Lower Uric Acid to Prevent Degenerative Diseases, with Dr. David Perlmutter @DavidPerlmutterMD

Foreign. Hello and welcome to this episode of the Five Journeys podcast. Live. Like you matter. I'm Dr. Wendy Trubo. My co host is Dr. Edward Levitan. And I'm always saying this, but our guest today is Dr. David Perlmutter. And I am so psyched to interview him.

Me too. Me too. Me too.

Well, I'm psyched to be here.

Delighted. So let me tell our listeners, I don't know who'd be listening to our podcast who wouldn't know about you. But let me tell anyone who's listening. He's a board certified neurologist. He's a fellow of the American College of Nutrition. He's a frequent lecturer at symposia sponsored by institutions including the World Bank, Yale, Harvard. He serves an associate professor at the University of Miami, Miller School of Medicine. I've seen him speak, he's brilliant. He's also a five times New York Times best selling author who has published books such as Brainwash, Grain Brain, Brain Maker, and his latest book, drop Acid. So of course you have to tell us, like, how'd you come up with that title and welcome.

Well, no, first I gotta tell everybody that I'm a groupie.

Yes. I'm a groupie of a leftio. And you're. He's a groupie of definitely.

Well, there you go. The title came from, you know, we wanted something snappy, attention getting, and it has to do with dropping acid. The specific acid acid we're talking about is something called uric acid, which is, you know, what we all learned about in relationship to things like gout and kidney stones. And now we know. Brand new research that was just published in 1898 reveals that uric acid is a much bigger consideration than just related to the gout in your big toe and kidney stones. So it's a fascinating story. Beyond that, what I find so intriguing about it is it opens the door to have a new lever to pull in terms of helping people regain their metabolic health.

So let's talk about that. What is uric acid? Do you look like you had a question, Ed, before we jump in?

No, I'm just excited too.

Well, we've already jumped in as well. So uric acid is, we've previously considered to be sort of a metabolic end product or waste product that when we would digest certain things like the DNA and RNA in the foods we would eat, for example, that became what are called purines, that ultimately that would form this acid called uric acid, and it would accumulate and we would ultimately excrete it through the kidneys. And, you know, you guys learned it, I learned it. And if it wasn't excreted appropriately or in good enough quantity, we would develop these crystals that would form in various parts of our bodies, like the toe, like actually the coronary arteries and even the prostate gland. That's kind of new information. So we considered it the end product. We didn't pay it much heed. Maybe we spent one lecture in pharmacology to learn how to get rid of uric acid, for crying out loud. But we now recognize that it is. We've known for a while, for decades, that we see it elevated in conjunction in association with things like hypertension, insulin resistance, full blown type 2 diabetes, and other metabolic issues. And we thought, well, isn't that interesting that uric acid happens to be elevated in these conditions, Therefore, these people are at risk for gout. But in more recent years, we've learned that it isn't just happening to be elevated in these individuals. It's actually playing a role in causing the very metabolic issues that I just mentioned. So one study that came out of a paper that came out of a collaborative study from Japanese and Turkish researchers called, the title says a Lot Uric Acid in Metabolic Syndrome. From Innocent Bystander to a Central Player. And that is a major shift in how we conceptualize uric acid, that it's not just happening to be elevated, but it's actually leading to these issues that we dreadfully fear, that we really recognize are playing such a central role in chronic degenerative conditions that the World Health Organization is telling us are the number one cause of death on our planet right now. Not Covid, not trauma, not war. It's the chronic degenerative conditions, the diabetes, the Alzheimer's, the coronary artery disease, et cetera. These are at their core caused by metabolic mayhem, if you will. And now we recognize that uric acid is playing a functional role in leading to that metabolic mayhem. Therefore, we should ask ourselves, well, why is uric acid so elevated these days, number one. And once we understand that, then how do we implement strategies to help people bring their uric acid levels down to better levels, to safer levels? We had said to people over the years that, you know, a normal uric acid level is anything under 7 milligrams per deciliter. But again, that number was derived in the context of gout, meaning that above 7, you are at much higher risk for gout. Above 7, uric acid tends to precipitate in the blood and form the very crystals that lead to things like gout, et cetera. But now we know that our goal should be actually much lower levels of uric acid below 5.5, above 5.5, we start to get into various mechanisms that are dangerous to the human body. And we'll talk about those in specific, from the perspective of they're really cool. A and B, we can do things to help in those mechanisms that can help people be healthier.

I have a million questions, I have.

A million questions, but go for it.

All right. Age before beauty, I guess.

So.

You referenced, now you kind of referenced this is a problem. Now, has it always been a problem, we just didn't recognize it? Or is there something in our environment that's altering our response to uric acid and making it much more harmful, prevalent?

