How Uric Acid Disrupts Your Metabolic Health | David Perlmutter, M.D. | 906 | Dave Asprey

You're listening to the Human Upgrade with Dave Asprey. Today is going to be a lot of fun because I'm interviewing a dear friend and a fantastic human being who's moved the needle on our awareness for health and much of his career. Dr. David Perlmutter. He's been on the show several times and is one of those guys who's connected the gut and the brain and how we treat kids, how we treat ourselves for decades of writing books. So one of the greats and someone I've recruited, recorded interview on his boat. It tends to be in my part of the world some of the year, so it's always good to get to interview him because he knows stuff that no one else does. And in our interview today, we're going to talk about what I think might be the next big biomarker. You've already learned about levels, health, and what you can do with continuous glucose monitoring. You've learned about ketone monitoring, all the different ways you can do that. But do you know your uric acid levels? You probably don't, but it turns out there's equipment and there's reasons to measure this. So what you're going to learn, as I promised you this year, I'm going to tell you exactly why. To listen to a show before the show so you know that it's a good idea to listen to it. Or you could say, I just don't care. So you're going to learn in this one from one of the great functional medicine doctors out there what uric acid does to you, why it's a key health marker and a major indicator of whether you are getting chronic dejection of diseases. And this is true at any age. If I had known this when I was 20, it would have changed everything and it probably would have saved me a million dollars later. So in the show, you'll learn how to measure your uric acid levels, what they mean, and you'll also learn about a new book that has the best name of a book I've seen in a long time, and it's called Drop Acid, which is like the best, most kind of creatively naughty, yet completely accurate title ever. So, Dr. Perlmutter, my friend, welcome back to the show and thanks for a hilarious book title.

Oh, thank you. As we were saying before we went on, just great to see each other.

So what you've done in Drop Acid is identified. Okay. There's a level of something that medicine has looked at for a specific condition and said, oh, wow. Fluctuations in that level tell you all sorts of things, including an early indicator for diabetes, obesity, cardiovascular disease, and Alzheimer's. Those are the big four killers from my anti aging book. Those are the things that take out most of us. You have to take care of those if you're going to live a very long time. Like, first, don't die so you can live a long time.

It's not, you know, the number one cause of death isn't a virus or anything infectious. It is a consequence of our disrupted lifestyle. And it really. The history of this mismatch, if you will, between our genes and our current environment, or we call evolutionary, environmental mismatch, goes back as it relates to uric acid and the metabolic issues that we're suffering from. This can be traced back to about 15 million years ago, during the middle Miocene period, when the Earth became cooler. And there was a strong selection pressure on our primate ancestors, favoring those who had whatever genetic mutations might let them make a little bit more fat, make a little bit more blood sugar to power their brains, and they would survive and pass those genes on to the following generations. And that happened all the way to us. And we've identified that there was a suite of genes in mutations that took place over more than a million years in an enzyme called uricase that breaks down, as you would guess, uric acid, such that these primate ancestors lost the ability to break down uricase. So their uric acid levels were higher and that provided a signal in their bodies and that food was scarce. Make fat, store fat, raise the blood pressure, raise the blood sugar. And we inherited that thrifty genome even to this day. It was helpful for our hunter gatherer forebears because they might not know when their next meal was coming. But, you know, ever since agriculture and certainly a lot more recently, we've been kind of targeting that whole mechanism to make body fat and store it. And now we have this mismatch whereby fructose, which is the signal, fructose, fruit sugar, becomes uric acid in your body, in my body, in the bodies of everybody on the planet. And that's a signal saying that we've got food scarcity is coming, we better make fat. So now that we understand that we can target uric acid, you can measure it at home, you can get your doctor to measure it, and then we can lower it. And that is turning out to be a really powerful player to rein in a whole suite of metabolic issues.

All right, this sounds really promising for all the biohackers out there. And also, you might not be a biohacker you might just say, well, I have this weight that won't go away, and I'm tired of going to the gym all the time and it not moving. And I'm tired of trying a keto diet and it not moving and saying something's wrong. Well, this is an early indicator, so we can incorporate this. And what you brought to my attention when a box arrived and I open it up and it says drop acid, and there's.

What did you expect would be in.

That box coming from you? You never know.

Vinyl. Hendrix albums, first of all.

Exactly. I dug through those. The tie dye. Now, it didn't just have a copy of your new book in it, it had a meter, right. One of these meters, which measures uric acid from a little bloodstick. Same as you would with an older blood sugar meter if you don't have the continuous glucose ones, or you would with a keto meter. So it turns out a little tiny prick on the finger really, really helps. And first off, you sent me one. Thank you. But what does a meter like this normally run?

