How Fructose Drives Metabolic Disease | Rick Johnson, M.D.

1. 0:00 – 0:10

   Intro

   1. PAPeter Attia0:00

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

2. 0:10 – 9:00

   Unique features of fructose metabolism and why it matters

   1. PAPeter Attia0:10

      Hey, Rick. Great to see you again.

   2. RJDr. Rick Johnson0:12

      Great to see you too, Peter.

   3. PAPeter Attia0:14

      Um, you know, we had a lot of follow-up questions from our first podcast, which actually was probably about two years ago. So, um, in addition to kind of just the other topics that I wanted to follow up on, um, we sort of asked listeners, you know, "Hey, we're gonna do another round two here. What do you have?" So, so, so much of what we're gonna talk about today is a combination of things that I wanted to double-click on, coupled with that of what others did. But, uh, I think a number of people have asked the question to, you know, "Hey, can you explain again this whole, why is it that fructose metabolism is kind of unique from a nutrient standpoint in terms of creating this transient s- intracellular energy deficit?" This is something that becomes very important, and we get into sort of the metabolic effects of fructose.

   4. RJDr. Rick Johnson1:05

      Absolutely. So just to re- reiterate what you're saying, all nutrients, uh, are there to produce energy, you know? So when we, when we eat any kind of food, we're using it to generate energy or ATP in our body, and, but there's a cost to producing energy, and there, you know, and so some energy is used to digest foods and some energy is used to metabolize, uh, the f- foods.

   5. PAPeter Attia1:32

      It's the idea, the old adage, you have to spend money to make money. So you have-

   6. RJDr. Rick Johnson1:36

      Exactly

   7. PAPeter Attia1:36

      ... you have to spend ATP. Now, you're gonna get that ATP back in spades if you just stay with the program.

   8. RJDr. Rick Johnson1:43

      That's absolutely true.

   9. PAPeter Attia1:44

      All right. So let's talk now about fructose. And, and is, is fructose unique in what you're about to describe?

   10. RJDr. Rick Johnson1:51

       Well, alcohol can also activate this process, um, s- uh, and so alcohol can cause rapid ATP depletion as well. Um, but w- in terms of most nutrients, um, you know, fructose is pretty unique, yes.

   11. PAPeter Attia2:07

       Okay. So how does that work?

   12. RJDr. Rick Johnson2:10

       Yeah. So with fructose, the very first enzyme in fructose metabolism is called fructokinase, and this is gonna become an important enzyme to remember. Its, s, n- nickname is ketohexokinase or KHK, but it's, turns out to be the, the k- one of the key enzymes in fructose metabolism. And it phosphorylates fructose to that, the one position. So it's fructose 1-phosphate. That enzyme will literally phosphorylate the fructose as soon as it sees it, and it doesn't have any negative feedback. It, it just... So if there, if ATP levels start to drop, that's fine for the fructose metabolism. That's what fructose metabolism is aimed at doing. And, um, and so if you have a large concentration of fructose, it's concentration dependent. If the fructose concentration's very low, you know, there won't be as much ATP depletion, and it may actually go undetected. If it's very, a lot of fructose present, uh, the ATP depletion will be quite severe. So the, the degree of ATP depletion, uh, varies with the concentration of fructose. And as we talked last time, the fructose concentration relates to not just the amount of fructose, but how rapidly it's absorbed. So if you drink liquid fructose, like a soft drink, um, on an empty stomach, um, that liquid fructose can get absorbed very quickly and, and, and even more quickly, for example, with high fructose corn syrup prob- I mean, there's some debate on this, but high fructose corn syrup, the fructose and glucose are already separated, so that it may be absorbed differently than sucrose, where it's glucose and fructose bound together, but they, they're broken and they, they have to be, uh, degraded to the individual fructose and glucose in the gut before they're absorbed. So anyway, so, uh, so if you drink liquid fructose, uh, you get... It will be absorbed very fast, and, uh, and then the concentration will be higher when it hits the liver, and the liver is kind of the, one of the key sites that drives this whole process. So and what happens is the, when the fructose gets there, the fructokinase phosphorylates it, and the ATP levels acutely fall. But then there's a series of, of reactions that try to help maintain the low ATP state, and that low ATP state is maintained primarily by, uh, a drop in intracellular phosphate that accompanies this, and that activates this enzyme system that removes, uh, the, the breakdown of ATP products. It removes it so that the A, uh, that it, the ATP cannot be regenerated easily. So the ATP levels fall. There's, uh, the accumulation of ADP and AMP, um, and a- adenosine monophosphate is, is one of the key ones, and then that is swept away. So normally, AMP and ADP get reformed to make more ATP. They're really important to make the ATP. But if they're r- if the AMP is removed, then it's hard to replenish the ATP because you've removed a key, uh, building block for ATP. And that AMP is removed by an enzyme called AMP deaminase, which turns out to be a very, very important enzyme in this pathway. And that can, dri- breaks down the AMP stepwise until it produces uric acid, which is the end product of purine metabolism. And so ATP is, basically has purines in it, the adenine, and that gets broken down eventually to uric acid And then the uric acid inside the cell actually causes oxidative stress to the mitochondria, and the mitochondria are also, uh, really important in ATP production, and the oxidative stress causes, uh... affects this several ways. First, it, um... I don't know if you want me to go into all the biochemistry or not, [laughs] but-

   13. PAPeter Attia6:41

       No, no, let's do it. I, I... We're gonna bring it back and summarize it, but let's-

   14. RJDr. Rick Johnson6:44

       Okay

   15. PAPeter Attia6:44

       ... let's keep going deep.

   16. RJDr. Rick Johnson6:45

       So it inhibits an enzyme called aconitase, which is involved in the Krebs cycle, and it, it basically leads to citrate accumulation and the stimulation of fat production, and it also blocks an enzyme called enol-CoA hydratase. [laughs] Sorry. Uh, and that enzyme's involved in beta fatty acid oxidation, so it blocks the ac- the burning of fatty acids. And so what happens is, um, it reduces the production of ATP by blocking, uh, by... And, and, and shunts those, the components to make fat and to block the burning of fat. So it, what it's trying to do is it's trying to stimulate fat storage. And, uh, uric acid also in- inhibits this enzyme that's activated in starvation to help bring back, uh, to raise energy levels, called AMP kinase, AMP-activated protein kinase or AMP kinase. And, and by inhibiting that, it also blocks energy production. So the whole thing is a brilliant... I mean, it's a brilliant system to set the energy levels down in a cell, and it mimics the condition of starvation. And that, by, by reducing the energy in the cell, it triggers an alarm signal. It's like a mayday. And that is what leads to a survival response to try to gain... You know, makes the animal get hungry, thirsty, forage for food, try to store fat, try to store glycogen. It, it, it's like an alarm signal saying, "Hey, you're, you're gonna be in trouble, and what we need to do is we need to store energy as a means to help you because winter's coming." You know? Or, you know, "You're gonna be without food. You're gonna have to travel 2,000 miles and, you know, by air, [laughs] by flying to a place, and you're not gonna be able to eat or anything when you're flying over that ocean." You know? And so, uh, it, it's a survival pathway.

3. 9:00 – 21:04

   A primer on fructose metabolism and uric acid

   1. PAPeter Attia9:00

      All right. So let's, let's go back and summarize that, 'cause there's obviously a lot there that you-

   2. RJDr. Rick Johnson9:06

      [laughs]

   3. PAPeter Attia9:06

      ... you, you put out there. So let's start from the beginning. Fructose enters a cell. Uh, by the way, is this typically a hepatocyte? Is this a liver cell that is doing the lion's share of this metabolism, or is it an enterocyte, a gut epithelial cell? What type of cell is doing this type of metabolism typically?

   4. RJDr. Rick Johnson9:26

      Okay. So first off, uh, you know, uh, one step back, fructose can be metabolized like glucose through some of the glucose enzymes. So fructose can be metabolized by glucose enzymes, but it prefers to be metabolized by fructokinase. We would say it has a higher affinity, uh, and will p- preferentially be metabolized by fructokinase if the fructokinase is present. Normally, fructokinase is present a little bit in the, uh, gut. It's in the gut, actually modest amounts, actually fairly modest amount, and it's also in the liver, but it's also in the brain. It's in the islets of the pancreas. Very important, 'cause that's where insulin and glucagon are produced. It's also can be in the... Some of it is in the white fat. Uh, it's... A fair amount is in the kidney, and then it has the ability to be induced, meaning that it's not normally present, but it can be turned on. And one place it can be turned on is whenever there is, like, injury, tissue injury, like a heart attack. It can be turned on and produced in the heart during a, in it, following a heart attack, or it can be produced in the kidney further or be activated further, uh, y- you know, if you have kidney failure, like from a COVID infection. So it can be induced in sites, and it's probably trying to pr- provide some, quote, "survival mechanisms" in these sites, but what happens is it tends to be over-activated, um, and end up causing worse injury rather than protection from injury. And this has been a common issue when, when it's been studied, in that it, it was probably originally meant to be protective, but when it's turned on big time, and part of that is driven by our diet, you know, and so forth, but, um, it, you know, it, it can actually be injurious. So its main sites, uh, are the liver, you know, the brain, the islets, the kidney, and the intestine. Now, where it causes the energy depletion seems to be in all those sites ex- except the intestine. In the intestine, there's a tendency f- in, during the metabolism to, uh, to use up... Uh, well, there's work done by Dr. Josh Rabinowitz from Princeton, beautiful studies, that has shown that the fructokinase in the gut, um, is Probably at high concentrations, you do get the energy depletion. But, um, when there's just small amounts of fructose, it actually tends to, to not cause the energy depletion and to actually convert the fructose more along the lines towards glucose. Like, fructose can be converted to glucose, and glucose can be converted to fructose. Um, and so i- it tends... the intestine tends to be a shield, um, that at low concentrations kind of just helps remove the fructose without it being a problem. And this is one reason why fruits, which have like four grams of fructose, or, or vegetables that are-- have small amounts of fructose, like two to five grams, they actually are, um, protect-- they don't cause the energy depletion mainly because this intestinal f- fructokinase seems to inactivate small amounts. But if you h- hit it with a large, large dose of fructose, um, the fructose gets through the intestine. It probably causes, uh, ATP injury to the intestine, and we can talk about that 'cause I've done some studies to show that it causes gut leak, um, and that it can cause, um, uh... it, it may be responsible for anaphylaxis, uh, to certain foods, for example, food allergies. So it's a good story to talk about that. But, but, um, but most of the fructose, you know, gets-- ends up getting metabolized in the liver, and the liver seems to be the primary place that drives the metabolic syndrome and obesity and diabetes. And if we knock out fructokinase just in the liver, we can protect animals from, uh, obesity and diabetes and high blood pressure. So the liver is the king when it comes to metabolic syndrome. The kidney is actually important for kidney disease, and the brain is really important for diseases like Alzheimer's and so forth that we can talk about. But, um, but yeah, fructose turns out to be... have been meant to be this wonderful system for s- for survival. But in our culture, with the amount of sugar in foods that we are eating that, that either provide sugar or can be turned into fructose, uh, it's, it's... this pathway has become hazardous.

