, quote-unquote, "essential," there's an inflammatory response mediated by both T cells and macrophages-

   6. RJDr. Rick Johnson13:57

      Right

   7. PAPeter Attia13:58

      ... that injures the kidney ischemically, meaning it, for the listener, that results in reduced blood flow and tissue damage due to reduced blood flow and reduced oxygen, and it's that injury that then leads to aberrant retention of sodium.

   8. RJDr. Rick Johnson14:12

      So there's actually been really a lot of studies looking at the mechanism of the inflammation, and originally it looked like it was-- people thought it might be a reactive response of the kidney. So we think that there may be external stimuli that initially cause a decrease in blood flow to the kidney, like a sympathetic nervous system response. You can do it transiently by giving medicines or drugs that can cause a constriction of blood vessels. When you do that, you get a transient reduction of blood flow to the kidney. That induces an inflammatory response that then causes persistent reduction in blood flow. And what we've learned in the last few years, and I'm an author in one of these studies, is that this inflammatory reaction can actually be an autoimmune reaction. And we've even identified certain proteins that there's an autoimmune response to, and one is a heat shock protein. You can actually create high blood pressure in animals by inducing an immune response to this, and you can block the immune response and block the high blood pressure. And, and now there's even data showing that in humans that there's evidence for an autoimmune response to heat shock proteins in people with essential hypertension.

   9. PAPeter Attia15:24

      Which is not to say heat shock proteins are necessarily bad because so many of the benefits we get out of sauna or exercise may be transmitted through these, but you're saying in a subset of people where the heat shock protein itself becomes the nidus for inflammation via an autoimmune mechanism.

   10. RJDr. Rick Johnson15:40

       Yeah, so heat shock proteins are great, just as you say. They do all these really good things. But what happens is they're involved in the clearance of misfolded proteins, and they're helping keep a clean system. But what happens is when you trigger injury to the kidney, for example, these heat shock proteins get produced to help fix problems, but the immune system can sometimes get confused and make an immune response that actually is against the heat shock proteins. And when that happens, you can develop high blood pressure in the animal, and there's some evidence for it in humans. So anyway, so that's one of the big breakthroughs has been the discovery that inflammation in the kidney can be a mechanism for triggering persistent elevations in blood pressure and probably has a big role in the cause of primary hypertension.

   11. PAPeter Attia16:30

       Before you go on, Rick, how prevalent do you think that particular mechanism is that you just elucidated?

   12. RJDr. Rick Johnson16:36

       Oh, it's very major. In fact, we've even looked at genetic polymorphisms that link with the development of primary hypertension, and most of them are involved with the immune response, and it looks like this is a major pathway.

   13. PAPeter Attia16:48

       This creates a bit of a quandary for someone who's trying to rid themselves of hypertension because wouldn't the implication of this be that exercise or things like exercise that induce heat shock proteins may paradoxically increase their hypertension?

   14. RJDr. Rick Johnson17:03

       I don't think so. So hypertension's kind of a complicated pathway, so there's several different aspects. But exercise is extremely good for improving mitochondrial function, improving the ability for your blood vessels to dilate. It improves kidney function. The benefits of exercise are so much greater, and releasing heat shock proteins, that really occurs with very... I don't know if just general exercise would have a big effect on heat shock proteins.

   15. PAPeter Attia17:33

       Yeah, so you're saying basically the net effect of exercise is still going to far outweigh-

   16. RJDr. Rick Johnson17:38

       Yes, absolutely.

5. 17:39 – 23:22

   How Salt Becomes Fructose and the Basics of Sugars

   1. RJDr. Rick Johnson17:39

      But I'd like to get back to this, the link between salt and sugar, if I could, okay? Because there is this data, as I say, that salt, when it increases the serum sodium, is what drives the acute blood pressure response, and when the kidneys have trouble getting rid of salt, it's easier to get that effect with a salt load. But even with a normal person, you can, with normal blood pressure, you can raise their blood pressure transiently by giving them salt, and you can block it by giving water. Interestingly, in the process of developing high blood pressure, there's the initiators, and then there's the things that make it persistent. And the inflammation in the kidney is involved in the persistence. But what i- is involved in the initiation turns out that sugar has a major role. And what we discovered is that when you give a high salt diet to animals, that the high salt increases the serum sodium, and the serum sodium, when it goes up, it activates an enzyme that converts glucose, which is in our blood and in our tissues, to fructose. And that conversion to fructose is driven by a, a high salt diet, and it's driven by an increase in serum osmolality or increase in serum sodium. Once the fructose is made in the body, so this is not fructose coming from the diet, this is made in the body, the fructose gets metabolized and raises blood pressure. And when we gave high salt to animals, they developed an increase in blood pressure, and they also were making fructose. And when we block the metabolism of fructose, we actually block the rise in blood pressure, as well as the hypertrophy of the heart.

   2. PAPeter Attia19:37

      So let's pause for a moment. You know, I've had Rob Lustig on the podcast before, so anyone who's listened to that will be familiar with what fructose is, what glucose is, what sugar is, all of these things. But can we spend one minute just defining these things for people who haven't listened to that podcast?

   3. RJDr. Rick Johnson19:54

      Sure. So there's different types of sugar, and the main one that we call blood sugar is glucose, and this is the primary sugar that our body uses to make energy. It's the main sugar that's used to make energy, and it can be stored in the tissues as glycogen. And when it's too high, we call it diabetes. When the blood glucose is too low, it's hypoglycemia. And so glucose is like the principal energy fuel, the carbohydrate fuel that we use.

   4. PAPeter Attia20:26

      And as you said, we store lots of it in our muscles. Once it gets in the muscles, it can't get out, and we store maybe a quarter to a third of it in our liver, and that's mostly there to buffer the blood supply, in particular the brain. What does glucose taste like, a pure drink of glucose?

   5. RJDr. Rick Johnson20:42

      People like it, animals like it, but it isn't as sweet as classic sugar. But it is often very much liked by animals. Humans like it. There-- You can buy these dextrose pops and stuff like that. Dextrose is another word for glucose. And also the kidneys store glycogen and produce glucose too. The second type of sugar is fructose, and the best way to think of fructose is it is a fuel... First off, it's present in fruit, but it turns out to be the sugar that is involved in energy storage rather than energy production. And so when you eat glucose, you use that to produce energy. But when you eat fructose, it will actually trigger changes in the body that will favor the storage of energy. And this is the sugar that animals use to store energy. So-- And you store it in the way of fat, in the way of glycogen, and all those kinds of... Anything that will facilitate storing energy is done by fructose.

   6. PAPeter Attia21:47

      And fructose and glucose, if you were looking at pictures of them in a biochemistry book, look pretty similar.

   7. RJDr. Rick Johnson21:52

      Yeah.

   8. PAPeter Attia21:52

      They're both ringed carbon structures. They both have six carbons. One of them has a five ring versus a six ring. But, you know, it's sort of interesting to think that molecules that look almost identical, with the exception of a couple of bonds different, can have quite different properties. Now, fructose tastes a lot sweeter as well.

   9. RJDr. Rick Johnson22:10

      Yes. And so fructose is like in honey and in fruits, and then... That's right. So it tastes a lot sweeter. And the other thing is if you mix the fructose and glucose together, you can get what's called high fructose corn syrup. And if they're bound together, you get table sugar. So table sugar or sucrose is one molecule of glucose and fructose bound together.

   10. PAPeter Attia22:33

       And that occurs in nature in sugarcane and-

   11. RJDr. Rick Johnson22:36

       Yes

   12. PAPeter Attia22:36

       ... beets and things like that, right?

   13. RJDr. Rick Johnson22:37

       Yes, and maple syrup and things like that.

   14. PAPeter Attia22:40

       Right. So just to clarify for everybody, we, when we get a little comfortable with this terminology, throw the word sugar around quite liberally, but it's always important for people to think when we talk about sugar, we could be talking about blood sugar, glucose. We could be talking about fructose by itself. Oftentimes, when we talk about sugar in diets, we're talking about added sugars such as the sucrose and high fructose corn syrup you just alluded to. I want to go back to what you just said about the ability of fructose to store something. But if you don't mind, can we do it through the lens of a beautiful story that you've written about in the past about a mutation that basically allowed that to happen, this thing that took place about twelve to fifteen million years ago?