I think they're about $90 or somewhere between $80 and $90. And I think they come with 20 stick. And the good. You know, unlike measuring your blood sugar every day, for people who don't have a cgm, this is something you do every two to four weeks, because it's not going to vary that quickly, depending on, of course, how aggressive you are about lowering it. But the nice thing is it records. I don't know if you're able to see that. That was my most recent measurement, 4.7. But it will record your history of measurements and allow you to see what the impact is of your change in lifestyle, which is what it's all about. I mean, it's why we wear, you know, wearable devices to track our sleep, to track our blood sugar. Because once we know where we are, we can observe how our lifestyle changes affect those parameters. And now we have a new parameter to. To look at, which is measuring our uric acid.

Okay.

And I just want to say that, you know, here in the United States, we're. We're kind of a little behind other countries. For example, Japan has been studying this and really actually intervening with patients who have elevated uric acid and other metabolic problems for decades, for at least a couple of decades. They put out a really fascinating study back in 2009 where they followed a group of individuals, 90,000 people, adults, 42,000 men, 48,000 women. They followed them for eight years. They measured their uric acid at the beginning of the study. And they found that with people who had a level of seven, which is very common or greater, their risk of what we call all cause mortality, meaning dying from anything whatsoever, was increased by 16%. Their risk of death from cardiovascular issues was increased by 39%. Risk of death from stroke increased by 35%. And what I found really fascinating was that for every point elevation above 7, there was an additional 8 to 13% increased risk of death from again what's called all cause mortality, meaning you died from something. So you know, this is a big study, went on for a long time. That's compelling information. Especially now that we know that uric acid is signaling our bodies. It's sending an alarm signal to our entire body saying winter is coming. And it's telling our bodies get ready. Reduce your metabolism so it compromises mitochondrial function, make body fat, lock up the body fat, store it so you can't tap into it, and even raise your blood sugar. So you can do what power your brain. So you can avoid two things. You can avoid starvation and you can avoid predation, meaning getting eaten by another animal. We, you know, we have a pretty sizable brain, we need to power it. So this is a signal then that's telling us to get ready. And it's, it's very interesting because what it does, and I think many of your viewers, especially those who really consider them kind of deeply in entrenched in the biochemistry, what uric acid does is it shuts off AMP kinase. And I'm certain that many of your listeners, viewers know that we want AMP kinase pathway lit up all the time.

Because, which is why coffee, right?

Why coffee, why exercise, how metformin works to keep diabetics blood sugars lower, quercetin, berberine, lots of things we could do to keep our AMP kinase lit up. Because when uric acid is elevated, shuts that down and it tells us don't burn your body fat, store your body fat. It actually shifts this all whole metabolism over to another way of dealing with amp. And that's through what's called AMP deaminase. And this is exactly the shift that happens for example in bears prior to their hibernation. They're trying to make as much body fat as they possibly can and ratchet down their metabolism so they could live in the cave for however many months. And they need to make this body fat during the fall when they're eating the fructose, eating the berries. So unless you know, any of your viewers think they're going to hibernate for Several months. It's not what we need to do. We want to be burning our body fat. We want to be keeping AMP kinase active, keeping our blood sugar lower. And I think you mentioned something a moment ago. I think it was really very important about people who are struggling with their blood sugars, their blood pressures, their body weight, doing all the things right. They're listening to every podcast, trying to do their best, whether it's keto or paleo or whatever. But they're sticking to these plans and maybe making progress. But they're always wondering if there just isn't something missing, some other little piece of the puzzle, that little corner piece in the jigsaw puzzle that when you get it, you go, yeah, finally. And I would submit that for many people, it's going to be targeting specifically, and we'll talk about it, their uric acid.

I have to say, having looked through your book and having just chatted with you about this, I wish that I had included this in Superhuman, because the percentage risk of lowering of all cause mortality, it's a major thing you do when you're looking to live a long time. And the percentages that you cited there are very meaningful. I went through many, many interventions in there saying, okay, this one looks like it works for this, this one looks like it works for this. But uric acid as a signaling molecule is something that a lot of people haven't talked about. So maybe this came out of Japan or something. But how come you're the first person in the west who's talked about this? It seems like it's a big enough thing. We should all be talking about it.

