#261 – Uric acid-raising foods to avoid for metabolic, gut, and overall health | Dr. David Perlmutter & Dr. Casey Means

High uric acid can cause gout, but it’s also a marker for worsened metabolic health and gut health and a contributor to neurodegenerative diseases, such as Alzheimer’s. Consumption of purines can lead to high uric acid levels, but other ingredients in our food system are also culprits. Dr. David Perlmutter and Dr. Casey Means discuss the problems with high uric acid, the foods and drinks that can lead to higher levels, why uric acid can be a driver of worsened brain health, and concerns regarding leaky gut and the immune system.

Helpful links

David Perlmutter, MD: https://drperlmutter.com

David Perlmutter, MD, books (Drop Acid, Brain Wash, Brain Maker, Grain Brain, etc.): https://drperlmutter.com/learn/books/

David Perlmutter, MD, on Instagram: https://www.instagram.com/davidperlmutter/

David Perlmutter, MD, on Twitter/X: https://x.com/DavidPerlmutter

Casey Means, MD: https://www.caseymeans.com/goodenergy

Good Energy: The Surprising Connection Between Metabolism and Limitless Health: https://www.caseymeans.com/goodenergy

Casey Means, MD, on Instagram: https://www.instagram.com/drcaseyskitchen/

Casey Means, MD, on Twitter/X: https://x.com/CaseyMeansMD

4:24 — Why your uric acid level matters for metabolic health

Uric acid has long been a biomarker for determining if someone has gout. However, a high uric acid level can be a risk factor for other conditions.

Uric acid is a central regulator of metabolism, and what I mean by that is that uric acid is a way that the body is instructed in terms of so many different pathways that are involved in the process of using energy sources to create energy so that can be viable. That’s really very, very important because of its central role in metabolism. It therefore regulates things like inflammation. It even regulates things like the complexion of the gut bacteria. Who knew? So uric acid is a huge player in terms of our immune system physiology and in terms of our path of physiology across a wide spectrum of chronic degenerative conditions, well beyond gout, including cognitive decline, cardiovascular disease, diabetes, dysregulation of insulin and elevation of blood glucose, inflammation, as I mentioned, and even more interesting from my perspective based upon where my work is going these days: elevation of uric acid is damaging to the function of our cells’ energy providers called the mitochondria, meaning that when uric acid level is elevated, it’s messing up the way our cells can use fuel for energy. And that is a bad thing.

8:02 — Fructose is a driver of high uric acid levels

As an ancient survival mechanism, fructose is directly metabolized into uric acid.

Sugar fructose is directly metabolized into uric acid. This is a survival mechanism for us. In our ancient times, when we would have fructose—meaning fruit sugar—it meant that because fructose comes from ripened fruit in the late summer, early fall, it meant that winter was coming, a time of food scarcity. And having said that, this is a way that our environment would cue us in to make some physiological changes so that we could survive when there was less food available. So we eat the ripened berries that we might find as we are hunting and gathering, and suddenly in our diets there’s fructose and it triggers uric acid level to get higher and that higher level of uric acid does some important things in human physiology that allowed us to survive. It allows our body to make and store fat, which nowadays is not really ideal. But when you’re facing starvation, that’s really very important. It raises the blood sugar from turning on a process called gluconeogenesis, glucose sugar neogenesis creation in the liver to give us more blood sugar to power our brain so that we can avoid predation … and starvation for obvious reasons. And third—I mentioned it before—this elevation of uric acid threatens the function of mitochondria, reduces our energy utilization, which when we’re trying to conserve calories is a good thing. But nowadays, we are triggering this survival pathway 365 days a year because of our constant exposure to fructose.

11:52 — High-fructose corn syrup contributes to the obesity epidemic

High-fructose corn syrup was introduced to the food and beverage industry in the 1970s and has been contributing to rising rates of obesity.

A lot of people are out there right now confused about why do we have an obesity epidemic? Why are 50% of adults and upwards of 30% of teens obese? We’re literally eating ourselves to death. And a lot of the mainstream media would make us think this is so confusing: we don’t really know why. And I love that you really cut the noise here. High-fructose corn syrup was invented in the 1970s. It’s now in most of the products in the grocery store. It’s creating uric acid, damaging our mitochondria, causing us to not use energy properly. And we 3D print fat. And it’s a weaponization of a non-natural form of this molecule that is damaging the fundamental way that we power our bodies and therefore shunting us towards fat storage.

13:18 — The key difference between fruit and fruit juice

A serving of whole fruit doesn’t overload the intestine with fructose the way that fruit juice or beverages with high-fructose corn syrup do.

Let me first say, we’ve got to stop drinking fruit juice. Can you imagine a doctor saying that? Yes, we’ve got to stop drinking fruit juice and we’ve got to stop giving it to infants in their bottles … I think an apple a day is a good idea. We’ve known known that aphorism for a long time because there really isn’t a huge amount of fructose in an apple depending of course on the size and the type of apple, but it’s about five grams. It is delivered in a way that it does slow its availability. The fiber and vitamin C that apples contain also help us excrete uric acid. So have an apple or two a day. It will keep the doctor away. It’s not an onslaught. Our small intestine can handle about five grams of fructose at any given moment.

23: 32 — What is an optimal uric acid level?

David Perlmutter, MD, recommends aiming for a uric acid level of 5.5 or less.

I think that 5. 5 is not really aggressive. It was a level that I and Dr. Richard Johnson settled on based upon review of literature and also what is pretty easily achievable by most people. Having said that, there are some interventions that people can engage if there is a bit of a recalcitrance of that uric acid to come down. Diet can be leveraged in hopes of bringing that uric acid level down a little bit further. They include the addition of things like quercetin. Quercetin 500 milligrams per day, along with luteolin 100 milligrams per day, perhaps some vitamin C 500 milligrams per day. These are really very helpful in finalizing getting that last little push to get that uric acid level down. You can expect maybe half a point, or I’ve seen some people as much as a full point drop just by starting those nutritional supplements.

26:39 — Alcohol consumption contributes to higher uric acid levels

Regarding alcohol, beer is the biggest offender when it comes to raising uric acid levels.

Uric acid is made from alcohol, but I think it’s like fat. When we talk about, “Well, you should eat fat, you shouldn’t eat fat,” well, no, we need to talk about what kind of fat. And the same kind of paradigm exists as it relates to alcohol. In women more than men, there’s actually a benefit of drinking wine in terms of lowering uric acid, within reason, two drinks or two glasses of wine. Men don’t really get that benefit. Hard alcohol tends to raise uric acid pretty significantly in both men and women, and beer being the worst. Beer is the most offensive, raising uric acid quite substantially—the thought being that, yes, beer is an alcoholic beverage, but beer contains a lot of those purines, the breakdown products of cells, because it’s made with brewer’s yeast, and yeast is a very hypercellular kind of thing. So you’re getting both purines and alcohol in beer … My vote is that women do not consume alcohol during pregnancy. And I think that adults should be reducing, if not eliminating, their alcohol consumption. There is an upside of the socialization and perhaps some of the polyphenols in red wine. I get that. But I think the neurotoxic effects of alcohol are very real and we can no longer ignore that.

30:12 — Ultra-processed foods contribute to higher uric acid levels

Ultra-processed foods make up a substantial portion of the standard American diet and can drive disease processes.