Well, the response to the elevation of uric acid is nothing new. I mean, that's a genetically programmed part of our physiology. And we'll get back to that in just a moment because it actually is a survival mechanism. Who knew? But the sudden elevation of uric acid that we see began around the 1920s when we began dramatically increasing the amount of sugar in our diets. You know, traditionally, if you were trained to help somebody from a nutritional perspective, to give them tools to lower their uric acid, you would put them on what's called a low purine diet. And to this day, when you go on the websites of some of the very popular so called clinics that have fancy name, you'll see them emphasize that, you know, low purine diet is the way to go for a gout patient. Well, we're now even seeing those websites start to talk about sugar, and in particular the sugar fructose. Fructose is directly metabolized through the action of several enzymes, most importantly fructo kinase, to become uric acid. That's the end product of fructose metabolism. Metabolism in your body, it follows the exact same metabolic pathway as alcohol. So both alcohol and fructose undergo several transformations to become uric acid. The purine, by virtue of the foods that we eat or the breakdown of our own tissues, is a bit of a different pathway. But interestingly, and we'll get to this also as well, we're gonna have a lot to check off later on. The final step enzymatically is the action of an enzyme called xanthine oxidase. So that if you can block or slow down this enzyme, xanthine oxidase, you will lower uric acid. That's where the gout drugs work. That's where quercetin works. For example, is by reducing the action of the final step. Now, to answer your question, I'm not sure you meant to pose it this way, but it does open the door for me. And that is, why does it happen? I mean, why does uric acid do all of these things when it's elevated in human physiology? And that is because elevation of uric acid, strangely, is a survival mechanism. When uric acid is elevated, it became a survival mechanism for our very distant ancestors. We used to have enzymes in our bodies called uricase. When I say we, our ancestors, our primate ancestors had uricase enzymes such that when they would form uric acid in their bodies, then ultimately uricase enzyme would break it down into something called urea and a lantoin. But around 14 to 18 million years ago, during a time of food scarcity, there was a very powerful selection pressure on our ancestors to select out those who could survive on minimal amounts of food and, to a lesser extent, minimal amounts of water. It turns out that having higher uric acid was a good thing for them. So this was a population then that selected for higher levels of uric acid, such that with time, the uricase enzyme, basically, suite of enzymes, actually disappeared in those who survived. Having a higher uric acid was a superpower for our ancestors. Why? Because it caused them to make a little bit more body fat. It caused them to reduce the oxidation or the utilization of body fat as a fuel. It caused them to raise their blood pressure during times of water scarcity, led them to be a little bit more insulin resistant, such that they would have a slightly higher level of blood sugar, such that they could power their brains during times of food scarcity and find food and avoid being eaten by other animals, what we call starvation and predation. They could avoid those things because they were able to power their brains. So in the context of our distant ancestors, having this higher level of uric acid was good as survival mechanism because they raised their blood pressure, made them fatter, made them insulin resistant. And in the context of today, when we have this mismatch, we don't have food and water scarcity, raising our blood pressure, raising our blood lipids, raising our body fat, reducing mitochondrial functions, so that we don't burn as much energy reducing oxidation of fat as a fuel source. These are not good things. These are things that are at the center of metabolic syndrome and therefore at the center of, as mentioned earlier, the most common causes of death on our planet today. So we have to look at insulin resistance and becoming hypertensive and diabetic in the context of our ancestors, that was a good thing. Who knew that? On your podcast today, I'd be saying diabetes is a good thing in the context of our ancestors today, of course, you know, it's pretty much the center of so much evil as it relates to other things. Heart disease, some forms of cancer. And as much as quadrupling an individual's risk for developing Alzheimer's, a disease for which we have no meaningful treatment, affecting 6 million Americans around today. And that number expected to go up dramatically in the next eight years as we move towards 2030. But that said, that's the overview of why we're in the fix that we are. Because we're suffering the consequences of what we call an environmental evolutionary mismatch. We evolved this ability to have higher levels of uric acid to survive in the context of food restriction, the ability that we have to create uric acid from fructose or eating fruit that we might find then making more body fat. But that's certainly not what we want to be doing today.

So thank you. This is amazing. Question. You mentioned the. So I think people can understand the relationship between diabetes and hopefully they can understand the relationship between heart disease. That makes, at least in my mind, sense. But you mentioned something that, as I'm, I'm sure you deal with them on a daily basis as a neurologist. Alzheimer's. Can you kind of weave the.

What's, what's the right way relationship between diabetes and Alzheimer's.

Yeah, or diabetes, Alzheimer's and uric acid. And just how does that work? Because everybody's so worried about Alzheimer's as the population gets older. I mean, older, sick or fatter, that is just on everybody's mind, at least on our patient's mind. So can you speak a little bit more to that?