I'm absolutely not. You'll note that drop acid, which is something I think we should all do in the context of uric acid, is dedicated to a man named Richard Johnson, M.D. Dr. Richard Johnson, University of Colorado. He's done the pioneering work and really began to raise the level of understanding of uric acid's role. But again, this is something that's not uncommon in many other countries around the world. In America, it's all about, you know, lowering your cholesterol and hope for the best. You know, we really see that the mentality here in North America is kind of live your life however the heck you want, and when you're finally cognitively impaired, your blood sugar's going through the roof or whatever it is, we'll fix it for you. Don't worry. Pharmacy is here. You know, mainstream pharmaceuticals are here to save the day. That is just a perversion of reality, especially as it relates to the brain. And, you know, that's what really got me started when I reviewed studies like a Japanese study looking at 1600 people and followed them for 12 years. And every two years, they did an assessment of how well their brains were working. What they found was, after the 12 years, those who had the higher levels of uric acid above 7, they experienced an 80% increased risk of. Of developing dementia, a 55% increased risk of developing, specifically Alzheimer's disease. Oh, did I say. A disease for which there is no treatment. And they had 166% increased risk of what is called mixed or vascular dementia. Now, you know, I'm a neurologist, and in dealing with these problems from a interventional, pharmaceutical perspective, there's very little. From a pharmaceutical perspective, there's really nothing yet that we have that can arrest this problem. It's very, very challenging. And it gets me both from my professional perspective and from a personal perspective, having dealt with this in my dad as well. So anything that we can do that has an impact like that, I think is very, very valuable. But the thing about this metabolic signaling is it has huge impacts on cardiovascular disease, on hypertension. We mentioned Alzheimer's, and even various forms of cancer like pancreatic, colon, and breast cancers that are related to this metabolic mayhem. And that's being kind. So it's a new and very exciting tool. And the exciting thing about it is it's something that we could take home. It's not like you have to have your genome sequence and then send it off someplace and hope that you get back an interesting interpretation that might or might not be effective for you. This is really very, very straightforward.

All right, everyone in the Upgrade Collective, and if you're listening to the show, Upgrade Collective is my membership and mentorship group. And we've got a bunch of people in our live audience in a real active chat thread, all making jokes about acid at the same time, going, come on, what do we do to lower it? But first, I want to know, what do we do to raise it? What are the things that are cranking this up in people?

So for many years, people have known that elevated uric acid can be a problem, generally in the context of something called gout, where you develop painful crystals that accumulate in your great toe. And it's traditionally been described as the king of diseases and the disease of kings, meaning people who ate a lot of rich food. A lot of food rich in what are called purines. That's a lot of meat, but specifically organ meats, liver and kidney. And it turns out that while those can relate, in our modern world, the big player is fructose, or fruit sugar. Not necessarily the fruit sugar found in an apple, but the fructose that's found in soda added to sauces, actually, you know, found in more than 60% of packaged foods in the grocery store. Things like fruit juice, for example, that there's nothing natural about fruit juice. The fructose content will knock your socks off. Fructose is metabolized directly into uric acid. There are only three things that make uric acid. Alcohol, purines that I mentioned earlier, and fructose. And so when you see, for example, a combination drink that has both high purines and alcohol, which is beer made from yeast, so it's got a lot of purines, then we begin to understand why people get a beer belly. Because it's telling the body aggressively through two inputs, purines and fructose. And alcohol rather make fat because winter is coming and gaining body fat and raising your blood sugar and your blood pressure are terrific things. They're wonderful things for 99% of the time on this planet, but not now. So until just recently, if you could make a little more body fat, you would survive because you had that backup resource for calories so that if there was no food, you might make it through, whereas the next person might not. And this, again, we call this the evolutionary environmental mismatch. And I actually wrote my first paper on this whole concept of environmental mismatch 50 years ago, a half a century ago, published that in the Miami Herald in 1971. I was 16 at the time. And I concluded that paper by op ed by saying, but what about us living today with the outdated machinery, meaning we have machinery that's really set up for the hunter gatherer times or even, you know, prior to that, when the world was a different place. And what I'm saying is if we can emulate those signals to our DNA and our physiology that have evolved to keep us healthy, we're going a long way to offsetting these incredibly powerful metabolic disruptions that are paving the way for, as we talked about earlier, the biggest cause of disease on our planet. And you know, to be clear, this uric acid is screaming, winter's coming. Make fat. And also important to recognize that it raises our blood pressure because it's a signal that we're facing dehydration. Now, that's a little bit more complicated, but understand, let me preface this by let's think about a camel, and a camel is getting ready to walk is walking across the desert. It's not drinking water for three weeks, and it has this great big hump. What do you think's inside that hump? Not water. Fat. Because when we burn body fat, we create two things. Carbon dioxide and what's called metabolic water. So fat is a powerful resource for us as humans. Yes, as a resource for calories, we get that. But also a hedge against dehydration, because it, when we burn that fat, we're making metabolic water. So it turns out that when our bodies think we're dehydrated, we turn on fat production. And why do we think we're dehydrated? Well, we might be dehydrated if we're not drinking enough water. But we can also signal that by raising our sodium when we don't have enough water to drink, our sodium level goes up and that turns on a pathway whereby our bodies make fructose. Then that fructose becomes uric acid. And what happens? Our blood pressure goes up. We make fat so we can make metabolic water. How do you raise your sodium? Well, either with the playoffs or the super bowl, you park yourself on that couch and eat that bag of pretzels with a lot of salt, and your serum sodium goes up. You start making fructose, making uric acid, making body fat, and the next thing you know, you're signaling this entire alarm cascade. In this case, thinking that your body's becoming dehydrated and it's trying to protect itself.

