The Melanie Avalon Biohacking Podcast Episode #141 - David Perlmutter

TRANSCRIPT

Melanie Avalon: Hi, friends, welcome back to the show. I am so incredibly excited about the conversation that I am about to have. Okay, so, backstory leading up to this conversation. A few years ago, now, I think I listened to an interview on Peter Attia with Dr. Rick Johnson and that was the first time I really started diving deep into the metabolism of fructose and how that affects metabolic health. Fast forward to a few months ago or actually probably a little bit more than that now, but Dr. Johnson was coming out with a new book, Nature Wants Us to Be Fat and I actually interviewed him for it recently. In that book, I learned more about not only fructose, but the connection to uric acid. Around that same time, Dr. David Perlmutter actually wrote the foreword for that book and he had a new book coming out called Drop Acid: The Surprising New Science of Uric Acid - The Key to Losing Weight, Controlling Blood Sugar and Achieving Extraordinary Health. 

When I realized this book was coming out, I reached out to his agent, because he had been on the show before for Brain Wash and I was basically, begging them, "Please, let him come back on the show," because I'm just so obsessed with this topic. I think people are becoming more familiar with fructose, but the uric acid connection is just something that is, it could be profound and its implications and nobody is talking about this until now. So, I am so, so excited to have you back on the show. Dr. Perlmutter, thank you so much for being here.

David Perlmutter: I am so excited to be here. I would agree with you that, this is all really new and very exciting information. Like yourself, I was introduced to the topic by listening to that Peter Attia podcast with Dr. Richard Johnson one day when I was running, and I ended up doubling up on my run just to hear the end of the podcast, and then the beginning again, and did what anyone else would, I guess, do. I called Richard Johnson immediately when I got home. I grabbed a shower first, then I called Richard Johnson, and said, "Hey, this is really exciting stuff." Because it really connected some dots for me that were hanging chads for an awful long time. We've known since 1970, published in the journal, The Lancet, that fructose threatens metabolic health, despite what the corn refiners would like us to believe. We know that fructose is a powerful threat to metabolic health in terms of diabetes risk, hypertension risk, obesity risk, but we never fully understood the how and why it happens. Dr. Johnson made it very clear how it happens and I then explored, interestingly, why it happens. It happens for very important reason that is to keep us alive. It's a survival mechanism to help keep us, humans and our primate ancestors alive giving us the ability to survive when we didn't have access to food or water. 

Suddenly, what that did for me was and we'll unpack all the mechanisms in the uric acid connection in a moment. But what it did for me was I think life changing, because I started looking not just at this issue, fructose consumption, but all of the mismatches that we experience in our modern lives that threaten our health, in terms of how these things that are now potentially bad and the reason they persist today is because they may have actually been survival mechanisms for us. Having a raised blood sugar, raising our blood pressure, increasing our body fat, how all of these things through the context of survival and our ancestors may be looked upon as actually being good things, though. Becoming insulin resistant, we talk about frequently is such a terrible threat to our health, but in the context of our ancestors, becoming insulin resistant and then raising the blood sugar proved to be a powerful way of powering up the brain, and allowing us to remain clever, and pave the way for our survival. So, it really is game changing.

Ultimately, we know that one of the things that fructose consumption does and we'll talk all about this is it increases the production and the level in our bodies of this emergency signaling pathway, that is uric acid. Our uric acid elevates and it's yelling to our bodies, "Prepare for winter and do all the things that our bodies need to do to prepare for food scarcity in our time of food plenty." Therefore, it's a mismatch that's leading to health issues.

Melanie Avalon: Actually, a broader question about the whole narrative of all of this, because you talk in the book about how it takes 40,000 to 70,000 years for significant changes in our genome. These changes, because you just mentioned and like you said, we'll dive deep into it. But you just mentioned how these changes had beneficial effects for survival, because clearly, things were not panning out and we're having metabolic syndrome and issues now from these changes. Do you think we'll adapt to that or have we reached the point, where it's not something we're going to adapt our way out of? Well, there'll be a future mutation or change to address how these things are not working or do you think it's all downhill?

David Perlmutter: [chuckles] All downhill. Things are going downhill. When you look at the numbers in terms of whatever, obesity will currently affect rather 33% of American adults in the distant future in the year 2030. That's eight years from now. That'll be 50% of American adults, not overweight, but actually obese. Right now, 10 and a half percent of adults in America have type 2 diabetes, 33% are pre-diabetic, that's 88 million adults, our life expectancy is declining year after year, and that began pre-COVID. We're going in the wrong direction. What we're talking about here is basically a mismatch between our genetics that had been refined over literally millions of years and the influences on our physiology brought on by our environment, the variables, the sleep we get, the exercise, sunlight, food, a very important informer to our physiology as to what's going on around us, what's our environment. We're experiencing this environmental evolutionary mismatch. 

Our genome has been so refined to keep us alive and to pave the way for our survival under a given set of circumstances that have changed so dramatically beginning about 14,000 years ago with the advent of agriculture. Then, the past 200 years with the refinement of sugar, the production of sugar, that is virtually exploded globally from sugarcane and now, more recently from corn, high fructose corn syrup. These are challenges to our more primitive, if you will, a physiology that is dictated by our genes. To get these things back in line, we're not going to be able to change our genome anytime soon that I'm aware of. Again, you mentioned, the amount of time it takes for these genetic changes to take place and I began to puzzle over this mismatch and wrote my first article on this topic 50 years ago, half a century ago, published in the Miami Herald in 1971 when I was 16. I concluded that paper by asking the question, "What about those of us living today with this outdated machinery?" That calls to question our ability to change rapidly enough to adapt to our current environment. That's not going to happen. 

