Dr. Richard Johnson on the Shocking Truth of Uric Acid, Sugar, Obesity, Liquid Poison, & much more

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Hello, longevity friends. I'm your host, Claudia von Boeselager, and welcome to the Longevity and Lifestyle Podcast, where I invite pioneers and thought leaders in all things longevity and lifestyle to give you the strategies, tools, and practices to live better and reach your highest potential. Today's guest is Dr. Richard Johnson. Rick has been at the cutting edge of research into obesity and, together with his team, discovered the fructose-powered survival switch, a metabolic pathway that animals in nature turn on and off to store fat as needed, but with our modern diet has permanently been fixed in the on position, revolutionizing the way we think about gaining weight. Rick has led for over 20 years research on the cause of obesity and diabetes with a special interest in the role of sugar, fructose, and uric acid. Rick is a professor of medicine at the University of Colorado, author, and is highly cited in top medical journals with over 700 published papers. His most recent book, Nature Wants Us to Be Fat, is out now. In this episode, we dig into the shocking truth of uric acid, uric acid as the underlying cause of diseases from obesity to diabetes, hypertension, Alzheimer's, and more. The keto versus low carb versus other diets. How one bodybuilder ended up in hospital through dietary mistakes. Fructose's impact on leptin, our hunger hormone. The body's own fructose creation process. The poison of liquid sugar, juices, sodas, and more. Testing and modifications to reserve and control uric acid, and much more. Before we begin, please hit subscribe to the podcast to get your weekly dose of longevity and lifestyle inspiration, and share this episode with those you love. I would also love to hear from you, so please leave a comment below or let me know what you think by reaching out on Instagram @longevityandlifestyle. Please enjoy.

Welcome to the Longevity and Lifestyle Podcast, Dr. Johnson. Rick, such a pleasure to have you on today.

Thank you, Claudia. It's really a great pleasure to be on with you.

Rick, I'd love to start with a question on your journey through medicine, if you will, to where you've landed in, in essence, today focusing on the role of sugar and uric acid. But where did the interest and the research curiosity, if you will, come from along your journey?