Okay, a couple questions for you there. Low sodium diets make people feel like crap and raise risk of heart disease. The current levels that the RDA has for sodium, for total sodium, raise levels of renin in the blood enough that it increases your very substantially your risk of cardiovascular disease. Higher stress means higher demand for sodium. And from many of the things I've seen, you get enough sodium. And for me, it's about 6 grams a day, roughly three times more than the RDA. Then I have a clearer head. I make stomach acid better. Increases in bone density. There's all this good stuff from salt. And then we've got guys like Paul Saladino and Liver King and me, I've been recommending raw liver since my first book on fertility. Yet it's high in purines. So how do we. How do we look at that? I don't want people to lower salt because they're going to feel like crap if they do and they won't handle salt.

Let me. Let's first tackle the salt question and we'll get back to the liver. And first, the important thing about salt consumption is that, yes, you're right, we do need some sodium. But there are two things that are extremely important, and that is the rate that we consume it and the concentration by which we consume it. So if a person's eating a salty food that is going to give them sodium, which has, as you mentioned, some retrospective studies indicating that there are benefits, and we know we need serum sodium to be balanced, the trick is to follow it with water, and therefore your sodium level isn't going to change. So you're right. But eating just salt in and of itself tells the body to make fat. I mean, this is something that cattle ranchers have known for a long time. Why do they put a salt lick and out? So the, the cattle are going to lick salt all day long because it's making them. Your physiology thinks it's dehydrating and they increase their fructose production and make body fat. Now, as it relates to liver, which has huge properties that are helpful, the B12 availability, iron availability, et cetera, it's really all about the individual. I would say that the biggest issue by far and away isn't eating high purine foods. It's always been the fructose. In the day of gout, it was always the fructose. Back in the 1800s, the amount of sugar consumption in England was actually quite substantial, especially in its. In being mixed with alcohol. Then you layer on top of that the purines. And to this day, and we can speculate, we don't need to speculate, we know why to this day, when you look at a diet for gout or a diet to lower uric acid, go online, go to one of the institutions, their websites, it's all about lowering purines. And they're so loathe to talk about sugar. It's the sugar. It is sugar. Whether you want to talk to Nina Teichol or Robert Lustig or you know, any of these people who are trying to get this message out. Casey means it's all about the sugar. And yet, oh, no, no, you need to stop eating liver. You need to stop eating organ meats and venison and scallops and mussels, really, as it relates to uric acid, by far and away, it's the fructose. That's the thing that increased 1,000% in American adults consumption going from 1970 to 1990.

In order, then, the things that are going to raise your uric acid the most would be, number one is sugar or Let me give you the top. Fructose then liver.

Number two. Fructose. Number three is fructose. Number four, purines. Number five, alcohol. And I don't know purines worse than alcohol.

Really?

Alcohol and purines. I don't know if the order is right. Really depends on the individual.

Okay, fair point.

Alcohol needs a little bit of. We need to double click on that for just a moment. Because wine, it turns out, doesn't really have much of an effect because wine has offsets. Like fruit has offsets. You can eat fruit. Wine has offsets, probably the bioflavonoids that target an enzyme that makes uric acid. So in women, retrospective food frequency questionnaire studies demonstrate that women who drink wine have a slightly lower uric acid than those who do. Not men. It's about a wash, it's about neutral. Hard liquor is associated with a slight raised uric acid level. But as I mentioned before, beer, beer is, you know, a big issue because of the alcohol. Yes. But also the purines. And once again, Japan is ahead of us on this by creating and marketing purine free beer.

Wow.

And I can assure you in Japan this is well beyond the small percentage of their population that has gout. They recognize that purines make uric acid, which leads to high blood pressure, which leads to high blood sugar and obesity. So now you find purine fee. Purine free beer.

Wow. I did not know they did that. Why does Japan do so many of these cool things that we don't hear about here for many years?

Well, I think they got into trouble earlier than we did. Japanese people tend to eat a lot of umami flavored foods. Umami flavored umami foods are, are going to be very, very high in purines. And so they, they have a risk for high uric acid. And, you know, have been dealing with this actually for quite some time and then began to study, well, what is it? What else may be going on? What are the correlates that we're seeing with high uric acid? And they began to unravel and reveal to the rest of the world these really high relationships with various metabolic diseases. One study published I think 2016 by both Japanese and Turkish researchers is entitled Uric Acid in Metabolic Syndrome from an Innocent Bystander to a Central Player. Meaning, yeah, we've known that there's elevated uric acid that correlates with obesity, diabetes, hypertension, known there for a long time. But that study really made it clear that it's not just happens to be elevated in Conjunction with these issues, it's causing it, it's playing a role. With lots of research, I delineated it in the book, showing that when you intervene and stop uric acid production and don't even make a dietary change, that you can reduce hypertension, you can reduce weight gain. Wow. In some of these studies, they actually raise the uric acid by giving humans what, fructose, placing them on a high fructose diet. But you know, frankly, you don't need to even do that. When you see the amount of fructose that adolescents and young adults are consuming these days in the form of energy drinks and sports drinks, along with soda and fruit drinks, it's breathtaking. And it's no wonder that uric acid levels, which were averaging about 3.5 in America in the 1920s, now are averaging 6.0 in American adults. And that increase is in lockstep with our increase in fructose consumption. So, you know, there have been variations in alcohol consumption, certainly going through prohibition, etc. And period consumption. As, you know, more people adopt a plant based diet. But what we're seeing is still uric acid levels are skyrocketing. It's been estimated right now. We know that in America, one third of adults isn't just overweight, but is obese. A third of American adults is obese. And in the distant future, in 2030, that's way in the future, some distant future, that number is going to be 50%. The flip of a coin, obese, not just overweight. Right now, more than 70% of Americans is either obese or hypertension or overweight. And this isn't that there's been a sudden change in our genome. It's an environmental issue. It's really based upon our choices that are so heavily influenced by industry.