This is the thesis behind the so-called paleo movement is to revert our lifestyle choices to be more in line with our paleolithic genome. That's not always easy to do. But we know now, some of the big players, and what we identified, and what both Dr. Johnson and I have talked about in our books is the signaling pathways that are brought about to lead to increase body weight, increase blood sugar, increase blood pressure. The primary signal for that these days is fructose. There are three inputs to uric acid. Fructose, alcohol, and a type of chemical called purines. The biggest player that we are exposed to is of course, fructose. When we recognize that more than 60% of packaged grocery store foods contain added sweeteners. That by and large, these are from high fructose corn syrup. We begin to get a sense as to how we are bombarding our bodies with this signaling mechanism. 

Fructose, yes, it's a carbohydrate and yes, we can deconstruct our foods to look at fat, protein, and carbs, and micronutrients like minerals and vitamins. But at its core, what food does is serves as a signaling mechanism? It serves as a way of informing our bodies. Food is information. And what fructose, which we got only in the late summer and early fall informed our ancestors about was the fact that winter is coming. That fructose signaled the body through increasing uric acid to make and store fat, to decrease our metabolism to affect how our mitochondria works, our metabolism would be decreased, so we wouldn't burn as much fuel. To raise our blood sugars, so that we could power our brains, and find food, and avoid being eaten, and even raise the blood pressure, so that we would have a bit of ability to resist becoming dehydrated. This is a long-standing pathway in humans that evolved somewhere in our primate ancestors between 14 and 17 million years ago during what is called The Middle Miocene period, when the earth was a bit cooler. Therefore, access to food was a little bit sketchier. 

Those individuals of our ancestors, who had this mutation, so that they had higher uric acid level when they consume fructose were the ones who survived. They passed that genetic predisposition for a higher uric acid level on to each and every human walking the planet today. We're all geared. We have a thrifty genome. We want to make the most out of the calories that we come upon. We're all geared to make as much fat and lock it up as best we can to prevent us from dying of starvation. Nowadays, we're triggering that pathway 365 days a year for the winter that never comes. When I say winter, I mean, the time of food scarcity. This is what's going on. When we call it out like that, people begin to understand that this is a pathway in each of us in our physiology that is telling us to become metabolically dysfunctional, because that was a survival mechanism. When you get that, then you begin to understand, "Hmm, what are the markers, uric acid, simple blood test? What are the inputs?" Fructose, fructose, fructose and also alcohol and purines. But by and large, it's the fructose. It's the reason we shouldn't be drinking soda, it's the reason we shouldn't be drinking orange juice and apple juice. Those are very powerful, concentrated sources of this signaling molecule called fructose that tells us to make fat. There's nothing natural about a carton of orange juice. Our ancestor didn't suddenly come upon groves of trees that were growing cartons of apple juice or orange juice. It didn't work that way. We ate the whole fruit, and that far less stimulated our ability to make uric acid, and therefore, increase body fat production. So, again, this validates the whole notion of the paleo approach trying to emulate the lifestyles of our paleolithic ancestors, meaning, prior to agriculture as a way of bringing our genome back into alignment with our environment.

Melanie Avalon: Evolutionarily, when we were consuming fructose, when the winter was approaching and so we were preparing to stock up on fuel in our bodies, essentially, so, do the issues with fructose require fructose in a calorie excess? Do you have to gain weight with the fructose to create the problems or does fructose independently of weight gain cause issues?

David Perlmutter: Well, it's an excellent question. Fructose in its metabolism, then, it's not just the calorie component. Fructose, it's the actual metabolism of what that fructose becomes, that stimulates the body to make and store body fat, to turn down metabolism and actually increase blood sugar production. It isn't the fructose is that we're loading up on the calories that are derived from fructose. You might see from eating a high carb meal or eating glucose. That's not how it works. If you block the metabolism of fructose by inhibiting a specific enzyme called fructokinase, then, the downstream damaging effects actually don't happen. We don't see the non-alcoholic fatty liver disease, for example, the increased production of fat, the insulin resistance, even the hypertension, those things are not happening when we block fructose metabolism either at the stage of the initial enzyme fructokinase or further down in the production of uric acid by blocking actually the production of uric acid by using drugs that happened to have been developed as an attempt to treat a disease called gout, which is characterized by having a high level of uric acid. 

When we inhibit enzymes involved in the production of uric acid, then, those downstream effects actually do not manifest. That's been seen in laboratory animals, it's been seen in human interventional trials as well. I think that answers your question. The good news is that, yes, we can limit uric acid production by reducing our fructose consumption, that's for sure. But we can also emulate or imitate the action of the drugs that are used to treat gout with things like quercetin, a bioflavonoid. Quercetin acts exactly the same as uric acid-- as allopurinol, the drug does in terms of inhibiting uric acid production and has the benefits of those interventional trials, then, that are seen to reduce hypertension, and elevated blood sugar, and fat production that are seen when fructose is given to test subjects, along with inhibition of the uric acid production.

Melanie Avalon: One more question about the fructose and then, I'll jump more into the uric acid. This is a question that has been haunting me, and I was wondering it while reading Rick's book, and then, I was wondering it while reading your book. You talk about how the metabolism of fructose actually creates less energy or depletes energy in the cell. Normally, with something like AMPK, we see it as a good thing to have energy depletion state. So, why does fructose deplete energy in the cell? Why is that not a good thing? Why is it not similar to AMPK activation?