Anything that raises blood sugar will ultimately increase fructose and raise uric acid. Why so? Because we have a survival pathway in the body called the polyol pathway. And through the action of an enzyme aldose reductase—if anybody wants to put that on the quiz—we are actually able when blood sugar is elevated to shunt some of that blood glucose to actually form fructose. And that fructose then, as mentioned, metabolizes into uric acid. So, you know, these are all of the things that you’ve been talking about for the past several years that will raise blood sugar, including these ultra-processed foods will actually raise uric acid as well through this and other pathways. For me, it really closes the loop to then understand the relationship between these ultra-processed foods now making up about 58% of calories consumed by the average American adult on a daily basis, 58% coming from these highly ultra-processed foods. It really helps us close the loop in terms of understanding the relationship of the consumption of these foods to the metabolic issues like brain changes and cardiovascular disease and certainly type 2 diabetes and weight gain that we see. We know there’s a relationship between higher consumption of these ultra-processed foods and even risk for certain forms of cancer and the cognitive issues and threats to the brain begin at a much lower level.

39:03 — Gut permeability can challenge the immune system

Dr. Perlmutter discusses leaky gut syndrome.

Keep in mind that the master regulators of gut permeability are the bacteria living within the gut. This is one of their most important functions and that is maintaining gut-wall integrity. And there are various species that are directly involved with that, like Lactobacillus plantarum, for example, and the new kid on the block Akkermansia muciniphila. These are bacterial species that are involved in the maintenance, keeping those walls up to keep the invaders out. When I say “invaders,” I mean all kinds of things: yes, pathological organisms, that for sure, but even the breakdown products of some of the normal bacteria that live within the gut, that normally stay in the gut. But when the gut is permeable, those products of bacterial breakdown can make their way in through the wall, challenging the immune system, and set us up for big issues.

49:14 — Immunometabolism is the link between our metabolism and immune system

The metabolism of our immune cells determines whether they are beneficial or harmful.

There’s a term called “immunometabolism.” I just think is a beautiful term because it relates the function of our immune systems to our metabolism but also lets us begin to understand that how our immune cells metabolize—in other words, how they make energy—regulates how they function. Maybe people don’t get it yet, but let me walk through it because it’s huge in terms of what you and I are going to talk about a year from now and five years from now. It’s huge. It’s really very, very important because it turns out that the metabolism of various immune cells regulates whether they’re going to be helpful or hurtful, whether they will be the angel or the assassin in the peripheral part of our body. We call them the macrophages, and they exist in multiple forms.

56:28 — What causes immune cells in the brain to become dysfunctional?

High blood sugar and insulin resistance corrupt microglial cells.

Some of the worst things we can do for our microglia are allowing our blood sugar to elevate and allowing us to become insulin resistant. That immediately tends to shift those microglial cells from being friend to foe. So for all of those who are interested in looking at their blood sugars and doing the best they can to keep their blood sugars under control that are wearing continuous glucose monitors and having their A1Cs checked frequently—this becomes really important through the notion of understanding what you are doing to change, either for the good or for the bad, the function of these brain immune cells. Microglial activation, in other words, the shift from good to bad, is central to chronic neurodegenerative conditions like Alzheimer’s, like Parkinson’s, like multiple sclerosis.

David Perlmutter (00:00:00):

One can only wonder why it was that the textbooks that we were given and the websites more recently of the major clinics have said No, it’s purines and alcohol and really kind of avoided what clearly is the biggest threat in terms of raising our uric acid levels. And that is the sugar fructose. Sugar fructose is directly metabolized into uric acid. And interestingly, we’ve connected this dietary shift in human nutrition favoring much higher levels of fructose to the elevation of uric acid, which puts the body into survival mode and threatens our health.

Ben Grynol (00:00:55):

I’m Ben Grynol, part of the early startup team here at Levels. We’re building tech that helps people to understand their metabolic health and along the way, we have conversations with thought leaders about research-backed information so you can take your health into your own hands. This is a whole new level.

Casey Means (00:01:24):

Hello and welcome to A Whole New Level. My name is Dr. Casey Means. I am one of the co-founders of Levels and I am here today with Dr. David Perlmutter, Levels advisor and absolute luminary in the field of metabolic health. Dr. Perlmutter is a board-certified neurologist and a five-time, New York Times Bestselling author. He’s written Grain Brain, Brain Maker, Brain Wash, Drop Acid, and several other books. He serves on the board of directors and is a fellow of the American College of Nutrition. He’s a world expert on the intersection between neurology, gut health, mental health, dementia, metabolic health and nutrition. He’s on the editorial board of the Journal for Alzheimer’s Disease and has published extensively in peer-reviewed journals. He speaks all over the world at conferences and at leading universities and institutions. This episode is incredible. You’re in for a treat. We follow up on many of the questions that came up during our first episode together about his book Drop Acid, which was all about uric acid and metabolic health. And that video got over three million views.

(00:02:34):

And so we’re going to get into some of the key questions that came out of that episode, like what specific foods impact metabolic health, what specific lifestyle activities impact metabolic health, whether a carnivore and keto diet are good for uric acid? What about fruit and fruit juice? We go all over to really flesh out the full picture, very actionable. We also talk about leaky gut and gut health and how that relates to inflammation and metabolic health. And very excitingly, we talk about a new interest in Dr. Perlmutter’s research and world, which is about the intersection between gut health, immunity, inflammation, the brain, metabolic health, and really, the future of how we think about mental illness and neurodegenerative diseases like Alzheimer’s through the lens of metabolism and the inflammatory cells of the brain. It’s absolutely fascinating, tip of the spear information and he even gives some really actual tips for how to protect our brain health, now and in the future. I so hope you enjoy this incredible conversation with Dr. David Perlmutter. Dr. Perlmutter, we are back. I am so excited to see you. Welcome back to A Whole New Level.

David Perlmutter (00:03:55):

I’m so excited. I think we had such a great time last time. We covered some really interesting information and it was several months back and there’s been a lot of evolution in that science, so I’m delighted to be with you.

Casey Means (00:04:07):

I can’t wait to talk about what’s next for you, what you’re thinking about in health. And our last episode together on uric acid, we dove deep into your groundbreaking book, Drop Acid. That video has over three million views. People were fascinated by that. So I think just to kick off, let’s recap a little bit about uric acid. People had a lot of questions, more they wanted to learn. Let’s just start with the basics. Why is uric acid so important and what levels should people be shooting for, both men and women, for optimal uric acid levels?

David Perlmutter (00:04:36):

Well, an overview would be that we always thought uric acid was something you needed to check in terms of gout. If your uric acid levels elevated, then those crystals of this uric acid can precipitate out in your joints, et cetera, and you get gout and it hurts. And that’s why you need to know your uric acid level. That’s what you learned and that’s what I learned in medical school. And it’s true, but what we were myopic about is the notion that uric acid is playing a far more important role than just giving us pain in the toes from time to time. Uric acid is a central regulator of metabolism and what I mean by that is that uric acid is a way that the body is instructed in terms of so many different pathways that are involved in the process of using energy sources to create energy and so that our cells can be viable.

(00:05:31):

And that’s really very, very important. Because of its central role in metabolism, it therefore regulates things like inflammation. It even regulates things like the complexion of the gut bacteria. Who knew? So this uric acid is a huge player in terms of our physiology and in terms of our path of physiology across a wide spectrum of chronic degenerative conditions, well beyond gout, including cognitive decline, cardiovascular disease, diabetes, dysregulation of insulin and elevation of blood glucose, inflammation as I mentioned. And even more interesting from my perspective based upon where my work is going these days, that elevation of uric acid is damaging to the function of our cells’ energy providers called the mitochondria. Meaning that when uric acid level is elevated, it’s messing up the way our cells can use fuel for energy and that is a bad thing. I think that’s probably what you and I are going to focus on for the next, who knows how long.