   5. PAPeter Attia14:44

      So let, let me go back and make sure that folks are following along here, Rick. So, um, as, as you pointed out, the, the gut becomes the first place of contact, right? So, you know, you're... by definition, we're pretty much all eating things through our mouth. Um, and so they're gonna wind their way through the stomach into the duodenum and into the proximal part of what's called the jejunum. You have these, um, epithelial cells that line the gut, and as you're saying, at low doses of fructose, so if you're, you know, eating a piece of fruit or some vegetables, which, you know, have some amounts of fructose in them, they can be absorbed there without creating that, uh, phenomenon you've described. But when you override that system, when you expose the gut to higher concentrations and presumably higher doses, so it is really a dose concentration problem, which we'll come back to, it, it basically manages to get through the gut without the gut doing the metabolism, and then it's going to enter the portal system. We didn't really explain that, but the reason that it preferentially makes its way to the liver is that the venous system that drains the gut has a, another very beautiful and unique to the body property. Almost unique to the body. It occurs in one other place. But, um, where the superior mesenteric vein, inferior mesenteric vein join the splenic vein, vein, these things become the portal vein, and you now have a vein that becomes an inflowing conduit to the liver. So now that's why the liver plays, as you said, such an important role in metabolism. It has two incoming blood supplies, the arterial supply, which supplies its oxygen, and its venous incoming supply, which supplies these nutrients on first pass from the gut. Now, they get into the liver, and the first thing that happens is we need to phosphorylate fructose. And by definition, we're already in a high fructose state because we've already exceeded the gut's capacity to metabolize this. And so now it's basically a free-for-all with unlimited fructose becoming fructose 1-phosphate, and we're generating in the cell lots of ADP. So we need... we start with ATP, which has three phosphates. We rip off a phosphate to put it on our fructose in the number one carbon position. That leaves us with ADP, adenosine diphosphate. It's shy of one phosphate. That, that thing d- reaction doesn't slow down. ADP further gives up a phosphate becoming AMP, adenosine monophosphate. ADP and AMP are being shunted elsewhere in the further degradation of their adenosine component, and that's being turned into uric acid. So uric acid being the final breakdown product of these, um... of, of adenosine. And so you're doing two things, which is you're taking away the base that you could rephosphorylate to repopulate ATP. You're running more and more fructose through this. And if that weren't enough, the uric acid goes on to be metabolized into other molecules that both increase the substrate for de novo lipogenesis in the form of citrate and also create other molecules that inhibit the process of beta-oxidation Which is the process by which we break down fatty acids to make ATP. Do I have that right so far?

   6. RJDr. Rick Johnson18:32

      You're right on the money. It's a fantastic, uh, review. The, the only difference, the only thing I would correct is that when the uric acid is generated, it actually doesn't f- further break down, but rather... I mean, it does break down a little bit, but the w- the way it works is it stimulates oxidative stress in the mitochondria, and it does that by stimulating a specific enzyme called NADPH oxidase, which I hadn't mentioned. And that enzyme produces oxidative stress, and it actually translocates that enzyme to the mitochondria. So the enzyme not only is activated, but it's, it's moves into the mitochondria. That oxidative stress then inhibits different enzymes, and that lead to fat synthesis and blocks, uh, f- maybe fatty acid oxidation. So the uric acid, uh, accumulates in the cell, and you can measure the uric acid, and the levels go up in the cell. And, um, and it's, and it's the uric acid turning on these processes that seems to, uh, really drive this, this whole mechanism. It, it, it, it, it... One can view it, um, Peter, like there's two pathways for fructose metabolism. One is the caloric pathway. You know, fructose gets metabolized to CO2 and water. In that sense, the caloric pathway, it's, it's sort of similar to glucose. But unlike, uh, glucose, it, it triggers another pathway in which the... uh, an ATP degradation pathway, and that is, um, not considered a caloric pathway. It's not part of the calories. But what it's, um, but what it's doing is it's activating, um, metabolic processes that lead to the development of diabetes, obesity, um, uh, hypertension, and all these things are driven by this side chain reaction. So it's not the calories of fructose that are driving obesity. It's not the calories from fructose. It's the fact that fructose lowers the energy and keeps the energy levels low, and this is due to this runaway renegade enzyme fructokinase that just takes all the ATP it can [laughs] to... I mean, it take to phosphorylate the fructose as, as it sees it.

4. 21:04 – 28:20

   Endogenous fructose production, the polyol pathway, and the effect of non-fructose sugars

   1. PAPeter Attia21:04

      Yeah, so, so couple things I would say there. One is, um, going back to the why, this is an amazingly engineered system in a food-scarce environment because every one of those things that you said, which is an enzyme that is by definition not telling the organism to stop eating, it's not signaling that we have enough energy. It's signaling the exact opposite, which is the more of this you eat, the more of this we want you to get, and it's turning off your ability to oxidize fat and turning on your ability to store and make more fat out of the byproduct here. Those are really incredible, valuable adaptations without which we wouldn't be having this discussion 'cause we wouldn't exist.

   2. RJDr. Rick Johnson21:55

      Exactly. So it's like a very fundamental mechanism that developed in nature. Um, uh, you know, it, it evolved. It... One could, um... It, it's like a process that is so key for survival that all animals use this pathway. And what's interesting is that, um, one of the breakthroughs was the discovery that it's not just the fructose we eat, but that the body can make fructose. And when the body makes enough fructose, it can activate this pathway. So the... When we were originally studying this, we said to ourselves, "Okay, you have... It looks like it's fructose is the problem. So if we just go on a low-fructose diet, uh, maybe this is how low-carb diets work," because low-carb diets would be low-fructose diets. And we were originally thinking, "Yeah, we found this is the, the pathway that's activated, so let's just go on a low-fructose diet." I actually wrote a book, The, The Sugar Fix, where, uh, back in 2008, 'cause I thought that was the solution, just go on a low-fructose diet. But the problem is that the body can make fructose, and, um, and it turns out that the favorite way it makes glucose... I'm sorry, the favorite ma- way it makes fructose [laughs] is through high glucose levels. And so, uh, high glucose, like in, you know, the classic is diabetes, is a high glucose state. In diabetes, it's been known for decades that there's a, an enzyme that gets turned on in high glucose states called the... It's called the polyol pathway, and that enzyme can convert glucose to sorbitol, and sorbitol then gets converted to fructose. By the way, sorbitol is considered one of the artificial sugars, so be aware. It actually gets turned into fructose in the body. So glucose gets converted to sorbitol, c- which conver- converts to fructose, and that occurs under high glucose conditions.

   3. PAPeter Attia24:11

      S- say more about what that means, Rick. Does that mean under high plasma glucose conditions?

   4. RJDr. Rick Johnson24:18

      So this was... W- we, we always were thinking high plasma glucose conditions, but then we thought to ourselves, "Actually, it's not the plasma that's so important. It's what's going on in the liver that's so important."

   5. PAPeter Attia24:32

      So high glycogen conditions?

   6. RJDr. Rick Johnson24:34

      Or high-- when glucose gets to the liver. Now remember that, um, uh, when we eat carbs, we're generating glucose. And so, uh, you know, if you eat, you know, broccoli, you're gonna generate some glucose because it's a vegetable that has carbohydrates in it. But it doesn't produce a lot of glucose, so the glucose concentrations in the liver and the blood don't go up with broccoli. But if you eat bread or rice or potatoes, chips, cereals, these are what we call high glycemic foods, and which means that they re-re-- have a fair amount of, uh, starch that gets broken down to glucose in the gut. Uh, so when you eat bread, you actually generate a fair amount of glucose, and if you have like a continuous glucose monitor or things like that, you can actually see a rise in your blood glucose when you eat bread or rice or potatoes. It, it will go up, and it's also going up in your livers.

   7. PAPeter Attia25:39

      And do we know what the difference is in the portal vein? So if you're wearing a continuous glucose monitor and it's showing before you eat your glucose is 90 milligrams per deciliter, and after you eat it's 150 milligrams per deciliter, do you have a sense of how high it is in the portal vein at that peak level?

   8. RJDr. Rick Johnson25:57

      You know, we have not done those studies, but it would be very, very helpful to understand because, um, uh, y-y-it-- there is this what we call first pass effect where food, when it goes through the liver, the liver uses up some of it before it gets into the blood. So a lot of the glucose that enters the liver is quickly seq-uh, sequestered in the liver cells and metabolized, and some of it passes through. So we-- the h- the b- glucose in our blood is, is like the tip of the iceberg, you know? The-there's-- the glucose levels in the liver are likely higher. Now, th-th-this enzyme that converts glucose to fructose is normally in-- when we're born, it's, it's very, very little of it's in the liver. Um, and, um... and in fact, uh, but it, but it gets induced over time. And, um, and I would love to develop, uh, a, an assay for looking at peripheral blood, for example, to see, you know, w- if you've turned on your, your aldose reductase is the name of the enzyme, whether or not that enzyme is elevated in your liver or not. Because if it is, bread is gonna be much more fattening than if, if you don't have that enzyme. So-

   9. PAPeter Attia27:21

      And where would you, where would you be measuring that, Rick? Do you think measuring that in the-- literally in the plasma, would there be enough of it there? Or is this something that's particularly inducible in the liver?

   10. RJDr. Rick Johnson27:32

       Well, it's inducible in the liver, but there you can measure... So sorbitol is kind of a, a good marker of the conversion-- of the activation of this pathway. And, uh, sorbitol-

   11. PAPeter Attia27:43

       And, and is it, is this the enzyme that turns glucose into sorbitol or sorbitol into fructose?

   12. RJDr. Rick Johnson27:47

       Yeah. The, the-- so the, the rate limiting enzyme is the enzyme that converts glucose to sorbitol.

   13. PAPeter Attia27:52

       Okay.

   14. RJDr. Rick Johnson27:53

       And that enzyme's called aldose reductase, [chuckles] and, uh, it's normally low in the liver, but it gets induced, and it can be induced by high glucose. It's induced by high uric acid, so there's a positive feedback system 'cause fructose is metabolized. And when fructose is metabolized, you generate uric acid. Uric acid then goes back and tries to turn on the enzymes that can lead to more fructose metabolism.

5. 28:20 – 45:06

   Findings from animal studies of glucose and fructose consumption

   1. PAPeter Attia28:20

      What's the evidence for those two, uh, claims? What's the evidence that glucose and uric acid both induce the enzyme that turns glucose into sorbitol? Is there human data for that or is that all in mice?

   2. RJDr. Rick Johnson28:36

      So the glucose can-- being con-- high glucose activating aldose reductase is been shown in humans as well as in animals, as well as in cell culture, and it's was the very basis for the original concerns about this pathway being important in diabetic complications. Um, and so this p- this has been known for f-fifty years. The-- but the uric acid as a stimulus for, uh, aldose reductase was published by our group based on animal studies and cell culture studies, but it was not based on human studies, so it would have to be shown in humans. But I, I, you know, I believe it's very likely true based upon the animal data, the cell culture data. Um-

   3. PAPeter Attia29:26

      And at what levels of uric acid does it start to become clinically relevant? Meaning do you get enough, um, sorbitol production that it leads to meaningful amounts of fructose generated de novo?