I have a question for you. This comes from the Upgrade Collective. There are a variety of what's called biogenic amines, and these are things that are formed in the gut and purines are one of them. But so is spermidine, there's putresine and which strangely enough, has benefits and negatives. But are the, are all of these going to raise uric acid?

No, I mean, these are metabolites there from. So they're not. And these are actually, you know, created to some degree by our microflora, by the gut bacteria. But, you know, having. That does kind of segue nicely though into the notion that there's an interplay then between uric acid and our gut bacteria, such that higher levels of uric acid Favor more or the, what are called the pro inflammatory bacteria. And you know, I always want to break it down, say, oh, that sounds terrible. We don't want more inflammation. That's always bad. No, diabetes isn't always bad. Body fat retention isn't always bad. It could be a life saving situation. Let's look at it in context. So having an increased amount of inflammation can be life saving and would have been life saving for our ancestors in helping them deal with various types of infection. Inflammation is an important life saving mechanism within your physiology. So the notion that a higher level of uric acid by increasing inflammation and increasing gut permeability might have an upside, I think, you know, it just changes our perspective a little bit. Similarly, the ApoE4 genetic allele is associated with increased risk for Alzheimer's. So obviously under any circumstance it's a bad thing, right? Well, no, we know that in certain cultures that are equatorial and live in a, in a very agrarian or hunter gatherer like environment, carrying the APOE4 allele that we used to call the Alzheimer's gene is actually associated with a lower risk of Alzheimer's and certainly a better ability to combat certain infections, specifically parasitic infections. So getting back to the uric acid relationship to the microflora, we know that, for example, gout can be treated with what is called a fecal transplant by giving gout sufferers normal gut bacteria in the form of a fecal transplant. We've talked about it before, their frequency of gout attacks goes down. So it's a two way street. And again, hey, the various things that uric acid can do in your body are generally in the context of our modern world where it's 365 days a year that we're signaling our bodies to get ready for winter. Make fat, raise the blood sugar, raise the blood pressure. You know, we have to think of it in the context of, gosh, for our ancestors, that was life saving. And that's why we're in this situation today whereby everyone walking the planet has inherited this uricase mutation. Wonderful review about this in Scientific American about how this all happened. And therefore, when we come upon the blueberries in the late fall and early, late, late summer and early fall, and it signals our body to make fat, well, that might have been great for our hunter gatherer forebears, but for you and me, who have access to fructose 365 days a year, it's sending the signal, oh my gosh, you're not going to have food. Winter's coming and it doesn't work for us.

This is one of those things about eating seasonally. If you do that, you're supposed to fatten up in summer and towards the end of summer you would eat more omega 6 fats because there are more of them available which slow down your metabolism.

Exactly.

Make you tired and put you into hibernation. That's why bears do it. It's designed that way. But if we don't want to put on fat all summer long and then go through a winter without carbs where our brains are slow and we're tired, you might want to eat seasonally, but maybe you don't need to load up quite as heavily even on fruit towards the end of summer when it's available.

Yeah. And I would say if not just eat seasonally, but if you're planning to eat seasonally, in other words, load, not loading up, but eating more of those fructose rich carbohydrates in the late summer, early fall, you've got to be all in on the entire rest of the plant. Meaning that once winter comes, your body should experience fasting and, or at least the very least time restricted eating. So it's not really pick and choose from the, from the paleo menu. And so I'm going to do part of it, but not all of it because it's either, you know, it's a whole program. If you're going to emulate our ancestors, then you need to go to bed when it's dark. You need to have, you know, high quality sleep and every aspect of what we assume our Paleolithic ancestors experienced.

Okay, I'm getting you there. And this is a way of monitoring. If you get your measures every two, every four weeks, you can see if what you're doing to probably just reduce your fructose, which you and I have been recommending for at least 10 years in the books that we write and all. But there are other markers that matter. Now I'm going to ask you this as an md, as a neurologist. If you had a random person from the population out there, you don't know much about them and you wanted a marker to predict if you got Covid, would you be hospitalized and you could either get their vitamin D level or you could get their uric acid level, which one of those markers is likely to be more important?

