The Diet Linked to Up to 50% Lower Dementia Risk | Dr. Austin Perlmutter

Why are people so sick? Why is it that we're seeing these largely preventable conditions? One of the big variables, of course, is food. We're eating the wrong foods, we're sedentary, we're not getting enough sleep, we're watching too much stressful media. When we look at the variables that predict brain health over decades, food is at the top of the list. You know, it's food, exercise, and sleep. And as we look at how food is capable of influencing our brain health, we don't get to opt in or out of eating food. We have to eat food. Even though the science continued to progress, I feel like the public understanding of food These are big issues. We need to understand how food acts on the exact same pathways as pharmaceuticals, how food can be reliably used as a way that can help us to live longer, healthier lives. The best studied way to live a long and healthy life has nothing to do with supplementation. It's specifically to do the—

Hello everyone, I'm Dr. David Perlmutter. Welcome again to The Empowering Neurologist. What are polyphenols? We're hearing so much about why we need to have, uh, A diet that's rich in polyphenols. What are they and why are they important? Our guest today is Dr. Austin Perlmutter, and he has really become one of the leading authorities on this topic. We're going to explore what polyphenols are all about and his research in this area that is actually really very, very exciting. What we can do to increase polyphenols in our food and why that needs to happen in terms of our health outcome. I'm very, as you can imagine, excited. About this interview today. So let's jump right in. Dr. Austin Perlmutter, welcome to The Empowering Neurologist.

Thanks so much for having me back.

You are a repeat offender on The Empowering Neurologist, which is great. And I think the reason, you know, you always have new information to share with us. And I think, you know, as I said in the introduction, we're going to be looking at food, food in the brain, and then we're going to do a deep dive into polyphenols, as well as your really exciting 2024 research that Uh, looked at the effect of polyphenols on aging, and we'll call it like it is. But let's start off by, uh, talking about your interest and, and why you became interested in, in the role of food as it relates to brain health.

So if we look at brain health issues around the world and we see mental health issues being what they are, hundreds of millions of people struggling from mental health issues. Now we have dementia, roughly 60 million people estimated to hit about 150 million people in the coming decades. These are big issues and You know, I think as listeners to your podcast know well, they're the most important issues. If your brain health isn't good, nothing else matters. And so then the question is, well, what can we do about it? And certainly there are a range of options, and I'm not anti-pharmaceutical in the right set and setting, but here's the thing. When we look at the variables that predict brain health over decades, food is at the top of the list. You know, it's food, exercise, and sleep. And as we look at how food is capable of influencing our brain health, we don't get to opt in or out of eating food. We have to eat food. So the question then becomes, are certain dietary patterns and certain foods more likely to support good brain health, not just in the long run in terms of decreasing risk for conditions like Alzheimer's, but even in optimizing brain health on a given day? And as it turns out, certain foods absolutely have these correlations. So various dietary studies have shown that people who adopt certain diets may have up to a 50% lower chance of developing dementia compared to the people who eat more of a standard American or a Western pattern diet. And so the reason that I've been so fascinated with this research is number one, there's so much to leverage if we can just get people to eat a slightly healthier diet in terms of preventing and optimizing brain health issues. But beyond this, we're starting to understand how certain nutrients, certain molecules within our food may have an outsized potential in terms of helping to mitigate certain brain health conditions. And that's really where getting into these plant-based nutrients is so fascinating because as we'll discuss, there are some studies now showing that people who eat more of these very specific plant nutrients may themselves be at a dramatically lower chance for developing brain health issues. And beyond this, now what we're seeing is some studies showing that even acutely, an intervention with these nutrients can augment, can boost certain aspects of brain function. So it's very exciting stuff.