It really began in college when I was really into anthropology and nature, nature biology, and that whole thing. My father, though, was an academic physician, always wanted me to go to medical school. And he told me that there's a great joy in taking care of patients and that I would enjoy that. And I began to gravitate towards that. I ended up going to medical school, and during my residency where I was seeing a lot of patients, I really enjoyed patient care, but I became more interested in kind of the diseases they were suffering from and why they were getting those diseases. And, you know, there was such a cluster with diabetes and high blood pressure and kidney disease and heart disease and many of these patients would come in with, you know, a list of diseases that were all in this group along with obesity. And so I realized it was a real cluster of diseases. I ended up going into kidney disease mainly because I just found that particular group of diseases interesting. I started doing research trying to figure out what caused different types of kidney disease. I became intrigued with high blood pressure because high blood pressure is a problem of the kidneys. The kidneys have trouble excreting salt. And a lot of people handle salt really easily, but if you develop this kidney alterations, then you can't excrete the salt very well, and then you can develop hypertension. So I became interested in that, came up with the idea that maybe there was subtle acquired damage. And when we created subtle acquired damage, suddenly the animals developed hypertension just like humans. You're salt sensitive and everything, and a normal animal, you could give a lot of salt, no problems. But once you created this lesion, it was very, very similar to what we see in high blood pressure. And this became one of the main theories for what could cause high blood pressure. And suddenly I was kind of like leading this field. And the question was, okay, Rick, subtle kidney damage might cause high blood pressure, but what causes the subtle kidney damage? And it's sort of like you go from one step to another. And there was a big association of uric acid with subtle kidney injury and with hypertension. And uric acid is the substance that everybody makes. You know, you make it when you break down DNA and RNA, you know, what's in our nucleus, and also it's a breakdown product of energy. So when we, you know, make energy, it's called ATP, and when you break that down, it gets broken down to uric acid. And when it builds up in the blood, it causes a disease, gout, which many people suffer from. It particularly increases as we get older, and especially men, but a lot of older women will get it too. And it's Inflammatory pain arthritis, and often the big toe. Many people view it as a nuisance because you can treat it and, you know, it's incredibly painful, but you treat it and after 2 weeks you're fine. But it's also associated with high blood pressure, and most people with gout actually have low-grade kidney damage. There was one study that found like 95% of them at autopsy have some type of kidney disease. I thought, wow. And it was also extremely associated with high blood pressure. And there are a lot of times when the onset of gout is associated with the onset of hypertension. And so I thought to myself, well, you know, maybe, maybe gout is somehow involved in hypertension. And I was thinking that it was the crystals in the uric acid that not only— when the uric acid gets too high, it forms crystals in the joints. And I thought, well, maybe they're crystals in the kidney, and there were some reports that you could find uric acid crystals in the kidney. I thought, well, that could cause low-grade inflammation, and maybe that's the cause of hypertension. Big question. So what we did was we raised uric acid in animals, and they developed hypertension. And I go, what? People should know this already. I mean, it's been around. But, you know, there were like 25 studies showing that if you had a high uric acid, it predicted the development of hypertension. And here we took these animals, we raised their uric acid, and they developed high blood pressure. So we said, okay, there's going to be crystals in the kidney. And we looked and there were no crystals. And now we go, oh my God, so what have we discovered here? When we first did this, I made my fellow, who was a Brazilian doctor, I made her do like 100 animals because I couldn't believe that the data would be real, that it was real. But it was. And so Suddenly we kind of had discovered a major mechanism for high blood pressure, at least in the animal. So we wanted to show it in people, and a young doctor named Dan Fye came into my office, and he was working with adolescents. He was a pediatrician, and he had a clinic, these overweight adolescents that would come in with high blood pressure. And we had found evidence that the high uric acid could cause high blood pressure on its own, But over time you'd get kidney damage, and then once that happened, then you could even correct the uric acid, but the blood pressure would stay high. So it was a two-step process. The uric acid caused high blood pressure, but then the kidney disease that occurred from the high uric acid also could cause high blood pressure. And so we knew that once you had the kidney injury, that the uric acid lowering, it wouldn't be of so much benefit. But if we got it early, it might. And so when these adolescents who had never been treated for high blood pressure. They come in with high blood pressure. They couldn't have had it too long because they're adolescents. And so we studied them, and the relationship between uric acid and blood pressure was like linear. It was better than the animals. And then Dan did a study, you know, with me— I was his mentor— where he lowered uric acid in these adolescents and their blood pressure corrected to normal. And this was a big discovery. It was published in the JAMA. And sort of changed the way we think about blood pressure a little bit. And so suddenly we realized that uric acid was very likely a cause of hypertension. And there are definitely people who challenged it, but I think that the data continues to be strong that it is. And so then the question was, okay, uric acid is driving blood pressure, but what's driving the uric acid? And there was some thought that, you know, it could come from things like purines. Purines are these substances that are in a lot of foods. It's particularly in beer, and alcohol also can make uric acid, but the brewer's yeast in beer is really powerful. So beer has both alcohol and brewer's yeast, so it tends to drive the uric acid up, and certainly beer is associated with hypertension. And there are other foods, you know, there's some classic foods I like. Certain red meats, for example, can do it, and some other foods, particularly like shellfish, shrimp. But there's another source of uric acid, and that is sugar. And at the time, you know, most of the rheumatologists were focused on the purines, and no one was really talking about