Hard to say. You know, we've seen the data on vitamin D and we've seen the data on blood sugar upon entrance. I think that one of the most powerful tools for predicting outcome is called a Tape measure around the world, very sophisticated. But as they would have it, In May of 2021, a study came out. Chinese researchers actually looked at 1854 people and measured their uric acid when they presented to the hospital. And what they found was really quite interesting, that the risk of being one of three things going in the icu, being put on a ventilator, or death. And all three is what they called the composite score. But the risk of these things was between two and three times increased if you entered the hospital with a high uric acid level. So why would that. That shouldn't be a surprise because that uric acid level is going to be seen in people with diabetes and with hypertension and certainly with a high body mass index or obesity. So it does have an effect on immune function. It does. I think we're just beginning to see how it relates to inflammation, like we talked about a little while ago. But, you know, again, there are interventional studies being done now where pharmaceuticals are used to lower uric acid. And they're. And we're seeing results in terms of things like body fat and blood pressure. How the pharmaceuticals work, like allopurinol, which is a gout drug, is it targets a specific enzyme called xanthine oxidase. That'll be on the quiz that's fundamental in the production of uric acid. Well, it turns out that that xanthine oxidase is dramatically inhibited by some exotic thing called quercetin. Who knew Quercetin and luteolin, another bioflavonoid available at the health food store, target this xanthine oxidase enzyme almost as effectively as the drug. And so we see studies. One study from Oxford in British literature showed that giving Quercetin 500 milligrams a day in a group of 22 young men with elevated uric acid lowered their uric acid by 8% in two weeks. No other changes, just quercetin. And, you know, we mentioned it earlier, quercetin powerfully targets AMP kinase. Who wouldn't want that? It's a senolytic, it's an anti inflammatory, it's an antioxidant. So I'm all in as it relates to taking 500 milligrams of Quercetin. I been doing that for quite some time, along with 100 milligrams of luteolin.

Wow.

Luteolin and strong medicine. It really, really is. I mean. Right, right. Just those two nuggets, I think for your viewers, going to have a really significant effect on lowering their uric acid. And you know, you were alluding to the fact that, you know, you do have friends who are all in as it relates to things like eating organ meats for example. And I'm not saying you shouldn't do that. I' not saying, even though they're high end purines, do you necessarily have to go on a program that eliminates them? You do not, depending on your uric acid level. But let's say you do your best to eliminate the fructose. You're taking the quercetin, you're monitoring your sleep, you're doing all the right things and it's still a little bit recalcitrant. It's not reaching 5.5. That's the number. That's our goal. It's still around 6. That's better, but not good enough. Then that person may want to maybe cut back a little bit on the purine rich animal foods and see what happens. But I think again, third time I've said it. The big players, the fructose, add in the quercetin, add in some luteolin and certainly I think generally in most people they're going to see a pretty dramatic lowering of the danger signals screaming in your body telling you to make fat and store fat.

Now I got curious as we were talking about specific types of probiotics that produce uricase which breaks down uric acid. What's your take on probiotics for this?

Well, I don't think there's really much in the way of marketed, nothing marketed probiotics that do in fact supply uricase. Again to remind everybody, the uricase is the enzyme that in other words mammals, for example, breaks down uric acid to allantoin. We don't have uricase, we have really zero as it relates to uric ACE enzymes. So we don't have that. Nor do the great, any of the great apes, the orangutans, for example. All, all of us have elevated uric acid four to five times higher than that of other mammals. Because it was a good thing, it was a good thing for us to become insulin resistant. Think about it, you know, we're always castigating insulin resistance and all those things. You know, you can input whether it's talking to Gary Taubes or Rob Lustig, whoever, and that's in the context of our modern world. But you know, again a survival mechanism. But, but that said, I think we're going to see it. I think more importantly, what we're going to see will be targeting an enzyme called fructokinase and that is the. That's step one. It's so. It's so interesting. That's step one in the changing of fructose through several other intermediates into uric acid. If we can inhibit fructokinase, that will be the home run. There are a group of people who have fructokinase inherited deficiency, and they develop a disease called fructoseuria, where their urine is full of fructose because they can't metabolize it. They can eat sugar all day long. They don't gain weight, they don't develop any metabolic issues. So there's a lot being done to look at what would happen if we inhibited fructokinase.

Wow. So there's a whole pack of pharmaceutical or lifestyle things to do that I want to make sure that listeners. Because I'm seeing questions from the Upgrade Collective. So anyone listening to this lute tioliant. L U T E O L I N. Can you take that every day? And question, what was the dose of luteolin that you recommended?

100 milligrams a day.

100 milligrams a day. So I. I take that almost every day. I don't always take the same thing every day, but that's certainly in my stack.

I don't either. And, you know, I. I was giving a talk recently. They talked about full. You had to do your disclosures because it was a continuing medical education talk, and I had to indicate I was a advisor to a certain CGM company and whatever. And then I said, another disclosure, I don't take the same supplements every day. And another disclosure is on occasion, I've eaten gluten and I'm still here. And another disclosure, my wife and I binge watch shows sometimes on Netflix, truth be known. And believe it or not, yes, we're still here. But.