6. 23:22 – 34:13

   The Uricase Mutation and Ape Evolution

   1. RJDr. Rick Johnson23:22

      Sure. So fructose, again, is a... it's in fruit, and many, many animals use fructose as a means, as their primary nutrient, or, and also as a way to help store fat. And for example, um, animals before they hibernate will often eat a lot of ripe fruit, and the ripe fruit gives them the sugar that allows them to store fat. And orangutans will eat huge amounts of fruit at one sitting to try to increase their body fat. And we don't get fat from eating fruit, but that's because we eat tart fruit that has less sugar content, and we tend to only eat a few fruit. Whereas if we actually drink fruit juice, that large amounts of fruit juice can actually increase fat. So anyway, so fruit is a nutrient that, you know, is used by animals to help store fat. So if you go back about twenty million years ago, [chuckles] the very first fossil apes show up in the world, and they, they show up in West Africa. And the original one was called Proconsul. They, they were living about twenty-two million years ago, and they were-- these apes were a big breakthrough in evolution because the prior-- the monkeys were-- had already been around, but these were bigger creatures, the apes were. They had bigger brain size. They were tailless. But they did live in the trees, and they lived in tropical rainforest and woodland rainforest, and they would eat primarily fruit. And they were quite successful, and by about 18 million years ago, there were almost, uh, at least 10 to 20 species of ape that were living in this area of Africa. There was a change in climate. There was some global cooling, and the Antarctic started building up ice, and the Arctic started building up ice, and sea levels fell. And when the sea levels fell, land bridges developed that connected Africa, which had been separate, separated from the other continents. These land bridges opened up so that there was now a way to get out of Africa into Europe and Asia. And many, many species migrated across those land bridges about 17 million years ago, and some of them were the apes. And we see the first apes fossils in places like Pasalar, Turkey, and different places of Europe right around 16 million years ago. At that time, there were still forests that were fruiting trees, woodlands, there was fruit all year round. And so the animals, when they moved into Europe, they didn't have to change their habits at all. They were able to continue to eat fruit pretty much all year round. But unfortunately, it continued to get cooler, and by 12 million years ago, the apes started to starve in Europe. And you can tell that from the fossils because they actually have these, like, tree rings on their teeth that... The de-developing teeth get this enamel. The enamel doesn't lay down correctly, and they get these, like, tree rings that shows intermittent starvation. They would get a ring every time they would go through a period. And the, the starvation was seasonal, so it was during the cooler months when suddenly the fruit was not available. And the primary reason was there was a loss of the fig tree, and the fig is a cool fruit that can fruit all year round because the wasp that fertilizes the fruit does so at its own discretion. So the fruit will... of a fig tree kind of can occur all year round. So when the fig tree died, suddenly there weren't too many, uh, because of the global cooling, or perhaps it was the wasp, but the fig trees disappeared, and suddenly these a-apes did not have enough food to survive during the cooler months, and they started to starve. And by six to eight million years ago, the last ape became extinct in Europe. But Africa, although there was global cooling there too, it wasn't as cold, and the fruit trees survived all year round. The forest just retracted, so the apes there were able to maintain their normal habits. Well, there was a lot of evidence that there was a lot of evolutionary change occurring in our ancestors during this Miocene period and this period of time when there was the global cooling. And one of them was a mutation in uric acid metabolism. And as I mentioned, sugar, and particularly fructose, when it's metabolized, generates uric acid. Glucose, when it's metabolized, does not. But fructose, when it's metabolized, makes uric acid. And this mutation led to a much stronger uric acid response to fruit because this mutation was of an enzyme that degrades the uric acid. And when you block that and you eat fruit, your uric acid levels go up much more. And this mutation basically allowed these apes to maintain a very prominent uric acid response. Our group has shown that the way fructose stimulates fat, as well as its other properties like insulin resistance and raising blood pressure, that those abilities are driven in part by the uric acid. So when this mutation occurred, for the same amount of fruit, they were able to store more fat. And so it was like a survival mechanism for this mutation when it showed up. It allowed apes that did have very little access to fruit to suddenly maintain more fat stores, and so they could live longer and survive those winters. And we were able to show with Peter Andrews at the Natural History Museum in London, who studies these apes, that this might account for a very interesting finding. And the finding is that although we thought the apes became extinct in Europe, and they certainly did become extinct in Europe, the fossil record shows that it was a European ape that made it back to Africa and also to Asia to become our ancestors as well as the ancestors of, of the great apes that live in Africa and in Southeast Asia, like the orangutan, that they all came from a common ancestor that was in Europe and that went back to Africa. And we know from the genetics that that ape carried the uricase mutation. And so this mutation probably occurred at a critical time that provided survival for those apes in Europe to be able to get out of there and make it back to these other regions. But it was now equipped with this mutation that made it sensitive to sugar. And so humans are much more sensitive to sugar than most animals, and it's because of this mutation. And in fact, we actually resurrected the extinct uricase and proved this using the extinct uricase that-- showing that when you put it into human cells That it suddenly made us less sensitive to fructose.

   2. PAPeter Attia30:39

      So, so the phenotype there, I mean, I guess just to recap that story, which I find so fascinating, by the way, you guys wrote a story about this in Scientific American many years ago, right? I know there was a paper that came out as well, but I mean, the sort of the layperson version in SciAm was really great. So basically, these apes go from Africa up to Europe. It gets too cold. We sort of think they die out, but the evidence emerges, actually, a sub-sub-subset of them developed a mutation in uricase that gave them a superpower, which was now they could be much more efficient at turning fructose into fat. They had this little byproduct, which is they would also make a boatload of uric acid along the way, but they actually came back to Africa and ultimately seeded the rest of the species. And ultimately, that's why we as humans are among the very rare animals that have uric acid levels that are quite high relative to cats and dogs, for example.

   3. RJDr. Rick Johnson31:29

      Yes, that's exactly correct.

   4. PAPeter Attia31:31

      So when we were in medical school, Rick, we learned a lot about uric acid through the lens of a disease called gout. And it didn't get a lot of airtime in school. Maybe it gets more today, but at the time, it was basically gout is a disease of civilization. It's from eating too much meat, and there's no real problem with it except for the nuisance of your toe hurts because uric acid crystallizes, it gets inside joints. It seems to favor the first joint of the great toe, and it's a very painful inflammatory condition, and it's what happened to sort of the wealthy people of the last few hundred years as they started getting and acquiring too much meat and protein. And that was sort of the story. What you're describing is a little bit more nuanced. So tell us more about uric acid.

   5. RJDr. Rick Johnson32:15

      Yeah. So the big problem with having too much uric acid is gout, just as you say. And all the animals that have the uricase mutation are prone to gout. But humans, in particular, are very prone to gout, and it's because of our diet. So we do eat diets that are high in meat and purines that increase our risk for gout.

   6. PAPeter Attia32:35

      Can you tell folks what purines are specifically, since it always shows up in this terminology?

   7. RJDr. Rick Johnson32:39

      Sure. So we have proteins, we have fat, we have carbohydrates, but we also have things like RNA and DNA and what we call nucleic acids. So these are the kind of acids that are in the nucleus and that are also in the cell that help drive gene formation and protein, you know, our genetic material, and also help dictate the production of proteins. And so DNA and RNA are made up of nucleic acids, and when they're broken down, they're made up of purines. And then uric acid is a purine, and it's basically the ultimate breakdown product of DNA and RNA.

   8. PAPeter Attia33:20

      So the reason protein consumption versus fat or carbohydrate would lead to this is 'cause if you're eating protein, you're eating the DNA and RNA that presumably were still in that tissue?

   9. RJDr. Rick Johnson33:31

      Yes. So the way you get gout from protein is from the DNA and RNA in the protein. And so... And that relates to some extent to the s- how dense the nuclei are. And so, like, if you have a very cellular thing like, uh, anchovies and these small fish that have lots of DNA and RNA, if you have that, they will develop-- You can get gout from that much easier than from, um, other types of meat. And so beer, for example, has brewer's yeast, and that is filled with RNA. And so that's why beer can precipitate gout.

7. 34:13 – 40:50

   Uric Acid Beyond Gout

   1. PAPeter Attia34:13

      Now, I follow uric acid levels very closely in all of my patients and myself, and there is an unmistakable difference between men and women, at least in my small sample size of patients, where men, on average, have higher uric acid levels than women. Is that true across the general population?

   2. RJDr. Rick Johnson34:31

      Yes. Even in boys, they'll start to have a higher uric acid than girls. However, after the menopause, uric acid levels go up in women, and that's because estrogen helps excrete uric acid.

   3. PAPeter Attia34:45

      Ah, so it's not... I had sort of, I guess, incorrectly assumed it was that just on balance, men consumed more protein than women.

   4. RJDr. Rick Johnson34:53

      I think that also plays a role. I think that's right.

   5. PAPeter Attia34:56

      But it sounds like this estrogen explanation makes more sense if it can also explain the observation of menopause.

   6. RJDr. Rick Johnson35:02

      Yes. Going back, gout is also increased by sugar. And even Sir William Osler, the famous physician from the 1890s, in his book Principles and Practice of Medicine, pointed out way back in the 1890s that, that sugar was a major risk factor for, for gout, as well as very sweet fruits, he wrote. Anyone who's had gout usually will know that real s- significant sweets can also precipitate gout, and the reason is because of the fructose content, and when the fructose is metabolized, it generates uric acid. When people were developing gout in the 1800s, it was linked to the wealthier groups. In England, for example, they were eating a lot of, as you say, rich foods that included proteins and, and so forth. But one of the things they were eating a lot of, they were drinking a lot of alcohol, to which they added sugar. I actually did write a paper where we reviewed how much sugar was put in drinks, alcoholic drinks back in the 1700 and 1800s, and it was much more than today. They loved sugar. They put it in, in many of their drinks. And in fact, I even have a picture of an old pub outside the Tower of London called The Sugar Loaf. They talk about the old drinks that were served, like hippocras and some of these drinks, and sack and sugar was a name for a drink that they had. They... I mean, they added a lot of, of sugar to their drinks. And so part of the rise in gout back in the 1800s and 1700 and 1600s relates to not only just the alcohol and the rich foods, but also to the sugar they were adding.

   7. PAPeter Attia36:44

      So You were sort of the person who brought onto my radar that there are other things besides gout that one needs to be concerned about when it comes to uric acid, and one of them is blood pressure. So how did that understanding come about?