sugar. But there was this big relationship of sugar with uric acid. And table sugar is actually a carbohydrate, right? And it's a glucose and fructose molecule that are bound together. And so it's two sugars combined, and we call it sucrose or table sugar. And we love sugar because it tastes so good, right? We have sweet receptors on our tongue and we love sugar, and we put it in a lot of foods. And also there's another sweetener called high fructose corn syrup, and that's also a mixture of fructose and glucose. And we love that because it's a liquid and it can be mixed into foods very easily. And the food industry knows that. So it turns out that when you break down fructose, you generate uric acid, and uric acid is produced and it goes up in the blood even. And actually, the old physicians of the 1800s, they knew about this association of sugar with gout. And so it was actually in the old books, but it really wasn't in the current books. Now it is. Anyway, so when I look at uric acid levels have been rising in the world, but particularly in Europe and the US, it had been increasing linearly from about 1700, and then it kind of took off and went up exponentially in the last— between 1970 and 2000, it really went up. And so the sugar intake has been going up, and we went from about 4 pounds of sugar a year in 1700 to about 150 pounds a sugar person in 2000. And so it correlated with the rise in uric acid and with the rise in blood pressure. And so we said, aha, this might be it. So what we did is we gave sugar to animals and their uric acid went up and their blood pressure went up. And we lowered the uric acid with a drug and the blood pressure came down and everything looked just like what we expected. Except that when we lowered the uric acid, we also improved the obesity that developed. They became less fat. There's less fat in their blood, what we call triglycerides. They had less fatty liver. They had less insulin resistance. I mean, it didn't make it go away, but it improved it significantly across the board. And then suddenly I realized that uric acid was a little bit more important than just blood pressure. And blood pressure is pretty important, but I mean, this was like directly involved in this. And also when we started looking at it, made us realize that fructose was really important. And so we started studying fructose and we said, okay, you know, is it the fructose or the glucose that's doing it? And when we gave fructose to animals, they developed this whole metabolic syndrome. Especially if we gave it in the drink and this whole thing of the metabolic syndrome was clearly present, they became insulin resistant and diabetic over time and the whole bit. And we could reduce that or improve that by lowering the uric acid. So the, you know, the first thing that struck us was we said, well, geez, you know, uric acid isn't in the caloric pathway. I mean, when you eat fructose, you make calories But uric acid is like this spinoff. It's like a little waste product that comes off in the very beginning, and it's not, you know, if you block the breakdown product of this spinoff, the actual caloric pathway is still going. They're still able to metabolize fructose. You're just affecting a little metabolite. So it told me that the way fructose was working couldn't just be through its calories. And you know, sugar only has like 4 calories per gram in certain foods like Fat have 9 calories per gram, and that's why the world at that time was thinking fat was the cause. But here was this evidence that it wasn't the calories, and all these people were beginning to debate, is it calories or not? So we thought, well, I know how we can test that. What we can do is we'll take a group of laboratory rats and we'll give them fructose, or we'll give them some kind of control diet. And we'll force them to all eat the same amount. And the way you force them to eat is you line them all up, they each get their own cage, they each get— the first day they all get as much food as they want, and then you measure how much food everybody eats, and the guy that eats the least, that's the guy that everybody has to eat the same amount that he does or she does. What you do is you find out who ate the least and then the next day everybody only gets that amount. And of course many of them would like to eat more, but there's no extra food, so they're all eating the same amount. We've done those studies like 5, 6 times, and every time we get the same finding that the fructose, it drives obesity and diabetes and so forth independently of the calories. It's not through the calories that they become insulin resistant, fatty liver, and so forth. There's one thing that is driven by the calories, and that is their weight. And so the amount of weight and the amount of fat they get— so it turns out that when you give sugar or fructose, they actually become hungry. So it doesn't satisfy, doesn't make them feel full, so they start eating a lot more food. And it's because they become resistant to a hormone called leptin. And normally leptin is this hormone that's released and it says, hey, you're full, okay? You're full. And if you're full, then you tend not to eat more unless you're bored or fidgety and you're eating not because you're hungry, but because you're stressed or something. Comfort food. Yeah. And that can be a mechanism to eat, of course. But one of the main things that drives food intake is hunger. So if you eat a plate of food and you're still hungry, you're going to go back for seconds. And so hunger is a really important thing. So when we gave the fructose, the animals became hungry, but they couldn't eat because they were pair-fed. So it turns out that they still became insulin resistant, they still got fatty liver, they still got hypertension, they still got elevated lipids in their blood. Compositionally, they were changed to a kind of a fat animal, but their weight gain is related a little bit to how much you eat. So if you do eat a lot more, you'll gain weight. Now there's also, they drop their energy metabolism, so they gain a little weight even though they're not eating any more food than the other guys, but because they're burning less, they gain a little weight because they're not burning off as much. But that's a very small amount. Over a year would make a difference, over 2 years it would make a difference, but over 3 weeks or a month of this study, it's not enough. So what drives weight gain is primarily eating extra food. So there's a twist. Sugar, it works independently of calories, absolutely, but it makes you hungry so you eat more, and that's where the high-fat diet diet comes in. Because, for example, if we gave them sugar until they became leptin resistant, okay, so now they're hungry. Now we can remove the sugar, and if we put them on a high-fat diet, they rapidly get fat. And the reason is, is because they are leptin resistant. But if you give an animal and you don't give them the sugar, and then you put them on that same high-fat diet— this was a lard-based diet, there was like minimal weight gain.