David Perlmutter: Well, AMPK actually enhances fat metabolism. It is as you mentioned, what we are trying to do, we want to enhance AMPK, while at the same time, we want to reduce the action of its evil twin, which is AMP deaminase. When we activate AMP kinase, which is what we're all trying to do, we do that with exercise, we do it with the drug metformin, we do it with quercetin, for example, we are actually doing a couple of things. We are reducing the generation of glucose in the liver. We call that gluconeogenesis. That's why it's an anti-diabetes strategy. But we're also enhancing fat metabolism. We're liberating fat, mobilizing fat, reducing fat storage, and enhancing fat metabolism. In those ways, this is the reason we want to keep AMPK lit up. AMP deaminase has the exact opposite activity. AMP deaminase is instructing our bodies then to reduce fat metabolism, increased fat storage, ratchet down generally metabolic activity, so that we don't burn as much energy and we're able to conserve energy, and actually, stimulates the production of glucose at the level of the liver, again, gluconeogenesis. 

Now, we have this teeter-totter, this balance between AMPK on the one hand, the good guy on the other hand, AMP deaminase, which in context of our modern world is not really what we want. One would think there might be a circumstance in which we'd rather have AMP deaminase split up and that would be, for example, if we were getting ready to hibernate, if you're a bear and you're getting ready to hibernate, then, by all means, you want to make as much body fat as you can, store it up, you want to ratchet down your metabolism, that's the way you're going to survive for the months that you are hibernating by having this fat resource. That's exactly what happens. A bear feasting on berries has got his or her AMP deaminase turned on, AMP kinase is shut down. It turns out interestingly that what controls which way we go is uric acid. As uric acid is elevated, this is the switch. It shuts down AMP kinase and it turns on AMP deaminase. As it shuts down AMP kinase, we make more blood sugar, we make more body fat, we lock up our body fat, and we reduce our metabolism. That's the danger of having an elevated uric acid. 

Interestingly, I think mainstream medicine still to this day, although we're watching it change very, very quickly and as such, you are way ahead of the game here. Mainstream medicine focuses on uric acid really in the context of gout almost exclusively, at least here in America. Globally, there's certainly a very big interest in elevation of uric acid as it relates to a variety of metabolic components like elevated blood sugar, elevated biomass index, elevated blood pressure, dyslipidemia, elevated triglycerides, et cetera. There's a global concern for elevation of uric acid. But in America, not so much. We'd like to pigeonhole it in terms of gout end of story. To this day, we are seeing patients that I refer to their physicians for other reasons. Happen to have an elevated uric acid level, they come back either on allopurinol or being told, "Hey, pat on the head, don't worry about it. You don't have gout." Well, that's not what our literature is telling us. Our literature is telling us that, for example, having a uric acid over seven milligrams per deciliter, which is common. The average uric acid level, the average in America is six. Having a level just over seven is associated with a 16% increased risk of what is called all-cause mortality over an eight-year period, meaning, being coming dead for any reason. A 39% increased risk of what is called cardiovascular mortality, basically, meaning dying of a heart attack. A 35% increased risk of dying of stroke. 

For every point elevation over seven and again, seven is very common. For every point elevation, there is between an 8% to 13% increased risk of all-cause mortality. These are real numbers and they're real important. As it relates to my specialty being neurology, one recent study published in the Annals of the Rheumatic Diseases in 2018. Interestingly, that's a gout journal, followed people for 12 years, 1,600 people and those with the highest level of uric acid had an 80% increased risk of dementia, a 55%, increased risk specifically of Alzheimer's disease, and the 166% increased risk of what is called vascular or mixed dementia in correspondence with this elevation of their uric acid levels. When we, again, revisit the connection of elevated uric acid to high blood pressure and high blood sugar, we see that those are powerful threats to the brain. Then, when we get that, we see what uric acid is doing then to these metabolic markers. It's no wonder then that we can understand why high uric acid level formerly only appreciated in the context of gout is now associated with diseases of the brain for crying out loud. 

What is really interesting is that and I wrote about this in Drop Acid that, we've known this since the late 1800s and this was written about by Dr. Alexander Haig wrote a book about this about elevated uric acid being a powerful risk factor well beyond gout. He talked about dementia, and depression, and so many other-- and high blood pressure, and did experiments on blood pressure with uric acid in the late 1800s for crying out loud. But that information was lost until about 20 years ago, when researchers primarily in Japan and also Turkey, but now, in the United States as well, began to revisit this and have made some really startling and empowering if I may, discoveries.

Melanie Avalon: A question about this connection and causation correlation, uric acid's actual role as an independent risk factor, because I was looking at a 2020 review last night that looked at the U-shaped mortality curve of so many different diseases and how it connected to uric acid. They were proposing, "We shouldn't actually be looking at uric acid bubbles," because they were saying it had to do more with comorbidities and gender, and that it was ultimately a U-shaped curve. The actual role of Uric Acid, because you talk about this in the book a lot. You point out how it's an independent risk factor, how it often precedes these diseases. Is it causing these diseases, or how do we know it's not a correlational factor, or to be even super controversial and play devil's advocate? Antioxidant benefits that it has. How do we know it's not protective? 

David Perlmutter: This is a very interesting question and I'm glad you asked it. I will tell you, you're not the first person to ask that question. In fact, in 2016, this was the title of a research study and that is Uric acid in metabolic syndrome: From an innocent bystander to a central player. Meaning, originally, it was noted that in people with high blood sugar, high blood pressure, obesity, that oh, coincidentally, their uric acids are elevated. We knew that and it was known in passing. We didn't really pay much attention to it, because of course, uric acid only has a role to play as it relates to gout. Then, researchers began doing experiment in humans, where uric acid was the only variable. They were lowering uric acid with drugs that inhibit an enzyme called xanthine oxidase, which is the final step in the creation of uric acid. Basically, giving people as I mentioned earlier, gout drugs and seeing improvements in their blood pressure, in their blood sugar, and even in their body weight. I put these studies in the book. 