So when people think about their food, they're thinking macronutrients, fat, protein, carbs, you know, that's the big discussion today. How much, what's the ratio of these types of foods? How much protein should I get per gram body weight and all that? That's the big discussion. There's, you know, secondarily some discussion about so-called micronutrients, vitamins and minerals. But you've, uh, you were speaking at a recent conference about the so-called dark matter, uh, in food and how influential that is. Let's, let's double-click on the dark matter idea because I think, I, I'm not sure that's a term you developed, but it really, I think, says a lot that there's a lot going on in the background that most people don't appreciate.

Well, one of the themes that I've been talking about now for a bit is this incredible hubris that humans have in general. in terms of our belief that we understand nature, and I think food is probably the best example. Right. So, we as modern-day humans have this belief that we understand what is in our food because we've been able to compartmentalize and lock down the key macronutrients. So, we can say this has this many grams of fat, this many grams of carbs, this many grams of protein, and therefore we understand the food, and it's really only in the last 100 or so years that we started to say, oh, Turns out there's more to it. There are vitamins that we actually need. There are minerals that we actually need. So we'd say, well, this food is a good food because it has enough calories to keep us alive, enough macronutrients to where we're getting fats, carbs, and proteins, and then some vitamins and minerals. And honestly, even though the science continued to progress, I feel like the public understanding of food really stopped because what we did was we carved out the actual nutrient profile in a real food, and then we started to retrospectively, or I guess after the fact, we started to add these things back in. So as an example, take some whole grains. You strip away all the fiber, you strip away all the plant nutrients, you bleach it, you refine it, you make a loaf of white bread. Now that loaf of white bread, as we know, is mostly refined carbohydrates, and now we understand probably not the best thing for your overall health. But we recognized decades ago, researchers recognized, hey, because we've done all of this stripping out of nutrients, we probably need to add some things back in. So then we fortify these foods. We throw in some B vitamins. If you look at, for example, cereal that you buy on the store shelf, you'll see that it's been fortified with nutrients because the idea is we understand food so well and nutrition so well that even though we've destroyed the actual architecture of the food itself, we're able to toss in some vitamins and minerals, and now all of a sudden that food is good for us again. But coming back to the hubris piece of it, now what we understand based on research that was published in the New England Journal of Medicine and other leading journals is is that food contains over 100,000 different molecules, and that's again the so-called dark matter of nutrition. It is an incredible universe of data that we're just scratching the surface of. Why that matters so much is coming back to the central conversation: why are people so sick? Why is it that we're seeing such high rates of especially chronic and these largely preventable conditions? One of the big variables, of course, is food, and it's easy to default to simply saying people are eating too many calories, people are eating Not enough fruits and vegetables, and people just need to make sure that they are eating less of the junk food and more of actual food. And yes, that's true, but the why, right? So, the why is in part because there are these incredible groups of these nutrients found really only in minimally processed food, some of which can have an outsized effect specifically on brain health. So, that's the dark matter of it.

So, why has it been overlooked? Glossed over for so long.

Yeah, I mean, from a marketing perspective, or I mean, I guess purely from a bulk production perspective, that's just not the goal. So kind of post-World War II, the goal was to mass-produce foods that were readily available for people, make sure everyone has enough calories. And you can see in the United States what that led to was the growth of monocultures, right? We want enough corn and we want enough wheat. We want to ensure that there's enough calories for the population. That wasn't necessarily the wrong decision in terms of optimizing towards a variable. Yes, it's important that we have enough calories enough calories, but we've lost things in the process. And the other piece of this is it's not just about optimizing towards other variables, it just wasn't known. We've only more recently started to understand how to analyze food to be able to understand what is in it. And a good kind of corollary to this is think about the microbiome, right? So even when I was in, you know, elementary school, which you know very well, not so long ago, right? The sign in the bathroom was telling us about germs. Germs are bad, bacteria are bad. I never learned in those days, hey, you know, you really need to be paying attention to what antibiotics might do to your microbiome because there are good bugs in your gut. It's the exact same parallel. It's just a blanket statement of we understand what's good and bad, and beyond that, nothing else really is that valuable. Sure, there's a little bit maybe of additional value you could get from back in the day maybe eating some kefir or having some sauerkraut, But it wasn't until recently that we started to understand that there were specific microbes that could have an outsized effect within our gut. And I want to bring that up too because one of the things that we've just recently learned is, you know, we think about these probiotic foods. It turns out that all foods have some sort of a combination of microbes that live on them. So if you buy an apple in the farmer's market, you don't think of an apple as a fermented food because it's not, but if you were to eat that apple that comes from, you know, Farmer Joe's— farm down the road versus some other guy's farm, which has been shipped over from across the country, there are different bacteria on that apple, and it turns out that those bacteria also colonize the gut and can have health effects. So really what all of this is that we're talking about is just reopening a little bit our spectrum of input and asking these questions about, is there something we've missed along the way that nature provides that when we bring back can provide health benefits to people?