All right, Doctor, probably, what's your favorite show? You have to tell us that Suits. Suits are hands down.

And the problem is we're at season eight at the end. Oh, we know we're at the end. Anyway, Meghan Markle has probably already met Prince Harry, so I think she had to drop out of the rotation. So we know we're near the end. Anyhow, I mentioned a moment ago that this really critical enzyme called fructokinase is what is needed for fructose to do its dirty work. For fructose to become uric acid and signal the body to really disrupt its metabolism. Uric acid enhances this enzyme, fructokinase, so it stimulates Even more and more of its own production. And we rarely see in physiology a situation where something feeding back actually makes itself even more active. Normally we have what's called feedback inhibition, like we see with insulin regulating blood sugar. In this case, it's so desperately important for our survival that uric acid amplify itself. So, gosh, now that we know that, man, oh man, knowing what your uric acid level is, taking the quercetin, cutting your fructose, taking the luteolin, restorative, sleep, get some monitoring device. I use an OURA ring. I'm not on their board. I'm just saying I do. And it's very helpful. Know how well you're sleeping and really get in touch with your uric acid level and finally take that last edge off in terms of your metabolic challenges.

I love it. I just did a little quick sleuthing as we were going through this, looking at probiotics, and it looks like there are some species of Lactobacillus plantarum, which is a common probiotic. In fact, you probably use plantarum in some of the things that you've created.

All of the things I create?

All the things you created. And there are specific subspecies that grow on buffalo milk, which is probably similar to yak milk, but it's grass fed. It has to be. So likely from grass fed milk. Would be the same from cows or cassava or sweet potato. Right. And cassava and sweet potato are generally lower toxin carbs that I recommend. I think those are ones that you would also recommend that don't have any fructose in them.

Right? Hard to say. I would say probably what you're saying is true. But, you know, fructose in trace amounts is seen in a lot of vegetables, though. The name fructose comes from fruit sugar. And I want to be clear, we're not saying in any way the data does not indicate that we shouldn't be eating fruit. You know, an apple a day keeps the doctor away. Five apples a day, and the doctor you will pay. Meaning, you know, if you want to have an apple, go for it, have an apple. Or to make sure, eat the skin. Cherries are actually a great idea for people who want to control. That's if you look at the. The O on drop acid, that's a cherry and falling from the sky. The indication there is that it's bringing down your uric acid. So tart. Cherry has been used as gout therapy for. For decades. And why? Because it works. It does lower uric acid specifically targets that enzymes Anthea oxidase that's involved in the creation of, of uric acid. I think the other thing I want to just get back to just a moment is the notion that not drinking enough water, you know, grandma said or mom said, you got to drink a lot of water. They said a lot of stuff to us and they always said breakfast was the important meal of the day, most important. But I think, you know, nowadays it's not necessarily what mom told us to eat. But I think the bigger story is when do you break your fast in the day? But, but having said that, you know, the idea of, of eating some fruit is appropriate. You know, an apple has in it some bioflavonoids that are helpful in reducing uric acid formation. Has vitamin C, which helps us excrete uric acid, and it's got fiber that slows our absorption of fructose. So the liver can handle it. We're not going to spill it over into the intestine or where we then absorb it and again pave the way for activating uric acid. So by all means, fruit is still very much on the table. But again, there is nothing really salubius about drinking a 16 ounce glass of fruit juice. It may as well be a Coke.

Well said. And when people give that stuff to kids, it even drives me crazier. Kids don't need that. It's just bad for them. And kids can drink water, right? They have this weird thing called thirst.

That regulates how much water they drink.

Yeah, totally. Who would have thought, right?

It's a great thing to ask somebody. When were you last thirsty and when were you last hungry? That's one of the great things about fasting, for example, is you, you get in touch with being hungry again. And that does two things. Yeah. You know what it feels like to think that you need to eat A and B, you know, hunger, sort of, for me anyway, triggers gratitude because we do have food and we have food whenever we want food, and good food at that. So you can reestablish a relationship with that sense of gratitude by fasting as well.

That, that is something that certainly is in alignment between the stuff that, that we, that we both teach. And it's interesting that your background is neurology as well. So all this, you look at the metabolism because you're also looking at the nervous system and the brain. What do we know about uric acid and lining of the nerves, myelination, neurotransmitters, things like that?