   4. RJDr. Rick Johnson29:43

      You know, it's a good question. In the human, uh, most of our studies, like when we do it, um, a high uric... When we go from a normal uric acid to a high uric acid in a, in a, like a laboratory rat, uh, the, the levels of high versus low are different in humans, but they seem to translate when we've done studies like in human cells versus w- w- rat cells. Um, the, the correlation's beautiful. So generally speaking, I would say that a high uric ac- the, that levels of uric acid that might turn on this pathway are, are-- would probably be over seven milligrams per deciliter in a human. Um, and certainly that's what you see in metabolic syndrome. What, what's very common is, um... So in our s- in our studies, when we gave glucose to animals, um- You know, originally I, my theory was that, uh, that that would not cause obesity, right? Because glucose will maintain the ATP levels, blah, blah, blah. The fructose is activating this metabolic syndrome through dropping ATP levels. And so I did not think that glucose would really cause obesity. Um, and, and so when we gave it, we found that the mice, uh, over time became very, very fat and insulin resistant. And, a- and I, I was a little depressed, but I was hoping that we would find that the glucose was being converted to fructose. And when we looked in the livers, we found that about m- you know, maybe as much as 25% of the glucose was being converted to fructose, um, in, in this laboratory mice

   5. PAPeter Attia31:25

      No, no. Help, help me understand this a, a bit, Rick. Just, um, I wanna make sure we understand the conditions of which these-

   6. RJDr. Rick Johnson31:29

      Sure

   7. PAPeter Attia31:29

      ... experiments are being done. Are these animals being force-fed glucose? And if so, how much of a caloric surplus are they experiencing, and what other macronutrients are factoring into this? I mean, are they literally just eating pure starch?

   8. RJDr. Rick Johnson31:44

      Yeah. So, so the way we did this experiment was we gave glucose in the drinking water.

   9. PAPeter Attia31:51

      Okay.

   10. RJDr. Rick Johnson31:51

       So it was like 10% glucose in the drinking water, and we gave it to laboratory mice.

   11. PAPeter Attia31:56

       Which strains?

   12. RJDr. Rick Johnson31:58

       Uh, I would have to look it up, but, um, but s- um, the, the C57, I think it's called.

   13. PAPeter Attia32:06

       And it... This, this strain's propensity for obesity is, uh, how, how much compared to... Like, the wild type behaves how here?

   14. RJDr. Rick Johnson32:16

       So the wild type mice, the control mice, they, they get fat, uh, when you give them fructose in the water. They get fat when you give them glucose in the water. It's pretty significant. Um, and, um, so but it takes weeks to months, uh, and really to, to see the effects of glucose or fructose to cause obesity, it goes through a period of, of, uh, of time, several months. And what happens is initially when you put, uh, when you give glucose or fructose in the drinking water, the animals like it, so they drink a lot more water than they normally, and they- they're getting s- a fair amount of caloric intake, uh, from the water, from the drinking water 'cause it has sugar in it, right?

   15. PAPeter Attia33:01

       So what are the control animals drinking? Just, um, same chow, access to the same chow, but no glucose in the water?

   16. RJDr. Rick Johnson33:09

       Right. Or we can do things like give artificial sugars. So we, we can... have done that, like give Splenda, where they'll drink increased amounts of water similar to, uh, to glucose or fructose, but there, but there's no... Uh, they're getting an artificial sugar. And what happens is that when an animal is getting calories in its water, it will reduce how much food it eats, and that's a normal process, and it's true for sugar as well. It's true for table sugar, it's true for fructose, and it's true for glucose. But what happens is, um, that over a period of a month or so, uh, suddenly they start eating more and more despite still drinking a lot. So they s- they end up being in a high caloric state. And that when we look at that, it's because they, they start developing leptin resistance. And the leptin resistance, um... Leptin is a hormone produced in the fat cells that, um, sen- tells the brain that it's full. So when, when leptin levels go up, they te- they te- say, you know, uh, you, you've eaten enough. Uh, it's like a s- what they call a satiety signal. It says, "Okay, you've eaten enough."

   17. PAPeter Attia34:23

       Doesn't it work-

   18. RJDr. Rick Johnson34:24

       And-

   19. PAPeter Attia34:24

       ... more in the reverse? I mean, isn't it really more that low levels of leptin tell you that you are sort of low in your fat stores? But I mean, in... If you don't look at leptin receptor deficient animals, I didn't realize that high leptin had a satiety component. Otherwise, uh, injections of leptin would curb appetite, but I don't think they do in, in normal mice. But why does this not work in humans?

   20. RJDr. Rick Johnson34:52

       Because people become... When you become overweight, you become resistant to leptin, and the leptin resistance is at the hypothalamic level. So people who are overweight almost always have very high leptin levels, and the leptin is not signaling, is not working. And, uh, and th- we call this leptin resistance. And it turns out that leptin resistance, um, is what f- is how fructose causes animals to eat more. Because when you give animals fructose, uh, it takes like a month, but eventually the animals become resistant to leptin. Uh, then you can inject them with leptin and there, there's no... They, they continue to eat. So the way we test them is to actually inject them with leptin. So we do those experiments. So we, we... Normally animals are sensitive to leptin. Uh, and if you inject leptin, the, uh... they'll, they'll reduce their intake. If they're born with low leptin, they're gonna be, uh, hungry, uh, and they're gonna eat more. And if they become resistant to leptin, they can have a high leptin level, but they will not, uh, respond to it, and so they'll eat more. Um, and so, uh, if you don't-

   21. PAPeter Attia36:05

       So you, you, you diagnose leptin resistance based on the response to a lecti- a leptin injection?

   22. RJDr. Rick Johnson36:11

       Correct. And we do that in all of our studies. And then we also look for the evidence of leptin resistance by studying the hypothalamus because, uh, there's a characteristic, uh, change that occurs, uh, that you can look for with leptin resistance. It's ca- And so we, we also test for that.

   23. PAPeter Attia36:31

       What is that change?

   24. RJDr. Rick Johnson36:31

       Um, a stat... It's, I think, stat five phosphorylation. I'd have to look it up again, but, but, but we do it. Um, and so that helps determine if the animal is leptin resistant.

   25. PAPeter Attia36:43

       And, and what's the mechanism of this, Rick? What causes leptin resistance?

   26. RJDr. Rick Johnson36:49

       Well, it's not fully known, but there's some evidence from s- uh, some groups that it might be due to uric acid. Um, and you can kind of induce a leptin resistance state, uh, by, I think, injecting uric acid in, in, uh, the brains of animals. Uh, there's a group from China, uh, that has done s- this experiment. I, um, you, you know, I, I, I believe that that was what they sh- uh, they showed that it caused leptin resistance. But they definitely showed that it can cause inflammation in the hypothalamus, and the inflammation in the hypothalamus is thought to be the driver for leptin resistance. So anyway, so, uh, what, what happens, getting back to the experiment, when we give glucose to animals, initially they reduce their chow intake. Over time, they start increasing their chow intake. They become very fat. They become insulin resistant. They, they develop all features of metabolic syndrome, and when we look in their livers, they're making fructose, and they've turned on this enzyme. This polyol pathway is high, and so they are, you know, gaining weight and becoming fat related to fructose production. And to prove that it was the fructose, we gave glucose to animals that lack fructokinase. These are genetically manipulated mice where we've removed the gene or knocked out the gene for fructokinase. And so what happens, uh, is these animals cannot metabolize fructose through this ATP depletion pathway. And when we give them glucose, they, uh, can drink the glucose. They get a tiny bit of, of... They, they gain some weight, um, and fat, uh, probably related to the effects of insulin, but, um, because glucose stimulates insulin, and insulin can decrease fat, uh, breakdown in the, in the, in the peripheral fat. But what happens is these, uh, uh, these animals do not, uh, develop insulin resistance. They do not develop fatty liver. They do n- you know, they're really protected from the metabolic syndrome, and they, and they gain much less weight and have less fat than a, a normal animal. So it turns out that the-

   27. PAPeter Attia39:11

       And, and just to be clear, Rick, these are absolutely isocaloric, these two animals?

   28. RJDr. Rick Johnson39:18

       Yeah, it's very close. Uh, yeah. W- the... It, it's, it looks id- identical. Yeah. It's super close. I, I, I, I don't know if, if each individual mouse-

   29. PAPeter Attia39:28

       Like, can you do this and pair feed the animals so that you have a fructokinase knockout pair fed with a wild type, and they're otherwise getting the same glucose in the water and the same chow, and they're pair fed to match?

   30. RJDr. Rick Johnson39:44

       Yeah. Well, we do a lot of pair feeding studies. In this case, the, the animals are drinking basically the same amount of glucose. I mean, I, I think that it's, uh, you know, within 5% or 3%, uh, difference. I mean, it's... was very, very similar. Um, so the lacking-
6. 45:06 – 56:45

   What calorie-controlled studies say about the claim that a “calorie is a calorie”

   1. RJDr. Rick Johnson45:06

      it, what we've identified is that fructose, uh, stimulates obesity and metabolic syndrome, and it does it through two major ways. One way is by encouraging an animal to eat more, and it basically stimulates hunger and stimulates food intake. Part of that is through the brain and part of that is through this, uh, leptin resistance, which is also kind of a brain effect. Um, and so the animals eat more, and they also drop their resting energy metabolism. So they're both metabolizing less and they are eating more, and that causes the weight gain.

   2. PAPeter Attia45:46

      And, and what's the relative contribution of those? Th- this is very important to me because look, I think, Rick, there are a, a lot of people out there who will argue vociferously that calorie for calorie, they're all the same. It doesn't matter if you're eating a calorie of glucose, a calorie of fructose, a calorie of fatty acid. If, if you can regulate the intake, it, i- it's, it's, it's all the same. So, so when you look at what you just said, which is fructose ingestion can lead to weight gain through two mechanisms. One, it can drive you to eat more. So on the intake side of the ledger, it's causing you to eat more. But it can also lower your energy expenditure, and I assume that could be both deliberate and non-deliberate, right? It could reduce, if that's true, r- resting energy expenditure, and it could presumably even reduce, uh, drive, energetic drive, which would be spontaneous energy expenditure. What's the contribution of these?

   3. RJDr. Rick Johnson46:52

      No, so actually that is still the first mechanism. The first mechanism is it makes you gain weight by increasing energy intake and dropping energy metabolism. And, and so what happens is a lot of weight gain from sugar is because you are eating more and exercising less, or, or-

   4. PAPeter Attia47:17

      Moving less

   5. RJDr. Rick Johnson47:17

      ... having less res- yeah, moving less. Less resting energy metabolism. So that's the first-

   6. PAPeter Attia47:22

      Ca- can you quantify those two? I, I want to get a sense of-

   7. RJDr. Rick Johnson47:25

      Yes, I, I, I, I, I... Yes

   8. PAPeter Attia47:26

      ... yeah. How much is the increase in ener- how much is the increase in intake? So, so the way, the way you would do this, I think, in animals would be because you're pair feeding them, uh... Or be- sorry, because you're letting them eat ad libitum. In this case, you'd have to let them eat ad lib. You could quantify the difference in energy intake, and you could say, "Does that difference explain the weight gain fully?" If it does, then none of it has to do with the decline of energy expenditure. If it doesn't, you would see what the gap is, right?

   9. RJDr. Rick Johnson47:52

      Right. Let me ex- explain that. Very good question. So s- most f- weight gain, uh, from f- sugar is due to eating more.

   10. PAPeter Attia48:04

       Okay.