   8. RJDr. Rick Johnson36:58

      So originally, we were studying what causes high blood pressure, and there was a lot of epidemiologic studies that linked uric acid with high blood pressure. And as I mentioned, we, we also knew that there was subtle changes going on in the kidney associated with high blood pressure, and people with gout often have low-grade kidney disease. So I said, "Aha, maybe uric acid could have a role in causing kidney disease through causing high blood pressure through its ability to cause kidney disease." And so we took animals, and we gave it this uricase inhibitor to raise the uric acid of an animal, and by gosh, they developed high blood pressure. And then we could lower the blood pressure by lowering the uric acid. And when we looked, we were thinking it was, might be like crystals of uric acid in the kidney, but-

   9. PAPeter Attia37:48

      Although that was my thought is the crystals would cause the inflammation in the kidney, and that would... Based on what you just said.

   10. RJDr. Rick Johnson37:53

       That was my thought, too. [laughs]

   11. PAPeter Attia37:54

       And that, and that turned out not to be the case.

   12. RJDr. Rick Johnson37:55

       And when we look, we looked in the kidney, there weren't any crystals there. So then we realized it was an effect of soluble uric acid. So we started putting soluble uric acid on cells and so forth, and we saw that it had all these biologic effects. And we always had thought uric acid was kinda like a dead end product of something or even might be a good thing 'cause some people said it was an antioxidant. But it was causing pro-inflammatory effects. So then we said, "Aha, fructose, sugar raises uric acid. Maybe sugar could have a role in blood pressure."

   13. PAPeter Attia38:30

       What year is it that you're having that thought, Rick?

   14. RJDr. Rick Johnson38:32

       2002. We gave some animals fructose, and they developed high blood pressure, and we gave them allopurinol, which is a drug to lower uric acid, and it made their blood pressure go back to normal, and it was like this big discovery. But what was totally exciting [laughs] was these animals also developed insulin resistance. They also developed elevated triglycerides in their blood. They had other fatty liver. And when we lowered the uric acid, we showed benefits on all of those parameters.

   15. PAPeter Attia39:07

       How does allopurinol work? What's the mechanism by which it lowers uric acid?

   16. RJDr. Rick Johnson39:11

       It blocks uric acid formation. So uric acid is generated from other purines. And when we block that, we blocked a lot of the effects of sugar to cause metabolic syndrome. And so we, when we first did it, we said, "Ah, there's gotta be something wrong here." So we repeated it, and we did it different ways, and didn't matter. It looked like uric acid had a role in how sugar worked. So as we studied this, we started realizing that the process by which uric acid is generated is important in how sugar causes disease. No one believed us initially. I have to tell you that everybody said, "Ah, yeah, sugar causes gout," but the idea that sugar raises uric acid that causes gout, but the idea that sugar raises uric acid and that is involved in the obesity and the insulin resistance, we don't believe it. What's happened since then is we've learned that the metabolism of fructose is extremely different from the metabolism of glucose. The two look alike, but when fructose is metabolized, there's this process that causes the energy in the cell to fall before it goes up. So normally, when you eat a calorie, when you eat any kind of nutrient, we use it to make energy. That's what we do. But when you eat fructose, the energy in the cell falls before it goes up. It's the only nutrient that lowers energy in the cell.

8. 40:50 – 53:59

   ATP Depletion and the AMPD Fat Switch

   1. PAPeter Attia40:50

      Say more about what you mean by that. So are we talking about a cell in the liver, for example?

   2. RJDr. Rick Johnson40:54

      Yes. I'm talking about the cells that metabolize the fructose.

   3. PAPeter Attia40:58

      Okay. So we'll contrast it with glucose. So if glucose enters a cell, it gets turned into pyruvate, and ultimately, ATP is made. So you're saying total energy goes up as a result of metabolizing that glucose.

   4. RJDr. Rick Johnson41:11

      So whenever you metabolize any kind of calorie, any kind of food, you eat food, you're gonna metabolize it to make energy. That's what we do. We try to break down the food, and we use it to make energy. That energy is called ATP, and ATP is the currency in our body that we use to make us run, walk, think, talk, everything. So this ATP is pretty critical, but to make ATP, you have to spend a little of it to make it. So the process of breaking down and metabolizing food or glucose or fructose or requires spending a little bit of ATP before you make it. Well, what happens is when you metabolize glucose, you do spend some ATP, but the body has a system whereby feeds back to stop the process before any significant ATP depletion occurs. So for example, there's an enzyme called phosphofructokinase that's used in glucose metabolism. If ATP levels fall, that enzyme gets turned off to stop glucose metabolism, to allow ATP levels to come back up. But when fructose is metabolized, the enzyme that metabolizes fructose is called fructokinase, and when that metabolizes fructose, it consumes ATP in an unregulated way. So if the cell sees a lot of fructose, the ATP levels can plummet by 40% or 50% in the cell, and that signals A huge number of effects throughout the body. It's like a mayday signal. It says, "We're under attack. We're running out of energy." And so it switches the animal into a condition in which they're trying to preserve their energy, so they reduce their metabolism, they reduce their expenditure, their resting energy expenditure. They shunt the energy that they're eating, the calories they're eating, into fat and glycogen as opposed to making more ATP. They're trying to protect the body by putting you into a system where you try to store fuel. It triggers hunger and thirst that makes you want to eat more, so you eat more to restore the energy, but at expense that you're shunting much of it into fat and into s- fuel storage. So fructose turns out to be used by animals as a mechanism to store fat. Normally, animals will regulate their weight beautifully. They just maintain their weight normally. If you take an animal and you put a tube down its throat and give it extra food to make it gain weight, if you take the tube out, the animal will go right back to its normal weight. If you starve an animal and so it's below its normal weight, and then you let it just eat, it will eat back to its regular weight. But when it wants to gain fat, it will do so usually through a mechanism that involves fructose. So what they do is they, like a hibernating animal, will start eating a lot of fruit in the fall to increase its weight. An increase induces insulin resistance. It gets hungry. It drops its metabolism so that most of the energy it eats goes into fat, and the same thing with a long distance migrating bird. They'll start eating fruit to get the fructose, and so this is a very common pattern, and it's driven by that ATP depletion.

   5. PAPeter Attia44:51

      And this is distinct or in parallel, of course, to this uracase mutation so that... Can you separate these two phenomenon? In other words, if you can restore uracase to the non-mutated version, do you still have this problem around the ATP depletion?

   6. RJDr. Rick Johnson45:08

      Yeah, so the ATP depletion triggers a series of reactions, and what happens, what the key one is, not only does ATP decrease in the cell, but intracellular phosphate also falls, and that activates an enzyme called AMP deaminase that converts the broken down product of ATP, which is AMP, and it converts it to uric acid. And that process has multiple steps, and we know that that whole pathway is involved in the generation and stimulation of fat, di- insulin resistance, fatty liver, elevations in blood pressure, a variety of effects, and that pathway is what seems to be critical for inducing obesity from sugar.

   7. PAPeter Attia45:58

      Let's go through that again, 'cause that, what you sort of talked about at the very end, is effectively the thesis of your book, The Fat Switch. You explained what ATP is, adenosine triphosphate, and the T, of course, stands for tri. There are three phosphates. It's the liberation of a phosphate that is the production of energy. So when you need to breathe, you need to move, when you need to do anything, you have to turn ATP into ADP. So the chemical reaction is adenosine triphosphate becomes adenosine diphosphate. One phosphate escapes, and that's what gives us the energy. Now, that can happen again. ADP can lose one of its two remaining phosphates and become AMP, adenosine monophosphate. What you said after is the really critical, critical piece of this, which is when you have a molecule of adenosine monophosphate, it stands at a proverbial fork in the road. It can either go down a path that is driven by something called AMPK or AMP kinase, or it can go down the pathway of AMPD.

   8. RJDr. Rick Johnson47:13

      That's right.

   9. PAPeter Attia47:14

      Now, let's go back to this point, 'cause I, again, it seems everything comes down to that choice. What happens if AMP goes down the AMPK pathway versus the AMPD pathway?

   10. RJDr. Rick Johnson47:26

       Yeah, so if it goes down the AMPK pathway, it actually is burning energy. It's burning fat. It does a lot of really positive things. If it goes down the AMPD pathway, it goes down a fat storage pathway. So it's, they're exact kind of opposites. AMPD, if you stimulate it, it will cause insulin resistance and eventually diabetes, whereas if you stimulate AMPK, you can actually use that, like metformin, to actually treat diabetes. So that fork is critical, and what drives that switch is the fall in intracellular phosphate, and the reason that phosphate falls is because it's taken up in the fructose 1-phosphate, or it's taken up by fructose. So the fructose gets phosphorylated by the ATP, and it becomes fructose 1-phosphate that sequesters phosphate, and there is this process where both ATP levels fall and intracellular phosphate falls, and that triggers this AMPD pathway. And if we interrupt the AMPD pathway, we can block a lot of the metabolic effects.

   11. PAPeter Attia48:31

       Do other animals also have this phenomenon?

   12. RJDr. Rick Johnson48:35

       Oh, yeah. No, we can show this. We actually showed it in hibernating squirrels. So wh- when a squirrel wants to gain weight, it will activate the pathway for AMPD. When it's hibernating and burning the fat, it activates the AMPK pathway.