(00:06:39):

But the point is that we need to know our uric acid levels just as we need to know our blood sugar levels, our average blood sugar levels, our blood pressures, our body weight, et cetera. It’s one of those fundamental parameters. When Drop Acid came out and we presented 400 references about why this is reality, I think it caught a lot of mainstream medicine off guard not recognizing that, hey, this is a new player that we didn’t really understand in medical school, but now I think it’s been really substantiated, which is always good when you write a book that the stuff that follows, supports your original hypothesis and contention. So now, people are getting their uric acid levels checked quite regularly, more than just their annual blood tests. We like to see levels in men and women and children at 5.5 or below. Now typically, if you get a uric acid level from the lab, the normal range is going to say anything below seven.

(00:07:39):

And that really relates to gout. As it relates to cardiovascular risk and other things that I had just mentioned, those risks begin at a lot lower level at 5.5, and so we want to do everything we can to keep uric acid under control. And to summarize briefly, which is I think what you’re wanting to know, what are the biggest [inaudible 00:08:02] that these days are causing elevation of uric acid? And you and I learned while it’s these purines that are the breakdown products of animal products and certain vegetables as well that contribute to make uric acid, well, we were steered off the scent, off the track, for reasons that we could speculate on because the reality is, it’s fructose. It’s a type of sugar that is ubiquitous now in the Western diet, really the global diet now, to sweeten up our foods. And one can only wonder why it was that the textbooks that we were given and the websites more recently of the major clinics have said, “No, it’s purines and alcohol,” and really kind of avoided what clearly is the biggest threat in terms of raising our uric acid levels.

(00:08:51):

And that is the sugar fructose. Sugar fructose is directly metabolized into uric acid. And interestingly, this is a survival mechanism for us, that in our ancient times when we would have fructose, fructose meaning fruit sugar, it meant that because fructose comes from ripened fruit in the late summer, early fall, it meant that winter was coming, a time of food scarcity. And having said that, this is a way that our environment would cue us in to make some physiological changes so that we could survive when there was less food available. So we eat the ripened berries that we might find as we are hunting and gathering, and suddenly in our diets there’s fructose and it triggers uric acid level to get higher. And that higher level of uric acid does some important things in human physiology that allowed us to survive. It allows our body to make and store fat, which nowadays is not really ideal. But when you’re facing starvation, that’s really very important.

(00:10:01):

It raises the blood sugar from turning on a process called gluconeogenesis, gluco, sugar, neo, new genesis creation, in the liver to give us more blood sugar to power our brains so that we can avoid predation, meaning we’re not going to be a meal for somebody and starvation, for obvious reasons. And third, mentioned it before, is this elevation of uric acid threatens the function of mitochondria, reduces our energy utilization, which when we’re trying to conserve calories is a good thing. But nowadays, we are triggering this survival pathway 365 days a year because of our constant exposure to fructose. Fructose is by far and away, the most widely used sweetener because it’s really, really sweet. You don’t have to use a lot of it and it’s really, really cheap. And our government tends to support the growth of corn, which is from where… We get a lot of fructose through the creation of something called high fructose corn syrup. So I think back at a time in February 21st 2021 when you and I wrote an op-ed in, was it MedPage Today, I think, right?

(00:11:22):

Really just calling out the notion that we’re supporting the provision of this dangerous sugar to the American population and saying that it’s okay for 10% of calories to come from added sugar. Yikes, that was certainly good for the industry, that’s for sure. But in terms of our health, that is what sets the stage for our most pervasive chronic degenerative conditions that according to the World Health Organization, are the number one cause of death on planet earth. Via this question, we’ve connected this dietary shift in human nutrition, favoring much higher levels of fructose to the elevation of uric acid, which puts the body into survival mode and threatens our health. So it’s where information becomes extremely empowering to recognize that this is happening, to read the labels, to understand that there’s 36 grams of sugar in a 12 ounce glass of orange juice from Florida with great vitamin C and fiber. Well, let’s be clear. These are powerful onslaughts of and assault on our physiology with this incredible signaling molecule, fructose, that becomes the uric acid, which is where you and I started today.

Casey Means (00:12:56):

This is Dr. Casey Means, co-founder of Levels. If you’ve heard me talk on other podcasts before, you know that I believe that tracking your glucose and optimizing your metabolic health is really the ultimate life hack. We know that cravings, mood instability and energy levels and weight are all tied to our blood sugar levels. And of course, all the downstream chronic diseases that are related to blood sugar are things that we can really greatly improve our chances of avoiding if we keep our blood sugar in a healthy and stable level throughout our lifetime. So I’ve been using CGM now, on and off for the past four years since we started Levels and I have learned so much about my diet and my health. I’ve learned the simple swaps that keep my blood sugar stable like flax crackers instead of wheat-based crackers. I’ve learned which fruits work best for my blood sugar. I do really well with pears and apples and oranges and berries, but grapes seem to spike my blood sugar off the chart.

(00:13:55):

I’m also a notorious night owl and I’ve really learned with using Levels, if I get to bed at a reasonable hour and get good quality sleep, my blood sugar levels are so much better and that has been so motivating for me on my health journey. It’s also been helpful for me in terms of keeping my weight at a stable level much more effortlessly than it has been in the past. So you can sign up for Levels at levels.link/podcast. Now, let’s get back to this episode. You know, a lot of people are out there right now confused about why do we have an obesity epidemic? Why are 50% of adults and upwards of 30% of teens obese? We’re literally eating ourselves to death. And a lot of the mainstream media would make us think, this is so confusing, we don’t really know why. And I love that you really cut the noise here. It’s like [inaudible 00:14:54] corn syrup was invented in the 1970s. It’s now in most of the products in the grocery store. It’s creating uric acid, damaging our mitochondria, causing us to not use energy properly.

(00:15:02):

We 3D print fat and it’s a weaponization of a non-natural form of this molecule that is damaging the fundamental way that we power our bodies and therefore, shunting us towards fat storage, which like you said, in the past that would’ve been useful for an animal preparing for winter and need to hibernate and build fat. But right now, it’s playing out every day in every breakfast table in America and you are sounding the alarm on what’s happening and how simple this is to actually get on top of with food. So I’d love to talk a little bit more in detail about diet because we got a lot of questions after our first episode about what do people really need to be eating. What I’m hearing here is we need to cut the liquid fructose, obviously, but what about the fructose in fruit? This was a big question we got. Does the natural fiber in fruit mitigate this issue we’re dealing with with fructose. Is it really the high fructose corn syrup we need to worry about? How should people think about fruit when it comes to uric acid?

David Perlmutter (00:15:57):

It’s a great question. Let me first say, we’ve got to stop drinking fruit juice. Can you imagine a doctor saying that? Yes, we’ve got to stop drinking fruit juice and we’ve got to stop giving it to infants in their bottles. I mean, that is absurd. Is fruit something we should consume? I think yes. I think an apple a day is a good idea. We’ve known that to aphorism for a long time because there really isn’t a huge amount of fructose in an apple, depending of course on the size and the type of apple, but it’s about five grams. And as you mentioned, it is delivered in a way that it does slow its availability because of the fiber and because vitamin C that apples contain also helps us excrete uric acid. So have an apple or two a day. It will keep the doctor away and this is not an onslaught.

(00:16:51):

Our small intestine can handle about five grams of fructose at any given moment, but when you suck down a big gulp or whatever it is, a soda that is your favorite, some of them have incredible amounts of sugar. I mean, it’s mind-boggling and energy drinks, sports drinks. You think, well, I’m going to the gym, I’m having a sports drink. I watched that happen at my gym because there’s a vending machine and you talk about offsetting the value of your workout. That’s a really good way of doing that. It’s a huge override in terms of what the small intestine is able to deal with so that fructose is absorbed and then is directly shunted to the liver, where the processes that I just overviewed are activated and it’s very, very worrisome. I think I really want to call out Good Energy because you did such an excellent job in that book, you and your brother, of really just making it very clear what an assault this has become on our health and importantly, our children’s health.