Absolutely. So, you know, there are many unifying so called theories of Alzheimer's disease. Some would have you believe that Alzheimer's is simply the manifestation of the accumulation of a particular protein in the brain that is called beta amyloid. Therefore, if we can rid the brain of beta amyloid or reduce its production, why, that might be something really very valuable. And I think this amyloid hypothesis has really now been aggressively questioned because we recognize that hanging our hats on one idea here, we are kind of molded to appreciate that approach because it lends itself quite handily to the production of a single pharmaceutical intervention based upon whatever that paradigm may be. And that has failed dramatically and that has failed in a heart wrenching way for families of Alzheimer's patients and for clinicians dealing with Alzheimer's trying to treat, trying to treat patients using so called monotherapy. We don't have a pharmaceutical fix for Alzheimer's today. So we have to ask ourselves, well, who's getting Alzheimer's? Who's at higher risk? We know, for example, that two thirds of Alzheimer's patients are women. And that should cause us to explore, for example, are there hormonal influences that differentiate between men and women that might explain it? Are there other things that are carried on the X versus Y chromosome, for example, that may be at play here that are underlying this incredible disparity that women are 50% more involved with Alzheimer's than are men? Unfortunately, I will digress for a moment. That relationship doesn't get much attention and we could speculate why. Because it's primarily a women's disease. We don't talk about it as much as. But we should from the perspective of women deserve it, number one. Number two, they're much more involved. And number three, there's some valuable information there if we would take the time to look. We know that diabetes, to get to the root of your question, having type 2 diabetes, by and large a preventable disease, a disease based upon lifestyle choices, is associated with a dramatic increased risk for Alzheimer's and a disease for which we have no treatment. Having said that, we should ask ourselves, well, what can we do in the first place to prevent ourselves or reduce our risk for becoming diabetic since it seems to be so strongly associated, and that is, you know, again, something that doesn't get a lot of attention. We are bombarded by television commercials saying, I lowered my A1C below 7 because I'm taking XYZ drug. It's as if the population is being told and mesmerized to believe that you should live your life however you choose. And then when your A1C is above whatever that magic number may be, then we have something to fix that. To bring your A1C below 7 as if 6.5 is a reasonable goal. It is not. The change is the risk for Alzheimer's begin at a level of 5.3 and 5.4 as published in the New England Journal of Medicine in 2013. So the whole notion of getting my A1C below 7 by taking this wonderful drug is kind of a perversion of reality in terms of what's best for people. Now, elevated blood sugar, by virtue of its ability ultimately to compromise how our bodies and specifically brain cells are able to respond to the hormone insulin, is very, very important. The important concept underlying Alzheimer's causation is one of what is called bioenergetics. And there are many other things we need to talk about. We know that inflammation, excessive free radicals are important as well. And yes, misfolded proteins are of course important, but really a central player seems to be the bioenergetic theory. And this supposes that because of insulin resistance, the brain cells, which require glucose by and large to work day in and day out. And we can talk about how brain cells are able to utilize ketones, perhaps later on. But primarily, the main source of fuel for brain cells remains glucose. Either the glucose that is consumed in the diet or the glucose that our bodies are able to produce, either by breaking down glycogen or de novo synthesis, what we call gluconeogenesis. Liver is able to actually make glucose when we need it. Brain cells need glucose. And many important parts of the brain depend upon the functionality of insulin so that that fuel can get in and power those brain cells. When brain cells are not powered appropriately, they don't work well, as would your car not work well if you gave it the wrong kind of fuel. Put compromise the gasoline flow to your car engine and it's not going to work well. Same thing happens in the brain. The problem is that when brain energetics, meaning the utilization of fuel, are compromised, ultimately those cells will die. And that is certainly not a good thing. When we compromise energetics, we're compromised. The function of the little energy factories in each and every a brain cell called the mitochondria. And any given brain cell may have several thousand of these mitochondria that are depending upon fuel supply to create the currency of energy in the brain called ATP. But that said, this is the relationship then between the functionality of insulin and brain function and brain risk for degenerative disease. But it goes beyond just the brain energetics in the brain, ins which we need to work, which we need to be sensitive to, is what we call a trophic hormone. It nurtures brain cells. If you take brain cells, human brain cells, and put them in a dish, if you want them to grow and function appropriately, you add insulin to the petri dish and lo and behold, that will nurture the brain cells. So, you know, we, we need to get away from just thinking about insulin in terms of its role, in terms of allowing glucose to get into the the cell and therefore power the cell. It's a trophic hormone as well. And this is actually very, very important. And interestingly, just last week a very important study came out of Germany demonstrating that individuals who are overweight, obese and sedentary, meaning they don't do much, they don't exercise, they don't get around much, are generally at great risk for having insulin resistance in the brain that can be easily quantified. How do you quantify that? The beginning of the eight week study, the 21 people had an MRI, what's called a functional MRI of the brain. But prior to undergoing this brain scan, they shot some insulin in their noses and then they were able to evaluate how the various parts of the brain were, were able to use the insulin and therefore work. When the brain cells work, they demand more blood supply. So they're basically measuring blood supply after people get insulin and seeing if insulin is working. And what they found was that these individuals were at risk for having multiple areas of the brain not respond very well to insulin, not able to utilize glucose, they were insulin resistant in their bodies and brains. The intervention then was really quite powerful. The intervention had these individuals, 21 individuals, 14 female, seven male, exercise for eight weeks, and then the researchers shot some insulin in their noses again and repeated their brain scans. And lo and behold, those areas that were not functioning as well came back online, meaning that their brains regained insulin sensitivity by this bizarre medicine they use called exercise. That exercise was able to restore insulin function in the brains of these people in whom it wasn't functioning very well. Mitochondrial function improved as well, Even cognitive function, as measured by a test called the trails B test, where they have to draw a line between the number one and the letter A, the number two, the letter B. And they timed them. They had a dramatic improvement in their cognitive function on that study just by virtue of the fact that they exercised. We know peripherally that exercise is really very handy in restoring insulin functionality as well, but now in the brain. So that's kind of a bit of a circuitous, but certainly long winded answer to the question of how does it relate, how does glucose and diabetes and insulin functionality relate to the brain in terms of how your brain is working right now, but also in terms of an individual's long term risk for developing brain degeneration, ultimately Alzheimer's itself.

So you're saying you're having this radical, you're saying something really radical. You're saying that that exercise can actually help prevent Alzheimer's disease.

Completely rapid, demonstrated for, actually for quite some time. You know, the, the epidemiologic studies have clearly demonstrated that people who are less sedentary have a dramatic as much as 30% reduction in risk for developing a disease for which There is no treatment Alzheimer's. That's been known for an awful long time. As a matter of fact, research from the University of Pittsburgh that came out about 14 or 15 years ago now demonstrated that in comparing two groups of elderly individuals, one group got a stretching program and one group got an actual aerobic exercise program to perform that. In the non aerobic group, the stretching group, there was shrinkage over the course of one year of their hippocampus, their brain's memory center, whereas the hippocampus actually increased in size in the exercising age matched group over the period of one year. The researcher's name, Dr. Kirk Erickson. And what we know exercise does in addition to now looking at the incredible results that were published this week with reference to insulin sensitivity. Exercise increases the production in the body of something called bdnf, brain derived neurotrophic factor. And what BDNF does is it turns on the growth of new brain cells and also the connection of brain cells, how they communicate to each other. We call that synaptogenesis. It protects brain cells against trauma. And it's really something we want to have a lot of. So we've known that exercise increases B eating F for an awful long time. And that study now 14 years ago demonstrated that, oh, here's the payoff, a bigger memory center, better cognitive, better executive function, better memory. My gosh, why doesn't everybody talk about that? Well, because it's not a, we can't patent it, you know, but what you hear about are, you know, the wonderful new drug developments that are coming soon. Just hang on. And yes, there's something I'm going to tell all of your viewers. They need to buy and that is a new pair of sneakers. And I don't even think they use the term sneakers anymore. I don't know where that term came from, but a new pair. Go and buy some athletic equipment. You can walk, you can jog, you can bike, you can whatever.