   13. PAPeter Attia48:50

       I got it. So even though humans and our most close descendants in primates- Have the uricase mutation. This ability to toggle between AMPK and AMPD is unique to any species that has the potential to gain weight and wants to use it to their advantage.

   14. RJDr. Rick Johnson49:07

       Oh, absolutely. Part of the pathway through which AMPD is working involves the generation of uric acid. So we know that the uric acid, when it's going up inside the cell, is doing all kinds of biologic effects, and the AMPD is driving that. There may be other things besides the uric acid.

   15. PAPeter Attia49:26

       So the hummingbird or the squirrel can still store fat. They just don't get the bump in uric acid that comes with it 'cause they don't have the uricase mutation.

   16. RJDr. Rick Johnson49:33

       Well, actually, the hummingbird does have the uricase mutation.

   17. PAPeter Attia49:36

       Oh, really?

   18. RJDr. Rick Johnson49:36

       Yeah.

   19. PAPeter Attia49:36

       I don't know my evolution well enough.

   20. RJDr. Rick Johnson49:38

       Yeah, so birds have the uric-

   21. PAPeter Attia49:39

       Birds bifurcated off after then.

   22. RJDr. Rick Johnson49:41

       Yeah, and rep- and reptiles have the uricase mutation. Even dinosaurs had the [laughs] uricase mutation. Sue the dinosaur, the Tyrannosaurus rex, actually had gout.

   23. PAPeter Attia49:50

       I mean, that's got to be why Tyrannosaurus rex was so ornery.

   24. RJDr. Rick Johnson49:53

       [laughs]

   25. PAPeter Attia49:53

       'Cause if you think of the size of the T. rex great toe, I mean, that would be infuriating-

   26. RJDr. Rick Johnson49:58

       [laughs]

   27. PAPeter Attia49:58

       ... to every Brontosaurus out there.

   28. RJDr. Rick Johnson50:00

       Yeah, I think so.

   29. PAPeter Attia50:01

       He's eating too many of the Bronchosauri. Sorry to get back into the minutiae of this, but I, I... it's important. You still have to phosphorylate glucose during its metabolism. Why is it that the phosphorylation of glucose during its metabolism to pyruvate doesn't result in a strong enough drop in intracellular phosphate to cause the same problem?

   30. RJDr. Rick Johnson50:19

       Because, uh, the reaction stops. Whenever there's, um... the phosphate and ATP levels start dropping a little bit-
9. 53:59 – 59:32

   Fructose and the Features of Metabolic Syndrome

   1. PAPeter Attia53:59

      So all these things you're talking about with fructose seem to fit almost directly into the five characteristics of metabolic syndrome, which are elevated glucose, so that insulin resistance would be manifested as an elevated glucose, elevated blood pressure, elevated waist circumference, so storage of fat, elevated triglycerides, which you just said, and the only one we didn't address is low HDL cholesterol, which is the fifth finding. Now, of course, three out of those five are sufficient to put you in the category, but-

   2. RJDr. Rick Johnson54:37

      Fructose does all five.

   3. PAPeter Attia54:38

      What is the mechanism by... So you've already described the mechanism by which it does three of them. We alluded loosely to how it raises triglycerides, but I'd like to talk about that more, and then, of course, I'd like to hear how it lowers HDL cholesterol.

   4. RJDr. Rick Johnson54:50

      Okay, so the uric acid generated by fructose has a very pronounced effect to stimulate oxidative stress In the mitochondria. And fructose also generates lactate big time, and the lactate also has effects on mitochondria, as you learned from Dr. Sam Milan's talk. And in addition, fructose preferentially decreases mitochondrial function and stimulates glycolysis. And so all those things cause you get this big oxidative stress to the mitochondria, and there's an enzyme in the mitochondria that drives fat oxidation called enoyl-CoA hydratase. I mean, sorry to-

   5. PAPeter Attia55:34

      Throw it out there

   6. RJDr. Rick Johnson55:34

      Yeah, I'm so sorry

   7. PAPeter Attia55:35

      ... this is what we're here-- No, no, no. We're here to talk about it

   8. RJDr. Rick Johnson55:37

      But basically, um, the oxidative stress inhibits that, so fatty acid oxidation goes down, so you block fat burning. And then in addition, you block an enzyme called aconitase with oxidative stress to the mitochondria, and that increases citrate, which drives fat generation. And so you end up with fatty liver that's driven by both increased fat synthesis and a block in fat burning. The mitochondrial oxidative stress also is very much linked with the development of insulin resistance. And then uric acid is also... The generated uric acid's also causing oxidative stress to the islets, to the pancreatic islets as well. So-

   9. PAPeter Attia56:17

      Uric acid is actually harmful to the islet cells of the pancreas?

   10. RJDr. Rick Johnson56:21

       Uh-huh. In fact, if you give sugar... We did a study where we gave sugar to animals where we, we actually restricted the amount of calories. The rats were getting-- They were on a diet, basically. They were on a diet.

   11. PAPeter Attia56:35

       They were on a high sugar, low calorie diet.

   12. RJDr. Rick Johnson56:37

       Right. And then we had as a control rats that got the same number of calories, but they weren't getting the sugar.

   13. PAPeter Attia56:44

       Right, so just a low calorie, low sugar diet.

   14. RJDr. Rick Johnson56:46

       Yeah. And when we gave the high sugar, low calorie diet, all the animals developed fatty liver, hypertension, insulin resistance.

   15. PAPeter Attia56:57

       Did they actually gain weight?

   16. RJDr. Rick Johnson56:58

       No. No. Uh, this is a trick. Weight gain really requires increased calories, really to show it. You know, long term, maybe just decreasing metabolism will do it.

   17. PAPeter Attia57:09

       But this is interesting. You're saying both animals lost weight. Did they lose about the same amount of weight?

   18. RJDr. Rick Johnson57:12

       No, they maintained their weight. Even though they were eating 90% of what they normally eat, they were able to maintain.

   19. PAPeter Attia57:19

       So both groups slowed their metabolism enough to maintain weight-

   20. RJDr. Rick Johnson57:22

       That's right

   21. PAPeter Attia57:22

       ... at a 10% reduction of calories.

   22. RJDr. Rick Johnson57:24

       Right.

   23. PAPeter Attia57:24

       So on the outside they look the same, but the high sugar group still developed fatty liver.

   24. RJDr. Rick Johnson57:29

       Severe, and they all became diabetic.

   25. PAPeter Attia57:31

       Do you recall in that study, Rick, what the actual percentage of their macros that came from fructose?

   26. RJDr. Rick Johnson57:37

       20%.

   27. PAPeter Attia57:37

       Right. So the critic will say, "Well, that's highly unnatural," although in reality it's not that unnatural. There are lots of people unfortunately walking around getting 20% of their energy input from that. So it's not physiologically completely out of whack, but as a proof of concept, these animals got diabetes without gaining weight. They got fatty liver disease without gaining weight. They were by definition insulin resistant.

   28. RJDr. Rick Johnson57:58

       Right. And when we measured their insulin levels, they first became insulin resistant with high serum insulin levels, which is what we see-

   29. PAPeter Attia58:06

       Early diabetes, basically

   30. RJDr. Rick Johnson58:07

       ... with early type 2 diabetes. But over time, the serum insulin levels started to fall.
10. 59:32 – 1:09:55

    Fructose, Cancer, Fructokinase and Fructokinase Inhibitors

    1. PAPeter Attia59:32

       When you sort of pause for a moment, Rick, do you ever worry that talking about fructose this way just seems... I don't know what the word is. I don't think it's necessarily being too much of a reductionist, but it almost seems too simple that this one molecule could simultaneously have probably allowed our species to survive during this very cold spell 6 to 12 million years ago, and obviously evolution wasn't thinking 12 million years into the future that we'd be flush with fructose, and yet here we are today. One could interpret what you're saying to mean if you simply had no fructose in your diet, most of the bad things we think about metabolically would go away. Is that a fair assessment?

    2. RJDr. Rick Johnson1:00:19

       Yeah, I think that's true. So let me give you another one where we've really learned a lot. I don't know if you are aware of the relationship with cancer, but what we've learned is that fructose was a incredible survival nutrient in the setting of near starvation. So as I mentioned, what we're learning is all these animals use fructose. They either get it from their diet, or they make it in their body, and they use that to help them survive. And we can talk about it, but it involves not just storing energy, but they use fructose to store water. And we can talk about that, and they use it to become insulin resistant. Insulin resistance is a survival mechanism where by increasing blood glucose and preventing glucose from taking up in the skeletal muscle, it preserves it for the brain, which is what you want to do if you don't have enough food around. You want to be able to think so you can escape predators and so forth. So it was a survival tool to increase energy, and it actually also protected animals from a low oxygen state. So by switching, by reducing mitochondrial function and stimulating this thing called glycolysis, it allowed the animal to survive with a lower oxygen state. And so we know, for example, that the naked mole rat, which lives in burrows, very low oxygen burrows, they make fructose to survive when they're in those burrows. So suddenly the fructose goes up in their blood, and they use it to survive the low oxygen tension there because they switch from mitochondrial metabolism to glycolysis.

    3. PAPeter Attia1:02:00

       But why can't they just rely more on glucose for which we have such an abundant apparatus to store it at large amounts? Is there an energetic reason for fructose?