(00:17:58):

I mean, we were just setting children up for all the damaging metabolic issues that are so pervasive in adults. And I have to say, people say to me, well, when should people start the Alzheimer’s prevention diet? Because we know that, and I’m being a bit tangential here, I understand. We know that the metabolic changes in the brain take place 20 to 30 years prior to the beginnings of cognitive decline. And again, let me reiterate that, that what’s going on in the Alzheimer’s brain begins two to three decades prior to forgetting the Wi-Fi code and your grandchildren’s names. That’s when people seek assistance from a doctor for a medication which does not exist. So these issues take place two to three decades ahead of time. To respond to when should we begin the Alzheimer’s prevention diet, well, maybe it’s two to three decades prior to when Alzheimer’s typically presents. So maybe we should start paying attention in our thirties and forties.

(00:18:59):

And I won’t respond with that answer any longer for reasons that you and your brother called out In Good Energy and and that is because of what’s going on with children, that we are setting the stage for metabolic dysfunction in adolescence, in children and even in infants. And the reality is that there are things going on in utero that play a role in an individual’s lifelong metabolism that are important and are modifiable. And even method of birth is important as it relates to inflammation in the body and metabolism, vaginal birth versus cesarean section. We live in a country where about a third of births are C-section, and it’s clearly hard to imagine that a third of pregnancies are that complicated that a C-section is required. I think that there are other reasons that C-sections are so prevalent here in America, but understand that the mode of delivery is really fundamental as it relates to the influential microbiome, i.e. the bacteria living within the gut and upon the surface of the body, and in the mouth as well.

(00:20:13):

These are all highly influenced by the method of birth. When a child is born vaginally, that child is anointed with a specific set and array, a diversity, a functionality, a family of organisms that sets the seeds in place to grow that microbiome. When a child is born by C-section, then he or she gets bacteria from whatever’s floating around the operating room or on the surgeon’s gloves or gown, and those are not necessarily one would expect the best for the developing microbiome of that newborn. It’s the reason we see the correlations of cesarean section with significantly higher risk for things like autoimmune conditions including Type 1 diabetes, so getting right back to metabolism. So when do we begin the inflammation/Alzheimer’s/metabolism diet? And I think very, very early, and again, I want to thank you for calling that out In Good Energy.

Casey Means (00:21:18):

Yes, in utero. I mean, I love that and it’s just so important and such an eye-opening thing. I’m in the year or two before hopefully having children and I’m just, so much of what I think about now, which I was not thinking about 10 years ago when I was in the conventional healthcare system, is how is my diet and lifestyle actually setting me up to be able to have ideally, the most natural birth possible because of what we’re learning about modifiable factors in mothers and in pregnancy, method of delivery, and then lifelong metabolic trajectory for kids. And so I love that you talk about that and find a way to weave all of this together in such a beautiful way.

David Perlmutter (00:21:58):

I would say that this method of delivery discussion is profoundly important and the issue is that how a woman chooses in terms of lifestyle issues prior to delivery, really sets the stage for complications or not, depending on is she exercising? Is she sleeping enough? What’s her alcohol intake? What are her medications looking like? What her recreation drugs looking like? So many factors. I mean, go into whether or not that’s going to be a healthy pregnancy and therefore ,more likely to end up as a vaginal delivery.

(00:22:37):

So these are, it’s not well, you need to take a multivitamin, make sure you got a lot of folate in there, and… We’ve got to do better than that. We’ve really got to emphasize to women that what’s going on during that pregnancy and delivery are going to be fundamental as it relates to that new child, new human being’s health for the rest of her or his life. And there’s a lot to discuss there. And I think that the notion of just capriciously recommending a C-section without the discussion of the long-term consequences saying, “Well, you know, you’ll have a scar and then the next child, maybe that has to be C-section because you did one.” We got to do better than that, I believe.

Casey Means (00:23:18):

Beautiful. So a couple other questions that we got about diet and uric acid. There’s definitely a trend towards people being very passionate about regenerative meat and keto and carnivore, and just eliminating the sugar altogether. But as you said, purines and these foods that, animal-based products can also cause the production of uric acid. But you alluded to that really not actually being the core of the problem, it’s the fructose. So what would you say about different diets like keto and carnivore and how they impact uric acid levels, and how can someone on these diets think about their uric acid levels and how to manage them effectively?

David Perlmutter (00:23:53):

I think that as it would be with measuring blood sugar, I think it really depends on how any particular diet is affecting that individual, i.e., they should be checking their uric acid levels and see. We do know that an aggressive ketogenic diet can, in fact, raise uric acid transiently, that that seems to subside and actually then improve, in comparison to baseline once that hardcore ketogenic diet is left behind. Certainly fasting because of the fact that tissues are being broken down, will liberate purines from the cells of your body as those tissues, muscle in particular, are being broken down and will raise uric acid.

(00:24:36):

But fasting ultimately seems to improve uric acid in comparison to baseline as well. But again, as it relates to what would be the best recommendation, I think this is where personalized medicine comes into play, knowing that we can check our uric acid levels at home with a simple finger stick and if we decide we’re going to make a significant dietary change, that would be something along with looking at your blood glucose that you’d want to know, how is this new regimen affecting my blood sugar and how is it affecting my uric acid level?

Casey Means (00:25:08):

And some people will actually say that on a ketogenic diet, they actually will tolerate a slightly higher fasting glucose level, so like upper nineties, maybe even low hundreds because insulin is so low and it may be having an impact on gluconeogenesis but not in a pathologic way. Do you find that there’s anything with having a slightly higher uric acid level on a particular diet if it’s an otherwise very metabolically healthy diet, very low insulin levels, that that there’s some leeway there or do you really want to see people pretty firmly in that tighter range, below 5.5 most of the time?

David Perlmutter (00:25:42):

I think that 5.5 is not, respectfully, is not really tighter range. I think that when we look at what’s happened as average uric acid levels have climbed dramatically since the 1920s in lockstep with fructose consumption I might add, or sugar consumption prior to high fructose corn sharp becoming so ubiquitous. So I think that we’re, that at 5.5 is not really aggressive. It was a level that I and Dr. Richard Johnson settled on based upon review of literature and also what is pretty easily achievable by most people.

(00:26:20):

Having said that, there are some interventions that people can engage that if there is a bit of a recalcitrance of that uric acid to come down based upon the current diet, can be leveraged in hopes of bringing that uric acid level down a little bit further. They include the addition of things like quercetin. Quercetin, 500 milligrams per day along with luteolin, 100 milligrams per day, perhaps some vitamin C, 500 milligrams per day. These are really very helpful in finalizing, getting that last little push to get that uric acid level down.

(00:26:55):

So you can expect maybe half a point… I’ve seen some people as much as a full point drop, just by starting those nutritional supplements. But I think 5.5 is typical. I mean, there are some people who have polymorphisms of you’re at one gene and as such, are going to have by virtue of their genetics, going to have higher uric acid levels. And these are the people, who despite the supplements and the dietary changes, still have a significantly elevated uric acid and they may need medication. They may need something called allopurinol, and I’m in favor of that, even if they haven’t had a gout flare-up.