Yeah, we noticed it. it was correlational in the past, there's a lot of correlative data, I've already reviewed some of that for you. But here is human interventional data that shows, when you manipulate uric acid exclusively that you see changes in these very important metabolic parameters like blood sugar and blood pressure, for example, so important for general health and really important as it relates to the brain, and the heart, and the kidneys. That I think, that's a great question that you asked. How do we know that it just doesn't happen to be interesting a correlation that we just happen to notice this elevation of uric acid along with these other metabolic problems? I think that study that I mentioned, that research paper from 2016 really takes us away from the notion that it's an innocent-- I love the way they called it. An innocent bystander, just happens to be there. Well, no. Nature, in her wisdom, typically multitasks the various types of measurements and things in our bodies, the variables, and as such for us to think that uric acid is just a gout consideration. It is really quiet with all due respect myopic. Just because that's how we learned it and the quick fix for the elevated uric acid was allopurinol, end of story, takes a little bit more of a deeper dive now, when we realize, it's a much, much bigger issue. We name things and we tend to pigeonhole them. Testosterone is a male hormone and progesterone is, pro meaning for gestation and that's all it's for. Cholecystokinin has only a role to play in the gallbladder. We realize that it just not what we know. We know that women's bodies make testosterone and need testosterone. Men make estrogen and cholecystokinin receptors are in the brain for crying out loud. We had to take a step back and realize, maybe we were a little bit narrow minded in our understanding. There's new data out there, and we have to accept that, and now move forward, and ultimately, that as we mentioned earlier is empowering, because it's giving us a brand new and very important tool to reign in this pervasive metabolic mayhem that we talked about originally.

Melanie Avalon: It sounds like a lot of things we've experienced in analyzing the causes of health and thinking things are just like the study said, innocent bystanders when maybe they are playing a much larger role. So, can you have metabolic syndrome and not have high uric acid levels or is it pretty much usually always elevated?

David Perlmutter: No, of course, metabolic issues are multifactorial. They have to do with things like ratio of brown fat to white fat or beige fat. Certainly, diet is important. What the research is showing is that, when uric acid is brought under control, it has a significant effect on the panorama of metabolic issues. There's nothing that's really one factor. Maybe pregnancy, I guess, there's one thing that causes that. But aside from that, there're a lot of things that ultimately conspire to form our various disease states.

Melanie Avalon: You mentioned multiple factors going into these high uric acid levels. The fructose connection, also the alcohol, the purines, so, what is the role in actually addressing this? Maybe we can talk a little bit about the purines in foods. Does that play a major role? Do people need to be looking at their purine intake?

David Perlmutter: I'm not going to say, it plays a major role, it's playing a role. Purines are the breakdown products of the DNA and RNA found in cells. Foods that are very hypercellular, liver for example and kidney tend to create more purines. Frankly, the reality is that, in your body, two thirds of the purines generally most people that are floating around are actually from your own breakdown of your own muscle tissue, for example, when you exercise and only a third come from the diet. If you go online and try to read about dietary recommendations for gout, for example, it's all about limiting purines. It's all about avoiding the purine-rich foods. Again, that the organ meats, the game, the sardines, anchovies, etc. The reality is there's always a pushback in being derogatory towards sugar, especially fructose. I think we can understand why that might be. There's great interest in making sure we keep eating a lot of sugar. It's worrisome how that comes about, but anyway, beyond that, so the gout diets have always been low purine diets.

But the reality is that, even dating to the late 1700 our sugar consumption had already begun. Well, into the 1800s, when gout was fully recognized, we'd already started eating more sugar than in the history of humankind, especially in various European countries, especially in England, our sugar consumption began-- along with alcohol consumption increased quite dramatically. If you were asking the five sources of uric acid, they would be number one, fructose, probably number two would come in at being fructose, and number three, I'd have to settle on fructose, and then four and five would be alcohol and purine. It's a player. There's no question it's a player. The reason we talk about it in Drop Acid is because if an individual were to still have an elevated uric acid and he or she was really a circumspect as it relates to reducing their fructose consumption, then purines become something you want to look at as does alcohol. You want to look at those things. But I would tell you that by and large people who become really careful with their consumption of fructose and by that I don't mean necessarily fruit, we'll talk about that in a moment. But eliminate the fruit juice, and the sugar sweetened beverages, and the other sources of fructose in the 60 plus percent of foods in the grocery store that have fructose in them, that really helps a lot. When you add in 500 milligrams of quercetin a day and some vitamin C, maybe around 500 milligrams, this is going to be what is needed for most people. 

We know that there are genetic-- We call polymorphisms, genetic variations in people that in some people could cause them to be at risk for higher uric acid. There's something called the URAT1 gene. People have variations of that gene and some people are genetically more predisposed. We know that people from Micronesia, Polynesia have more likelihood of having higher uric acid level. But that said, if in fact, you've done what we've talked about and then uric acid cast is still elevated, then you want to target the purines, then you want to choose wine over beer. Beer is an issue because it has alcohol, but it's also very rich in purines, because it's made from yeast, which is very cellular. A lot of genetic material, nucleic acid, so higher levels of purines. Then, there are people that are even treated. In Japan, people are treated without gout with gout medications to get their uric acid levels down just because A, they're at risk for gout and B, they might have high blood pressure, they're treating people who have high blood pressure and they have elevated uric acid with gout medicines in Japan now with good results.

Melanie Avalon: Is it stored anywhere? If you were to check your uric acid throughout the day, is it blood sugar where it would fluctuate?

David Perlmutter: Yes, it does fluctuate entirely, unlike the reason that your blood sugar fluctuates during the course of the day. It fluctuates based on your activity, based upon the foods that you're currently eating, drink a glass of coke and your uric acid is going to go up very, very quickly. Will there ever be a time that we have continuous monitoring available to us for uric acid? 