    4. RJDr. Rick Johnson1:02:11

       A lot of the fructose is converted to glucose and to lactate, which can be converted to glucose, and then it's driven through this glycolysis pathway. So it turns out, though, that what happens is when you metabolize glucose, a lot of it will go through mitochondrial metabolism. And so if we can inhibit mitochondrial metabolism, which uses oxygen, we can live off glycolysis, which doesn't require oxygen. So what happens is in a low oxygen state, like the naked mole rat will use fructose to survive. But cancers-

    5. PAPeter Attia1:02:46

       But wait, I'm still confused about this, Rick, because wouldn't that fructose-- But they're not storing that fructose as fat then because that would be the worst fuel they could have around in a low oxygen environment, right?

    6. RJDr. Rick Johnson1:02:57

       Well, so fructose is increasing glycogen and lipid, but it's also reducing mitochondrial use. When you're eating fructose, you actually are, are not burning the fat. You are storing the fat. And then so what it's doing is it's putting you into a glycolytic state. So animals use it to store fat, and then they, they fast, and then they burn the fat. So they hibernate or they go flying long distances where they have no food, and then they switch, and then the fat that they've stored suddenly becomes their survival. But during the time that they're in a low oxygen state, they want to have fructose on board because the fructose is helping them to survive low oxygen by switching their metabolism. But unfortunately, like cancers also live in a low oxygen state, and so these cancers love fructose as their fuel because it helps support them surviving in a low oxygen state. So recently, it's been shown that many cancers, colon, liver, kidney, breast, brain, all these cancer cells, intestinal, they all tend to like fructose as, as their preferential fuel. There was just a paper in Science a few weeks ago, and if you block that fructose pathway, the cancers don't do as well.

    7. PAPeter Attia1:04:20

       And when you say block it, do you mean block fructokinase?

    8. RJDr. Rick Johnson1:04:23

       Yes.

    9. PAPeter Attia1:04:23

       Which pathway specifically?

    10. RJDr. Rick Johnson1:04:24

        The fructokinase. So if you take intestinal colon cancer, you put high fructose corn syrup on it, they love it. They grow, they metastasize. And if you block fructokinase and block fructose metabolism, you can block a lot of the growth of those cancers.

    11. PAPeter Attia1:04:39

        Do you have a sense of how much you're blocking it?

    12. RJDr. Rick Johnson1:04:42

        It's pretty remarkable. It's like fifty percent or more.

    13. PAPeter Attia1:04:45

        And we know it's the fructose, not the glucose, presumably because we don't impair glucose metabolism at all in that experiment.

    14. RJDr. Rick Johnson1:04:52

        That's correct. And also, they were able to show that this was driven by that shift from a mitochondrial-based metabolism to a glycolytic metabolism.

    15. PAPeter Attia1:05:01

        And what happens to lactate levels in that setting?

    16. RJDr. Rick Johnson1:05:03

        Oh, very high.

    17. PAPeter Attia1:05:04

        Like, meaning the more fructose they have, the higher the lactate level?

    18. RJDr. Rick Johnson1:05:07

        Yes.

    19. PAPeter Attia1:05:07

        Again, very counterintuitive because aren't we sort of taught that the liver is the only organ that can really process fructose and that it all sort of accumulates there and... I mean, conventional thinking is that fructose really doesn't have much of an interaction outside of the liver unless converted to glucose, correct?

    20. RJDr. Rick Johnson1:05:26

        That was said by a lot of people, but the findings show that about twenty percent of fructose is used by the intestine and maybe forty percent by the liver, and at least ten to twenty percent can escape into the circulation. And of course, if the larger the dose, the more that will pass. And the kidney's a big target. There's fructokinase in the brain. There's fructokinase in the islets. There's fructokinase in the adipose tissue.

    21. PAPeter Attia1:05:55

        Does the muscle have fructokinase?

    22. RJDr. Rick Johnson1:05:57

        There's some thought that fructokinase may be in the muscle. It's got to be very low, but there's some thought that fructose is being metabolized in the skeletal muscle. And one of the things that's interesting is there was a paper in Nature that showed that the heart normally doesn't have fructokinase, but when you have a heart attack, the low oxygen state there induces the fructokinase, and there's probably production, endogenous production of fructose, and it seems to be involved in cardiac remodeling. So it's probably involved in more things than we think of. And certainly, it's in the brain.

    23. PAPeter Attia1:06:32

        Which means that in theory, the brain could actually use free molecules of fructose to make ATP in addition to the mainstay of its energy metabolism, which is glucose driven and lactate. I think we're now seeing lactate.

    24. RJDr. Rick Johnson1:06:47

        There is actually some evidence that first off, we know that fructokinase is in the brain. We know the brain can make fructose. And there's increasing evidence that insulin resistances can occur in just in the brain and may be a forerunner for the development of Alzheimer's. And there are actually reports that AMP deaminase is high in the brains of Alzheimer's patients, and it raises the possibility that local fructose metabolism could be involved in disorders like that.

    25. PAPeter Attia1:07:17

        Are there any people with naturally occurring mutations in fructokinase that render it less capable?

    26. RJDr. Rick Johnson1:07:22

        Yeah. So there are people with a condition called essential fructoseuria where they are born without active fructokinase and they live normally. No one's ever been reported to have type 2 diabetes or obesity.

    27. PAPeter Attia1:07:33

        So these people, if I'm understanding you correctly, are genetically immune to the harm of sugar?

    28. RJDr. Rick Johnson1:07:39

        Yes.

    29. PAPeter Attia1:07:40

        And they pee out all the fructose.

    30. RJDr. Rick Johnson1:07:42

        Yes.
11. 1:09:55 – 1:16:28

    Using Allopurinol and Lowering Uric Acid in Clinical Practice

    1. PAPeter Attia1:09:55

       So the work that we've just discussed has sort of been-- you've been at this since two thousand two basically, specifically with respect to this. Let's go back to allopurinol and uric acid. In your clinical practice, because you're still-- you've spent seventeen years as the division head of nephrology across three world-class medical centers, most currently the University of Colorado, and yet I was surprised to learn over dinner the other day that you still have a very pretty heavy clinical practice. You still actually take care of patients in the inpatient ward, and you probably spend a quarter of your time in clinic. So how do you put some of this stuff into practice? Do you liberally use allopurinol even for patients who have high uric acid but have not developed gout yet?

    2. RJDr. Rick Johnson1:10:38

       I do. So our data s-strongly suggests that lowering uric acid could be beneficial. So what I do is the following, so it turns out that allopurinol is not totally safe. There's some people who can develop reactions to allopurinol drug reactions, especially Asians. About three to four percent of people who are Asian can develop an allergic reaction to allopurinol where they can get rashes, and it can be pretty severe, and it's about two percent in African Americans and it's about point five percent in Caucasians. You can test for it. There's a test called the HLA-B58 test, but the point of the matter is that no drug is fully safe. Every drug has side effects. So ideally, you'd want to really be certain that your drug's gonna provide the benefit that you want, and you have to consider the risks versus benefits. Now, although in animals allopurinol is totally protective or protects a lot against sugar-induced metabolic syndrome, the data in humans is suggestive. So there's been, for example, four pilot studies showing an improvement in insulin resistance with lowering uric acid in humans. All four are positive. There's a lot of trials in kidney disease showing that lowering uric acid may benefit kidney disease. There's data on blood pressure. We had a paper in the JAMA showing that y- lowering uric acid could improve blood pressure control in adolescents with hyperuricemia. So there's a lot of supporting data. There are some negative studies too, but the overall weight is now in favor of lowering uric acid to benefit.

    3. PAPeter Attia1:12:17

       What would the target be?

    4. RJDr. Rick Johnson1:12:18

       So what I do is when I see a patient in clinic, I measure the uric acid and currently we know that the risks start to go up when the serum uric acid is over five point five. So once the serum uric acid is over five point five, they really start to have increased risk for pre-diabetes, insulin resistance, hypertension, kidney disease, et cetera.

    5. PAPeter Attia1:12:41

       And what's interesting is most labs, like my lab for example, doesn't even flag it until it hits about six point five as a sort of intermediate risk, and it's really not until about seven point five that it says, "Well, this is high risk." But of course, that's only through the lens of gout, I assume.

    6. RJDr. Rick Johnson1:12:55

       Yes, that's right. So if a uric acid comes back really high, like nine or ten, I have no doubt that that, based on everything I've done, I have no doubt that that's not good. You-- not only does it increase the risk for gout, but it increases the risk for kidney disease and all these things, and I talk to the patient about the pros and cons of treatment. I talk about the rash. I tell them to stop the drug if they get a rash and then call me. But I always start allopurinol when the uric acid's like eight or higher. And certainly when it's nine or higher. When it's between 5.5 and eight, I'll talk to them about the pros and cons, but we don't have full proof yet, but I tend to do it, especially with patients with kidney disease where the data's probably the strongest to start treating. I'll even do it with uric acid of six and a half, for example, with chronic kidney disease. But anyway, it's worthwhile discussing it with the patient.

    7. PAPeter Attia1:13:51

       But outsides of, outside of the risk of Stevens-Johnson syndrome, which you've alluded to, what are the other potential risks of allopurinol?

    8. RJDr. Rick Johnson1:13:57

       That's by far the big one. Some people will get just a mild rash without true Stevens-Johnson syndrome. There are rare cases where liver function tests may be elevated, but it seems to be rare. If you start at a huge dose right away, it can increase xanthine levels in the urine. Theoretically, there could be risk for xanthine stones, but I've never seen it. So it's really the risk of Stevens-Johnson that-

    9. PAPeter Attia1:14:24

       And do you have to use allopurinol or can you use Uloric or other drugs that also lower uric acid?