   11. RJDr. Rick Johnson48:05

       And some weight gain is due to a decrease in energy metabolism. And, uh, and i- if you do isocaloric diet, so all the animals, you know, the controls and the sugar-fed animals are eating the exact same amount, weight gain is hard to sh... There's, there's ba- basically minimal difference in weight gain in the short term, like, uh, if you go for s- two months or sh- and, and so if you give sugar versus starch, after two months, uh, in, in, in animals, there's very little difference in weight gain. There's a little bit of weight gain because of the decreased energy metabolism in the fructose group, but it can be hard to show, and the High fructose corn syrup industry loves this. So they say, "Hey, um, you, you, you... The problem is people are eating too much, but if you control for how much sugar you're eating, um, it, there, it..." And we do isocaloric studies, and we look at short-term studies. There's no difference in weight gain. And they publish this, like, in the annals of internal medicine, and they say sugar's safe. But they miss the point that the sugar is actually causing hunger, and by con- by forcing an isocaloric diet, the people are hungry, but they're not able to eat because they're not allowed to eat. And so if you do a short-term study, like several weeks to months, you can't show a difference in weight gain. If you went longer, like a year, you probably would show a difference in weight gain 'cause of the difference in energy metabolism.

   12. PAPeter Attia49:49

       Yeah, just to put some numbers to that, right? I- if, if feeding somebody a, a high fructose isocaloric diet compared to a high glucose diet, it... If the high fructose group was driven to eat an extra 300 calories per day while simultaneously experiencing a reduction of energy expenditure of 25 calories per day, the increase in the drive to eat 300 calories a day would be readily apparent. Again, this is very back of the envelope math. And-

   13. RJDr. Rick Johnson50:20

       No, no, you're totally right

   14. PAPeter Attia50:21

       ... but, but, and, and, and-

   15. RJDr. Rick Johnson50:23

       You're 100%

   16. PAPeter Attia50:23

       ... and this is overly sim- simplifying things because it, it, it doesn't work out to be quite this straightforward a math. But by the numbers I gave, every 12 days you could gain a pound on the-

   17. RJDr. Rick Johnson50:36

       Right

   18. PAPeter Attia50:36

       ... intake side, but it would take months to show a gain of a pound on the energy expenditure side.

   19. RJDr. Rick Johnson50:46

       You're, you're absolutely right. And the other problem is, like, in the industry, they'll compare fructose to glucose, but we know that glucose, some of the glucose is being converted to fructose, so it's really, uh, not a fair comparison, right?

   20. PAPeter Attia50:58

       That's right.

   21. RJDr. Rick Johnson50:59

       So, so the... But there's another major mechanism, and the other major mechanism is that you, even if you pair feed animals so that they're eating the exact same amount, yes, there may not be a difference in weight gain because they're all eating the exact same number of calories, and even though these guys are leptin resistant, they can't eat what they wanna eat.

   22. PAPeter Attia51:25

       So presumably they're less happy.

   23. RJDr. Rick Johnson51:28

       [laughs] Yes, they're less happy. They're hungry. They're, like, feeling they're on a diet, right? Um, and, uh, but even when you control the exact same diet, all the other metabolic effects of fructose are still going on. They're still becoming insulin resistant. They're still getting fatty liver. They're still getting hypertension. And, and you can see this, um, beautifully, uh, you know, in animals it's very easy, but you can actually, um... I've seen clinical evidence of this in people, too. And, and, um, a, a great example, uh, and I may have told this story last time when we were on, but, uh, we, we were doing a pair feeding study of 40% sugar versus starch, and so the animals were getting the exact same amount of food. And pair feeding means you take a group of animals. Let's say you have 10 animals in this group and 10 animals in this group, and they all get, um, they all get the same amo- They, they have to eat the same amount of food each day. And what that means is that the animal that eats the least amount of food, all the other animals have to eat that least amount of food. So if you have one guy who's not... who's got a problem and isn't eating a lot, all the animals are forced to do that. So we were doing this study, Carlos Roncal and our group was doing this study, uh, to s- to look at pair feeding, and he did not know that one of the animals had cancer, and that animal was eating [laughs] hardly anything. So we had a, a, an experiment that went for four months in which all the animals are eating, like, hardly anything. They're all eating the exact same food. They are on a severe diet. But one group was on a 40% sugar diet, and the other was on a f- a starch diet, and every- everything was eq- equal. They were eating the exact same amount. At the end of the four months, the sugar-fed animals tended to be more... tended to be, uh, higher weight, but it wasn't significant, but it was from that resting metabolism, uh, the, from the fact that they had a lower energy metabolism. And it looked like it would've been significant we'd gone a little bit longer.

   24. PAPeter Attia53:41

       How long did you go?

   25. RJDr. Rick Johnson53:42

       Uh, four months, I believe. It might have been... Yeah, four months.

   26. PAPeter Attia53:45

       Okay. So, uh, just to put that in perspective and give a sense of magnitude, four months in mice is about 10% of their life. It's, it's more.

   27. RJDr. Rick Johnson53:57

       Yeah.

   28. PAPeter Attia53:57

       It's about 15% of their life. So that's a-

   29. RJDr. Rick Johnson53:59

       Yeah, they, they live two and a half years. So-

   30. PAPeter Attia54:02

       Okay. Yeah, yeah, yeah. So, so that's like 15 years in a human.
7. 56:45 – 1:08:58

   Implications for aging and disease

   1. RJDr. Rick Johnson56:45

      if you don't have that extra food because you are becoming leptin resistant and you're eating more, uh, as part of this, uh, problem.

   2. PAPeter Attia56:54

      So, so is it safe to say that neither of these animals were overweight at the end of this study, but one of them became very skinny fat, you know, to use the term that we now-

   3. RJDr. Rick Johnson57:04

      Yes

   4. PAPeter Attia57:04

      ... describe for the lean metabolically unhealthy phenotype?

   5. RJDr. Rick Johnson57:10

      Yes. And, and we can see this in, uh, uh... You're right. These people exist, uh, y- out there that, that are, you know, uh, calorically restrict themselves but are still eating the wrong foods. So-

   6. PAPeter Attia57:22

      So if you had done that study long enough, Rick, which by the way, it's an elegant study that you, you, you sort of did accidentally, um, it, it would be interesting to see if there was a survival difference.

   7. RJDr. Rick Johnson57:35

      I think that, uh, this whole pathway is very important in aging. And, um, we, we did-

   8. PAPeter Attia57:41

      Well, it's hard to imagine it's not.

   9. RJDr. Rick Johnson57:44

      Yeah.

   10. PAPeter Attia57:44

       So, uh, it's like, so it's one of those studies where I feel like if you can devote the resources to, to do the experiment for two and a half years and say, "Look, we're going to go after the Holy Grail outcome," which is all-cause mortality... And, and again, I like the way that these animals were calorically restricted, right? Because it gets you away from the obesity is the problem. I... You see, I, I've always felt that obesity is a passenger that comes along for the ride, but it's the metabolic derangement that lies under obesity that's highly correlated with obesity, but is, is, is actually quite separate from obesity, that that's the, that's the root cause of our mortality, and this would be an experimental way to demonstrate that, um, that, that I think would be, again, not beyond the realm of, of, of, of doing, right?

   11. RJDr. Rick Johnson58:37

       Yeah. No, it would be... It... I've actually proposed to do that study. Um, but I'll, I'll tell you some, some things that really suggest that this is important in aging. Um, the, the first thing to talk about is that, you know, there have been studies done in fruit flies looking at the effects of sugar on aging. And, um, you know, it's sort of interesting. The fruit fly actually, you know, is eating fruit. Uh, I mean, that's what they like, and so they, they are always on some fructose. But they're not getting, um, highly concentrated fructose 'cause the fruit also has lots of other things in it, fiber and other things that they're, they're probably getting, you know, and, and the flavanols and everything in there that some of them kind of neutralize some of the effects of sugar. But if you, uh, give a fruit fly sucrose or table sugar, which is really fructose and glucose together, a liquid, uh, sucrose, they'll love it, and, uh, they actually, uh, there's studies showing that they will develop obesity, believe it or not. [laughs] So you'll have obese insulin-resistant flies, and they die early. Uh, and also, uh, when they die, they die from complications related to uric acid production, uh, which is really interesting. They develop, uh, equivalently, uh, kidney failure for their, uh, their equivalent of their kidney. Um-

   12. PAPeter Attia1:00:12

       I don't know

   13. RJDr. Rick Johnson1:00:13

       ... but what we did-

   14. PAPeter Attia1:00:13

       I'm, I'm gonna wait and see the mice data on that. I, I, uh-

   15. RJDr. Rick Johnson1:00:15

       Yeah, yeah

   16. PAPeter Attia1:00:16

       ... I think there's enough confounding there.

   17. RJDr. Rick Johnson1:00:16

       Okay. So and now I'm, and now we're gonna move to the mice. So, um, we were interested in whether or not, uh, mice that lacked, uh, fructose metabolism might live longer than normal mice. And, uh, we happened to have some that we were keeping around, and they were on a normal mouse chow diet that is very low in fructose. So these animals are eating almost no fructose. It's like less than 3% of their chow.

   18. PAPeter Attia1:00:46

       Hm.

   19. RJDr. Rick Johnson1:00:47

       So, uh, but we do know that animals make fructose-

   20. PAPeter Attia1:00:51

       And how, how much glucose-

   21. RJDr. Rick Johnson1:00:51

       ... in their body

   22. PAPeter Attia1:00:52

       ... how, how much glucose on their chow?

   23. RJDr. Rick Johnson1:00:53

       Well, you know, so they get a, they get a fair amount of starch, um, and protein, uh, in the chow. So they're, they're actually, uh, they are getting- A fair amount of carbohydrate

   24. PAPeter Attia1:01:05

       So what, what are the approximate macros of the three?

   25. RJDr. Rick Johnson1:01:08

       I would have to look it up. I, I can't, uh, tell you at the moment, but, but, but it's the standard chow, which is basically, uh, there's not a lot of-

   26. PAPeter Attia1:01:16

       But it's a very low sugar chow

   27. RJDr. Rick Johnson1:01:19

       ... it's a low sugar chow. And, uh, we took them out to, like, a little bit over two years, and we found that they, they had stayed lean compared to the control mice. So they were, they were more lean. Uh, and you know, when, when an animal age develops kidney disease and-

   28. PAPeter Attia1:01:37

       Sorry, was that statistically significantly lean?

   29. RJDr. Rick Johnson1:01:40

       Y- I, yes. And they also had, um, they were, uh, uh, they, they, uh, they tended to have normal blood pressure or lower blood pressure, uh, than the, um, than the control animals.

   30. PAPeter Attia1:01:56

       How do you measure blood pressure in the mice?
8. 1:08:58 – 1:12:43

   Impact of endogenous fructose production on obesity and metabolic syndrome

   1. RJDr. Rick Johnson1:08:58

      But now we know that it isn't just the fructose you drink, it's the fructose you make, and we know that high-

   2. PAPeter Attia1:09:04

      Oh, yeah. Sorry. So I, I kinda got off track there-

   3. RJDr. Rick Johnson1:09:05

      Yeah

   4. PAPeter Attia1:09:05

      ... and I apologize.

   5. RJDr. Rick Johnson1:09:06

      Yeah.

   6. PAPeter Attia1:09:06

      That's really where I wanted to go with that observation, which was-

   7. RJDr. Rick Johnson1:09:09

      Yeah

   8. PAPeter Attia1:09:10

      ... um, do we know what the average American consumes in terms of fructose per day?

   9. RJDr. Rick Johnson1:09:15

      Yeah. So, um, uh, f- first about 15 to 20% of the diet is from sugar, and, um, and sugar is half fructose and half glucose.