I understand the exercise, but as long as you don't say anything more radical like what you put in your body, what you eat makes a difference, we're okay, we're getting. Exercise is okay. But as long as you.

Whatever my next comment is, you know.

It'S so important and you know, for a long time we've been talking about aerobic exercise and you know, I still pretty much hang my hat on that. But resistance as well. We know when we, when we challenge our muscles that various things we increase BDNF and cathepsin B, which also is a Tonic for the brain. And you know, again, this is, as you just said, this isn't. We haven't even gotten to the nutrition part of our discussion yet. If we could end by saying to everybody, you really must exercise six days a week, why not make it seven days a week? And if you find it very difficult to walk to the. To the mailbox. Okay, walk halfway to the mailbox tomorrow you'll go the whole way to the mailbox. Not saying everybody needs to run a half marathon tomorrow. Find out what works for you. Get your heart rate up. A target might be at the number 180, minus your age or who knows what kind of shape a person's in. Work with a trainer. But you got to get started. And it's not just to keep your body in shape. It's the most important thing you can do for your brain. We could end our podcast right now. That's a home run message that everybody needs to get.

Yeah, that's amazing.

I'm really struck by what you were talking about around uric acid. That where some people are genetically more likely to become diabetics and gain weight and have heart disease and yet it's like we're circling the drain. Right, because the standard American diet is going to make that more likely, but then you're genetically more likely. So it just keeps feeding itself. So I'd like to transition over to food because you do it every day, most of us. So from what you've said so far, my leap is should most people who are either on the spectrum of diabetes, pre diabetes or have heart disease, should that be a keto style, High, high nutrient density vegetable content meal eating plan? Let's low in carbs. That that's sort of what I get from what you said, is that.

Yeah, I mean semi click leap. So let's unpack a little bit if we can. Wendy, the the number of diabetic adults and pre diabetic adults in America is a very, very small number. We' about about 45% of adults. I mean it's a incredible. So you know, we're talking about near 100 million individuals. And you know, the reality is if you were to do any sort of more sophisticated testing than simply a morning fasting blood sugar on people, you'll find that at least as it relates to insulin resistance, we're talking about, you know, a lot of people and a lot of adolescents and even a lot of children. So it starts young. And you know, from the metabolic perspective, we've got to do everything we can to improve that because if, you know, these are individuals on the insulin resistance spectrum who are paving the way for what I just explained, issues related to the brain. And it's, you know, diet is playing a fundamental role. We definitely need to be more involved in getting towards being in ketosis, a more ketogenic diet. Recognize the incredible detrimental role that highly processed or ultra processed foods are having or even minimally processed foods are having on our blood sugar, on our insulin response, on our insulin sensitivity. And, you know, it's very unfortunate that this is not mainstream medicine. Mainstream medicine will say, you're fine at fasting blood sugar at 105, but what am I in the afternoon? What's my postprandial glucose? In other words, what's my glucose after I eat? And how would anyone ever know that? Well, you know, there's a time and a place for wanting to go a little bit deeper. The time is now. The place, in my opinion, is everywhere. We need to get better metrics on adults to intercede at time before they're even minimally insulin resistant and nip that in the bud. Because mainstream medicine functions such that they look upon it like pregnancy. Either you, you are or you're not. And that's, you know, diabetes is not binary. Everything is not great until you suddenly have a blood sugar, a fasting blood sugar of 120. Now everything's terrible. Or your A1C is suddenly 6 or above. Now everything's terrible. Or 6.5. Whatever the number is, chosen that once your A1C begins to creep up or your insulin resistance begins to increase with time, or your fasting blood sugar increases. I mean, I haven't even gone to continuous glucose monitoring yet. We hopefully might have time to go to that. But this is the, this is the order of the day. Because the downstream manifestations of this blood sugar issue, insulin resistance issue, span every organ system in the body and are really at the root of our chronic degenerative issues, which are continuing to expand. You know, our life expectancy began to decline pre Covid. Everybody says, well, yeah, Covid, everyone's dying. And that's why our average life expectancy is going down. Well, it began before there ever was a Covid. And, you know, to consider that adolescents, now, young, young people can expect to live a shorter life than we did. That gets to what you guys mentioned a while ago about, you know, some people being genetically predisposed to having an elevated blood sugar, insulin resistance, diabetes, and even Alzheimer's. Yeah. While that's important, in my opinion, it's minimally important. There are polymorphisms that relate to Alzheimer's risk, I will grant that, that relate to higher risk for insulin resistance, that's for sure. That relates to even higher risk for having a higher uric acid level, I will grant you that. But by and large, if that were the case, then we wouldn't be suddenly, in the past 100 years, seeing such a dramatic increase in rates of obesity. You know that 50% of Americans will be classified as being obese by the year 2030. That's not the distant future. I know you want this to be evergreen, but, you know, we're talking about eight years from now, half of American adults, not just overweight, but obesity by BMI standards. Man, oh, man. And when we look at what are the risk factors that are downstream from obesity, it's devastating. Including the brain. You know, the bigger the belly, the smaller the hippocampus, if you really want to know. I have been on record as saying for a very long time that one of the most powerful and very sophisticated tools that we have for predicting Alzheimer's risk is a very expensive piece of machinery called a tape measure. Think about it. A tape measure, you put it around your waist, and right off the bat, you can determine to some degree what is your Alzheimer's risk. And with the proposition that half of adults will be obese eight years from now in America, it's worrisome, that's for sure, because our shared brain bank, our shared cognitive ability as a nation is threatened by this statistic.