    10. RJDr. Rick Johnson1:14:31

        Well, the xanthine oxidase inhibitors are the best because the way uric acid works to cause cardiovascular disease and kidney disease and all these things appear to be through its actions inside the cell, as we said, works on mitochondria and it does all these things. It's not its work outside the cell. So gout is really an extracellular deposition, but when you're thinking about uric acid and its biologic effects, that's an intracellular action. So xanthine oxidase makes uric acid inside the cell, so one of the best ways to reduce intracellular uric acid is to give a xanthine oxidase inhibitor like allopurinol or febuxostat. Now febuxostat, I think it's probably just as good as allopurinol, but there was a big clinical trial that was published in The New England Journal that showed that allopurinol was associated with less cardiovascular risk than febuxostat. There seemed to be an increased cardiovascular events in the febuxostat group.

    11. PAPeter Attia1:15:30

        Meaning less of a reduction or more events?

    12. RJDr. Rick Johnson1:15:33

        Well, see, the problem was there was no placebo group.

    13. PAPeter Attia1:15:36

        Oh, yeah. That's a disaster.

    14. RJDr. Rick Johnson1:15:37

        Yeah, that's a disaster.

    15. PAPeter Attia1:15:38

        This is the Vioxx problem-

    16. RJDr. Rick Johnson1:15:40

        Yeah

    17. PAPeter Attia1:15:40

        ... with naproxen.

    18. RJDr. Rick Johnson1:15:41

        Yeah, yeah. I mean, so the problem is allopurinol is less than febuxostat, but there's no placebo group. Theoretically, the placebo group would be-

    19. PAPeter Attia1:15:49

        Could be higher than both of them.

    20. RJDr. Rick Johnson1:15:50

        Yeah, could be higher than both of them. And there's actually evidence that that's probably true, but because of the care study, the way it was designed, we don't know. So the FDA is worried about giving febuxostat to people with cardiovascular problems because they would prefer you to give allopurinol, but the trouble is it's not necessarily that febuxostat is bad, it's just that it's not as good as allopurinol.

    21. PAPeter Attia1:16:15

        And it's like 100,000 times more expensive too. I mean, it's a-

    22. RJDr. Rick Johnson1:16:18

        Although it's, I think, becoming generic now, so we may see a change in that.

    23. PAPeter Attia1:16:22

        [chuckles] I'll believe it when I see it, and of course, will you trust the generics? But that's a whole separate issue.

    24. RJDr. Rick Johnson1:16:27

        Ri- exactly.

12. 1:16:28 – 1:21:43

    Salt, Water and Whether Salt Really Is the Problem

    1. PAPeter Attia1:16:28

       So w- what about, uh, sodium restriction, going back to how we started the discussion? I'll tell you a story from... I may have even told this on the podcast once before, but in medical school, I remember when we were doing renal physiology, we had a great nephrology professor who was teaching something, and I think he was quite ahead of his time because this was more than 20 years ago, and he was not sort of part of this salt is bad bandwagon, even though he was a nephrologist. And in a, I won't do it 'cause I won't do it justice, but in a beautiful Southern accent, he made the point that if you lined up all of the nephrons in the world, all the functional units of the kidneys in the world, from dumbest to smartest, and then all of the nephrologists in the world from dumbest to smartest, and you took that dumbest nephron and put it next to the smartest nephrologist, it's still smarter.

    2. RJDr. Rick Johnson1:17:15

       [laughs]

    3. PAPeter Attia1:17:15

       His point being, of course, like, the kidney is a brilliant organ that is exceptional at autoregulation of everything from flow to osmolarity to anion, cation exchange. Again, his point being he didn't buy this argument that salt is the problem. You're saying something much more nuanced, and I want to kind of go back to it because I think there are important clinical implications of it. You're saying, "No, no, no, salt does play a role, but it's dose, timing, bolus concentration that matters. It can also be amplified or mitigated by the state of inflammation." So how do you then translate that information to your patients, acknowledging that they're a very select group of people? By definition, they have kidney disease or they wouldn't be seeing you.

    4. RJDr. Rick Johnson1:18:02

       So it's the combination of salt and water. So if you don't drink any water as you eat salt, you're gonna raise your serum sodium, you're gonna get thirsty, and as soon as you're thirsty, you've triggered... That in itself is a sign that you're already making fructose from the salt. So when you eat salt, you're making fructose in your body, and the fructose is then driving a lot of effects. Now we know that high salt diets are associated with obesity, not just high blood pressure. They're associated with the development of diabetes. There's many studies now, but high salt looks like it works by producing fructose. So if you drink water with salt, the danger of the salt is much less. If you drank water and then ate your pretzel, you would be safer than if you ate your pretzel and then drank the water because what triggers it is the rise in salt. And so when you see someone in the clinic, what we try to do is to tell them to drink a lot of water and to reduce their salt, but it isn't the amount of salt, it's the balance of salt and water.

    5. PAPeter Attia1:19:06

       Now, that can be sometimes challenging for patients in a kidney clinic 'cause that would be one population in which you do have to be mindful of volume.

    6. RJDr. Rick Johnson1:19:14

       Right. But most patients with chronic kidney disease, they will excrete water normally or just minimally abnormal. And so there's actually clinical trials looking at the evidence that water may slow the progression of kidney disease. It might be working in part by blocking the effects of salt and so forth on the kidney, and we experimentally can show that giving water can slow kidney disease progression. So drinking water turns out to be good. Here's another thing. It turns out that many animals use fructose to make fat- as a means for making water. So when you make fat, although there's no water stored in the fat, when they burn the fat, they make water. So whales don't drink saltwater. They are fat because when they break down the fat, they're making the water. We call it metabolic water. So it turns out that fructose drives fat production, and in part to preserve water, not just energy. So animals will use that fat to provide an energy source, but also to provide water. So it turns out that if you take an animal on, on fructose and you give it a lot of water, you can suppress some of the obesity. You can suppress some of the effects of metabolic syndrome. And so the old wives' tale that drinking six glasses of water a day is good to help keep you skinny is true. It turns out that water suppresses some of the effects of fructose.

    7. PAPeter Attia1:20:41

       And does it need to be water? Could it be tea or coffee or something that's equally... The osmolarity of water is what? Serum is about 280?

    8. RJDr. Rick Johnson1:20:48

       Yep.

    9. PAPeter Attia1:20:48

       Okay, so anything with a zero osmolarity is good enough?

    10. RJDr. Rick Johnson1:20:52

        Yes.

    11. PAPeter Attia1:20:52

        Technically, a diet soda should have a zero osmolarity as well, right?

    12. RJDr. Rick Johnson1:20:55

        Yeah, di- diet soda would work, actually.

    13. PAPeter Attia1:20:57

        For the record, you and I are sitting here drinking just plain water.

    14. RJDr. Rick Johnson1:21:00

        Right, and diet sugars have their own issues, so.

    15. PAPeter Attia1:21:03

        We'll come back to that in a few seconds, 'cause that's super interesting. So Rick, you sort of, you toss these little nuggets out there like they're nothing, but they sound... I mean, again, just based on the sort of breadth of research you've put into this, it almost just seems too good to be true and so profound, yet you sort of throw it out there like an after the fact. "Well, look, as long as you drink enough water and don't eat fructose, and God forbid, don't drink fructose, manage your uric acid levels," etc., etc. It's like you make it seem like a lot of problems could go away from these things. How would you shape that advice for someone with normal kidney disease? Uh, pardon me, with normal kidneys. Would you basically just say the same thing, or can you be less restrictive with sodium, for example?

13. 1:21:43 – 1:29:21

    Endogenous Fructose from Glucose and High-Glycemic Carbs

    1. RJDr. Rick Johnson1:21:43

       If we could reduce our fructose intake, I think it would have a huge, huge effect. But the problem that most people face is that sugar and high fructose corn syrup are in almost everything. So if you go to the supermarket, like 70% of processed foods have sugar in it. In packaged foods, actually 70% of packaged foods have sugar or high fructose corn syrup in it, so it's very hard to avoid it. And here's another problem. Our bodies can make fructose. So our bodies, as I mentioned, we can make fructose from a high salt diet. We can make fructose if we get dehydrated. We can make fructose, high uric acid stimulates fructose production.

    2. PAPeter Attia1:22:25

       And we're making the fructose out of glucose in all-

    3. RJDr. Rick Johnson1:22:27

       Yes

    4. PAPeter Attia1:22:27

       ... of these situations?

    5. RJDr. Rick Johnson1:22:28

       High glycemic diets. Normally, if you take an animal and you give it starch, they will not really get fat. But we all know that french fries, which don't have sugar in it, they don't have fructose, they are fattening. But you've got potatoes which raise your glucose, and what we showed is that if you just give glucose to an animal, the high glucose as it hits the liver induces this enzyme to convert glucose to fructose.

    6. PAPeter Attia1:22:54

       Which enzyme is that that converts glucose into fructose?

    7. RJDr. Rick Johnson1:22:56

       Aldose reductase. So when we took mice and we gave them glucose and we were thinking we might not see much because we were believing that fructose is the culprit, but over time, these animals got really fat. They got insulin resistant, everything.