Wow, that's really incredible. I mean, I didn't— never heard that one before. So that correlation as well to understand and the trigger with leptin.

Exactly. So like, if you're on a low-carb diet, you can eat a high-fat diet because you're not getting that fructose and you're not going to really gain weight on a high-fat diet. And because you're on a low-fructose diet, low-carb diet, you know, it's a good way to lose weight, as you know. Yeah, the keto diet. But you can eat all that fat, but if you give the high fat with sugar, now you've got a problem because the sugar makes you eat more, but the high-fat diet is like 9 calories per gram. So one bite, you get a lot more calories. So, you know, what was cool about this research was that it allowed us to explain this, you know, the law of thermodynamics and the whole bit of What goes in has to equal what comes out, or if you put more in and there's less out, you retain it. I mean, the laws hold, but there's also this huge mechanism that's independent of calories, and that is the composition, you know, becoming diabetic. So actually, going back to this experiment, this is one of my favorite stories to tell. One time we did this, we did all the animals, you know, where they were all being eating the same amount. And remember, they can only eat as much as the guy that eats the least. And I was talking to my friend Carlos who was running the study, and I saw the data and I go, wait, these guys are really eating very little. I mean, they're eating like much less than a normal rat. He says, yeah, he said there was one rat that wasn't eating a lot, so they all have to eat that amount. And then we looked and we realized that animal had cancer. I mean, of all things, the poor guy had cancer. So he was eating much less. So everybody was like on a severe diet. But the ones that ate sugar still became diabetic. And so it turned out to be an amazing study because they were on a pretty severe diet, but we could still create fatty liver, diabetes, and so forth, proving that even if you're on a diet, you can restrict your calories, but if you're eating a lot of sugar, you're in trouble. And I had a young lady who was a friend of mine who was a bodybuilder at that time. This was when I was in the University of Florida, and she was like a professional bodybuilder, you know, and lifting weights. But she was doing this kind of carb loading and eating a lot of sugar, although she didn't eat much total food. And she got into the same problem where she got high blood pressure, fatty liver, all that, had to be hospitalized actually. And then, wow, and yet she was on a caloric restriction diet, you know. So that's sort of how it happened. And then I became interested in, you know, it turns out that humans have higher uric acids than most animals. And I was saying to myself, well, if uric acid is a bad guy and it's causing high blood pressure and all these things, then why do we have a high uric acid? And I kind of went back to my anthropology roots and I started reading about it and wondering You know, it's a correlation, right? Yeah, why is this? And so that took me into evolution and anthropology, and also I started realizing that, you know, if fructose does this thing, there must be some reason that it does that, or there must be some benefit. And I started realizing that animals in the wild need to sometimes gain weight as a mechanism when there's no food around. Suddenly my research moved into studying hibernating bears and hibernating squirrels, and I started doing things with anthropologists and resurrecting extinct genes and all this kind of stuff. And so my little world where I started off as a kidney doctor, you know, really, really expanded out. And what I've learned, you know, is that when you go into a field that you're not an expert on, find experts in that field. To work with and then bring in the ideas that you have that maybe they haven't seen because it's kind of coming from outside their field. And then you join forces and you can break through. It's a spectacular way to make discoveries because you come into a field where they've been preset about the way they think, but they know a ton of information. And then you come in with new information from outside the field and then you work together and then you can make progress. So that's sort of the story, and it's also kind of like the discovery. And one of the things that became really apparent was that fructose was activating kind of a— it was like an orchestra. It wasn't just increasing fat, it's a whole orchestrated events where there's development of insulin resistance, inflammation, rise in blood pressure, and they're all meant to be beneficial for an animal that's preparing for a time when there's no food. And this was a really kind of big insight that it was actually more of a survival switch the way it was meant. So, you know, when you eat glucose, it's more like instant energy. You use it to produce energy. But when you eat fructose, it's really to produce stored energy. And the way we kind of discovered this was we had to kind of understand how the fructose worked first. And what we found was that it's all about energy. Everybody uses energy to do everything we do. I mean, to think, to walk, to talk, to run, to bicycle, to work, to drive. Everything is driven by ATP, which is this energy we produce, and we produce it primarily in these things called mitochondria, and they are like little factories in our cell. We got thousands of batteries.

Yeah.

Yeah, and they're like a little battery and they generate energy. And interestingly, they're the main source of energy and they produce a lot. And then the energy, you know, that they produce, this ATP, is kind of immediate energy. We have to use it. And you can also make stored energy. So stored energy would be like fat. So fat produces energy when it's burned. So if you don't want to make immediate energy, your body could theoretically make stored energy. Energy, and that would be fat, or you can also store carbohydrates. In plants it's called starch, but in humans it's called glycogen. But you can't store that much glycogen. It's pretty much an energy for acute things like running and exercise. I mean, you can burn it off, but the fat is kind of a longer, bigger energy source that can last for days and months or longer.

A summer lifetime, I guess.