Yeah, it really gets back to what our friend, uh, Dr. Jeffrey Bland has, has been talking about for decades. And that's the idea that food is information. And I think, you know, we're gonna certainly go deeper into how these foods influence us at a genetic and epigenetic, uh, through epigenetic mechanisms. But let's talk about that if we can. These molecules that you're referring to, many of which are polyphenols, but there are others. How, what are the pathways by which they work? How do they, how do they influence us, uh, physiologically and, and what What's the play in terms of our health?

So let's back up for just a second before we jump into what polyphenols are. What I started by saying is that there are over 100,000 different molecules in our food, and some of these we're just starting to discover, and some of these may have a major effect on our health. Polyphenols are one group of molecules. These are— they're secondary metabolites made by plants, which means plants don't absolutely need them to survive, but they use them to kind of tweak survival pathways. So polyphenols are so named based on their chemical structure. There's 8,000+ that we know about, and they are molecules that are made by plants to allow a plant to optimize for resilience. So plants make polyphenols to defend themselves against UV radiation. Plants also make polyphenols to create communication pathways with microbes in the soil. Plants make polyphenols to defend against various pests. So they're found in plants. What's really interesting is if you look at kind of the history of how we have understand these polyphenols, they've actually been popularized in the last couple of decades specifically because they're associated with longevity pathways. And so resveratrol, good example, kind of peaked and now it's a little bit less popular. But one of the things that was understood about this polyphenolic is that it may act on pathways related to sirtuins. And these are key kind of NAD-dependent longevity pathways. We don't have to go down that kind of tangent too much, but these are These are actually molecules that have been studied in conjunction with some of the most hardcore longevity science because what they seem to do is activate some of these specifically longevity pathways. Now, taking a step back, that's just one of the things that they seem to do. So, polyphenols appear to act on the immune system. They change the microbiome. They influence metabolism, and maybe most interesting for the purposes of this conversation, they influence how our DNA is used, so-called epigenetics. They modify the way that our DNA is being used. Okay. I also want to ensure that we don't go too technical on this because the reality is that the best studied diets in the world, especially for brain health, so for example, the Mediterranean pattern diet, the MIND pattern diet, if you look at the research on those diets, one of the things that the researchers consistently say is these are diets that are rich in polyphenols, and it's actually one of the reasons why these are perceived to be some of the best diets for overall health. And so individual foods, some of the top foods people think about for brain health, whether that's something like green tea or coffee, or dark chocolate, or even, you know, this potential benefit of red wine, it's because of the polyphenols that are found in those foods. So they've kind of been there below the surface, and honestly just slightly below the surface of the public understanding. Most people have that base level of, oh, these are valuable, but the reason they've heard of them is because they're antioxidants. And what I want to talk about today is it's not about the antioxidant effect, it's about these far deeper pathways that can lead to long-term benefits to overall health, and then especially Hey