I think you've really highlighted something that I talk to people about a lot, which is humanity. One, humans expect to get worse over time. So when they get heart disease, obesity, weight gain, diabetes, whatever you want to call it, they're like, well, I'm just getting older. And I'm like, no, I reject that idea. But also the idea that most humans need a problem to respond to. So what you're talking about is completely foreign to most people. And I say to my patients, this isn't a moral discussion, but I need to understand, are you someone who needs a problem to respond to, or are you someone who believes in just prevention, which I would say is like, 97% of people need a problem to respond to, and maybe 3% of people are like, oh, no, just let's just fix it so I don't ever develop a problem.

Right.

So you're really highlighting an issue.

Again, that's not what we're led to believe, though. We're again, led to believe that we can live our lives, come what may Hang around, watch tv, eat garbage food. And then, you know, my doctor put me on a diabetes drug. I love. I saw somebody once in a restaurant, a breakfast restaurant in the Florida Keys, I'll never forget this, and take his Metformin pill and then eat a stack of pancakes with syrup. And it just so typified. I think pretty much the mentality of America is we'll fix it, there'll be a wonder drug that's going to come along and frankly, if there is, I'm all in. But maybe it is metformin, who knows? We can maybe unpack that at some point. But you know, what you say is very, very true. About 88% of American adults has at least one of the components of metabolic syndrome. That tells us that only 12% of American adults is completely intact from a metabolic perspective, meaning things like body weight and blood pressure and blood sugar and things like that. These are the metabolic markers, blood lipids and triglycerides, for example, that make up the so called metabolic syndrome, or what was originally called Syndrome X. The reason we need to talk about is because that, as I mentioned, paves the way for all kinds of horrible things to happen to a person. Yeah.

No, I'm just, I just go back to thinking about, you know, just to be technical, you can do all of those things. You can abuse your body, you can fail to sleep, fail to move, eat the standard American diet. You just can't do that and expect to live a vital, healthy, vibrant life for many, many years. What you can expect is a course of decline. But you can do that. You just can't do that and be vital, that's all.

And then wonder why it is that you're failing and why, you know, I just went to my 50 year high school reunion and you know, there are people there who are not going to be at the 60 year high school reunion, guaranteed. But some are, you know, and it's basically. Are genetics involved? Of course genetics are involved, but most of it is lifestyle. And you know, we talk about how important exercise is and it is, but these things work in concert. You cannot exercise away a crappy diet. And people try, oh, I spent two hours on the treadmill and I'm still fat, you know, and you can't. It's not a calories in versus calories out proposition by any means. There are so many more factors involved that are important in terms of maintaining health and disease resistance moving forward. And like you say, it's a long term, it's a long game. You mentioned that. Oh, people have to have something they're confronted by in order to respond. And not everybody wants to think about prevention. And, you know, it's like, you know, having a retirement plan. You think about the future, or life insurance for your loved ones. This is that long game that you have to play. And it's every day your cells don't know that.

It's Thanksgiving. Yeah.

Or Thanksgiving.

Where do toxins fall in all this? Because we're. We're all about toxins. And I. I feel like those are huge factors that alter your development of metabolic syndrome and obesity. And you have Alzheimer's. And Alzheimer's, but you haven't really mentioned that. Is that something that falls into your conversation?

Yes. When I was a little kid, my father challenged me. He said, what are the causes of disease? I don't know. He said, infectious, metabolic, toxic, degenerative, traumatic, infectious, neoplastic, toxic, metabolic, degenerative, traumatic. And so toxic. You bet. And, you know, ours is a toxic world. And again, it gets back to this evolutionary environmental mismatch whereby, yes, we have evolved detoxification enzymes to deal with toxins that are in the environment. And there are plenty, you know, aluminum is, I think, the second most common element in the earth's crust. So we have mechanisms on the board to deal with things, toxins made by mold that we might be exposed to, for example. But to think that we're suddenly going to evolve a detox system to deal with what we're being confronted by, with the thousands of new chemicals being unleashed upon us every single year, we don't have time to evolve those detox mechanisms. And I would say that one area that's getting a lot of attention now, and I'm glad, is the particulates in the air that we breathe called 2.5 micron particles. Because we're now seeing relationships between exposure to these 2.5 micron particles and dramatic risk for a slew of chronic degenerative conditions, including things like even weight gain, but certainly brain degeneration like we see with Alzheimer's research that shows the closer you live to a highway, for example, so, you know, everybody cannot move to live in the country and drink reverse osmosis water and live that type of life. But when we eat more appropriately, we do allow ourselves the opportunity to enhance the functionality of our endogenous detoxification systems, which are pretty, you know, pretty functional. We can enhance the ability that we have to deal with many of the toxins to which we are exposed. Cruciferous vegetables, for example, activate a system called the NRF2 pathway that'll be on the quiz. And what does the NRF pathway do? Well, it enhances our body's production of some really important detoxification enzymes and pathways. So there are things that we can do that relate back to other lifestyle choices that can help offset the damage posed by the various exposures that we have. You know, there's a lot being talked about these days. In fact, I'm interviewing somebody I think on Monday, next week on how so many humans, mostly in western cultures, are suffering from mold exposure and the toxins that are made by mold. But when you think about it, we've been in moldy environments always, whether we're talking about living in a cave or you know, a thatched hut that's, that's wet. So we've been exposed to mold for an awful long time. It's just lately that is become, it's becoming an issue. And I think that gets back to our environment. It gets back to perhaps this so called hygiene hypothesis where we're not equipped anymore to deal with environmental things like mold and various types of bacteria, et cetera, that had really challenged us for, you know, hundreds of thousands of years. And we did well in those situations because we are no longer challenging ourselves with those types of exposures, those types of infections.