Melanie Avalon: I was wondering that. Yeah, you think so? 

David Perlmutter: I can tell you that's going to be something we should anticipate in the future. But I don't think that it will be as valuable as CGM. CGM allows us to know moment to moment variations of our blood sugar based upon any number of inputs. I find it extremely valuable. Uric acid, I think, testing every couple of weeks is reasonable. Fasting in the morning on not the day following a real vigorous exercise protocol, so that you don't break-- not a day that you ran a half marathon the day before, because you're going to break down a lot of tissue, elevate your purines, uric acid level goes up. That's typically what we recommend. Once you achieve a good level, which is below 5.5 and that's important, because the so-called normal level is below seven milligrams per deciliter. 

Please understand that that is a level that relates to gout. That's the level above seven milligrams per deciliter, then uric acid begins to crystallize in your body, because it precipitates that form crystals in your joints. That's what gout is all about. The best recommendation is as it relates to the metabolic consequences of elevation of the uric acid. We want to get our levels below 5.5. Around the 1920s in America, uric acid levels averaged 3.5. Now, they average as I mentioned earlier, six. These increases in uric acid have been in lockstep with our increased consumption of sugar. Even table sugar, that's 50% fructose right there. It's not the glucose that's raising uric acid. It's uniquely the fructose as it relates to that input, that sugar input.

Melanie Avalon: I read in your book that you did that letter recently with Casey Means. I've had her on the show for continuous glucose monitors. So, I will put a link to that in the show notes for listeners, who would like to learn more. 

David Perlmutter: Well, that's right. We wrote an op-ed in MedPage Today. Actually, it was published February 21st of 2021. It was an open letter to President Biden that really just called out the fact that United States Department of Agriculture recommended that we allow up to 10% of our calories in our daily diets to come from sugar, which has no scientific support, it is not what the scientific inputs to the US Department of Agriculture. Think about that. They're the ones in charge of growing corn, helping our corn growers and refiners with their revenues. They're the ones, who supply that information to the USDA and then, they come up with a recommendation of 10%, which is-- The requirement for sugar and the human diet is zero grams per day. That's not very much. We said, "Let's get it down to 6% of total calories." There's been no change. So, what do we do? Well, we get out, and we speak, we write books, we go on a podcast like this with-- I see that you have featured so many of my friends out there, who we're basically coming ultimately to the same conclusions that in diet is everything, whether it's Maria Emmerich talking about proteins, very modified fast or Paul Saladino, all these great people. Saladino talking about basically what diet does to our physiology and more importantly, and this is the take home message. How does our diet interface with our genome? That's what is key. 

Suddenly, out of the blue, we have this mismatch between what our wonderful gift, our genome that has been refined literally for a couple billion years. If you really want to take it back, but as it relates to primates over the past 14 to 17 million years and more recently, humans 200,000 years, constantly refining our genome to pave the way for health, longevity, and our ability to survive during times of adversity. Suddenly, yesterday, we developed agriculture. Just this warning, we developed the ability to refine sugar and this has bombarded our genome with information that it's never experienced. We're suddenly activating a pathway, a survival pathway in our body to prepare for winter. We're elevating our fructose consumption, that's becoming uric acid that is screaming to our physiology, make fat, store fat, reduce metabolism, raise the blood sugar to prepare for winter, and it's the winter that will never come, because we're not going to have food scarcity. Instead, this is pathway that's operating 24/7, 365 and is responsible for these ramped rates of obesity, and hypertension, and diabetes that no one needs to call it out, because we all see it.

Melanie Avalon: Now, I'm just thinking about, because you're talking about the foundational role of diet compared to these genetic adaptations and how we're mismatched. So, taking, for example, the uric acid lowering jugs, allopurinol, since that's actually inhibiting an enzyme, is that taking a genetic adaptation in a pill? 

David Perlmutter: No, the genetic adaptation is, that would be countering a genetic adaptation. The genetic adaptation is the production, the high level of uric acid that we have. Let me take you back. 14 to 17 million years ago, our primate ancestors didn't really make a lot of uric acid. Why? Because they had the gene, an active gene to create an enzyme called uricase that broke down uric acid. Then, there was an environmental pressure that lasted about a million years. It was called the Middle Miocene period. When the Earth became cool, and food became scarce, and that was a powerful selection pressure selecting for survival those animals that could make a little bit more fat, not that they became obese, just a little bit of an edge, a little bit more body fat, and could ratchet down their metabolism just a little bit, and could create just a little bit more blood sugar to power their emerging brains, their enlarging brains over time. That genetic change was the loss of the uricase enzyme. So, these primate ancestors of ours lost the ability to breakdown uric acid and that allowed them, that signaled them to be able to make that little bit more fat and make blood sugar, etc. 

Every human walking the planet now has inherited that uricase gene enzyme issue such that we don't have uricase, humans don't have uricase other mammals do. Their uric acid levels are about a third of what ours are. We have this superpower that we inherited from our primate ancestors, this superpower that allowed us to survive, it allowed us to make just a little bit more body fat, and we pulled it off, and survived to this day. Now, suddenly, we developed agriculture, and our food shifts away from fat and protein to being much more involved with carbs, and then much more recently, we developed this ability to refine the carbohydrates in 0.004% of the time that humans have been on the planet. Not enough time for us to really shift our genome, and therefore, shift our physiology to adapt to that. We're stuck with this outdated machinery as I wrote about 50 years ago, when I wrote a paper on this in the Miami Herald half a century ago.

Melanie Avalon: Speaking of the carbs on the flipside low carbs and ketones, what is the significance of ketones competing with uric acid, or do they compete or what happens with that? 