    8. PAPeter Attia1:23:13

       But you had to overfeed them glucose. They-

    9. RJDr. Rick Johnson1:23:16

       We put the glucose in their drinking water, so they were drinking a lot of glucose. But they would eat less chow, so we gave them chow and glucose in their drinking water.

    10. PAPeter Attia1:23:25

        And their chow had... It was normal chow.

    11. RJDr. Rick Johnson1:23:27

        Yes.

    12. PAPeter Attia1:23:27

        It wasn't the high fat, high sugar chow.

    13. RJDr. Rick Johnson1:23:28

        No, just regular chow. And these animals started getting really, really fat. And when we looked at the portal vein, which goes into the liver, the glucose levels were high, and when we looked in the liver, we found that this enzyme was activated. It's also activated in diabetics, for example, because of the high glucose in the blood. And when that enzyme got activated, it started to make fructose. So even though these animals were eating no fructose, they were producing fructose in their liver. And then when we blocked their fructose metabolism, they're eating the same amount of glucose, no change. Exactly the... Suddenly they're not getting as fat. They have no fatty liver. They're not insulin resistant.

    14. PAPeter Attia1:24:13

        But this suggests, Rick, that a diet in excess carbohydrate, even if it's not high in sugar, could lead to fatty liver disease?

    15. RJDr. Rick Johnson1:24:21

        Yes. Yeah, absolutely, if you have that enzyme induced. But let's say that you are a young person. When you're young, this enzyme is really not present in the liver. Once you're eating sugar, though, if you eat a lot of sugar, it will induce that enzyme.

    16. PAPeter Attia1:24:38

        For how long?

    17. RJDr. Rick Johnson1:24:38

        I don't fully know. But let's say that you eat a lot of sugar and you get obese. So sugar itself, it looks like the induction of this enzyme probably would be reversible within a few weeks. But once your uric acid goes up, that will keep it elevated. So-

    18. PAPeter Attia1:24:53

        So that's another reason potentially to use allopurinol, if necessary, in addition to fructose restriction, to keep uric acid low, is to prevent or mitigate the induction of this enzyme.

    19. RJDr. Rick Johnson1:25:06

        Oh, yeah. Right. So it turns out that if you give a starch or potatoes to a, a skinny person who does not have aldose reductase induced, they can eat the potatoes they want. In Ireland back in the 1700s where potato was basically the main thing they were eating, there wasn't a lot of obesity. But you wait until you eat sugar and then develop the metabolic syndrome, now you stop eating sugar, but you continue to eat carbs, and the carbs are gonna continue to activate through the same pathway. So a low carb diet is really great because it's necessary if you're overweight or fasting, but that's basically reducing carbs too. But a low carb diet when you're overweight is removing the high glycemic carbs that are also driving the disease, but it's through fructose.

    20. PAPeter Attia1:25:55

        So it seems that Fructose reduction obviously comes with its own benefits. Do you have a sense of how much fructose can be produced in a fructose-free intake environment just from glucose? Is it a, a meaningful amount?

    21. RJDr. Rick Johnson1:26:10

        Well, we did our study by putting glucose in the drinking water. They're getting a lot of glucose. We haven't done the study is the one that you're talking about, trying to figure out what the range is. I do think that if you just give high glucose alone, you probably have to give a lot, but if you've already triggered the production of this enzyme aldose reductase, you probably don't have to give a lot.

    22. PAPeter Attia1:26:33

        What about fat? What if you did that same experiment with rats or mice, which would be hard, 'cause to eat pure fat is difficult, but if there was a way that somehow you could make it palatable enough that they could... You could overfeed them to the same extent using fat and protein. Let's say they're getting a normal amount of glucose, but the overfeed was coming through the fat. Would that induce any of these properties? In other words, is part of this due to an absolute sense of total energy s- being too high, or is this really about a particular carbohydrate?

    23. RJDr. Rick Johnson1:27:04

        It's definitely about a particular carbohydrate, 'cause we've actually done what's called pair feeding, where you control how much they eat, and you can have your control group. This fructose effect will still, as I mentioned, cause fatty liver.

    24. PAPeter Attia1:27:16

        Yeah, explain what pair feeding is for people, 'cause it's a clever little tool done in this type of research.

    25. RJDr. Rick Johnson1:27:20

        So the way fructose works is it works by making you eat more, and that's how you gain weight. But even when you control so that you don't eat more, fructose will s- not cause weight gain, but it will cause fatty liver, insulin resistance, and diabetes, and so forth, and the way we can show that is by pair feeding. In pair feeding, we give... Each animal eats the same amount of food. So if you give one animal sugar, which normally makes it wanna eat more, 'cause it causes this thing called leptin resistance, where they wanna eat more, but if we don't give them any more food, we only give them the same amount as the control, then there will be no difference in weight, but there will be differences in fatty liver, metabolic syndrome, and so forth. The sugar industry has used this to their advantage. So what they say is, "Okay, we're gonna look at clinical trials where we've given sugar, and we're gonna see if sugar causes weight gain." But it's only fair to do that if we have it controlled where we control the energy intake to be equal among groups. So they have a control group where they've restricted... There's a caloric restriction on both sides. So you have a high sugar and a non-high sugar group, but it's not where you get to... the people get to eat as much as they want.

    26. PAPeter Attia1:28:36

        Basically it's this problem of not having ad libitum feeding.

    27. RJDr. Rick Johnson1:28:39

        Yes.

    28. PAPeter Attia1:28:39

        So it's sort of like what the sugar industry is saying is, "Look, a calorie is a calorie. If I give you 100 calories of sugar and completely control what you can eat in response to that and compare you to another person who's eating the same number of calories, you're really not gonna gain weight." Now, the problem with that experiment is it's not the real world.

    29. RJDr. Rick Johnson1:28:59

        Yes.

    30. PAPeter Attia1:28:59

        In the real world, you don't have a clamp on your response.
14. 1:29:21 – 1:38:36

    Artificial Sweeteners, Umami, and the High-Risk Foods

    1. PAPeter Attia1:29:21

       Now, a second ago you sort of alluded to artificial sweeteners. So comparing... I mean, I'm sure you get this question asked all the time by your patients, which is, "I just really love Coca-Cola. Is having a Diet Coke... It must be significantly better, right? I mean, there's no fructose in it. There's no glucose in it." So is there a downside to it?

    2. RJDr. Rick Johnson1:29:39

       Yeah, I think there are downsides, but first let me just say the positive side. We have s- taste buds that sense sweet, and so when we eat sugar, the taste buds are activated, and it stimulates this dopamine response in the brain that tells us that we like the s- sugar. If you actually knock out the sweet taste buds, you just knock out the taste in general, animals will still like sugar. They will still eat sugar, a lot of sugar.

    3. PAPeter Attia1:30:10

       How hard is that to do experimentally, to knock out the sweet tasting capacity?

    4. RJDr. Rick Johnson1:30:15

       It's been done, and we actually have also done it where we knock out all taste.

    5. PAPeter Attia1:30:20

       Can you do it to me?

    6. RJDr. Rick Johnson1:30:21

       No. [laughs]

    7. PAPeter Attia1:30:22

       [laughs]

    8. RJDr. Rick Johnson1:30:22

       It's like a, it's like a genetic knockout.

    9. PAPeter Attia1:30:24

       [laughs]

    10. RJDr. Rick Johnson1:30:25

        Um, but anyway, these animals will still like sugar, but they won't like artificial sugar. So the artificial sugar is really driven by the sweet taste, but what makes animal like real sugar is through its metabolism. I mean, it is true if you knock out taste, they will tend to eat a little bit less sugar, but they actually still develop metabolic syndrome.

    11. PAPeter Attia1:30:45

        That's super interesting. So you're saying part of our affinity for sugar is not just in our taste buds and in our brain, but also in our periphery, where the metabolism takes place, and the elegant way you demonstrate that is you give something of equal sweetness concentration that's non-nutritive, and you completely reduce the appetite for it. Even though it might have the same central effect, it doesn't have the peripheral effect.

    12. RJDr. Rick Johnson1:31:09

        Probably the sweet taste bud developed to try to encourage us to eat these foods that at the time were survival foods. But the food itself, the sugar itself stimulates dopamine and other effects independently of the sweet taste, whereas an artificial sugar just is activating the sweet taste. Now, if you give a mouse or a rat artificial sugar, they don't gain weight, but if you give them regular sugar, they do. So there is some evidence that artificial sugars are better than sugar, and if a person says to me, "Oh, Doc, I'm afraid to drink this Diet Coke because it's got chemicals in it. I want to drink regular Coke because of that," that's an error. Regular Coke is more dangerous than a Diet Coke. However, there is truth that things like aspartame and sucralose, we don't know fully the safety of these

    13. PAPeter Attia1:32:11

        Aspartame, when last I checked, had been studied more by the FDA than any other molecule ingested by humans. It's hard to make the case that at the small doses that people would consume them, I'm talking about someone who has a serving of this stuff a day. I don't know. I've always found that argument that, well, we don't know the full safety profile of these things to be... It's like, what else do we need on this one? I think aspartame's kind of gross, truthfully. Like, I don't really like it that much, but I just think it's definitely the lesser of two evils, isn't it?

    14. RJDr. Rick Johnson1:32:41

        It's definitely the lesser of two evils. That part's for sure. But we don't fully know the safety of some of these. Like saccharin, for example, has been associated with little bladder tumors in mice. My recollection is that aspartame can generate small, tiny concentrations of formaldehyde. Do you-

    15. PAPeter Attia1:32:57

        I think it really comes down to dose.