Exactly. So what we realized that there was this balance where, you know, energy is being either made immediate energy or stored energy. And what we learned was that fructose tended to shift it to stored energy, and glucose wants to produce mainly immediate energy. And the way it worked turned out to be pretty cool. Whenever you make energy, you have to consume a little energy in the process. So when you eat food, which is an energy source, there's a cost. To digesting it, to absorbing it, and then to metabolizing it. So there's a small cost that comes with trying to take what we eat and then turn it into energy. But fructose has a system where it tends to drop the energy quickly. When you break it down, there's an immediate use of ATP where the reaction is so fast the ATP level can fall inside the cell. So normally you have this energy in your cell, the ATP, and when you metabolize the fructose, it drops a little bit, and that doesn't really occur with other nutrients. And when that drop occurs, it activates a reaction that keeps the energy level a little bit low, and the way it does that is through this generation of uric acid, and the uric acid acts on the mitochondria themselves to keep the energy level down a little bit, and it does it through a thing called oxidative stress, and when it does that, it keeps the energy production down a little bit. And so what happens is the cell normally wants to have a good energy level, and if you drop it like by 20%, you don't want to drop it too far, but if you drop it like a little bit, the cell reacts to that by activating this switch. And it's sort of like a mayday signal. It's sort of like creating the concept that you're at risk for starvation. It's sort of like placing you at risk. Your energy's low, you better do something, you better start storing food, you better start looking for food because your energy level's low. But it's a false thing because you actually can have a lot of fat already, but the body thinks that there's not enough food around, so it stimulates hunger, it stimulates foraging, it stimulates the production of fat, it stimulates the reduction of not burning the fat. It stimulates insulin resistance. And you say, well, no, why is insulin resistance a survival factor? It causes diabetes. Diabetes causes death. But insulin resistance, before you become frankly diabetic, helps animals when they don't have a lot of food. And the reason is we use glucose in our blood for fuel. It's like our main carb fuel. When the glucose is in the blood, so if you think that you don't have enough glucose or you're at risk of starving, You'd want to preserve that glucose mainly for the brain because it's the brain that does the thinking, and if you can't think, you're pretty much dead.

That's it.

So if you're insulin resistant, what happens is you preferentially save the glucose for the brain. And the way it works is there's some tissues are insulin sensitive and some tissues don't require insulin. And so like the muscle really requires insulin to move glucose into the muscle. And that way the muscle can use the glucose. But if you're insulin resistant, less glucose gets into the muscle, and so there's more glucose to go elsewhere. And most of the brain does not require insulin. So because it doesn't require insulin, the glucose can go into the brain easily. And when that happens, then you can keep going even if you didn't have enough fuel. Insulin resistance is a survival mechanism. So what animals that eat fructose, they use this to gain weight. Because now they don't recognize that they carry all this fat already. They think that they're starving, and so they eat more, and there's actually a biologic shift where the mitochondria makes less energy, immediate energy, so the calories can go to stored fat instead. So it shunts the energy coming in to fat as opposed to immediate energy. So you don't produce as much energy, you can become tired actually, and you become lazy. In fact, when we give fructose to animals, they start hanging out. They get fat and they just sit and become couch potatoes. And if you put a laser light, you can actually record their movement and you can prove that they're just hanging out. They're not active anymore. So they become less active, they burn less energy, but they're eating more. So it's— the food's going into fat Yeah, it's a downward spiral. And so the problem is, is that there were two problems. One is we have this high uric acid, higher than most animals. So it turns out that we are particularly sensitive to this pathway, so we can become fat easier than many animals. And so we have this genetic issue, but we also are eating a ton of sugar. And so the sugar and high fructose corn syrup is everywhere. We're eating about 15% of our diet of this stuff. Some people are eating 25% of their diet is sugar. And so that's like way too much sugar. Yeah, too much fructose. And we're genetically wired, and so we get into trouble. That is really the key. So like if you're a bear preparing for hibernation, you eat all this sugar, the fructose in the berries, to gain that fat and become insulin resistant. And you are fat, but then you fast, and then in the spring when you wake up, there's not so much fruit around and you have to eat other things. And so it doesn't really happen until the fall when suddenly all the fruit comes out and then you eat it, and it's this brilliant thing. Same thing with migrating birds. They'll stay thin and normal during the summer, then in the fall right before they migrate, they will start getting really fat, and it's been linked with a change in diet where they're eating a lot more.

Yeah, like the hummingbird, right? Drinks all the nectar, which is the fructose as well.