David Perlmutter: Well, interesting, what are you telling your body when you're in ketosis? 

Melanie Avalon: To use fat for fuel and ketones.

David Perlmutter: Yeah, what you're telling our body the signal is and how is it--?

Melanie Avalon: That you're starving. There's no food.

David Perlmutter: You bet. Your body is in ketosis, it's telling our bodies that we are starving. What does that do? Pull out all the stops. We've got to do everything we can to survive this time of food scarcity. That's what happens when we are deprived of food. As such as you might expect, a powerful signaling mechanism gets amplified and that is uric acid. When we're deeply in ketosis, our uric acid levels go up and that activates these pathways to take us away from AMP kinase oddly enough, and favors us to ratchet down our metabolism, and does indeed tend to lock our fat up. This is new and important information. Is it worthwhile to get into ketosis? You bet it is. But it's much more important to cycle through it and then allow your body to recover. Staying deeply into ketosis for a long period of time is associated with threats from cardiovascular disease, a variety of issues that are really threatening to our health. I'm all for ketosis, I'm all for certainly, the notion of even daily getting a little bit of a bump in terms of our body's ability to generate ketones via the notion of time restricted eating, as an example. So, I think the more we learn how to, again, emulate the environment and the influences of our paleolithic ancestors, not our neolithic ancestors, that will be the best way of relating to our genome of honoring our genome, and interfacing with our DNA in such a way as to pave the way for better health.

Melanie Avalon: So, to clarify, the potential issues of keto, are they parallel and similar to the issues created by uric acid or are they raising uric acid and creating the issues?

David Perlmutter: I think they run in parallel, where they differ is, there's really no benefit at all ever unless you're starving to having an elevated uric acid. Whereas we know that periodically being in ketosis is a good thing, as it relates to reducing mTOR activity, as it relates to transiently improving AMP kinase activity in the short run. Certainly, as it relates to mitochondrial biogenesis, as it relates to mitophagy, the degradation of defective mitochondria. So, I'm certainly all in. But if you read a James Clements book called-- [crosstalk] 

Melanie Avalon: I love James. I'm really good friends with him. 

David Perlmutter: Yeah, called The Switch. He very clearly takes us between-- You're not going to know this, because you're too young. There was a group in the day called The Byrds and they did a song called Turn! Turn! Turn! Time to build up, a time to break down, anyway. It was a very popular song Rock and Roll back in my day way before your time. Anyway, it turns out that, that song was written based upon a biblical section in Ecclesiastes about how it's good to cycle between building up and breaking down time to make war, time to make peace, all these things that they're saying about the song. With human physiology, we need a time to build up and a time to break down. Certainly, in our younger years, our teenage years we're building up as we should be in order to grow. But breaking down is also just as important. We need to activate these pathways of autophagy. Secondarily, downstream are included under the umbrella of autophagy becomes mitophagy, the ability that we have to break down mitochondria that are defective or energy producers. 

But let me digress from that for just a moment. Important to understand that there's more going on in the mitochondria than just the fact that they make energy. The mitochondria are involved in determining whether a cell will live or die and directly do that by influencing enzymes that are called the caspase enzymes, that are involved in determining whether the cell undergoes preprogrammed suicide that we call apoptosis or not. When the mitochondria are dysfunctional, and they're excessively producing free radicals, and not producing enough energy, ATP energy, it signals these pathways that ultimately activate the enzymes that kill the cell. In areas of the body, where the cells can regenerate like the liver, for example, not as big of a deal as it would be, for example, in the brain. A lot rides then on keeping mitochondrial function, where it needs to be, so that this apoptosis pathway isn't activated. Importantly, then we want to have healthy mitochondria. One of the ways that we do that is by allowing mitophagy to happen, whereby we activate pathways that both identify and then rid our bodies of defective cellular parts like defective mitochondria.

This has wide ranging implications because our immune cells, for example, are really quite dependent upon mitochondrial function, because they're so metabolically active. There's a lot of research going on right now in understanding how our bodies identify immune cells that are functioning as they should or are not, or have become senescent or old as a consequence of their mitochondrial dysfunction. There's a lot of research going on in terms of what is called senolytic therapy, allowing our bodies both to scavenge as well as then to rid themselves of these old or less functional immune cells. Again, their immune dysfunction is characterized by deficient function of their mitochondria. When we activate autophagy, we're helping our immune systems. If we never cycle between being perhaps close to ketosis, or even just making some ketone bodies not fully into ketosis, we never cycle between the two parts of the switch that James Clement talked about with you on the podcast. We never give our bodies that opportunity to identify the defective cellular components and get rid of them. Therefore, we basically just accumulate debris, which is really one of the key hallmarks of aging. Not only a hallmark, but a contributor to our biological aging. 

Again, we need a time to build up and a time to break down. That's the beauty of being involved in programs that help us make that happen by involving ourselves in intermittent fasting or even time restricted eating. We want to really do our best to allow that autophagy to happen and allow our bodies to recycle those components that are broken down during that process of autophagy.

Melanie Avalon: I'm so obsessed with all of the science of autophagy and that was something I found really fascinating in your book was you talked about how uric acid actually stops autophagy as well. That's a major role there. One other big topic to maybe tackle. Speaking to the context of everything and how there's nuance to all of this, what do you think is the role of gender when it comes to uric acid? I was reading about the correlations and oftentimes with the all-cause mortality, some of those would disappear when it would just be found for men, for example. You talked about the role of alcohol and, how it correlates to uric acid, and that it didn't apply to women and wine. Why? Why is that happening? Why are women maybe not experiencing as many of the negative effects as men?