(00:27:34):

I think when you see a patient with a uric acid level of 7 or 8, who’s on a low fructose diet, maybe taking some [inaudible 00:27:42], et cetera, I think it needs to be treated because there are a lot of downstream consequences, even high blood pressure related to having elevated uric acid. So uric acid by virtue of the fact that it stimulates lipogenesis, the formation of body fat, ultimately will lead to increased production of metabolic water and actually through that mechanism and through a mechanism involving something called vasopressin, actually increased blood pressure. I can think of several individuals who just by lowering their uric acid, had improvements of their blood pressure.

Casey Means (00:28:19):

Very interesting. Great to hear those actual suggestions too with supplements, if people have some uric acid that’s having trouble getting into the levels they want. I’m curious, being a neurologist, a metabolic health expert, a uric acid expert amongst many other things, your thoughts on alcohol. Because I know that beer, in particular, can have an impact on uric acid, but as you triangulate all these different fields that you think about so deeply, where have you landed on alcohol as it pertains to both uric acid, metabolic health and risk for dementia?

David Perlmutter (00:28:57):

I haven’t landed on alcohol. Maybe later today. I don’t know. My position has changed a bit over the years, and that’s a good thing that we change our messaging based upon research. Uric acid is made from alcohol, but I think it’s like fat. When we talk about, well, you should eat fat, you shouldn’t eat fat. Well, no, we need to talk about what kind of fat and the same kind of paradigm exists as it relates to alcohol, that in women more than men, there’s actually a benefit of drinking wine in terms of lowering uric acid within reason, two drinks or two glasses of wine. Men don’t really get that benefit. Hard alcohol tends to raise uric acid pretty significantly in both men and women, and beer being the worst. Beer is the most offensive, raising uric acid quite substantially. The thought being that yes, beer is an alcoholic beverage, but beer contains a lot of those purines, the breakdown products of cells, because it’s made with brewer’s yeast and yeast is a very hypercellular kind of thing.

(00:30:01):

So you’re getting both purines and alcohol in beer. And interestingly in Japan, they’ve known about this for quite some time, that it raises uric acid and have now created purine-free beer. So beer has significantly less alcohol than hard spirits and wine, pretty much. So there may be a way. Having said that, I think there’s no alcohol that is safe during pregnancy. It used to be, well, you might have a glass of wine or two, the benefits of the relaxation, et cetera, are good. My vote is that women do not consume alcohol during pregnancy and I think that adults should be reducing, if not eliminating their alcohol consumption. There is an upside of the socialization and perhaps some of the polyphenols in red wine, I get that. But I think the neurotoxic effects of alcohol are very real and we can no longer ignore that. So my vote is that we should really minimize our alcohol consumption.

Casey Means (00:31:06):

Okay. That’s where I feel like I’m landing more and more as well. Just I feel like sometimes there’s this confusion around or not confusion, it just it gets complex with like, okay, some wine may help with metabolic health, but how is that data done? And then the neurotoxic effects for dementia, and I mean, overall, it feels like the train is moving towards, we’re drinking too much as Americans. We’re just drinking far too much and we need to be reducing or getting closer to eliminating. So it’s really helpful to hear your perspective on that.

David Perlmutter (00:31:35):

Yeah, and if you drink two glasses of wine a day, it doesn’t seem like a lot. Fill it up once and then one more time. You are considered a moderate alcohol consumer. That’s moderate alcohol consumption and when you read the literature, what is moderate alcohol consumption associated with? So again, so I think that your positioning or change in positioning, is reasonable.

Casey Means (00:31:56):

Yeah. So I’m curious, closing out the conversation on uric acid and moving to some other topics around gut health. Just curious, aside from high fructose corn syrup that has been skyrocketing and sugar intake of this liquid form, we’ve also been eating so many refined grains in our country. Do refined, ultra-processed grains like white flour, that’s in so much of the processed food, does that have any impact on uric acid? Or because it’s not actually fructose, that it’s converting to in the bloodstream, it’s less of a impactor on this one, like gluten-refined grains?

David Perlmutter (00:32:32):

Here’s the answer to that. Anything that raises blood sugar will ultimately increase fructose and raise uric acid. Why so? Because we have a survival pathway in the body called the polyol pathway and through the action of an enzyme, aldose reductase, if anybody wants to put that on the quiz, we are actually able, when blood sugar is elevated, to shunt some of that blood, glucose to actually form fructose and that fructose then, as mentioned, metabolizes into uric acid.

(00:33:03):

So these are the things, all of the things that you’ve been talking about for the past several years that will raise blood sugar, including these ultra-processed foods, will actually raise uric acid as well through this and other pathways. For me, it really closes the loop to then understand the relationship between these ultra-processed foods now making up about 58% of calories consumed by the average American adult on a daily basis, 58% coming from these highly ultra-processed foods.

(00:33:36):

It really helps us close the loop in terms of understanding the relationship of the consumption of these foods to the metabolic issues, like brain changes and cardiovascular disease and certainly Type 2 diabetes and weight gain that we see. We know there’s a relationship between higher consumption of these ultra-processed foods and even risk for certain forms of cancer and the cognitive issues and threats to the brain, begin at a much lower level.

(00:34:05):

Probably all of the other issues do as well. But I’m referring to a recent article that looked at even 28% of calories coming from ultra-processed foods, poses a significant threat. Why so? For the reasons that I mentioned, but also because of what elevated blood glucose is going to do and I knew we were going to get together today. I think it’s really kind of valuable to ask ourselves, well then, what is the mechanism here? We say that having an elevated blood sugar is a bad thing for the brain. That’s what we’ll talk about. But why? I mean, what in the heck is going on in the brain? Maybe we could go there, but maybe you have a different agenda. So I don’t mean to steer the conversation.

Casey Means (00:34:49):

Oh no, I love that. I would love to talk about that because I think that’s going to really lead into talking about the brain’s immune system, inflammatory triggers, metabolic health, which I know you’re thinking about. So I will circle back to that, for sure, at the end of this conversation. I know people are going to want to know this question. How often should I check my uric acid and how can I check it? What’s the sort of quick high level on how people should be thinking about testing?

David Perlmutter (00:35:15):

Well, you could buy one of these things. This is a uric acid monitor and there, I don’t know if that’s backwards or forwards, that’s my last level. I don’t know if you [inaudible 00:35:25] 4.7. Yeah, and so this is… You know, you put a drop of blood on a strip, it’s in the machine and you get a reading. So it’s really quite simple and I think every six weeks, every eight weeks is reasonable, unless you engage in some kind of significant dietary change and you’re curious. I think that’s perfectly reasonable.

(00:35:44):

I would recommend that when you do check your uric acid levels at home, a couple of things. First, good to have a lab value at a regular lab at the same time. So do it when you’re getting your blood drawn, once at least, making sure that we’re reading apples and apples. The other thing I would say is that night before, don’t have alcohol and that day before, don’t really push the workout, especially anything in extreme that might break down muscle tissue like weights or maybe running a little further than you normally do, because that will liberate purines. You’ll increase your uric acid. So that’s how often you can do it and get a sense as to what direction you’re going. If it’s elevated, you want to check it more frequently, make sure you’re going in the right direction.

Casey Means (00:36:30):

Perfect. And I think that monitor that you just showed, people can get on Amazon. It’s pretty easy to get, very inexpensive.

David Perlmutter (00:36:37):

Yeah, this one’s called UASure and U-A-S-U-R-E. There are several on the market. Nothing could be, well, I guess something could be easier, but for those of us who used to check our blood glucose levels with a finger stick, it’s second nature.