Yeah, that guy, he eats the sugar pretty much all year, and he becomes fat during the day and actually gets fatty liver and diabetic, and then at night he burns it off. It's— yeah, they're an amazing animal.

Beautiful as well. Um, I saw a statistic which I find so shocking, that about 60% of supermarket products in the United States contain fructose, which just shows, I mean, it's this vicious cycle that it becomes more addictive. You want more of it. You're having insulin spikes and then drops. You're exhausted. So you look for more sugar and it's hiding in so many things. I mean, I've even looked at bread and I was looking that they put sugar in bread and I was thinking, you know why?

It's just exactly.

It's really reading the labels. And I think it's so important. And also the gram serving sizes. Right. So some of the tricks are to just say like, oh, there's only 1 gram of sugar, but actually the sugar is per 20 grams. Serving. Yes, it's so important to keep your eyes up. But would you say that glucose is a lot less detrimental for our health than fructose?

This is the other big thing to bring up in this podcast, is that, you know, so initially all our work focused on fructose and the uric acid. And, you know, I thought according to this, we could eat a potato and we wouldn't get fat because there's not much fructose in the potato. We could eat rice and we wouldn't get fat, or we could eat a lot of different kinds of breads. But there was something that was telling us, you know, that that's not the case. I mean, the low-carb diet is a low-carb diet for a reason. And, you know, I was on an interview actually with this guy Jimmy Moore, and Jimmy said, you know, I tried just reducing sugar, it wasn't enough. And so we started wondering what's wrong with our hypothesis. And so what we did was we started feeding animals just glucose. And we had this insight when we were doing it, and the insight is that the body can also make fructose. Up to this point, we were always thinking that it was the sugar we eat that was the problem, yet it's been known for 50, 75 years that the body can make fructose too. There's only one way that the body can make fructose, and it's to make it from glucose. Glucose. And it turns out there's an enzyme, we call it the polyol pathway, and it converts glucose to fructose. But normally that enzyme's not around much. I mean, it's very low, but it can be induced, it can be stimulated. And one of the ways to stimulate it is with high glucose. So if the glucose goes up in the blood, it will stimulate the production of fructose. So we were thinking about this, and we knew that humans make a lot of fructose when we're diabetic. Because our glucose levels are high. But we realize that if you eat a high glycemic carb like a potato, that if you actually measure your glucose with a continuous glucose monitor, that the glucose will go up in the blood a bit. We call it a high glycemic carb, is the nickname for it, because it raises the glucose and that stimulates insulin. A lot of people were focused on this carb-insulin pathway as being the mechanism for obesity. But another potential thing could be that it's still the high carb, but it's converting the glucose to fructose that's the problem, because fructose activates the switch. So what we did is we gave glucose to animals, and it was a very nervous experiment because, you know, I had been writing and telling people it was fructose, and these animals started to get fat and really insulin resistant. And we, you know, I thought, oh my God, there are probably two major mechanisms unless this fructose is being made. And when we looked in there inside them, they were making a ton of fructose and it was quite remarkable. And they were making in their liver and even in their blood, other tissues too. And so you could make fructose in the brain from a high glycemic carb. And so that turns out to be bad because fructose in the brain turns out to be a big problem and might be involved in things like dementia. So then we said, okay, well, how are we going to prove what's causing the problem? And we were able to make animals that genetically could not metabolize fructose. So these were called knockouts, where you remove a gene that's involved in fructose metabolism, but they could still metabolize glucose, they could still make insulin, you know, so that part was normal. It's just they couldn't metabolize fructose. And when we fed those animals glucose, they were really protected. They weren't fully protected, they were completely protected from insulin resistance, completely protected from fatty liver, but they did gain a little bit of weight. So there was definitely an insulin pathway involved as well. So then we started doing other studies, like we gave high fructose corn syrup or like soft drinks, sugar, and we found that, you know, even though they were getting both glucose and fructose together, if we blocked fructose, just fructose, that was enough to completely really, really block the development of metabolic syndrome. So then we realized the way soft drinks are working is that the fructose is bad and the glucose is bad, and actually, you know, the glucose accelerates the fructose absorption, the fructose is accelerates the glucose absorption. So they work together, and they're both bad, but they're working through fructose primarily. So the glucose gets converted to fructose, and so that turns out to be probably how high glycemic carbs cause obesity. I mean, it looks very much like that, and now there's some confirmation studies going on in humans, and so I think that's going to turn out to be the mechanism.