guys, we're going to get right back to the podcast, but I do have a very important message for you. I think many of you will recall a conversation I had here on the podcast with Dr. Michael Leone. He is a University of California, Irvine neuroscientist, and what he studied and what we talked about on the podcast is what is called olfaction, our sense of smell, and how things that stimulate our sense of smell are directly wired into the brain's hippocampus and amygdala. And these are the same circuits that govern things like memory and emotion. You know, most of our sensory inputs get routed through a bunch of relay stations, but our sense of smell actually doesn't. It has a direct line in through the centers that I just described. And Dr. Leone's work takes full advantage of that pathway and enriches this olfactory pathway with a variety of scents presented to you during your sleep. That's when your brain is already doing its nightly work of clearing out the metabolic debris, things like beta amyloid and other accumulated misfolded proteins. Dr. Leone has done some wonderful clinical research on the idea of stimulating the brain with a variety of different scents during the course of the night. And he has demonstrated that using this approach in some of his research has shown as much as a 226% increase in memory function and 22 minutes in addition of sleep, with his results published across healthy adults, older adults, and yes, even people who are suffering from what is called mild cognitive impairment, MCI, what we consider to be the harbinger for further brain decline. So he and his research team have built a device around this research, and that device is called Memory Air. It isn't a pill, it's not a supplement. You put it on your nightstand and it does its work while basically you're sleeping at night. Their website is memoryair.com. I've been working now with Memory Air and have developed a relationship such that you can get a 15% reduction in cost of your Memory Air device should you choose to buy one. You use the code PERLMUTTER, and this is also going to get you free shipping and a 60-day money-back guarantee. These statements have not been evaluated by the Food and Drug Administration, and this product is not intended to diagnose, treat, or cure, or prevent any disease. Let's get right back to our podcast. Well, you mentioned something a moment ago that people in my generation continue to be somewhat amazed by, and that is that something in our food, in this case, we're talking about polyphenols and other molecules, can influence the expression of my DNA life code. I mean, in my day, you know, DNA was locked up and it deter— it was a one-way street from DNA to basically, you know, transcription, protein formation, and that was inviolate. And now, you know, you guys of your generation sort of throw this around like, oh yeah, we know food can modify epigenetically expression of your DNA. That takes a lot for somebody of my generation to really embrace because, you know, the doctrine of this one-way pathway and the inviolate nature nature of, of our DNA was deeply inculcated into our, into our psyche. So yeah, you know, it's, it's great that I, I, I'm living at a time when we can see these incredible changes. So we are talking about—