So well, that's hold on to put onto that. In addition, not only are we cleaner, but we're also eating differently, sleeping less, stressing more, moving less and exposed to a boatload of other environmental toxins. So you put this into that whole sort of here's you. And it's not only that you, it's not only that you've just been exposed, it's all those other factors too that play a role.

It meshes, it's true. And let me give an example that I think will resonate. And that is not everybody who got, who was infected with SARS CoV2 virus had a bad situation, had a bad outcome, who did well. You know, by and large people with underlying metabolic problems like obesity, like type 2 diabetes, tended to do worse. And those are individuals whose bodies are chronically in a state of immune dysregulation, have higher levels of inflammation, for example, and their ability to respond in a balanced way to a challenge to the immune system is compromised. They suffer from a degree of what we call immunosenescence whereby their immune systems are older, senescent and less able to mount an appropriate response. And the default is increasing inflammation. Hence the so called cytokine storm, for example, that can be a lethal event. Where individuals get with COVID 19 suddenly have an explosion of inflammation in their bodies, damaging their heart, their lungs, other organs. And that can be a fatal event. But at the same time, I think we should embrace, because people have gotten this idea of the cytokine storm, an explosion of inflammation, we should think about something. Call it the cytokine drizzle, whereby even a low grade elevation of inflammation, not acutely but over time, can also become an issue for the human body. We know that Alzheimer's has a profound inflammatory component, as does coronary artery disease. And even various forms of cancer are inflammatory at their core. What is it that's dysregulating the immune system and leading to increased inflammation? We know that insulin resistance is responsible, that glycation or sugar, when it's elevated, binding to proteins. But really important to get back to our conversation a while ago is that changes in the gut bacteria can lead to overall increased inflammation in the human body by threatening the integrity of the gut lining. Let me walk that back a little bit. The integrity of the gut lining is maintained by our gut bacteria. That's one of their important jobs that they lovingly do for us because we feed them, we give them a nice warm place to live in return. They do many things, but one of their tasks is to keep the gut lining intact. When we threaten our gut bacterial friends by eating things that are wrong, certain medications, not getting the sleep, as you mentioned earlier, et cetera, exposed to chronic stress, they can't do their job. And when they can't maintain the health and integrity of the gut lining, it becomes permeable, or more permeable and leaky such that things in the gut get across that lining and get into the systemic circulation. Our immune system sees that and says, whoa, this isn't supposed to be here. And what does that do? It turns on inflammation. So what I've just done then is related our lifestyle choices and diet certainly at the top of the list here to ultimately changes in the gut bacteria, increased permeability, increased activation of the immune system, inflammation, opening the door to things like Alzheimer's and heart disease and some forms of cancer. That relates then the foods we eat to the risk of Alzheimer's disease. Who knew? I mean, it's. It takes a little bit of unpacking. It takes some dot connecting. I'm aware of that, you know, but we've known about this and it gets back to our original conversation when we started today about, you know, the notion of a more ketogenic diet being a good thing for a lot of people vis a vis diabetes and, and Alzheimer's. There's a wonderful paper that recently came out from a Dr. Matthew Phillips in New Zealand. An interventional trial putting Alzheimer's patients on a ketogenic diet and demonstrating improvement in their cognitive function. Black and white. Objective testing, wasn't it? You know, the doctor said, I think these folks are better. Or their family said, you know, I think they're better after going on this crazy diet. No, they were tested with objective testing and verifiably improved. Think about that. We don't have a pill that can do that.

How much, what percent is that? Was it like a 5, 10% improvement or was that like.

Well, it really depended. First of all, any improvement is a home run. Stabilization in the 16 week trial would be a home run because the people in the trial who did not get on ketogenic diet, they further declined. But it had significance. It had real significance to the extent that family noted it. Doctor noted it. But I mean, here were the objective tests. One of my colleagues, Dr. Dale Bredesen, with his multifactorial intervention for Alzheimer's disease, has demonstrated significant increase in size of the brain's memory center on MRI scanning the hippocampus to the extent that neuroradiologists do not even want to look at the scans because they cannot believe it. It's just out of their way. Sense of reality and therefore hippocampus never gets bigger. It only declines with time. And yet he's taken the scans to them and said, look, look what's going on here. And people tend to be down on what they're not up on.

I want to make sure to go back to where we started, just to finish the loop in terms of uric acid, just because I want to close that loop. Is there any. We talked about ketogenic diet. Is there any other either? And, and we talked about sugar.

So I had a question about fruit there because that basically sounds like fruit has fructose, so you shouldn't eat fructose. Is that like the line that I drew from that, that I should or shouldn't be drunk?

And I'm glad you brought it up. I, I can't say, I really can't say that I've ever done a podcast in the past two years where that question hasn't been asked. It's a terrific question because first, the food frequency studies show that people who eat modest amounts of fruit actually have a lower uric acid lower. Second, fruit, oddly enough in its whole form, doesn't contain much fructose at all. An Apple has about 5 grams of fructose in comparison to 36 grams of sugar in a can of soda, for example, or a 12 ounce glass of orange juice. So there's nothing natural about fresh squeezed orange juice or that you buy in a carton. Our ancestors wouldn't stumble upon a grove of orange juice with cartons hanging from the limbs. Right.