   10. PAPeter Attia1:09:26

       So 10% of the diet is-

   11. RJDr. Rick Johnson1:09:27

       Sugar, sugar or high fru-

   12. PAPeter Attia1:09:27

       So 10% of the diet is fru-

   13. RJDr. Rick Johnson1:09:29

       10 to f- 10 to 15%, because we also are getting fruit- fructose from fruits and, uh, and other foods besides added sugars. So, um, sh- sugar in the diet can vary. Some people are eating as much as 25% of their diet is sugar. Um, and so they're... the... And, and then tho- so people can be eating as much as 15, even 20% of their diet is fructose. Some-

   14. PAPeter Attia1:09:53

       But let, let's just do the math and say conservatively it's not hard to eat 100 grams of fructose a day. 400-

   15. RJDr. Rick Johnson1:10:02

       It's not

   16. PAPeter Attia1:10:02

       ... calories of fructose could represent 15% of your caloric intake.

   17. RJDr. Rick Johnson1:10:09

       Absolutely correct.

   18. PAPeter Attia1:10:10

       Okay. So if you take the average American walking around eating, let's just give a range, 75 to 100 grams of fructose, that's their exogenous consumption of fructose.

   19. RJDr. Rick Johnson1:10:22

       Right.

   20. PAPeter Attia1:10:22

       And that individual, who we assume is a little bit insulin resistant, maybe a little bit leptin resistant, but not off the charts, what would you expect their endogenous production to be? How much are they adding to that till?

   21. RJDr. Rick Johnson1:10:38

       I would suspect a f- a fair amount. Um, I know you want a, a quantitative amount, um-

   22. PAPeter Attia1:10:44

       Directionally, are we talking 10% of that amount, 50% of that amount, 100% of that amount? Like, where are we? What zip code?

   23. RJDr. Rick Johnson1:10:50

       Yeah. It, it, it would be a guess.

   24. PAPeter Attia1:10:52

       Okay.

   25. RJDr. Rick Johnson1:10:52

       But I would say 25 to 50% of more from endogenous production. And, uh, and there's three-

   26. PAPeter Attia1:10:59

       And that's based on animal data?

   27. RJDr. Rick Johnson1:11:02

       Based on our animal data. Now there's three major sources of fructose that we can make, and we've only talked about one of them. But the f- the first one is high glycemic carbs, and so rice, potatoes, bread, chips. We think maybe a quarter of that can be turned into fructose. Um, and if... And I think that that's playing a major role in ha- metabolic syndrome. So what, what happens is when you're young and you don't have this polyol enzyme pathway activated, eating things like potatoes and french fries may not cause so much weight gain. You, you, you may feel you're invincible. But, uh, as this pathway gets activated and aldose reductase starts being highly expressed in the liver, then, uh, potatoes and bread may cause much more weight gain. And so... And we think it's because of this fructose conversion. Because we actually did another study, Peter, where we gave soft drinks, a high fructose corn syrup to, to animals, and they got really fat and insulin resistant. But if we blocked fructokinase, uh, we completely blocked the, uh, development of metabolic syndrome. So with soft drinks, r- really was all fructose even though there's a lot of glucose in there. We saw a little bit of weight gain with glucose alone, but when we give high fructose corn syrup, we... it was pretty much all from the fructose that was causing the, them to gain weight and to get metabolic

9. 1:12:43 – 1:26:43

   Why vulnerability to the negative effects of sugar increases with age and menopause

   1. RJDr. Rick Johnson1:12:43

      syndrome.

   2. PAPeter Attia1:12:43

      Rick, before we go to the other two sources of substrate for making fructose, you, you mentioned almost in passing that when you're young, you can tolerate lots of high glycemic foods. I think anyone listening to this can relate to that, or probably 90% of people can relate to that. I know I certainly can. Um, what is it about just aging that alters our sensitivity or vulnerability, maybe is a more accurate word, to glucose? And, and, and I'll throw another quest- I'll throw another wrinkle at you because we've had a lot of questions about this from women. What is it about menopause that for many women also seems to, you know, almost overnight or certainly within the span of about a year, also alter the sensitivity or vulnerability that one has to glucose and, by extension, fructose?

   3. RJDr. Rick Johnson1:13:37

      Yeah. There's like three or four different reasons, and so let me just go through the list real quick. So the, the very first one is that when we're young, we tend to have very healthy mitochondria, and we're, we're... a lot of kids are active, and we keep the mitochondria healthy. And the way that this, um, fructose works is it has to cause oxidative stress to the mitochondria to activate these pathways. But if you're... have really, really powerful mitochondria, you, you won't, um, show these metabolic effects as easily because they're more resistant to the effects of fructose. And you can still see this in super athletes. They have fantastic mitochondria. They... Many of them feel like they can drink a lot of sugar, um, and that it, that they're immune, and it's because they have really, really healthy mitochondria.

   4. PAPeter Attia1:14:28

      Tell me more about what that means. Tell me, tell... What does healthy mitochondria mean? We talk about this, but, but give people a sense of what a healthy mitochondria does that an unhealthy one does not do, and why is mitochondrial dysfunction viewed as one of the hallmarks of aging?

   5. RJDr. Rick Johnson1:14:44

      Uh, so, so your mitochondria are your, your, o- one of your major places where you make energy, and in fact, it's the high output energy producer. And, and so it's producing the ATP that we need to drive everything we do. And, um, over y- many years, mitochondrial, the mitochondria get less good at making the energy because of damage, recurrent damage. And it's thought that, uh, oxidative stress to the mitochondria can cause, um, this damage. And so, um, when you're eating, uh, wh- when you wanna try to store fat, um, mitochondrial oxidative stress is part of the requirement to store fat, and fructose w- works to store fat by stimulating mitochondrial oxidative stress. And initially, that is a reversible, very easily reversible m- mechanism. The oxidative stress goes on, it, it's, in- inhibits these enzymes, uh, it leads to fat production and, and so forth, so it's of, um, it's a survival pathway, right? But what happens is, um, if you keep stimulating mitochondrial oxidative stress, and it's been shown with fructose, for example, the mitochondria start to decrease, and, um, and the mitochondrial change, they become smaller and less efficient. And what happens is the mitochondrial function st- starts to, to, to, to reduce in number, and, and so you have less mitochondria. And when that happens, you c- you make less ATP, and so you'll f- it, it's associated with feeling more fatigue, more tired. If you have lower ATP levels in your muscle, it's associated with muscle fatigue. Uh, your natural gait will slow down as your mitochondrial function, uh, decreases, and it's all associated with aging.

   6. PAPeter Attia1:16:45

      How do you, how do you quantify this in animals? So if you, if you were to take a four-month-old mouse versus a two-and-a-half-year-old mouse and you did muscle biopsies, uh, obviously there's a quantitative m- assessment that you would do. You would say per gram of muscle, there's this many mitochondria versus this. They're this big versus that big. Um, how are you assessing ATP output, and how are you quantifying the functionality on a per unit of mitochondria basis?

   7. RJDr. Rick Johnson1:17:14

      Well, first off, you can measure, you can measure the mitochondria themselves by looking at, uh, electron microscopy. You can measure it, uh, indirectly with a PCR technique, looking at mitochondrial DNA divided by nuclear DNA. You can measure ATP levels in the tissues. There's all kinds of ways to do it. Um, what we do know is that, um, mitochondrial function tends to decrease as we get older. Um, there's a very good evidence that, um, recurrent chronic oxidative stress to the mitochondria is involved in this. Uh, we think that, um, uh, th- that fat storage is associated with mitochondrial oxidative stress, so if you're continually stimulating these pathways with fructose, that that may actually wear down the mitochondria. We did do a study in humans where we put people on a low fructose diet and showed that we could increase mitochondrial biogenesis in people, uh, within 30 days, and, and we had a very dramatic increase in mitochondrial production. Fasting is thought to increase mitochondria probably the same way. Um, and, and actually, even caloric restriction, the, the concept that caloric restriction can promote aging is probably through this pathway because if you-

   8. PAPeter Attia1:18:31

      Promote or abrogate?

   9. RJDr. Rick Johnson1:18:33

      ... calorically... Promote... Uh, re- reduce aging-

   10. PAPeter Attia1:18:36

       Yeah

   11. RJDr. Rick Johnson1:18:36

       ... uh, by reducing mitochondrial oxidative stress. So with, uh, when you think about this, when you're eating, whenever you're storing fat, you are actually... It, it seems to involve some mitochondrial oxidative stress. And so if you eat, um, less food, you're gonna have less oxidative stress to the mitochondria, and you'll have less fat stores, but what will happen is you will, you'll live longer. So i- in an animal, they always wanna have some extra fat on board because they're living in the wild. They, they, they don't know if they're gonna be sh- uh, sh- food... there's gonna be a food shortage suddenly or not. So they wanna try to maintain a little bit extra fat. And so if you take animals and you put them on 70% of their normal caloric intake, their fat stores are very minimal. They have less oxidative stress to their mitochondria, and they're gonna live longer. Their mitochondria are gonna stay healthier. But if you take those animals and you put them in the wild And, and, and remember when they're in a, i- in a lab, they're being fed, you know-

   12. PAPeter Attia1:19:37

       Yeah

   13. RJDr. Rick Johnson1:19:37

       ... a certain amount of food every day, so, so they're safe, right? You put 'em out in the wild, now they have no fat stores, and the first big crisis, they, you know, suddenly kills half of them because they can't survive 'cause they don't have enough energy stores. So animals in the wild want to have a little bit of extra fat. Pregnancy-

   14. PAPeter Attia1:19:56

       But, but it s- it seem-

   15. RJDr. Rick Johnson1:19:57

       ... you wanna have more

   16. PAPeter Attia1:19:57

       ... it seems that we do too. I mean, the obesity paradox is hard to ignore, that low levels of obesity actually seem protective.

   17. RJDr. Rick Johnson1:20:05

       Absolutely. So if you, if you're, have cancer or heart failure or any kind of chronic disease, you'll actually live longer if your fat stores are, like, 20... If you have a BMI of, like, 27, that's gonna do better than a BMI of 20 when you have a chronic illness, and there's even-

   18. PAPeter Attia1:20:23

       E- even, even 28-

   19. RJDr. Rick Johnson1:20:24

       ... some e- with aging

   20. PAPeter Attia1:20:25

       ... 28 is gonna do better than 24 as you age-

   21. RJDr. Rick Johnson1:20:28

       Yes, yes

   22. PAPeter Attia1:20:28

       ... based on the overall data, which is-

   23. RJDr. Rick Johnson1:20:30

       Yes

   24. PAPeter Attia1:20:30

       ... again, quite a paradox.

   25. RJDr. Rick Johnson1:20:32

       Yes, and it's be- it's because of that need to have a little bit of fat stores. But, but, um, yes. So but a- anyway, if we get back to the, the ori- original question, which is, you know, why is it that when I'm young, uh, I can eat bread and there's no problem, one is that our mitochondria are healthier at that point, and, and so, um, we, we have what we call metabolic flexibility. We can metabolize things very easily because we're y- you know, everything's kind of young. But over time, um, uh, sugar, the more sugar we eat, the more we get better at metabolizing it. So normally in the beginning when we eat sugar, uh, the transporter for fructose in our gut is, is expressed at low levels, and, and animals that get fructose when they're young tend not to absorb it as well. But the more we get exposed to sugar, the better we get at absorbing it. We, we turn on the enzymes and the transporters that allow us to absorb fructose more readily. So if you've, if you give an animal sugar for t- a month, s- for example, you'll upregulate all these pathways, and then you can, like, maybe you can stop the sugar for one day, and then if you give them a bolus of sugar, they get a very dramatic, uh, activation of this switch and, you know, and the fall in energy. It's very dramatic com- it... compared to a normal animal that's not been exposed to sugar that gets a, a single dose, and that's because we turn on these pathways. So we turn on the ability to metabolize sugar. So we did a study in children, um, where we, uh, where we gave them a dose of fructose, and we had lean children, we had children that were obi- obese, and we had children that were obese that had biopsy-proven fatty liver. And when we gave them a dose of fructose, the lean people only absorbed about 70% of the fructose, and they metabolized it slowly.