Can I just say one thing? Let's just say one thing on that front, because I think it's easy to kind of lose the significance of what you've just said within the context of this larger conversation. So if we're thinking about the nature versus nurture piece, that's what I grew up learning. You know, you have these 2 variables. You have your genes, and then you have your environment. And the combination of those 2 things determines what happens as it relates to your health. What epigenetics does is it bridges the gap because what it says is that your life experiences can change the degree, not just a binary, does the gene get activated and turn into a protein, but the degree to which that happens, the dimmer switch. Hmm. And that's absolutely fascinating because as it relates to maybe the most important conditions that we worry about for most people, these chronic diseases, it turns out that epigenetics may play a significant role in driving those processes. So, You know, not to jump too far into Alzheimer's here for a moment, but we think about these various genotypes that are associated with higher risk. Now we're starting to understand that at least in part, epigenetics may determine the degree to which those various genotypes are expressed. And what's fascinating about this is it really makes a lot of sense if you were designing a mechanism in a human that was most likely to succeed, given the fact that environmental pressures would obviously be different decade over decade, whether it's the weather or scarcity of food. You would start with your belief that this is a good set of, of basic rules, right? So that's your genetic code. We only have around 20,000 genes, not that many, but you start with the idea of, hey, these are the basics that we're going to build. So a human's going to look basically this way. It's going to be around this height. It's going to have 2 eyes. And then what you would need to consider is why is it that humans only have 20,000 genes, whereas other animals, even incredibly small and seemingly simple animals, have so many more genes? It's because what humans have is the incredible potential to change the way they behave and the way their health goes as a reflection of environmental input. It's the whole concept of neuroplasticity. It's this incredible advantage. So the way I look at it is we started out with this genetic code, but then we built in all these mechanisms whereby we could fine-tune and tweak the way that those genes were expressed based on whatever was most relevant in our environment. And so it's one of the things I believe that's allowed humans to be able to differentiate and do so well across so many different parts of the planet. Other species tend to niche down. They say, you know, I can only handle these temperatures, I can only handle these foods. Humans have been able to generalize in a way that is absolutely unprecedented, and it's because we are capable of taking this environmental data and changing our physiology, changing various pathways in a way hopefully that benefits us. But the inverse of this, and the real issue, is when we look at what so much of the modern world has done in terms of the signals that it is sending to our genes and our epigenome, it's actually the exact opposite. So if we're programming epigenetics with a certain set of patterns that increases our risk for diseases because we're eating the wrong foods, we're sedentary, we're not getting enough sleep, we're watching too much stressful media, that's exactly what we want to try to mitigate. So it is really such an incredible opportunity because here what we're talking about is that bucket that we've historically said is untouchable, which is the genetic code, turns out to be modifiable. But we need to take that with a whole lot of consideration. Yeah. Because, you know, just like neuroplasticity, the rewiring of the brain, this isn't an opt-in, opt-out scenario. What we can do, however, is determine what inputs we want to feed our epigenome.