What's moderate for fruit intake? When you say moderate, what's moderate in your world?

An apple or two a day, A handful of blueberries, some strawberries. You know, there are some certain fruits that have higher amounts of fructose, like watermelon and other types of melon, like cantaloupe and honeydew. But, but have some fruit. But you know, when think about a bear getting ready to hibernate, what is that bear eating all day long? Berries, you know, blackberries, loganberries, salmonberries, whatever they are, they're just gorging on those berries. So that's not a modest amount. And what's happening in that bear is that that fructose is becoming uric acid. And it says to the bear, winter is coming. Make as much fat as you can because you're going to hibernate. Now, I use that example when I talk to people, hoping they're not getting ready to hibernate. And if, if they are, then you better make sure you pack on some pounds if you're going to go and, you know, into your apartment and hibernate for six months. Obviously, you know, it's a bit of a joke, but, but it really gets to some very, very fundamental mechanisms because that level of elevation of uric acid that people have and that bears have, people have day in and day out, bears have as they're preparing to hibernate. That elevated uric acid inhibits an important enzyme pathway in the human body called ampk. Shall we talk about that? I can break it down, make it simple.

Yeah, definitely. And also you had a question too, that I jumped in.

It's all good. I want to make sure we're going in the going.

Okay.

All right.

We're weaving.

So uric acid in our physiology can be broken down by AMP kinase. So that can, can be what helps to break uric acid down. Actually, it's not the uric acid, it's actually the amp part of uric acid's metabolism, to be fair. So when fructose is initially treated by its enzyme, fructokinase, ATP, which is an energy molecule, is ultimately broken down to adp, adenosine, diphosphate and ultimately to amplify. So the question is, how is AMP dealt with? Well, amp when it's broken down by this AMP kinase, and people will hear about that, so we'll talk about AMP kinase. There are YouTube videos about it. When that happens, amp kinase activation, to break it down, does some important things. It tells our bodies that the hunting is good and it says we don't need to turn on the production of glucose in your body. So it helps keep glucose under control, it reduces appetite, it helps with cellular breakdown so we can rid our bodies of accumulation of debris, and it helps the body use fat as a fuel source. All that sounds really good, doesn't it? And so we really want to keep our AMPK lit up because when AMPK is active, we're going to be thinner, we're going to have better blood sugar, we're going to just generally feel pretty well. But it turns out that AMPK has an evil twin. Who knew? And this is AMP deaminase. And it's AMP deaminase that is dealing with this adenosine monophosphate, the breakdown product of fructose metabolism. And when AMP D is activated, then it tells the body, whoa. Make fat, store fat, make sugar, decrease your mitochondrial function so your energy burn is less to get ready for winter or food scarcity, as the case may be. Uric acid elevation turns off the good guy, the AMP kinase, and favors AMPI deaminase. So that's one of the ways by which uric acid is so influential in our metabolism. It's basically telling us to prepare for either hibernation or for upcoming food scarcity. And that's why we've really got to do everything we can to not elevate and uric acid in our bodies. Now the big player, if you ask me, what are the top five things to think about in terms of elevating uric acid? First would be fructose. Second would be a sugar called fructose. And third would be fructose. Fourth would be purine rich foods like organ meats. And five would be alcohol. What I'm saying is it's all about the sugar in our diets. Table sugar is 50% fructose sucrose. Table sugar is half glucose, half fructose. The fructose that we get packaged with fiber and vitamin C, which aids in uric acid excretion in the form of fruit is great. You know, eat an apple a day, eat a couple of apples a day.

Wonderful.

Now you don't want to spend your whole day eating berries Like a bear. But some fruit on the table is great. Purine rich vegetables, cruciferous vegetables have a lot of purines. Eat them all day long, it's totally fine. There's great fiber. There are bioflavonoids that actually inhibit the most important enzyme for uric acid formation we talked about earlier, xanthine oxidase. So things like quercetin and luteolin are powerful in terms of reducing the body's uric acid. One study done in England looked at, I think, 22 young men with mild elevation of their uric acid. Put them on 500 milligrams of quercetin a day, and after eight weeks, their average uric acid level declined by about 8%. Quercetin health food store item. And guess what? In addition to reducing uric acid, quercetin amplifies ampk. That's what we want. That helps us lose weight, it helps control our blood sugar, it helps control our appetite. Another way to activate AMPK is exercise. Who knew?

And exercise increases the bdnf, the brain derived neutropenic factor also, right?

You bet. And you know what? You can do something. You know, I exercise a lot and I get injured probably as much as anybody else. You know, there are days when I can't run because my knee hurts. But then you walk or you use the elliptical machine or do a bunch of sit ups or something. You could always. In my opinion, there's something that you can do if you're confined to a wheelchair. You can do curls with dumbbells. There's something. Or use a band. There's something that everybody, probably most everybody can do each and every day to get their heart rate up and to stress their muscles.

Make some small improvement today that you didn't have yesterday.

Yes. And interestingly, when you do that, and therefore in a very minimal way, reduce inflammation in your body, you're enhancing the likelihood that you're going to make a better decision tomorrow. I'm going to need to digress here. Is that all right?

Sure.