And then, uh, groundbreaking research, I mean, really incredible. Your curious minds, if you will, has led you on this incredible path to human discovery and the different triggers. And I guess, as you were saying, you know, looking back at anthropology and the early humans, it was obviously necessary back then with the lack of availability of food, but with diets and overeating that society has these days, it's so detrimental. Can you talk about some of the health consequences? I mean, we talked about obesity, obviously metabolic syndrome will hit on this, but what about things like mood and behavior to also dementia?

Oh my gosh, yes. So as we realized that this was a whole orchestra of events, like foraging, we realized that foraging is actually a specific set of behaviors. Foraging is when you're looking for food, but when you're looking for food, it's under a situation where you think that you're potentially starving, so you have to move fast, look around different areas, you have to be constantly vigil. You can't focus on anything for any period of time. You have to be looking at the whole environment, and you have to be ready to make quick changes, quick moves. So there's a little bit of novelty seeking because you'll go into areas you've never been. You've got to be brave, and you've got to be potentially aggressive if you find— if you have to fight for the food. And so it turns out, like, if you activate this process— and we started wondering, well, how does it work? And we looked at how the fructose works in the brain to do this, and it turns out that it starts to affect the same areas of the brain where disorders like attention deficit occur. And we realize that attention deficit is sort of a foraging response because you having to— you can't concentrate on any one thing for very long. You know, you're constantly moving and thinking about things. You have to be a little hyperactive. And the interesting thing is the way this fructose works is that it increases the energy, it allows you to have that movement and to be hyperactive to find things, but when you rest, you actually reduce your resting energy metabolism. So at rest, you spend less energy, you're kind of like really quiet, but then when you do look, when you're active, you're actually allowed to forage So it's sort of this interesting balance that fructose does. But we realized that it was very involved in behavioral disorders, and then we started looking at dementia. And, you know, I've been talking to David Perlmutter a lot about this because he's a neurologist. Again, you go to the expert when you need to. And so it turns out that fructose levels are high in the brains of Alzheimer's patients, that the enzymes involved in the production of uric acid are high. In the brains of Alzheimer's patients. In patients with Alzheimer's, the earliest abnormality is a thing called insulin resistance of the brain. And I told you that much of the brain, you know, doesn't require insulin, but things like the memory centers and so forth, those are insulin sensitive. So there are certain regions of the brain that require insulin, and they become resistant. And that's what fructose does. It's been shown to cause insulin resistance resistance to those areas of the brain. So fructose doesn't want you to remember everything perfectly, because if you're going to go out there and forage and you're going to go into an area where there was a predator, you don't really want to have vivid memories of that predator when you're going back in there. So it turns out that the effects of fructose on the brain, on the memory and so forth, are very similar to what you see. You see insulin resistance, you see inflammation in the brain, you see abnormalities in the mitochondria where they're making less energy. This is exactly what fructose does, and fructose is elevated there. And the risk factors for dementia are things like high glycemic carbs, obesity, diabetes, sugar, you know, and salt. We didn't talk about salt. Maybe we can do another talk on it sometime, but salty foods also can activate this enzyme, the polyol pathway. So if you eat salted French fries, they're more dangerous than French fries. Without salt, and it's because of this very similar thing. And high-salt diets have been associated with Alzheimer's. So all the risk factors fit. And then if you give sugar to animals or high-glycemic carbs to animals, they actually have trouble walking, going through mazes and stuff like that. So the whole story fits. I think that we're going to find out that this very important disease has a dietary basis, and that the best we can do is to be aware of this. And, you know, one of the things about my book, which I will say—

yes, and I'd love to touch on that exactly.

Yeah, once you understand how this works, you can design diets that are healthy, and many of them are, you know, touch base on what people are doing right now. Almost all the diets that work out there, you can show how it interacts with the switch And so the book sort of brings together a lot of different diets, but it also has additional things because, you know, we talk about the benefit of water.

Let's talk about your wonderful book that's coming out soon. So Nature Wants Us to Be Fat. And can you explain some of the dietary— so we've obviously touched on a lot of the fascinating science and that this is really such a breakthrough, Rick, what you've discovered with your team and colleagues, of course, but What are measures that people with wide range of diseases that we've touched on, which I think is so fascinating that it all comes down to this uric acid levels, but what are some dietary restrictions? I mean, is fructose obviously associated with fruit? So is all fruit bad? Juice versus eating, you know, blueberries?