Casey Means (00:36:55):

That’s great. That’s perfect. And then Levels Labs, because of your advising, has added uric acid to our panels. That’s something that people can also get through the Levels’ panel as well or asking your doctor for it at a physical. So that’s amazing. Thank you for answering those questions about uric acid. I’d like to shift gears to one of the many things you have so much expertise in, which is gut health because I think there’s still confusion about the relationship between gut health and metabolic health. And you’ve written the books on gut health and how it relates to metabolic health and brain health. I will say that I have had several conversations the past year with academic physicians who believe that the concept of leaky gut is pseudoscience. When I use the phrase intestinal permeability, it gets a little more traction, which is basically the same thing. But can you give us the overview of what is leaky gut? How do you address the skepticism from some people regarding this idea of leaky gut and why does it matter for people listening?

David Perlmutter (00:37:54):

Well, first, I would say to you, Casey, that people are down on what they’re not up on. And that rings in my mind when I hear such skepticism. And the reality is, we’ve been talking about the term leaky gut actually for about a quarter century now with people who you know. I mean, Dr. Bland at IFM, this was, we’ve been talking about this for decades and because it seemed very clear that anything that assaulted the integrity of the gut lining seemed to be, at least in those days, associated with other non gut related pathologies or pathological conditions. But I think in the past 10 years or so, we’ve really begun to connect the dots and get a really good understanding through some really wonderful researchers like Dr. Alessio Fasano, for example, at Harvard, that permeability of the gut is really central to so many of the chronic inflammatory conditions.

(00:38:54):

Well, let me be clear first, what is a chronic inflammatory condition? Is that some kind of rare, exotic disease? No. Chronic inflammatory condition means we’re defining a mechanism that underlies Alzheimer’s, Parkinson’s, certainly a Type 2 diabetes, various forms of cancer, various forms of inflammation in the body, like arthritides or many types of arthritis, for example, autoimmune conditions as well. So we are understanding that the set point of inflammation, how high it is at its base, is very much regulated by what is called the gut-associated lymphoid tissue or GALT, meaning that clustered around the intestine are many cells of the immune system. Most of the important cells of our immune system, most of them live in juxtaposition to the gut. Why would they be there? They’re there because that’s where they get information about the environment, that molecules come through the intestinal lining and tell the immune system what in the heck’s going on in the environment. So that we can adapt, we can increase the production of inflammatory chemicals at times. That’s a good thing to keep us alive.

(00:40:16):

We can regulate our immune systems so that it’s not overactive and we don’t develop an autoimmune condition in a situation where our immune systems are reacting against our own tissues, like Type 1 diabetes, celiac disease, lupus, rheumatoid arthritis, ankylosing spondylitis. The list goes on. So the immune system is very much in touch with the gut to receive signaling from the external environment, far more so than is associated with respect to the air that we breathe, though a very similar mechanism is happening in the lungs. But by far and away, the largest representation is this relationship between our immune systems and what is going on within the intestine. Now, the intestine is very selective in terms of what it delivers to the immune system such that the immune system can then do what it needs to do to keep us alive.

(00:41:13):

But that selectivity in terms of what is presented to our immune cells, is controlled by what comes across the gut lining. Normally, that is very, very tightly regulated. There are guards at the gate to keep invaders out, such that we don’t challenge the immune system. There’s a very tight network of connections, cell to cell, that are very selective in terms of who gets in and who doesn’t. Now, we can threaten those connections. We can increase the ability of things to get in and then challenge the immune system when we damage the gut lining. First, we can directly damage it with the ingestion of various chemicals, primarily the types of drugs that we might be consuming and to a secondary degree, in many people, the types of foods that they’re consuming. But keep in mind that the master regulators of the gut permeability, are the bacteria living within the gut. This is one of their most important functions and that is maintaining gut wall integrity and they are various species that are directly involved with that, like Lactobacillus plantarum, for example, and the new kid on the block, Akkermansia muciniphila.

(00:42:36):

These are bacterial species that are involved in the maintenance to keeping those walls up to keep the invaders out. When I say invaders, I mean all kinds of things. Yes, pathological organisms, that’s for sure. But even the breakdown products of some of the normal bacteria that live within the gut. That normally stays in the gut, but when the gut is permeable, those products of bacterial breakdown can make their way in through the wall, challenge the immune system and set us up for big issues. So it’s sad on the one hand that mainstream to some degree, has not fully embraced this. I mean, there are drugs available to treat your autoimmune disease that will suppress your immune system. There are these monoclonal antibodies that we see advertised each and every night on television to treat your psoriatic arthritis or Crohn’s disease or whatever it may be. But we have to ask the question, well, why is the immune system overactive in the first place?

(00:43:36):

And the literature that connects those issues and virtually every other autoimmune condition with permeability of the gut, goes back an awful long time. That’s upstream of the activation of the immune system. That’s where we should be focusing our efforts so that people don’t have to take these monoclonal antibodies and experience the risks that are described in the 60-second commercial when they change the visuals to something really cool and you’re looking at people doing great stuff when they’re reading off the list of all the things that can happen when you start using these drugs. So I think I’m reading from the Good Energy playbook here. But that said, that’s why maintaining a healthy gut and as such a healthy gut wall integrity, is really so fundamentally important across the entire spectrum of these types of health issues.

Casey Means (00:44:29):

Just out of curiosity, is there an estimate that we have a sense of, I know it’s hard to do this, to understand how many people might be dealing or sort of really on the spectrum of leaky gut in our country or more broadly, what percentage of Americans based on lab data, do we know have sort of more inflammation going on in the body than they should?

David Perlmutter (00:44:50):

Well, I think you know the answer to the question because I think you’re very familiar with the number of people in America who are metabolically intact, and that number is very small, probably what, 5% of adults? So I would say that probably 95% have are involved in a situation where gut permeability is not ideal. It’s not as if we have a direct metric for gut permeability that we can get in the blood and it’s part of a panel. But we can infer permeability of the gut by looking at surrogates like blood sugar, like body weight, like inflammatory markers, c-reactive protein, sedimentation rate. These are all indicators of either directly of inflammation or as it relates to blood sugar and hemoglobin A1C, the likelihood of inflammation. So I would say anyone whose metabolically compromised, i.e. almost everyone, likely has some degree of hyper permeability.

Casey Means (00:45:48):

It’s astounding. I think about children and how so much of the culture that’s normal for our children today, really sets them up for gut dysfunction. And what I’m hearing from you is that it’s not just direct assault to the tissue, to the colon, and the small intestine tissue, it’s also anything that’s hurting the microbiome. So both damage the tissue or lack of resource into the tissue, and also anything that hurts or resurfaces the microbiome can have an influence. What would you say are the top few things, like if we’re talking to an adult or a parent of a child, the top set of things we can do to support really high quality gut lining and avoidance of leaky gut or healing of leaky gut?

David Perlmutter (00:46:33):

Well, the first three would be, dietary fiber, dietary fiber and dietary fiber. There are a few more that follow after that, but that is the component of, in the global diet now, that is suffering. And we spoke earlier about these ultra processed foods. Yeah, they’re ultra processed because we’re processing out the dietary fiber. I’ve heard comments recently, as in yesterday afternoon, that average American is consuming maybe two or three grams of fiber a day, which is… The reason it’s important is because that’s what nurtures the gut bacteria who are then going to shore up the gut lining. But the fact that we’re not consuming dietary fiber is a major, major threat. And that’s, again, from this pervasive consumption of ultra processed foods. That’s the biggest issue. I mean, we know that various medications that are taken so liberally like non-steroidal anti-inflammatory drugs and acid-blocking drugs and artificial sweeteners as well, not a drug, but things like aspartame, are clear and present dangers as it relates to the health functionality and diversity of the gut organisms.