And we're going to go to an unexpected place. And it has to do with our ability to make these good decisions. To eat right, to get sleep, to exercise, spend time in nature, et cetera. And our decision making is really dictated by a balance between, let's say, two brain areas. A primitive I want it right now, I don't care about tomorrow, I want it for me. Everyone else be damned area of the brain, the child in the room, if you will, called the amygdala and then the adult in the room called the prefrontal cortex. And the adults in the room saying, hey, this may not be good for me. How might my actions affect other people? How will this play out in tomorrow or 10 years from now? You know, and that gets back to our conversation about making these choices because of the long game. That's the prefrontal cortex talking. We want the adult in the room to rein in the amygdala to say, yeah, I know you want to eat that, or do stay home watching TV all day or playing video games. But that's not really what we're going to do. That's the adult controlling the child. That's the prefrontal cortex connected to the amygdala and calming it down. We deeply depend on that connection. So that pathway, that phone line that lets the adult talk to the child and make better decisions is threatened by inflammation. Think about that. That connection, that ability of our prefrontal cortex to do all those great things, make better decisions for the long game is threatened by inflammation. It's the reason when you're up all night and your body's inflamed, you eat crap that next morning. We've all been there. I mean, I remember in residency, it was baby food from the pediatrics ward. It was sugar, yummy. But it's the reason we don't make good decisions when our bodies are in inflamed. It's why even mild overweight becomes obesity, because you can't stop. You make worse decisions. You end up being sedentary and parked in front of the TV all day long. The goal is to break that vicious downward spiral in some way. And maybe it's a little bit of exercise today, maybe it's turning off your television and any other screen devices after 6pm and trying to get a better night's sleep, not having caffeine after 2pm Maybe it's reconnecting with nature or maybe you start off with the dietary changes. Who knew? Who knows? But any way that we can insinuate into that feed, forward, downward spiral to break it can be on ramps for better decision making, therefore better health.

What do you do for people whose frontal cortex, prefrontal cortex aren't developed yet because of their age? Were you going to ask that?

And you could say.

There, that's it's not developed.

It's very challenging. I mean, that's, it's really this prefrontal cortex gaining control that defines, you know, being able to make adult decisions. It's why you have to be a certain age to drive A car to vote to serve in the military, et cetera. But truly, with so many people, even into adulthood, they've taken their prefrontal cortex offline and are making impulsive, self centered, narcissistic decisions day in and day out. And it doesn't serve them, and it doesn't serve others, and it doesn't serve the planet.

I just find it. I mean, thank you for that connection because that actually gave me a lot of insight. One of the interventions I recommend is doing if, if somebody needs a reset, a great reset is just a fast. And I know for myself if I'm fasting three to five days, I'm gonna eat very differently afterwards than I did before. And that's sometimes actually, I know, as if I'm going down the wrong path. Like, I can see I can't control, sometimes I literally can't control the food because I just want it. If I do some kind of reset, it changes. So that gave me. Thank you. Because that gave me the insight to understand why, which is really cool.

Well, you know, I'll say from my perspective, fasting, the main, the most important thing that it, it amplifies in me is gratitude. You know, you're grateful to have food afterwards, but all types of gratitude that I think about during fasting are, are amplified. Family, friends, you know, the world, all the things that we need to be grateful for. And you know, you, some people get to those places with hallucinogens, through meditation, through, you know, aggressive exercise. They put themselves in a zone and. But I think fasting is a very, very handy way of doing it. You know, aside from, you know, the other health benefits that we could talk about.

Yeah, no, it's, I, I thank you for bringing up the gratitude because it's.

Just.

Makes time slow down and gives you time to reflect. And you bet it's, it's so important in this world where we're just going a thousand miles an hour and trying to do whatever we do. And even the people that are exercising so much, sometimes it becomes a routine. So breaking a cycle and just pausing, you bet.

Is there anything we didn't ask you that we should ask you? You want to make sure you say before, as we're drawing to a close, there's tons to talk about.

Yeah. I'm like, I don't want to stop, but this is our time.

I don't know what, where we would go with this. Let me just maybe make more mention about the uric acid connection. So just so people can. Because I think that was supposed to be the topic of the day again. So uric acid is playing a role in our metabolic health. We want to keep our uric acid level at 5.5 milligrams per deciliter or lower for anyone who's watching this from another country. Various countries have various units, so the numbers may be different. That the biggest player as it relates to elevation of uric acid in our modern world is our consumption of fructose sugar. That half of table sugar is fructose sugar that alcohol and organ meats contribute as well. The worst offender in the alcohol world is beer. Beer is high in purines from the brewer's yeast, but also has alcohol. And the best choice would be probably wine. And that with greatest respect, many of your viewers, healthcare providers, may not understand uric acid, aside from the context of having gout. It's the new kid on the block. I recognize that. But I'm very buoyed to see the number of research studies coming out that talk about uric acid control as it relates to metabolic health and the number of doctors and healthcare providers who are talking about it now in their podcast, their forums, their online, their postings, et cetera. So it's really starting to gain traction now. And you know, it's not going to be the end all, but it becomes another tool in the toolbox. And it's something that people can easily be made aware of. It's something you could test at home, just like you could test your blood sugar. So, you know, those are the key points on uric acid.

No. Appreciate it.

Awesome.

Where can people find you?

Yes.

Drpermutter.com is my website, drperlmutter.com that's probably the best place to start. That then segues to Instagram and Facebook and the Empowering Neurologist is my podcast. The Empowering Neurologist and I have a great time interviewing smart people like you guys and getting information out. People write books, we talk about their books. I have a lot of fun with that. So that's where I am.

Awesome. Do you want to close it out?

No, it's all you. I do want to say that for our viewers that we. I have been following you for a long time and a lot of what we do is based on your research and based on your knowledge. So just really want to talking about Grateful, extremely grateful for what you've done for me personally, for my patients and just the world. And it's. It's just been a pleasure and thank you for the privilege of interviewing.

That statement makes it all worthwhile. For me, so I appreciate that as well.

Thank you for joining us for another episode of the Five Journeys podcast. Live. Like you matter. Our guest today was Dr. David Perlmutter. Thank you for being here.

My pleasure.