Well, we're just beginning to understand that this process that we're talking about is clearly affecting the brain. And, you know, the fact that it would should not be a surprise for people like you and me, where we've known that metabolic issues have been correlated to declining brain functionality right now and also increasing our risk for things like Alzheimer's in the future. We see strong correlations between excess body fat, high BMI and risk for Alzheimer's. Incredible correlations between even subtle elevations of blood sugar and certainly the hemoglobin A1c, and dementia risk. Hypertension has been talked about as an Alzheimer's risk issue for many, many years. And that said, then, it shouldn't be surprising that uric acid is related to all of those things and therefore clearly related to Alzheimer's risk. Having said that, let me go back to what is called the polyol pathway, that is the body's ability to convert glucose into fructose. Because a recent. And there's several things that will do that. We talked about dehydration. Serum sodium goes up, activates an enzyme, aldose reductase, that turns your blood sugar into fructose because it's a survival mechanism. So that happens in the brain. The brain can convert glucose into fructose and therefore lead to elevation to uric acid that will threaten mitochondrial function. Alzheimer's is a, is at its core, a mitochondrial disease where the brain cells ability to make energy, which is the job of the mitochondria, declines. And these brain cells just basically stop working because they run out of the ability to use fuel. First fuel that they can't use is glucose. That's why there are studies by one gentleman in New Zealand, Matthew Phillips, putting Alzheimer's patients on a crazy diet diet called a ketogenic diet, giving the brain cells an alternative fuel. And he's demonstrating improvement in cognitive function in patients with moderate stage Alzheimer's disease. I interviewed him on my podcast. His name is Matthew Phillips. My point being, though, that the really seminal event seems to be a bioenergetic crisis in the brain of the Alzheimer's patient.

Yep, it's all mitochondria.

Pardon me?

It's all mitochondria. Like, how good are you?

And, and one recent study demonstrated that, you know, we, we think the brain is starved for glucose, but the actual glucose within the brain, but not in the cell, is as much as five fold higher in certain parts of the, of the Alzheimer's brain. The areas that are most involved, the temporal parietal regions, the memory center called the hippocampus, there's actually a backlog of glucose well, where does it go? What does it do? Well, it activates this polyol pathway and gets turned into fructose. Fructose is an alarm signal. It makes uric acid. Uric acid is toxic intracellularly to the mitochondria. Why? Because it wants to slow down the metabolism in the rest of the body to conserve energy, but it's detrimental to the brain. And the initial event here is again, insulin resistance. So however we get there, we're ultimately going to play this forward by through the mechanism of fructose and then uric acid. So getting back to conversations you and I have had for years, we really need to do everything we can not to become insulin resistant, because the brain desperately depends on the function of this hormone, insulin, to allow it to get blood sugar not only into the brain, but also allow blood sugar to do what it does in brain cells. Insulin in the brain is more than just a glucose story, more than a sugar story. Insulin is actually a trophic, nutritious chemical for brain cells. It's the miracle. It's the fertilizer. If you want to grow brain cells in the petri dish, you add insulin. So we tend to lock into our notions of, oh, insulin drives the blood sugar into the cell. What's the next question? No, no, we still need to unpack. Insulin. It does a lot of other things in the body. It signals the body to make fat, as an example. So all this stuff's coming together, and the incredible role that uric acid is playing in insulin resistance is really breathtaking. Uric acid is the signal telling our bodies to become insulin resistant and how it does it. One of the important mechanisms is, and I'm getting deep into the weeds, but I know that your guys are probably loving this. Uric acid, when it's elevated, shuts down the production and functionality of something called nitric oxide in the blood vessel.

It turns out everyone in the audience knows about nitric oxide because we did a couple episodes and people just want to talk about it. Right directions, just over and over. So that's got.

Elevated Uric acid is associated with a 34 increased risk of erectile dysfunction.

There you go, guys.

See, uric acid facilitates nitric oxide. We need nitric oxide. So blood vessels, not just in the penis, but in the. That supply the heart and the kidneys and the liver and the brain. Yeah, we need to supply our organs. When we can't keep nitric oxide functioning, we. We increase our risk. I mentioned earlier, of death from stroke. 35% increased risk when uric acid is elevated. So how does Viagra work? It increases how nitric oxide is able to do its job and allow blood vessels to dilate. That's what you need for an erection. And two very large studies came out just last month demonstrating a 70% reduction in Alzheimer's risk in men who regularly use Viagra. Now, I'm not promoting Viagra as an anti Alzheimer's regimen. This was a study looking at medical records of more than a million men. But what I am saying is we have to keep nitric oxide working. And when we now recognize that uric acid does its dirty work by compromising nitric oxide, you darn right you want to get your uric acid levels down.

Wow. This really is the smoking gun behind almost all of the things that people are looking to reduce through biohacking. The stuff that makes you not live longer. And I. I'm actually experimenting with taking between a 10% and a 25% dose of sildalafil, basically the Cialis, in order to enhance nitric oxide activity after all the studies on Alzheimer's disease and whatnot. The reason being that when I take the normal things that people say should work like beetroot, it tends to go down the inducible NOS pathway, which creates peroxy nitrite, which is highly inflammatory.

Well said. Absolutely.

Beets make you feel like shit. It's okay, don't eat them. Not to mention the other oxalic acid problem, which leads me to my next question. Oxalic acid versus uric acid and gout.

Talking about.