(00:47:47):

There are a lot of things that are not necessarily diet-related. We know that there’s a significant change for the worse in the array and functionality of gut bacteria if we don’t sleep well. We know that stress increases cortisol and cortisol changes quite dramatically, the milieu within the gut. There a lot of factors that people maybe don’t bring to mind right away that are involved in changing the gut bacteria as well. Certainly a big issue, especially as it relates to children, but adults as well in America, is the incredible overuse of antibiotics. I mean, antibiotics are weapons of mass microbial destruction. And we have the technology today to absolutely specifically determine what is the organism, that unique organism that’s causing a particular infection in some point of the body, at some part of the body. We have that technology. It’s not widely used. We can sequence and determine what is that organism and uniquely target with a very narrow spectrum antibiotic, what it will take to eradicate that organism, if it’s a pathological issue.

(00:48:57):

In fact, I reviewed a study that came out this morning talking about the use the development of an antibiotic for gram-negative infection that apparently had no effect on the microbiome. That’s going to be a little bit challenging for me to appreciate since most of the organisms in the gut are gram-negative, at least bacteria. But beyond that, at least people are thinking about it, that giving antibiotics that are broad spectrum are, as I mentioned, weapons of mass microbial destruction. We need incredibly focused narrow spectrum antibiotics for a number of reasons. First, because of the effects on the gut that we talked about with a wide spectrum antibiotic.

(00:49:46):

And second, because it would dramatically reduce the notion of antibiotic resistance, which is becoming ever more of an issue for us to be aware of. And yes, fear, that we may ultimately be in a situation where infections develop with organisms that are widely resistant to the armamentarium of antibiotics that we have. So the technology is there, I mean… And in fact, there is very old technology that needs to be revised and it’s called phage technology. We know that these viral particles called phages can be manipulated and created in such a way that they can be uniquely targeted against specific bacterial strains that may be a pathological and really, as has been demonstrated since the 1920s, are associated with only mineral side effects, if any.

Casey Means (00:50:40):

Incredible. That’s so practical and helpful. Fiber, fiber, fiber. I carry a bag of flax crackers with me everywhere I go, but it’s also astounding with the antibiotic conversation. When I was in residency and my lifestyle was a mess and I was getting sick, I had styes in my eye and I had acne come back. It went away after teenage years and then came back when I became metabolically dysfunctional in residency. Both conditions, the doctor, the ophthalmologist, and the dermatologist recommended three months of doxycycline, which is an antibiotic as you know. And I said no to both, knowing even at that time what I knew about the overuse of antibiotics. And obviously, both went away and my life could actually look somewhat different. I don’t want to be sensationalist or alarmist, but six cumulative months of antibiotics does a number on your gut for probably years. And so there’s often other solutions. And of course, we should save the antibiotics for situations where it could potentially be serious and life-threatening.

David Perlmutter (00:51:44):

I am all in. And getting back to the topic we had, we discussed earlier, that is, C-sections require, not that they require, but a standard part of a cesarean section is giving a blast of intravenous antibiotics.

Casey Means (00:51:59):

We need a paradigm shift. So in our last 10 minutes or so here, I would love to shift gears to talk about what I know is something that a new area of interest for you that you’re really diving into and your mind is so beautiful and you’re always on the leading edge of what’s important, I think, for health. And so I’d love to hear a little bit about what you’ve been thinking about regarding this nexus between the immune system, between metabolic health and between specific cells in the brain that seem to be mediators of both inflammation and metabolic health and what we can kind of learn about metabolism through this study of microglia. And I just would love to hear your perspective on how this has unfolded for you as a area of, I shouldn’t say new area of interest, but-

David Perlmutter (00:52:43):

So there’s a term called immunometabolism, that I just think is a beautiful term because it relates the function of our immune systems to our metabolism, but also lets us begin to understand that how are immune cells metabolize, in other words, how they make energy regulates how they function. Maybe people don’t get it yet, but let me walk through it because it’s huge, in terms of what you and I are going to talk about a year from now and five years from now. It’s really very, very important because it turns out that the metabolism of various immune cells regulates whether they’re going to be helpful or hurtful, whether they will be the angel or the assassin. In the peripheral part of our body, we call them the macrophages and they exist in multiple forms. But for ease of conversation, we’ll say M1 form and M2 form. M1 is the evil twin, M2 is the good twin.

(00:53:46):

We want to keep our immune cells in the M2 configuration such that they do good things for us. The M1 form does not such good things for us. Now, the analogous cells in the brain to the macrophages are called microglial cells. And when I grew up, those were considered supportive cells in the brain that kind of were a bit of a scaffolding of the brain. We didn’t really understand that they were the brain’s immune cells. And more recently, that they can change between M2 and M1 as well. They can go between being very supportive, nurturing the neuron, gobbling up bad proteins like beta amyloid, being supportive of the synapses where one brain cell connects to the other. Or they can shift when their metabolism has shifted, their mitochondria have become less functional to the evil twin, the M1 form, in which case they’re not supportive of neurons. They’re in fact damaging to the neurons.

(00:54:47):

They destroy our synapses, they destroy the connectivity of one brain cell to the other, and they actually enhance the formation of damaging proteins like beta amyloid, all as a consequence of the shift from being helpful to hurtful. And this shift, again, is triggered by a change in their metabolism. So what we’re exploring now is what is it first, that’s changing the metabolism of these immune cells in the brain and in the periphery as well. And many of the things that people are well aware of, higher levels of blood sugar, for example, infections can do it, inflammatory chemicals in the body, i.e., inflammation from anywhere in the body, i.e., leaky gut can relate back to the brain and change these important cells that make up about 10 to 15% of the brain cells that are involved in maintenance that can change these cells from being friend to foe. Think about that.

(00:55:48):

That’s the relationship then between, for example, a higher consumption of non-steroidal anti-inflammatory drugs and leaky gut and problems in the brain. It’s a relationship between taking acid-blocking drugs and increasing your risk for Alzheimer’s disease significantly. When you are using these drugs, you’re increasing gut permeability, increasing the production of the body of these inflammatory chemicals that changes in the brain how these cells go from being good to bad. Now, we’re accumulating beta amyloid. We’re damaging the synapses. We’re not nurturing the neurons any longer because these cells have been changed in what we call their phenotype and in terms of their metabolism. So what you want to do is ask then if that’s going on, well, is it reversible? And it is reversible. It’s challenging, but it is reversible. And there are various things that can be brought to bear that can reestablish these cells and bring them back to being helpful, not hurtful.

(00:56:57):

And basically, it involves targeting their metabolism, importantly targeting how they’re able to use energy, how their mitochondria work. And we get to a situation of trying to understand what are all the cool things that we could do to enhance mitochondrial function. We all remember from high school, energy that these mitochondria are the energy producer in the cell. They’re what is involved in metabolism. They’re taking in glucose and they’re making energy in the form of ATP. How can we enhance their ability to do that? Well, fasting, ketogenic diet. We know that Akkermansia muciniphila is a probiotic that may actually target that. So there are a lot of things that we can be looking at. Quercetin, various exercise, for example. There are a lot of things out there that look like they work and may ultimately have traction in terms of what they’re able to do to turn on metabolism.

(00:58:03):

Now, when you ask anyone these days, what’s hot in metabolism, what are people going to tell you? GLP-1 agonists. Yeah, Ozempic-like drugs. And it turns out that these drugs that stimulate GLP-1, that there are GLP-1 receptors on the microglia, and when you stimulate those GLP-1 receptors on the microglia, you improve their metabolism. So where are we going with this? Well, we’re going to a place of the idea that increasing GLP-1 might well be something really, really good for the brain. We saw, I guess two months ago, published in New England Journal of Medicine, an interventional trial over three years, where a GLP-1 drug, an Ozempic-like drug was used in Parkinson’s disease patients and virtually arrested the Parkinson’s, a generally considered chronic progressive, means it worsens with time disease, as any Parkinson’s patient will tell you. We have no drugs to treat Parkinson’s. Zero. We have drugs that we’ve used for decades to treat the symptoms of Parkinson’s. We treat the smoke. We treat the tremor. We treat the rigidity. But the underlying fire has never been approached until now.