David Perlmutter: It's a great question and there's a fairly straightforward explanation for that. That is that estrogen helps the kidney release uric acid into the urine. Women, by and large, have lower uric acid levels in comparison to men and that goes away after menopause. It actually does tend to explain a lot. Getting back to the alcohol, I just want to make sure that your listeners understand what the data is telling us about that. These are evaluation of tens of thousands of people, who complete what is called a food frequency questionnaire. In other words, evaluating what people eat over a period of time and then looking at various blood markers of whatever you want to measure. In the case of uric acid, what has been noted is that women who consume wine, their wine consumption is associated with a lower uric acid level. In men, they don't really have much change in their uric acid level when compared to wine consumption. Hard liquor in men and women, more so in men is associated with an increased level of uric acid. But by far and away, the worst player is beer. Beer has alcohol and also has purines again from the brewer's yeast. That's very, very cellular, lots of nucleic material broken down into purines. What is that doing? Dramatically raising a uric acid and telling the body make fat. There's very good rationale for understanding where the beer belly is coming from. The beer belly is a manifestation of activating an alarm system in the body telling it to make and store fat very quickly to prepare for a time of caloric scarcity, when you may not have any food. 

One of the areas I just want to unpack briefly, because I think it's really important. That is that our bodies actually make fructose. In the context of survival, that's a great thing that you could activate a mechanism in your body such that it would make more fructose, so you can make body fat and survive. But these days, maybe it's not the best news. You might then ask, "Well, what is causing our bodies to make fructose? If it's such a bad thing these days, what are we doing to make that happen?" It turns out that one of the most powerful influences on the pathway to make and it's called the polyol pathway. P-O-L-Y-O-L. The one of the most important influence is when the body feels as if it's dehydrated, when it's dehydrated or feels it's dehydrated, an enzyme is activated called aldolase reductase-- aldose reductase, sorry. Aldose is the sugar. Aldose reductase is involved in converting glucose, blood sugar into fructose and that'll be on the quiz. So, everybody has to remember that. Anyway, the body thinks it's dehydrated, it makes more fructose. How does the body think it's dehydrated? It does so because the body is very sensitive to sodium levels. When you get dehydrated, your sodium level goes way up. You see somebody in emergency room is really dehydrated, their sodium level is sky high and you have to very judiciously bring it down by giving them an IV slowly that is low in sodium. That's the body sensor that it's telling the body that we can't find water, sodium goes up. 

Well, it turns out that you can raise your sodium just by eating a bag of chips, just by eating a lot of added salt, and parking yourself in front of the playoffs, in front of TV eating a bag of pretzels with salt, your sodium levels going to go up and immediately you're going to activate the conversion of glucose into fructose. Uric acids produced and guess what? You make body fat. You become insulin resistant. For a long time, we've known that people on a higher salt diet have a dramatic increased risk for becoming obese, a dramatic increased risk for developing type 2 diabetes, and we've certainly known the hypertension part of that story for a very long time, but we didn't understand the mechanism. Then you might ask, "Well, why is the body making fat if it thinks it's dehydrated? How and why? Why would you want to make fat if you're dehydrated?" I think the image I'd like to give you would be a very unique animal that has the ability to spend three weeks without drinking water and walking across the desert, because it has a hump on its back. If you look inside that hump, what will you find? You're not going to find water. You're going to find fat. Inside the camel's hump is fat. Yeah, it uses the fat as an energy resource. Sure. But when the camel, and Melanie, and I burn fat, we form two things. Carbon dioxide that we breathe out and water. 

Body fat becomes what we call metabolic water. That's the advantage of making body fat when your body thinks it's dehydrated. It is why whales have so much blubber. Yeah, it's an energy depot, we get that. The whales don't stop along the way and find a spring in the middle of the ocean. Hummingbirds prior to their epic trips of thousands of miles, they have-- 40% of their body weight is fat. If you want a hummingbird in your backyard, what do you put out there? You put a hummingbird feeder and you fill it with sugar, sugar water, because it then makes the fructose and the sugar water becomes ultimately, stimulates the body to make fat. This is interesting. It really starts to fill in a lot of blanks. We knew this about salt consumption and obese. It's not just avoiding the fructose. But we've got to be cogs, in fact that, "Hey, your body can make fructose as well through this polyol pathway and that is stimulated by adding a lot of salt to your food." Now, if you do that, if you add a lot of salt or you have a soup that at a restaurant, you know darn well, it's really salty, drink a lot of water afterwards and that will tend to dilute it down, and reduce your production of fructose, and therefore uric acid.

Melanie Avalon: When we were evolving, wouldn't we have died from dehydration before we'd have the ability to store fat and relieve that dehydration?

David Perlmutter: Yeah, and understand these are processes that take place over hundreds of thousands, if not millions of years. In the acute sense, it isn't going to help you. But if generally over years and years and over generations and generations, there's less available water, because presumably, it's tied up frozen in the polar caps, less water available, then having a source of metabolic water would be an advantage. These are very, very minimal advantages, but they become relevant, because they play out over hundreds of thousands, if not millions of years. Again, those of our primate ancestors that ended up surviving didn't survive, because they became fat. They just had a tiny advantage, a little bit more body fat in comparison to those, who didn't have that uricase enzyme gene issue, and therefore, didn't make that little bit more fat. I'm not saying that are primates walking around with big bellies. No, not at all. But just a slight advantage played out over a long period of time is selected for in terms of genetic natural selection. It's a little bit of an advantage, but over time, it gets amplified.

Melanie Avalon: So, temporarily today, did we learn now sodium equals this effect? Is there a difference between somebody on a chronically, slightly high elevated sodium diet compared to a low-sodium diet with a bolus of sodium at one moment?