    16. RJDr. Rick Johnson1:32:58

        Yes, I think it is dosing.

    17. PAPeter Attia1:32:59

        I think those studies were really based on rats or rodents consuming doses that simply couldn't be replicated by humans.

    18. RJDr. Rick Johnson1:33:07

        That's probably true. Nevertheless, water's good.

    19. PAPeter Attia1:33:09

        Yeah, that's generally been my take to people as well is, look, all things equal, by certainly consume water, tea, things like that. But yeah, there's this lesser of two evils approach. But this point you made, this is completely news to me and very interesting because certainly much of the neurobiology today would suggest that the response we have to sugar is mostly centrally mediated. The, quote-unquote, "addictive"... 'Cause everyone loves to talk about functional MRI and what happens in your brain when you're eating sugar and all of these other things, but I guess I haven't seen this side by side, but presumably the fMRI would light up the same for non-nutritive versus, like aspartame and sugar, correct?

    20. RJDr. Rick Johnson1:33:47

        Yeah.

    21. PAPeter Attia1:33:47

        So let's talk about another taste, which is umami. I remember we were having sushi one night when we discussed this. What is umami? What is that taste?

    22. RJDr. Rick Johnson1:33:55

        So umami is the savory taste.

    23. PAPeter Attia1:33:58

        And this is different from salt, isn't it?

    24. RJDr. Rick Johnson1:34:00

        So there's five taste buds. So there's salt, there's sweet, and as I mentioned, both of these taste buds seem to drive a weight gain. Sugar is by far the fastest. It takes only, uh, two months in a laboratory animal, and salt takes four months, five months. So high salt generates fructose, but it's a s- much slower process than just eating sugar. Then you have umami, which is the savory taste, and then you have bitter and sour, and the bitter and sour are probably developed to help you avoid eating certain foods.

    25. PAPeter Attia1:34:31

        So coffee is an example of bitter, like a coffee bean or something like a ground-

    26. RJDr. Rick Johnson1:34:35

        I think so.

    27. PAPeter Attia1:34:36

        Yeah. Okay.

    28. RJDr. Rick Johnson1:34:36

        Anyway, so umami is driven by glutamate, but it's markedly enhanced by purines like IMP and even uric acid. So it turns out that umami is sort of a taste receptor for uric acid type foods, foods that raise uric acid.

    29. PAPeter Attia1:34:55

        Now, is MSG the purest form of umami that we would eat?

    30. RJDr. Rick Johnson1:34:59

        Yes. MSG is the primary stimulant, and people put it in foods to encourage food intake. Now, there's some link of umami with obesity in epidemiologic studies, and there are situations where you can give umami type foods, and especially if, if you can do it in a liquid form, you can induce obesity. So umami may not be as safe as we think it is. So it's got a, a lot of good things written about it in the literature.
15. 1:38:36 – 1:46:35

    Fruit, Dose, and Raising Kids with Less Sugar

    1. PAPeter Attia1:38:36

       This is the part that can sometimes drive a person insane when they're trying to think about all of these things, is it's very difficult to provide clear advice to people because there's so many caveats that are required because the dose makes the poison, the speed of delivery, what it's combined with, all of these things. I'm using that as a preface to ask a question that I'm sure you get asked a lot, which is really a dose question around fructose. So let's ask it in two questions. If a person is going to drink something in the form of fructose, whether it be fruit juice or soda or sports drinks, which are, from a fructose standpoint, all basically the same, is there a dose of fructose above which you think it really makes no sense under any circumstance, or below which you think once in a while is not the end of the world?

    2. RJDr. Rick Johnson1:39:20

       I mean, personally, I would not drink any liquids that have sugar in it or fructose or high fructose corn syrup.

    3. PAPeter Attia1:39:27

       That's fine. So we're gonna draw a hard line there. And, and-

    4. RJDr. Rick Johnson1:39:29

       Hard line

    5. PAPeter Attia1:39:30

       Okay. Now, what about eating fructose in the form of fruit? 'Cause remember, there's some big ass fruits out there. Like, you look at a Fuji apple, which is my favorite apple. I mean, I like these monster Fuji apples, so they're like half the size of my head or maybe a third the size of my head. That's got to have 30 grams of fructose in it.

    6. RJDr. Rick Johnson1:39:46

       I don't think it has that much.

    7. PAPeter Attia1:39:47

       Oh, really?

    8. RJDr. Rick Johnson1:39:48

       I really don't. Most apples, and that would be a big one, maybe 10 grams at most, I would think.

    9. PAPeter Attia1:39:54

       No way.

    10. RJDr. Rick Johnson1:39:55

        You think more?

    11. PAPeter Attia1:39:55

        Well, think about it.

    12. RJDr. Rick Johnson1:39:56

        These are the really big ones, huh?

    13. PAPeter Attia1:39:57

        Yeah, yeah. I'm not talking about a little McIntosh. I'm talking about a, a huge apple.

    14. RJDr. Rick Johnson1:40:01

        Okay.

    15. PAPeter Attia1:40:01

        And they're so sweet, too.

    16. RJDr. Rick Johnson1:40:02

        So you may be right then. Let's talk about natural fruit. So we've actually done trials in patients with a low fructose diet with or without natural fruit supplements, and generally speaking, natural fruit supplements do not seem to block the benefits of a low fructose diet.

    17. PAPeter Attia1:40:18

        Sorry, what does that mean? You mean that if you took a patient and restrict all fructose except fruit-

    18. RJDr. Rick Johnson1:40:24

        That's correct

    19. PAPeter Attia1:40:24

        ... they tend to do okay?

    20. RJDr. Rick Johnson1:40:25

        They did just as well as the low fructose alone.

    21. PAPeter Attia1:40:28

        And can you quantify how much fruit? 'Cause here's the problem. When you're talking to someone like me, Rick, I don't do anything in moderation. So we have these bowls in my kitchen. They're called manly bowls, which by definition, a manly bowl is a bowl that you can wear on your head like a hat. It will come over your head.

    22. RJDr. Rick Johnson1:40:43

        [laughs] Yeah.

    23. PAPeter Attia1:40:43

        And when I consume fruit, I consume it in that bowl.

    24. RJDr. Rick Johnson1:40:46

        Yeah, I would be careful.

    25. PAPeter Attia1:40:47

        So no manly bowls.

    26. RJDr. Rick Johnson1:40:48

        Yeah. So the data suggests that a single fruit, maybe not the giant Fuji apple [laughs]

    27. PAPeter Attia1:40:53

        [laughs] Okay. Listen, I don't know the last time I had a single fruit.

    28. RJDr. Rick Johnson1:40:55

        But a s... Yeah, but a single fruit has like... Some fruits like kiwi and lime and lemon have almost no fructose, and they're totally safe. And other fruits-

    29. PAPeter Attia1:41:04

        Like pineapple and stuff maybe

    30. RJDr. Rick Johnson1:41:05

        ... you have a fair amount of sugar. Berries, for example, blueberries, have so many good things in it. You can eat a big bowl of blueberries, no problem. Raspberries, strawberries, they're all... All the berries in general are very good. Grapes, they have a fair amount of sugar. You eat a bowl of grapes, you're gonna probably raise your uric acid and trigger the activation of the SPAD gene.
16. 1:46:35 – 1:50:46

    Closing Thanks and Membership Information

    1. PAPeter Attia1:46:35

       Well, Rick, this has been awesome. I want to be mindful of your time, and I know that this is a non-clinical day for you, which means every minute we're talking, you're not in your lab, and I want you to get back to the lab. So I want to thank you very much, again, not just for this discussion today, which for me is super interesting, and I think the listeners will agree, but much more importantly for the work you've done. You've taken a very different approach to, quote unquote, "the war on sugar." You're less involved on the policy side of this and the sort of advocacy side of this, but I think what your work has done is created the strongest scientific foundation to the harm of fructose. And you've done it in a largely, and I say this in a complimentary way, but in a largely unceremonious way, which is you've sort of had your head down, and a lot of people don't know who you are. So I hope that more people become familiar with your work because your... I mean, your CV is comical in terms of, like... It's like every week you seem to publish something in either JAMA, the New England Journal of Medicine. The paper we talked about yesterday, which we can't talk about today because it's not yet-- we're not there yet. I look forward to seeing that paper in Science, hopefully in the next six months, but that's an unbelievable tour de force that almost requires us coming back to have a talk about it, so.

    2. RJDr. Rick Johnson1:47:50

       Well, thank you very much. [laughs] Those are very kind words.

    3. PAPeter Attia1:47:52

       Thank you, Rick.

    4. RJDr. Rick Johnson1:47:53

       Really enjoyable, and thank you.

    5. PAPeter Attia1:47:56

       Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth, exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. Now, to that end, membership benefits include a bunch of things. One, totally kickass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode. The word on the street is nobody's show notes rival these. Monthly AMA episodes, or Ask Me Anything episodes, hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spiels like this. The Qualies, which are a super short podcast, typically less than five minutes, that we release every Tuesday through Friday, highlighting the best questions, topics, and tactics discussed on previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to every one. Steep discounts on products that I believe in but for which I'm not getting paid to endorse, and a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can find me on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up-to-date and active list of such companies. [outro music]

Episode duration: 1:50:46