(00:59:26):

These studies demonstrate that Parkinson’s not only can be arrested, but in the study published in New England Journal of Medicine, these people taking this drug actually showed some slight improvement in their Parkinson’s symptoms as was revealed on the Unified Parkinson’s Disease Rating Scale. In other words, there’s a scale by which researchers around the world are able to metricize the symptoms of Parkinson. So how the drug works is by targeting metabolism of these microglial cells. And interestingly, some of the worst things we can do for our microglia are allowing our blood sugar to elevate and allowing us to become insulin resistant. That immediately tends to shift those microglial cells from being friend to foe. So for all of those who are interested in looking at their blood sugars and doing the best they can to keep their blood sugars under control that are wearing continuous glucose monitors and having their A1C’s checked frequently, this becomes really important through the notion of understanding what you are doing to change either for the good or for the bad, the function of these brains immune cells.

(01:00:44):

Microglial activation, in other words, the shift from good to bad is central to chronic neurodegenerative conditions like Alzheimer’s, like Parkinson’s, like multiple sclerosis. We see it in autism as well. We can even image these cells in vivo, in living people. These cells can now be imaged when they transform from being helpful to hurtful. Imagine that. In terms of a diagnostic tool, but in terms of a research tool to be able to see if your intervention like caloric restriction, like exercise, like using metformin or using quercetin or minocycline or whatever it may be, to see if it’s working and it, see if it’s helping people using an extract of licorice, for example. All of these things are being explored in terms of being able to revert those damaged, I call them damaged or dysfunctional microglial cells, back to being helpful, back to being in a form that’s going to be useful.

(01:01:48):

Our research right now is looking at hyperbaric oxygen. When we talk about what do the mitochondria do when they’re functioning fully in the helpful form, they’re using oxygen to create energy. Interestingly, when they become the evil twin, the M1 phenotype, they shift away from using oxygen to process glucose, to using a different process in the cell called glycolysis, which is not aerobic. Metabolism does not use oxygen. But what we’re seeing is people have improvements in the function of their brains when they get hyperbaric oxygen treatment. And I think what we’re going to see, in fact I’m meeting with a research team next week, is that once we begin imaging these individuals in terms of their microglia, we’re going to see that they’re shifting back to being the M2 or helpful phenotype. So I sure hope that was not too complicated. Let me see if I can summarize it real quick.

(01:02:47):

The brain’s immune system is really important in terms of keeping the brain healthy. Normally, it functions to keep the neurons happy, the synapses established and clear away debris. Those cells can shift and do just the opposite, threaten the health of neurons, threaten and gobble up synapses and actually lead to accumulation of bad misfolded proteins like beta-amyloid. We want to keep that shift from happening. We do so by maintaining our metabolic health and keeping the gut healthy. But beyond that, we are developing the tools now to shift them back from being foe to being friend.

Casey Means (01:03:26):

Incredible. We could do an hour on that. I think, was it [inaudible 01:03:30] COVID, and even in the aftermath where I think a lot of people are… There was a couple months earlier this year where I feel like everyone was sick for several weeks. Everyone’s thinking about how do I support my immune system? And something that I just kind of want to yell from the rooftops is that every immune cell in your body also needs energy to function properly. So metabolism doesn’t just affect your liver and your blood vessels, it affects every cell. And so well-powered immune cells are going to do better work. And I think that’s all over the body. And what you’re talking about is also in the brain. If we have insulin resistance in our bodies, it’s not in one place, it’s everywhere.

(01:04:06):

And what I’m hearing you say is that when we’re insulin resistant, it’s affecting the brain. These cells, these microglia are not getting the power they need. They’re underpowered, they’re mitochondrially dysfunctional. They’re going to change their activity because they’re on a totally different program. And that shift in activity is going to lead to them not doing the helpful things that protect our brain, cleaning up the beta amyloid and all that. And so fundamentally, to get ourselves out of that, we have to figure out a way to have these cells be mitochondrially functional, make good energy, be insulin sensitive, which means the holistic support of metabolic health. And I’d be curious, maybe in our last question here, you mentioned exercise. You mentioned reducing leaky gut. There’s dietary strategies to improve insulin resistance. What about sleep? How does sleep impact the microglia?

David Perlmutter (01:04:55):

Well, there are a lot of mechanisms. We know that lack of restorative sleep, not just adequate amount of sleep, but the amount of restorative sleep that we can get, which we can measure using any one of a number of wearable devices, but lack of restorative sleep directly increases inflammation in the human body. A number of mechanisms, it also threatens the microbiome and that also increases the production of these inflammatory chemicals. These inflammatory chemicals are observed by these microglial cells and this is a powerful stimulus for them. When they bind to the surface of these microglial cells, it activates something called the NLRP3 inflammasome. That’ll be on the quiz as well. But basically, it activates a surface receptor on these microglia that ultimately changes genetic expression of these microglial cells and ultimately threatens their mitochondrial function. So this is the connection then between inflammation and changing microglial functionality and in this case, how sleep is involved with that.

(01:06:02):

Sleep also compromises the, lack of sleep rather, the ability that we have to rid the brain of the accumulation of various types of debris, including a damaged cellular debris and accumulated misfolded proteins, et cetera. That happens during deep sleep. When we activate something called a pathway in the brain that is involved, it’s called the glymphatic system that’s involved in clearing the brain of these harmful chemicals. When they accumulate within the brain, they bind to receptors on the microglial cells and they’re various receptors. But there are things that bind to these receptors that are called DAMPs, damage-associated microbial patterns and PAMPs, pathogen-associated microbial patterns, binding to these receptors and instituting these changes in the microglial cell. One other thing I’ll mention because the thing’s really interesting. What we’re doing here, you and I, we’re tying up all of loose ends that all these hanging chads that we’ve had for all these years. How in the heck does it work?

(01:07:04):

And here’s another connection that I think you’ll resonate with. There’s a very important receptor on the microglia that when it is stimulated, leads to these damaging changes and reverts them to their M1 bad phenotype, and it’s called the RAGE receptor. I love the name the RAGE. So you bind that RAGE receptor with these various things that accumulate when we don’t sleep well enough. Getting back to your question, you bind to the RAGE receptor and when you activate that RAGE receptor, it is very threatening to the metabolism of the microglia, which we cannot afford. Now interestingly, where did the RAGE receptor get its name? The RAGE receptor got its name because it’s the receptor for advanced glycosylated end products. So I know you’re getting chills right now because I am. These are the proteins that are modified by binding glucose when our blood sugar is elevated.

(01:08:07):

So now we’ve just connected some important dots, some missing pieces of the puzzle, another way that elevated sugar is so damaging to the brain. Yeah, when blood sugar is elevated, we know that it increases inflammation and it also compromises insulin functionality. We get that. Those are great mechanisms. But the fact that we glycate our proteins like hemoglobin A1C, the fact that we glycate our proteins in the brain and that signals, it’s picked up by a receptor on these microglial cells, that makes them turn from being the good twin to the bad twin. That is a powerful mechanism that argues so strongly for us to keep our blood sugars under control. And so to me, I guess my excitement is obvious, but gosh, because you wonder about this stuff. Maybe not everybody [inaudible 01:09:00] about this stuff, to be fair, but many of us do. But to have an answer to that question I think is very exciting.