Well, you know, an analogy that comes to mind is the idea that you have a symphony orchestra playing a beautiful symphony, but there might be one section that's too loud or too soft, the woodwinds, the strings, whatever it may be. And that's the job of the conductor, I think, is to regulate the volume of expression of each individual part so that ultimately there's beautiful music. And I would say to our viewers, if you wanna learn more about this specific topic, a podcast I recently did with Dr. Sarah Marzi from the Marzi Neuroscience Institute in England, talking about lifestyle and regulating epigenetic gene control over our gene expression and how that relates specifically to neurodegenerative diseases. Austin, you were talking about the idea that we shouldn't really focus on the antioxidant activity of polyphenols, that there's a lot more going on. Well, what's going on?

If we wanted to call polyphenols antioxidants, the reason we would do that is because their chemical structure allows them to be antioxidants in a cell model. They are able to quench oxidative radicals, and so they are technically antioxidants. But then some interesting questions. One is The question is, when you give humans high doses of antioxidants, does it dramatically enhance their health? If the whole problem, which some people might believe, is that life is just a series of developing more oxidative stress and that leads to every disease under the sun, then we would assume that just being capable of taking a high dose of an antioxidant would fix everything, but that's not what happens. When you give humans high doses of antioxidants, their health doesn't dramatically improve, and in some instances, it actually worsens. So, that's not quite the case. Beyond this, when we look at what actually happens in humans when either in an interventional trial or an observational trial they consume higher doses of polyphenols, the mechanisms don't necessarily fit with just a pure antioxidant effect. So, as one example, we now know that when you consume polyphenols, the majority of them can't be digested. They can't be brought into our bodies because they're kind of being bound to various other molecules, so they pass into the large intestine undigested. Now, you could say, well, sounds like we don't do anything with these molecules because clearly we're not able to absorb them, but what turns out to be the case is that the gut microbiome can use these polyphenols, so can actually metabolize these polyphenols and convert them into new molecules which may be more effective for us. We might be able to absorb them, and they might be more effective than the original molecule. Beyond this, research shows that certain polyphenols can actually influence the makeup of the gut microbiome. So as much as it might be nice to say, well, they're antioxidants, again, they may be driving effects by what they do to the microbiome in our gut. So very interesting stuff there. Beyond this, when we look at what they do in the body, what we're starting to see is that they're influencing various metabolic and immune pathways. So a study that we can talk about here in a moment, which we actually published a couple years back, showed that giving people a decent dose of polyphenols from a plant called Himalayan tartary buckwheat was associated with dramatic changes across almost 900 different epigenetic sites, and these were not necessarily associated with antioxidant status. They were linked to things like longevity pathways, the immune system, brain pathways, and what I find really interesting is when you start with observational data, so looking at certain patterns of polyphenol intake in kind of the top journal, I guess you could qualify this, but neurology, When you look at observational data on people who consume highest total amounts of certain polyphenols, you see that rates of developing Alzheimer's disease based on some studies are about 50% lower. So then we'd say, look, if it's just an antioxidant effect, then why not just give them high doses of various vitamins? And again, we just haven't seen anything even remotely as advantageous when those types of studies have been executed. Yeah. The one other study I want to highlight here before we kind of move forward is if you think about what's most interesting around brain health for, for I would say the average person, but hopefully for your audience, right? It's preventing Alzheimer's disease. It is optimizing brain function. One of the things that is kind of more specific to it is to try to prevent the shrinkage of the hippocampus or the hippocampi, right? The memory centers of the brain. I know your audience is obviously very familiar with Shrinkage of the hippocampi are kind of one of the hallmark features of Alzheimer's and correlates with the loss of memory, all the things that we don't want. There was a study that was done looking at people, specifically there were people in a nuclear power plant, so they had some degree of control over that population, but they gave them an intervention which was 18 months of a high polyphenol diet. So one group did a control diet, one group did a high polyphenol diet, which was the Mediterranean diet, and then one Mm-hmm. And then one group did a boosted polyphenol diet, so Mediterranean diet plus some additional polyphenols, so they were getting roughly 1,200 or so milligrams of additional polyphenols a day. What they showed is using imaging, so MRI at the end of this study, is that the people who were consuming this highest polyphenol amount showed the slowest rate of brain shrinkage specifically in the hippocampus. Consuming the polyphenols actually mitigates some of the age-related shrinkage within the brain, and I don't know of really any other study that you can look at that shows that a dietary intervention is capable of something like this. So then you talk about, well, what are the mechanisms within the brain? Again, it's immune, it's metabolic, it could be epigenetic. There's some good data— Dr. William Li likes to talk about this— that polyphenols can influence vascular health, which is obviously advantageous to the brain given that the brain brain is incredibly dependent on vascular supply for both oxygen as well as for glucose as well as for other molecules, but the bottom line here seems to be that consumption of higher levels of these molecules, especially as part of a diet similar to a Mediterranean pattern diet, seems to be associated with better overall brain outcomes through a variety of different pathways.

Well, so that's an interventional trial that you mentioned. You actually conducted an interventional trial using This Himalayan tartary buckwheat that you, that you talked about. And tell us about that study, because I think the remark— uh, the results that you demonstrated, uh, are really quite astounding. And, uh, tell us about that.