When we go through it, there'll be many ways that diets would be beneficial, right? So intermittent fasting would be good, a keto diet would be great, low-carb diet, a high-protein you know, carnivore diet. Each diet has some benefit, and you can see that, but it's possible to design a diet that incorporates all these kinds of things, and we talk about that in the book. But in essence, the first question is, do you want to have a diet that's, you know, restricts a whole food group, or do you want to have a diet that will allow you to eat some carbs and some proteins and some fats. And, you know, so for me, I think it's easier if people can eat a diet that has some features of all. And the goal is to become metabolically flexible. That's my friend's term, which means that you really, you want to get healthy where you can eat carbs or fat and your body can use them, kind of like when we were kids, when you thought you could eat anything and do anything. My dream is to try to identify a diet. I love the keto diet, okay? And there are many of these diets I love, and you'll see why when you read the book, and we talk about those. But my long-term goal is to have a diet where people don't have to be restrictive so much in terms of the big food groups. So, you know, the first rule is liquid sugar is the kiss of death. Liquid sugar is the kiss of death. I mean, Rob Lustig probably would say it even better, but the problem with liquid sugar is you absorb it very fast and then the fructose hits the liver in a wave, and it's the concentration that knocks the energy down. It's the metabolism, it's how much gets there at that moment. So if it trickles in the effects are much less than if it comes in on a whammy.

And so that's— so does that's orange juice concentrated?

Yeah, juices, juices. Yes. So the very first rule is no liquid sugar. Don't add sugar to your coffee. Don't add sugar to your tea. Don't drink lemonade. Don't even drink apple juice. Number one. That's it. Now the number 2 thing is natural fruits in small amounts are actually healthy. So we didn't get a chance to talk about this, but intestine kind of is— acts as a shield for small amounts of fructose. It blocks that fructose from getting to the liver. So a small amount of fructose, like 3 to 4 or 5 grams of fructose, is nullified in the intestine. Data is clear. So it means that you can eat a fruit you know, that has like 4 or 5 grams of fructose pretty much safely. Now some fruits have 8 to 10 grams, and I have a table, and so we'll have to kind of talk about, you know, we talk about that, but basically some fruit is actually good, okay? And we actually did a clinical trial in people where we did a low sugar diet with or without fruit supplements, and you can read about it. Anyway, so—

I think it also depends on the glycemic index of it, so like a— Right! Ripe banana versus some blueberries.

Oh yeah.

You know, for your gut health, right? So they eat the rainbow each week. So you want to hit like 30 different colors, and it can be some fruit as well. But I'd say, you know, on an apple, let's say if you include the organic apple, of course, if you include the peel, right? So you're getting some fiber there as well. I guess there's more of a tartness to it than high fructose.

Yeah, you're right. Like a banana— like, I have a glucose monitor because I want to know which foods raise my which don't, and it's a fantastic tool because not everybody gets a high glucose response to a food. For me, I can't eat bananas because I get that big high response, but some people can, and of course if you eat a greener banana, you won't get the same amount of sugar, so it's all a little bit, and then, you know, some things like a bread, high glycemic bread, I can't eat that because my glucose levels go up too much, But if you put avocado on it, for example, it slows the absorption so the glucose doesn't go up very high, and I think it's a lot safer. You know, so there are all these tricks. We talk about it in the book, and in general, you don't want to eat a lot of high glycemic carbs. So bread, rice, potatoes, chips, cereal— you have to be careful with those. Probably should avoid them for the most part, but it's often hard to. But there are tricks. And then, you know, protein is great. There's some proteins that— what we call umami foods— that can make a lot of uric acid. So you got to be careful with those: shrimp and shellfish, sardines, anchovies, some of these dark meated fishes. And, or they have a lot of nuclei, and so it's the nuclei that really has that RNA and DNA— actually DNA— but these tend to raise uric acid a little bit more. So you have to be a little careful with that. But basically, you can eat a balanced meat. Fats in general are good, although I'm not a big fan of the omega-6 vegetable oils.

I don't recommend that whatsoever.

Yeah, yeah, I think there's more and more data that there— but you know, so you'll see I try to include, you know, discussions of all these major diets that are out there and how I can interpret it in relation to what we've learned. So yeah, and drinking water turns out to be a great move. Drinking water is something that I just totally recommend— 8 glasses a day. You can get water intoxicated. Do not drink 25 glasses of water, you're going to be in the emergency room. You can read about it, but you can certainly drink 8 to 10 glasses of water a day. The average person—

great. Yeah, for the brain as well, and dehydration and grogginess, I think And most people don't realize that they're chronically dehydrated. I know, I think, you know, the 2 glasses of water in the morning, filtered water with fresh lemon. I mean, no, perfect day, you know.