   26. PAPeter Attia1:22:34

       And this was a liquid bolus?

   27. RJDr. Rick Johnson1:22:37

       Yes.

   28. PAPeter Attia1:22:37

       How much?

   29. RJDr. Rick Johnson1:22:37

       And then we, uh... It was, I think, one [laughs] you always ask. Uh, it's like one gram per kilogram body weight, as I recall. Um-

   30. PAPeter Attia1:22:46

       Okay
10. 1:26:43 – 1:43:56

    Dietary strategies to reduce the negative impact of fructose

    1. PAPeter Attia1:26:43

       Um, before we leave this subject and go on to the next thing I wanna talk about, which is blood pressure, kidney function, um, I, I wanna, uh, go back to something to kind of make this more practical for people, right? Which is what, what do people need to be wary of, right? I mean, I think the other question that emerges from a discussion like this for many people is, "Oh my God, do I need to not eat any fructose?" Right? "This means I can't have any fruit. Uh, you know, tomatoes have fructose in them. By God, I can't have tomatoes." You know? So, so how do we provide some insight to people so that they can figure out how to adjust the dose of something that only-

    2. RJDr. Rick Johnson1:27:32

       Isn't it? [laughs]

    3. PAPeter Attia1:27:33

       Yeah. I- it's something that it, by the way, is ubiquitous, completely ubiquitous. Uh, so if you wanna go on a zero fructose diet, boy, you're gonna have a hard time.

    4. RJDr. Rick Johnson1:27:42

       Yeah, no, it's not gonna work.

    5. PAPeter Attia1:27:43

       So how do, how do, how do people get a sense if they're consuming too much fructose?

    6. RJDr. Rick Johnson1:27:47

       Okay, so the very first thing I would recommend, Peter, would be to, um, really try not to drink s- uh, to drink liquids that have a lot of sugar in it. So immediately get rid of soft drinks, um, and fruit juices, I would drink minimal because there's a fair amount of fructose in that, and it can kinda overwhelm the system. Uh, sports drinks are sort of interesting. Um, some sports drinks ha- are relatively low in fructose. Um, and you know, so maybe they're 2 to 4% fructose with 4% glucose or 6% glucose. Um, it turns out that when you're exercising-

    7. PAPeter Attia1:28:25

       And, and let's explain to people what that means, right? So-

    8. RJDr. Rick Johnson1:28:28

       Okay. Yeah

    9. PAPeter Attia1:28:28

       ... a 6% glucose drink means there is 60 grams of glucose per liter.

    10. RJDr. Rick Johnson1:28:32

        Yeah. So soft drinks are like 11%. They have like 6% fructose and 5% glucose, and that really is bad stuff.

    11. PAPeter Attia1:28:41

        Yep.

    12. RJDr. Rick Johnson1:28:41

        Soft drinks should... I think they should be banned.

    13. PAPeter Attia1:28:44

        Right. So that's like 110 grams of total sugar per liter. That's-

    14. RJDr. Rick Johnson1:28:50

        Yeah. Yeah

    15. PAPeter Attia1:28:50

        ... gives you a sense of how sweet that is

    16. RJDr. Rick Johnson1:28:51

        ... so a huge, huge, huge amount. Teaspoons and teaspoons. Teaspoons. So, um, so soft drinks are really bad. Sports drinks, um, were developed b- uh, originally by Bob Cade and, and, and, and the invention of Gatorade. W- with the, the fact that, um, that people who are exercising a lot are losing salt, uh, lots of salt in their sweat. They're losing... They're burning up glucose, uh, and some of them were getting hypoglycemic on the fields. And, and sports drinks were, were really meant to help re- replenish the electrolytes and to, uh, fix the glucose problem and, um, and, and to provide glucose as fuel for the muscle, uh, during these heavy exercise spouts, 'cause you, we often use a lot of glucose during exercise. And so, um, the original soft drinks, uh, were mainly... I mean, excuse me. The original sports drinks were glucose rich, um, and had a lot of salt and, uh, and, and water of course. And, um, and then, uh, they, there were some studies that showed that you c- that muscle, uh, the, the oxidation of glucose could be facilitated by having a little bit of fructose in the drink. That the fr- having a small amount of fructose actually accelerated glucose uptake, um, and it, it's working in the gut primarily, and, and it, and it actually your performance was increased by having small amounts of fructose, like 1 to 2%, maybe 3% fructose. And, um, and the optimal glucose from sor- sports drinks was found to be around 5 or 6%. Um, now some sports drinks actually have more fructose in it because it tastes better, and so that's a problem, a little bit of a problem. But it, it, it... You know, if you're out there exercising, if you do- using it for what it's meant for, which is, uh, sport, and you're really... Uh, you know, I think sports drinks for the most part are, are fine. But if you're drinking sports drinks in front of a TV watching, uh, you know, a movie and, uh, you're drinking a lot of this stuff, it probably is not good. So, um, so but in getting back to other things, um-

    17. PAPeter Attia1:31:04

        Wanna go back to the, the, uh, juices. Um-

    18. RJDr. Rick Johnson1:31:08

        Yes

    19. PAPeter Attia1:31:08

        ... if, if I take oranges and I-

    20. RJDr. Rick Johnson1:31:13

        Yeah

    21. PAPeter Attia1:31:13

        ... squeeze them into... You know, I put my little juice squeezer and I-

    22. RJDr. Rick Johnson1:31:16

        Yeah

    23. PAPeter Attia1:31:16

        ... ratchet it down, and I just make concentrated orange juice, what is the concentration of glucose and fructose in orange, freshly squeezed orange juice?

    24. RJDr. Rick Johnson1:31:24

        It's pretty, pretty significant. It's probably about 2/3 of a soft drink. Um, if you made it with apple juice, it's eq- apple juice is so sweet, it's equivalent to a soft drink. Um, and so you can get a lot of sugar with, from, uh, juice unfortunately. So the Pediatric Society a long time ago realized that juice has so much fructose that it was being associated with obesity in children. So they made, uh, recommendations to limit fruit juice to like six ounces or less- Uh, for, uh, adult... I mean, for older children and like four ounces or so for really small children, and I think that, that we should even limit it more. And fruit juice is, I think, a, a, a real problem in, in children because of all the sweetness of sugar that's in it. Now, um, natural fruits are different. So natural fruits have like, uh, much less fructose, uh, e- because in an individual fruit. When you make fruit juice, it's like multiple fruits that are put in there. So if you ha- eat like a orange and it has like six grams of fructose, um, you know, that-

    25. PAPeter Attia1:32:34

        S- so Rick, I... That, that, that's news to me. I didn't realize an orange would only have six grams of, uh, fructose. That's, that's surprisingly low. I mean, I... We're talking about a real orange here, not like a little Christmas orange, right? Like a real orange would only have six grams of fructose?

    26. RJDr. Rick Johnson1:32:47

        I believe it's like six to eight grams. I don't think it's over eight grams. It's closer to six grams, I believe.

    27. PAPeter Attia1:32:53

        And equal amount of glucose?

    28. RJDr. Rick Johnson1:32:54

        Yeah, it has some glucose in it too, for sure. Um, but I think there's about six grams of fructose in an orange.

    29. PAPeter Attia1:33:01

        So if that's the case, really outside of someone maybe with NAFLD, you'd have a hard time making the case to not eat an orange.

    30. RJDr. Rick Johnson1:33:09

        Yeah, I think that natural fruits are fine, um-
11. 1:43:56 – 1:54:16

    The role of hypertension in chronic disease and tips for lowering blood pressure

    1. PAPeter Attia1:43:56

       okay, so let's talk a little bit about blood pressure. Um, it seems to play a very important role in really all of the major chronic diseases except for cancer, and if there's a role in cancer, I don't know what it is, but there Who knows? Maybe somebody knows that. But certainly when we come to neurodegenerative disease, cardiovascular disease, cerebrovascular disease, and renal disease, uh, which are really the main pillars of, of death, um, hypertension seems to work against you. Um, so what is it about everything that we've spoken about that ties into hypertension?

    2. RJDr. Rick Johnson1:44:34

       Yeah. So high blood pressure, which is sometimes called primary or essential hypertension, is extraordinarily common in our country, um, and throughout the world and maybe one-third of adults have high blood pressure. I mean, it's huge percentage. It-

    3. PAPeter Attia1:44:51

       How is it defined today?

    4. RJDr. Rick Johnson1:44:52

       In most p- places in the world, it's defined as a blood pressure greater than 140 over 90. 140 over 90 or higher. Um, but in this country, uh, recently it, it was redefined as being greater than 130 over 80. But I, I think that for the majority of the world, um, the definition is 140 over 90.

    5. PAPeter Attia1:45:15

       And from a physiologic perspective, where do you fit on that spectrum? I mean, you're the nephrologist, so you take care of the organ that is arguably the most sensitive to blood pressure. You could make a case that even more than the heart and the brain, the kidney is the first place that damage shows up. I don't know if you would agree with that, but is that, is that a true statement?

    6. RJDr. Rick Johnson1:45:37

       Well, well, the... There's actually three main sites where high blood pressure really causes problems, and the first one is stroke. It's the major cause of stroke. It's also the major cause of heart failure, and it's one of the two major causes of kidney disease. And so those are the three main pressure-related, uh, diseases. Pressure that related conditions where pressure is driving. The higher the pressure, the higher the risk for stroke, heart failure, and kidney disease. Um, the, uh, studies show that the greatest risk for stroke, heart failure, and kidney disease are when the blood pressure is like 170... 160 to 180 systolic is kind of the turning point where when it's above that level, there's really a dramatic increased risk for these conditions. Um, but it's been known for a long time that there's been... that there's a tendency for a linear relationship between blood pressure and stroke and blood pressure and heart failure going all the way down to 120 over 80. So, um, there, so there are a lot of people that would like to say that, you know, 120 over 80 or 130 over 80 should be our cutoff, um, because it's really a linear relationship. But most, uh, you know, studies done like, uh, around 1900 showed that less than 5% of the population had blood pressures of over 140 over 90. Um, and so, uh, based upon the, the normal Gaussian curve of the population back then, uh, probably about f- uh, 140 over 90 should w- was the cutoff for what was thought to be high. And I, I'm a, a believer that 140 over 90 is a good mark for where we should be, uh, viewing hypertension, um, as a condition that really should involve, you know, active management.

    7. PAPeter Attia1:47:41

       So Rick, does that imply that if somebody has a blood pressure of 135 over 85, which would be below the cutoff that you're saying y- you would deem the time to act of 140 over 90, at 135 over 85, you could roll around at that blood pressure indefinitely without any damage to the kidney?