Yeah. So, so my bias is always going to be look at food first, right? I think it's really tempting to go to saying, let's take a quercetin supplement or, or high-dose vitamin C, as opposed to, you know, eating some onions, which are high in quercetin, uh, or trying to consume more citrus What we are trying to do is trying to understand how is it exactly that when we say food is medicine, that that works. And so we've been using a plant called Himalayan tartary buckwheat. And just for quick background here for people who aren't aware, so tartary buckwheat is a type of buckwheat. There are multiple types of buckwheat. Common buckwheat is the most common type that you're gonna find in the store. So what makes tartary buckwheat so different? Okay. Okay. Is that it is kind of a— it's a very intense version of this plant. So, tardary buckwheat historically has grown in some of the most inhospitable conditions on the planet. And the way that it's capable of doing that is because it produces just an insane concentration of these polyphenols, specifically one called rutin. Rutin kind of interconverts with quercetin, which is one that people might be more familiar with. But tardary buckwheat can have almost 200 to 500 times more rutin than common buckwheat based on some of the analyses that we've looked So, it's very, very concentrated in certain polyphenols. So, we have known that people have consumed this plant for millennia. It's been used medicinally for thousands of years as well. We have been curious about the phytonutrient content or the polyphenol content of this plant because several recent studies have shown that when you replace wheat with tartary buckwheat, it improves metabolic parameters, it improves immune parameters, it improves weight loss, it also improves fatigue parameters. Okay. So we wanted to see what is it about this plant and the nutrients in it that could influence human health. So the first pilot trial that you're describing, which we published in Frontiers in Nutrition in 2024, we were looking at a concentrate of key phytonutrients or polyphenols from tardary buckwheat in healthy people to see what it did to epigenetics. So we used an epigenetic chip that looked at almost a million different sites on the gene at the start and at the end of this 90-day trial. And what we found was— I mean, I guess I should say we didn't go in with the expectation that we were going to find necessarily anything all that remarkable because it's really hard to change health within a 90-day period with just a dietary influence that you'll be able to see in statistically significant ways. What we found was almost 900 epigenetic sites that were changed with a p-value of 0.001 or less, so highly statistically significant. And then when we looked at it in more detail, what we found One is, for a population of people who are aging more rapidly, we saw based on a certain aging clock— these are how you use epigenetics to kind of determine longevity pathways— that they had a 47% slowing in their rate of aging from the start to the end of the study. But what was even more interesting to me is we were able to isolate certain pathways that had a dramatic change from the start to the end of the study. So, one was called ceramide kinase. Uh-huh. Another was the COP9 signalome. These are things that probably nobody has heard about before, but what makes them so interesting is that they're key governing pathways linked to the immune system and to metabolism as well as to longevity. We also found changes as related to things like glial cells and neuronal development in the brain. So there were a whole lot of incredible findings that we found, and this was, again, it was a pilot study. We were just trying to see, are we capable of seeing changes in healthy Humans using the polyphenols from tardary buckwheat over a relatively short amount of time, which is 90 days. And what's really exciting about this is what we're doing now, which is this incredibly large randomized double-blinded controlled trial, placebo-controlled trial, with a food here. So Himalayan tardary buckwheat, we're using a sprout powder on specifically cognition. So this is, from my understanding, the largest study that has ever been conducted on an individual food for cognition. It's ongoing right now. So stay tuned. I can't wait to talk more about that as the results come out.

So how many people did you recruit for this, and how long is it going to be?

So this newest trial is 850 people, 425 per arm, 425 placebo, 425 active. We've completed at this point, this will depend on when people listen to this, so completed enrollment, we expect to have the results about middle of the year, and so then we'll be looking for publication. But what makes me so excited about this study is, you know, we think about this idea of food is medicine. A lot of people, whether in the government or in academic institutions or in the general public, a lot of people love this idea, this belief that eating certain foods is something that we can do to help to improve our health. And then the question is, how does that happen and why does that happen? And generally it becomes a default where we say, well, foods can influence our health because, again, they're antioxidants. They have vitamins and minerals. and maybe they have an anti-inflammatory or a metabolic benefit, but it's not good enough, right? If we want to actually be able to use food as medicine, we need to understand how food acts on the exact same pathways as pharmaceuticals, how food can be reliably, reliably used as a way to bias key pathways that can help us to live longer, healthier lives. And as it relates especially to brain health, you know, we know that eating the right type of diet is probably one of the best things that a person can do, or is one of the best things a person can do to decrease their chances of developing dementia. But we have to go one step beyond simply saying, well, you should eat a Mediterranean pattern diet or a MIND pattern diet, and say, we know that food is capable of exerting these effects because food contains molecules that can preferentially bias these pathways. I know this is complicated stuff, but this is the bridge. This is the gap that exists right now between modern pharmaceutical medicine and what people would talk about You know, that you're picking out some healthy foods in your grocery store because, of course, you want to eat some colorful fruits and vegetables.