David Perlmutter: Yes, it is the bolus. It is the acute elevation of the sodium that is the real problem here. Again, if a person does get exposed to a high-salt food, by all means, that can be diluted down. Understand that interestingly, as you might infer or expect, the high level of sodium not only activates the production of fructose, but even its metabolism into uric acid by activating an enzyme called fructokinase, which is the first enzymes involved in fructose metabolism. I would say that one of the issues with people taking water pills is, of course, their sodium levels might go up, because they become dehydrated. Water pills, we call diuretics are traditionally, dramatically associated with elevated uric acid. There is a suite of drugs that are associated with elevation of uric acid and the diuretics are on that list. Are things like beta blockers for high blood pressure, omeprazole, an acid-blocking drug used by-- well, that type of drug used by 15 million Americans, many of them over the counter dramatically associated with increased uric acid. Even aspirin and even Viagra are all associated with increasing uric acid.

Melanie Avalon: Aspirin? What is the part of aspirin? 

David Perlmutter: I don't know the part of it, but aspirin consumption even 80 milligrams per day is seen to be associated an elevated uric acid level. Testosterone, drugs for Parkinson's like levodopa, a breathing drug, lung drug called theophylline, even the artificial sweetener, xylitol, a sugar alcohol, these are all associated with elevation of uric acid. I, Of course, put out this list in the book. We can come at this issue, the elevation of uric acid from so many vantage points. Look at the drugs you're taking. Certainly, look at your diet and consider the addition of some quercetin, some vitamin C, which augments our ability to excrete uric acid. A lot of things, a lot of tools, we put in the toolbox here to help bring uric acid under control without resorting to a drug. Now, I'm not saying that people shouldn't take drugs for elevated uric acid. But I am saying that as it relates, for example, to quercetin, one study of 22 males given, who had mild elevation, these are young men with elevation of their uric acid, 500 milligrams of quercetin over eight weeks dropped their uric acid level-- no other changes dropped their uric acid level by 8%, which is really quite significant. There's a lot that can be done without resorting to drugs. Again, I'm a medical doctor. Drugs are not foreign to me, they're not rejected, there's a time and a place. The purpose of the book, though, is to call out the importance of elevation of uric acid A, B gives you the tools to bring it under control.

Melanie Avalon: Well, I cannot thank you enough for doing all of that. Listeners, you have got to get Drop Acid. It is so incredible. It dives so deep into everything that we talked about. Then, Dr. Perlmutter said, it has so many resources for things to look at. He has his LUV diet that you can follow to lower your own uric acid levels. So, I really, really can't thank you enough and that actually is perfect, because my last question, I don't know if you remember it from last time, but it's just because I realize more and more each day how important mindset is, so, what is something that you're grateful for?

David Perlmutter: Well, there are a lot of things I'm grateful for every day and that's really part of my daily routine is to stop and just be with those aspects of my life that I'm grateful for. Having wonderful children, a wonderful marriage, it gives my life meaning. One thing I maybe didn't mention last time, I think when you ask me the question is, I'm grateful for the fact that I have a particular skill, and that I've identified that particular skill, and that I'm exploiting that particular skill, which is the ability to take seemingly complex information and make it understandable for many people. There are a lot of things I can't do. I'm terrible at ping pong, I'm not the best nose gear, and I don't like diving off the high dive. I'm here to admit that. But I have a particular skill and that is to look at-- As you see with Drop Acid, this can be daunting information. But to really break it down, so, as many people can benefit from it as I can reach. I'm grateful that that I was able to identify that and that I have this skill in the first place. I'm always grateful for people like you, who are out there exploring stuff and making information known. 

Maybe you don't fully subscribe to everything that your guests are talking about. But at least, it's out there and it's not judged. This is information, people are talking about it, here's the information. It's not presented in such a way that you necessarily have to subscribe to it. But it's out there and it's worth looking at. I honor you for that and I have to say I honor everybody, who gives me the opportunity to spend time with them and this was a particularly nice interview. Very kind, and in depth, and well researched on the front end. So, please know that was very much appreciated.

Melanie Avalon: Oh, thank you so much. I'm just so honored and grateful. I've been a follower of your work for years, years, years ever since Grain Brain. To have you on the show for Brain Wash and now, this for Drop Acid, it has just been absolutely wonderful and I am also so, so grateful that you touched on that one thing that's really important to me is just being open to all the information, because I really think that's the only way we can find truth is if we are just listening to everything and finding what works for us.

David Perlmutter: Well, you're right and it's unfortunately so missing in our day-to-day lives these days. It's called cognitive empathy and that is the ability to try on another person's point of view. You may not agree with it, but at least be with it. This was the agora, the marketplace, where ideas were shared and we just don't seem to do that so much anymore. My way is the only way and we won't make progress if it's only my way. I have to listen to the views of other people and be willing to accept the fact. Years ago, I was all in on the low-fat diet. Fat was the devil. I would put my patients on a low-fat diet, because it's the best I knew. How wrong that turned out to be, and it's so important to listen, and be able to change with the science, and be able to be malleable as it relates to ideology.

Melanie Avalon: I could not agree more. Thank you so, so much. Please, please keep doing what you're doing.

David Perlmutter: Oh, Melanie, thank you.

Melanie Avalon: Do you have another book coming out?

David Perlmutter: It's not in the works yet, but I think that the natural next book is going to be the Drop Acid recipe book. I'm sure that's coming. We haven't talked about it yet, but it'll be-- We have 40 recipes in this book, but it'll be a whole book dedicated to lowering uric acid or lowering uric values LUV.

Melanie Avalon: Awesome. Well, I will put links to all of that in the show notes. Thank you so much for all that you do and hopefully, we can talk again in the future.

David Perlmutter: Thanks, Melanie. Talk soon. Bye-bye.

Melanie Avalon: Bye.