    8. RJDr. Rick Johnson1:48:01

       Yes, exactly. So there, there's relatively minimal risk w- with a blood pressure of 135 over 85. It, it, it, it... But however, it's, uh, it... In epidemiology studies over many years, you can show that, you know, 120 over 80 is superior to 135 over 85. Um-

    9. PAPeter Attia1:48:20

       And, and the reason I bring this up, Rick, is, is not-

    10. RJDr. Rick Johnson1:48:22

        Yeah

    11. PAPeter Attia1:48:22

        ... to be a pain, but it's to talk about how, what our standards are really about, right? So-

    12. RJDr. Rick Johnson1:48:29

        Yeah. Yeah

    13. PAPeter Attia1:48:29

        ... um, I'm not a nephrologist, but boy, am I a freak when it comes to managing GFR in my patients.

    14. RJDr. Rick Johnson1:48:37

        Yes.

    15. PAPeter Attia1:48:38

        Why?

    16. RJDr. Rick Johnson1:48:38

        Good for you.

    17. PAPeter Attia1:48:39

        But, but why, right? Because I want people to live to 100. That's an aspiration.

    18. RJDr. Rick Johnson1:48:45

        Right.

    19. PAPeter Attia1:48:45

        Most people aren't going to, but we make that the aspiration. So if I'm talking to a 40-year-old patient and their GFR is 85, well, most people would say that's normal. But I want that 40-year-old not to live to 80. I want her to live to 100, which means I can't treat her like a 40-year-old. I have to treat her like a 20-year-old. I have to time shift her back to say, "I need her kidneys to survive another 60 years." So based on epidemiologic data, I can't treat her as a 40-year-old, and her GFR of 87 is not good enough. I want her GFR to be 107 because I need to know that at 100 her GFR is still 40. So, uh, that's why I push back on this idea, 'cause I, I really wanna understand this. If we're in the business of trying to get people's kidneys to have a GFR above 40 at the age of 100, do we have to revise our standards on hypertension?

    20. RJDr. Rick Johnson1:49:56

        It's a wonderful comment that you make there, and, um, I think that the, that the answer is, uh, we would prefer a blood pressure of 120 over 80, um, but, uh, if it's 135 over 85, to put someone on a medication Uh, y- that they'll have to take for the next 60 years, um, I'm not sure that that's the best way to go. I, I, I think that, um, doing nutritional and exercise-related maneuvers when you're 135 or 85 should be the way to go.

    21. PAPeter Attia1:50:33

        Mm-hmm.

    22. RJDr. Rick Johnson1:50:34

        Um, and, um, and it... And we can fix it by diet, by reducing salt and, and picking healthier foods and exercising. But when, when... The trouble with, with, um... When, when you get to 140 over 90, if you can't lower your blood pressure by, uh, by dietary means, I... You really probably should go on a antihypertensive because, uh, it will provide protection over time. But when your blood pressure's like 130 over... 135 over 85, um, I don't... I haven't seen any evidence that antihypertensives really provide long-term benefit to that group. Um, I do think that, um, dietary m- measures, though, make sense, and I agree with your general idea, the, uh, the idea that, you know, optimize health as best as we can and that's your best chance to maintain health for the longest you can. And so I like that idea. Uh, I think you're, you're right on, but I don't know if we should be doing interventions. The trouble with defining blood pressure hypertension at a lower level is it implies that antihypertensives should be used, uh, at those lower levels, and I don't think that the evidence is strong enough, uh, to, to warrant that.

    23. PAPeter Attia1:51:58

        Yeah. But unfortunately, the absence of evidence is not the evence- evidence of absence. In other words-

    24. RJDr. Rick Johnson1:52:03

        Correct

    25. PAPeter Attia1:52:03

        ... the challenge we would have in doing that trial, which by the way, I'm not advocating for that. I agree that I think most of the time a person's walking around at 135 over 85, you can fix it without medication. But it's an important point here-

    26. RJDr. Rick Johnson1:52:16

        Yes

    27. PAPeter Attia1:52:16

        ... 'cause it's the same problem that, uh, we face when we try to think about this through the lens of cardiovascular disease, which is-

    28. RJDr. Rick Johnson1:52:25

        Yes

    29. PAPeter Attia1:52:26

        ... you know, is a 30-year-old with an ApoB of 100 worse off than a 30-year-old with an ApoB of 70? Well, there's no study that can answer that question because if you study a 30-year-old for the next five years at ApoB of 70 versus, hell, 170-

    30. RJDr. Rick Johnson1:52:48

        [laughs]
12. 1:54:16 – 2:04:50

    The impact of fructose and uric acid on kidney function and blood pressure

    1. PAPeter Attia1:54:16

       um-

    2. RJDr. Rick Johnson1:54:16

       Yeah

    3. PAPeter Attia1:54:16

       ... let's now talk about-

    4. RJDr. Rick Johnson1:54:17

       These are very, very good points

    5. PAPeter Attia1:54:18

       ... uh, let's talk about the, the role that fructose, sodium play on hypertension through the lens of uric acid, vasopressin, fluid retention, whatever the effectors are.

    6. RJDr. Rick Johnson1:54:34

       So blood pressure, you know, w- I've, I've had a very, a longstanding interest in, in the mechanisms driving high blood pressure and, um, and what we w- the way we kind of tracked it back, and I'm gonna kinda track it back in the way that we dis- our work, uh, kind of uncovered it. The first issue was that, you know, it's known that, um, salt is important in blood pressure and, um, and that animals that are sensitive to high blood pressure, you can make blood pressure a lot worse by giving them salt and studies, you know, from 1900 showed that if you took people with high blood pressure and you put them on a salt restriction, that you can lower blood pressure. So it's been known for a long time that salt is very important in blood pressure and, um, this has led to restrict- you know, recommendations to restrict salt in people with high blood pressure. Um, not everybody is sensitive to salt and, um, a lot of people when they're young can eat all the salt they want, um, and, and they don't seem to have so much of a problem. But, uh, as we get older, we become more and more sensitive to the effects of salt on blood pressure, and you can show that as we get older, um, that, that when you give salt, blood pressure rises, uh, tends to rise more. So the question is, you know, why is that? And for years it was thought that the problem is that the kidneys in people with high blood pressure can't excrete salt as easily or as well as normal people, and so that there was some defect in the kidney that could cause that. To make a long story short, we're, uh, we spent, you know, over a decade studying this and we discovered that people with high blood pressure have, um, inflammation in their kidneys. They have low-grade inflammation in their kidneys, and it's due to, uh, T cells and macrophages, and they tend to be in the, uh, in the, um, main part of the kidney where we call the tubules and where, where the tubules are. And, uh, and around the little blood vessels. And, uh, we were able to prove that the inflammation was actually maintaining the kidney in a, in a state where it c- couldn't get rid of salt very well, and it did this b- by basically creating, uh, a reduced blood flow to the kidney. So in people with high blood pressure, they all have reduced blood flow to their kidney. When you reduce the blood flow, you, you, you, uh, affect the ability of the kidney to excrete salt and you start to retain salt. So when we, when we discovered this and, and others also followed, followed this by, uh, noting this association, it really emphasized the fact that high blood pressure is an inflammatory disease that is driven by inflammation. But then the question is, what was driving the inflammation? And, and, uh, what we found was that there are many things that can s- cause inflammation to the kidneys. Some things are, are, you know, there's, there's, there's drugs like, um, uh, things that are very vasoconstrictive. Um, you know, cocaine for example, and other things that constrict the renal arteries or, or, um, the activation of the renin-angiotensin system, for example, can cause, um, uh, ischemia to the kidneys and bring in this inflammation. But one thing that seems to drive it is a high uric acid. And when we found this, we, we did some studies in, in adolescents and we found that, uh, these adolescents who are overweight, many of them had a high uric acid and they were discovered to have high blood pressure. Uh, and we did some studies and we found that when we raised uric acid in animals, that they developed high blood pressure. And so we thought maybe the uric acid could be playing a role in blood pressure in humans. And so we did a study d- done by Dan Fike. Uh, we published it in JAMA, and what we did is we randomized adolescents with high blood pressure to drugs to lower uric acid or not, and these were kids with newly discovered hypertension. They'd never been on any kind of drug at all. We put them on, um, allopurinol, which is a drug that can lower uric acid, and we had a remarkable, 90% of them normalized their blood pressure when they lowered their uric acid levels.

    7. PAPeter Attia1:58:53

       Was this the study in, I wanna say '09, 74 men who were placed on a high fructose diet and then given allopurinol or not? Or is that a different study?

    8. RJDr. Rick Johnson1:59:05

       That was a different study. Um, so this was a study in adolescents.

    9. PAPeter Attia1:59:09

       Okay.

    10. RJDr. Rick Johnson1:59:09

        They were like 14 or 15-year-old, uh, kids. They were randomized to allopurinol. We had a big effect, uh-

    11. PAPeter Attia1:59:15

        How much blood pressure reduction did you see in the allopurinol group?

    12. RJDr. Rick Johnson1:59:18

        They, the blood pressure completely normalized.

    13. PAPeter Attia1:59:21

        Which was... But what was the starting point?

    14. RJDr. Rick Johnson1:59:23

        Oh, so it was mainly done by, um, ambulatory blood pressure, but also clinic blood pressure. Uh, it was like a five to eight, I, I would say five to eight millimeter drop.

    15. PAPeter Attia1:59:36

        So they didn't really have high blood pressure to begin with. I mean, they were high for teenagers, but-

    16. RJDr. Rick Johnson1:59:40

        Yeah, they were all defined as having high blood pressure.

    17. PAPeter Attia1:59:43

        But if they dropped by eight millimeters of mercury-

    18. RJDr. Rick Johnson1:59:44

        But, but they didn't, they didn't... Right. They, they weren't like 160 over 90 or-

    19. PAPeter Attia1:59:49

        But they weren't even 140-

    20. RJDr. Rick Johnson1:59:50

        It was-

    21. PAPeter Attia1:59:50

        ... right, if they were... How, how, how do we define-

    22. RJDr. Rick Johnson1:59:53

        Uh

    23. PAPeter Attia1:59:53

        ... a teenager's blood pressure?

    24. RJDr. Rick Johnson1:59:55

        There are standards of what, what is considered high. I'd, I'd have to go back to look exactly at what it was.

    25. PAPeter Attia2:00:01

        But that 2009 study where they were given 200 grams of fructose-

    26. RJDr. Rick Johnson2:00:06

        Yes

    27. PAPeter Attia2:00:06

        ... so a lot of fructose-

    28. RJDr. Rick Johnson2:00:08

        Correct

    29. PAPeter Attia2:00:08

        ... with and without allopurinol.

    30. RJDr. Rick Johnson2:00:11

        Yes. Yeah. They, there was, uh, five to 10... No, five, I think.
13. 2:04:50 – 2:11:18

    The potential role of sodium in hypertension, obesity, and metabolic syndrome

    1. RJDr. Rick Johnson2:04:50

       So let's, let's go back to sugar. So sugar is linked epidemiologically with the development of hypertension. Um, there are studies out there where people have put, um, uh, pe- uh, o- overweight people on low-sugar diets and blood pressure comes down. And, uh, there's evidence that, uh, the fructose component is what's driving the blood pressure response because acutely, if you give fructose, blood pressure goes up in a person. If you give glucose, uh, it does, acutely does not. So fructose ac- has something it does that raises blood pressure, and our group discovered that when you give a salty diet to animals, that they actually start producing fructose in their bodies. So salt, salty foods turned out to be another way to stimulate fructose production. And when you give salt chronically to animals, they get high blood pressure, they get hypertrophy of their heart, and they also develop metabolic syndrome. They actually develop obesity, insulin resistance, and everything. That s- may seem surprising because, uh, we don't think of salt as driving obesity. It's non-caloric, but actually, there's data in humans that high-salt diet also increases the risk for obesity and insulin resistance besides hypertension.

    2. PAPeter Attia2:06:24

       But what's the mechanism?

    3. RJDr. Rick Johnson2:06:26

       So the mechanism is that salt increases... When you eat salt, the salt concentration in your blood goes up. And when the salt concentration in your blood goes up, it, uh, activates the polyol pathway. It turns on this enzyme to make fructose.

    4. PAPeter Attia2:06:48

       Which one, the aldose reductase?

    5. RJDr. Rick Johnson2:06:50

       Yes, it turns on aldose reductase, and that helps convert glucose to fructose. And so when you eat potato chips, the, the chips provide the, the glucose, and the salt provides, stimulates the enzyme to convert the glucose to fructose. So french fries are particularly fattening because they have the s- the salt and the carbs that together really turn on this pathway to make fructose.

    6. PAPeter Attia2:07:24

       And how strong is the evidence for that in humans, that, that serum sodium concentration activates aldose reductase?

    7. RJDr. Rick Johnson2:07:31

       Very high. Very... I... That, that data is very strong. The data in humans that, that, um, increased serum osmolality activates this pathway, um, or increased salt concentration in the blood can activate the aldose reductase pathways is very strong in humans. It's very strong in all organisms. It's, um... The aldose reductase is really-

    8. PAPeter Attia2:07:53

       Is it the salt or is it the osmolality?

    9. RJDr. Rick Johnson2:07:55

       It's the osmolality.

    10. PAPeter Attia2:07:56

        So that's why elevated glucose could also do it because-

    11. RJDr. Rick Johnson2:08:00

        Correct

    12. PAPeter Attia2:08:00

        ... when you have someone who's... If you have someone with type 2 diabetes and their glucose concentration is 140 milligrams per deciliter, that's a huge-

    13. RJDr. Rick Johnson2:08:08

        Yeah

    14. PAPeter Attia2:08:08

        ... osmolar load. So even if they have normal salt concentration, that could be activating it. What, what is it about osmolality that activates this enzyme?

    15. RJDr. Rick Johnson2:08:17

        In the promoter region of the enzyme, there's a osmol-sensitive, uh, region that gets activated.

    16. PAPeter Attia2:08:24

        Hm.

    17. RJDr. Rick Johnson2:08:24

        It's, it's a transcription factor called TonyBP, and that activates aldose reductase, and that converts glucose to fructose. And it's a major mechanism, uh, to- that animals use when, when they get dehydrated. Interestingly, that dehydration or, or the increase in salt in when you eat salty foods, when you get thirsty, you've... it means the salt concentration in your blood is high. So the... when you eat salt, the salt concentration in your blood goes up, you get thirsty, and you start making fructose in your body from the glucose you've been eating. And then that fructose appears to be enough that over time it's actually driving the metabolic syndrome as well as sugar. So salt and, and sugar both activate the pathway. When we do it to ani- when we give salt to animals, it takes them a longer time to gain weight than sugar. Sugar's pretty a- uh, quick, but when you give salt, uh, it takes a few more months to f- before the animals really get overweight. And we've done epidemiologic studies in humans, and when salt concentrate- when salt intake is high, it increases the risk for fatty liver and diabetes, for example, in Japanese adults was this one study we did. It increases the risk for blood pressure. It's the salt concentration that's the greatest risk factor for high blood pressure. It's not the amount of salt you eat, it's the how, how salty the food is and how much salt it goes up in your blood. So for example, if you drink a lot of water s- and so the salt concentration go- doesn't go up, then the effect of salt to raise blood pressure is blunted. So we did a study in humans where we gave salty soup with or without water, and if we gave enough water to prevent the salt concentration to go up, we could prevent the rise in blood pressure. So, uh, we know that this osmol pathway, this, this, that salt increases the salt concentration in the blood, that activates this pathway. And if we give salt to animals that cannot metabolize fructose, what we find is they eat the same amount of salt, they get that salt concentration goes up in their blood the same, but they don't gain weight. They don't become obese, and they don't be- and they don't become hypertensive. So that this hypertension and that left ventricular hypertrophy and all these things that are happening are driven in a lot by the conversion of, of glucose to fructose in the body from the salt. And so the salt is work- and sugar are working together, and then they are, it's, th- it's what they're doing to actually, uh, drive the blood pressure response in obesity.

14. 2:11:18 – 2:23:38

    The role of vasopressin in metabolic disease

    1. RJDr. Rick Johnson2:11:19

       Now interestingly, when salt concentrations go up in the blood, so does vasopressin. And vasopressin is a hormone that's produced in the brain that helps to conserve water. And so, uh, when you eat salt or if you eat sugar, vasopressin levels go up in the, in the blood and, uh, f- and the vasopressin's released from the brain, goes up in the blood, and it helps con- uh, hold onto water and, um, to try to help you conserve water. But what we've recently found is that the vasopressin is also helping the fructose to drive fat. And when fru- when you eat fructose or you eat salt, you prod, um... the fructose that's produced from the salt stimulates vasopressin, and the vasopressin actually binds to a specific receptor called the V1b receptor, and that actually is important in driving obesity. And, and if you block that receptor, you can block the effects of sugar to cause obesity, metabolic syndrome, and so forth. So-

    2. PAPeter Attia2:12:28

       I'm sorry. H- H- How, how is that demonstrated?

    3. RJDr. Rick Johnson2:12:30

       So we took animals where we knocked out the different vasopressin receptors, and there's a vasopressin receptor called 1b. No one has known what the function of that receptor was. I mean, really, it's, it's been, been a receptor that's had no known f- real known function. And when we blocked that receptor, we had a remarkable, uh, finding. The animals could eat all the sugar they want, or they could eat salt, but they won't get obese because the obesity pathway is driven through that receptor. Exactly how the receptor works, we, we don't fully know, but it, it stimulates a hormone called ACTH that stimulates cortisol, steroids. It also pr- stimulates the islets to produce glucagon, which is, uh, kinda counters the effects of insulin, and it also, uh, works, uh, to s- upregulate the fructose pathways in the liver.

    4. PAPeter Attia2:13:29

       Where is this receptor found? Is it only central?

    5. RJDr. Rick Johnson2:13:32

       It's central, but it's also in the adrenal gland, and it's also in the islet. And in ob- in obesity, it seems to be expressed in the liver.

    6. PAPeter Attia2:13:39

       How does this effect compare to the, uh, fructose kinase knockouts? So if you took the fructose kinase knockout mice and compared it to the mouse that has normal fructose kinase but just has this receptor blocked and you give them the same amount of fructose, glucose, salt, et cetera, which one is more resistant to the obese phenotype?

    7. RJDr. Rick Johnson2:14:02

       So the fructose kinase knockout tends not to wanna eat sugar. They tend not to, to not like fructose, and so, uh, you have to kind of force them to eat the fructose, but even if you force them to eat the fructose, they'll never get fat. Uh, the V1b receptor knockout like fructose. They'll eat as a lot of sugar, but they'll n- they won't get fat.

    8. PAPeter Attia2:14:25

       So what... how are they disposing of their fructose?

    9. RJDr. Rick Johnson2:14:27

       They're totally regulating, uh, their caloric, total caloric intake. So although they eat more fructose, they'll eat less chow, so they maintain their energy balance.

    10. PAPeter Attia2:14:37

        Right, but how do they not turn into skinny fat mice who are lean because their overall energy balance is fine, but they still get fatty liver disease and they still get diabetes?

    11. RJDr. Rick Johnson2:14:47

        They do not get that. They don't di- they don't get fatty liver. They don't get insulin resistant. They stay normal.

    12. PAPeter Attia2:14:53

        But that's counterintuitive, right? Because you'd think that the... remember, the energy restricted high fructose animals ... were still getting-- They were lean, but they were inside fat, right? They had visceral fat, they had liver fat, they had hypertension

    13. RJDr. Rick Johnson2:15:08

        So remember that the metabolic syndrome is driven through the energy depletion pathway and, and, and the, uh, the actual caloric pathway is still intact. Um, so what, what's happening with th-this is that the, um... Well, what, what we know is that it's down-regulating fructokinase. This is probably the key, key point. The V1b receptor knockout have less-- They don't, they don't have as much fructokinase. They're turning it off.

    14. PAPeter Attia2:15:42

        Why?

    15. RJDr. Rick Johnson2:15:43

        They're reducing the amount. Uh, normally when you eat sugar, you, um, the fructokinase levels get higher and higher. They get turned on by sugar, and the V- V1b knockout doesn't do that. So the fructokinase stays at a low level. So my guess is that some of the fructose is being metabolized by other enzymes like glucose, glucokinase and stuff. But yeah, they, they, uh... What happens is they e-eat normal amounts, and they stay normal weight, and they don't develop metabolic syndrome, but they don't turn up their, their fructokinase.

    16. PAPeter Attia2:16:22

        Interesting.

    17. RJDr. Rick Johnson2:16:24

        Yeah.

    18. PAPeter Attia2:16:24

        Well, Rick, this has been an amazing discussion. We've, we've gone, uh... We've managed to go a lot deeper into things that I think we already covered in some depth in the first podcast, but I, I've certainly learned a lot more in the interval of just two years. Um, and I, believe it or not, think, uh, we got through many of the questions that people wanted to go deeper into. So again, thank you very much for, uh, for, for providing your wisdom as always and, uh, uh, we'll, we'll make sure that the show notes are, um, littered with a lot of the references that we spoke about and in fact-

    19. RJDr. Rick Johnson2:16:59

        Yes

    20. PAPeter Attia2:16:59

        ... some of the things that we didn't know, we'll make sure we track down.

    21. RJDr. Rick Johnson2:17:03

        Yeah. Yes, some of the fact-checking.

    22. PAPeter Attia2:17:05

        Yeah.

    23. RJDr. Rick Johnson2:17:05

        Thank you so much, Peter. It's great seeing you. I hope you can mention the book, you know.

    24. PAPeter Attia2:17:09

        I will mention it in the, uh, I, uh, in the intro, but cl- hold it up again. So we'll, we'll, we'll talk about that, yeah. So the book is called Nature Wants Us to Be Fat, and by the time this podcast comes out, it will already be on bookshelves. And I think the book, which is the follow-up to The Fat Switch, really goes into a lot of the stuff that we talked about today. It goes into this next level of insight around, uh, fructose metabolism, uric acid, uh, byproduct, uh, of that, and the, uh, sequelae of that. And do you mention also the vasopressin link and stuff in, in there as well?

    25. RJDr. Rick Johnson2:17:45

        Yeah, that's in the book.

    26. PAPeter Attia2:17:46

        Excellent.

    27. RJDr. Rick Johnson2:17:47

        The one thing that we might wanna s- point out i- you know, that's a very im-important finding is that when we s-studied the fructose survival pathway, we found that the, the, that the fat produced was not just being used as a caloric source, but it was being used as a source for water because when fr- fat is metabolized-

    28. PAPeter Attia2:18:10

        When it's oxidized, it generates a ton of water, yeah.

    29. RJDr. Rick Johnson2:18:12

        Yeah, it generates water. So animals in the wild, um, when they store fat, they're actually storing it not just for calories, but for water. So the hibernating bear-

    30. PAPeter Attia2:18:22

        Hibernating animals, right. Yep

Episode duration: 2:23:38