For close to 40 years, I have found myself in examining rooms watching families struggle through the loss of a loved one, not because that loved one aged, but because that loved one had lost his or her cognitive

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Where are people getting most of their polyphenols in, in, in the normal standard diet?

Well, the, the number one source, as I think you know, of polyphenols in the American diet is coffee. It's crazy. Thankfully. I'm, you know, I'm a huge fan of coffee, as you know really well, but we're not drinking coffee for the polyphenols. We're drinking coffee for the caffeine, and the polyphenols are a nice little bonus. Other top sources, of course, would be tea. I mentioned chocolate. They're widely distributed kind of across the spectrum of plant-based foods, and there's actually some interesting research being done by a guy named Stefan von Vliet, who's at Utah State, showing that in animal products there's actually polyphenol metabolites. So you can get some polyphenols from eating meat, but those polyphenol metabolites differ depending on what the animal consumed. So if you have a grass-fed cow, that grass-fed cow is going to have different polyphenol metabolites in its body than a feedlot cow. And so these— what makes them so unique, I think, is that polyphenols are this, this data signaling mechanisms— mechanism across ecosystems. So they go from soil to plant to plant Hmm. Animal, animal to human, and they can transfer into resilience signals if they're consumed in the right kind of context. And one of the examples I'll give you here, just in terms of how much they change, is we've been engaged in this sprouting process with this tardary buckwheat to see what happens when you take a seed and sprout it, give it about 4 days of sprouting. And what it does is it boosts the polyphenols by about 3-fold just over a couple of days, because what you're basically doing is activating these key pathways, including epigenetic pathways within the plant to interconvert these molecules into a different set of information, because what a plant that is growing needs versus what a seed that is, is trying to protect and, and kind of guard against the environment needs, totally different. So just like if you were going to eat a plant that had been grown organically versus a plant that had been grown more conventionally, those plants create different sets of signals and different polyphenols because of what they're trying to basically exert on their environment or what their environment is exerting around them. So at some point, this conversation transcends from just being, you know, this is what's good for me, for my personal health, to saying this is an interconnected web, right? And polyphenols are just one of the languages discussed by the soil microbes, the plants, the animals, and humans.

You know, I, I've had on the podcast a couple of times Dr. Steven Gundry, and your grandfather would have said, oh, that guy's a character. And I do I agree. He's a character and, uh, I, I enjoy talking to him. Anyway, he, he, and his last appearance, he was really making a point that in many ways polyphenols act, uh, towards our health, uh, because they're somewhat pro-oxidant. So that's a, a bit conjectural. What, what does that actually mean and what's the evidence?

Yeah, so the, one of the things that's been proposed is that polyphenols are actually hormetic stressors, meaning that when we consume polyphenols and polyphenol-rich foods, they do exert a low-level stress on our physiology. And because of this concept of hormesis, which is that a low-level stress can actually be advantageous, that in the aggregate this leads to a value to our health. You know, Dr. Gundry has a lot of perspectives on plant nutrients in particular and their potential downsides as it relates to things like lectins. What I would say is some of these things are true mechanistically, but at a population level are relatively unhelpful. And some of these things are true mechanistically and at a population level are incredibly useful. So right now we could debate exactly how polyphenols work. Is it because they have this hormetic effect that leads to a little bit of an oxidant stress or a bit of a positive stress at a cellular level? Is it because they regulate the immune system and help to dampen inflammation? Is it because they help to improve vascular tone? We don't know for sure, and it may be that different polyphenols have different effects depending on how they're consumed, what are the other molecules they're consumed with, what part of the body they're in. One of the things that's fascinating around epigenetics is we see that epigenetics changes depending on the tissue. So epigenetic aging could tell you something about what's happening in the liver versus what's happening in the brain. So it could be that the same polyphenol has a different effect on different tissues. We don't know exactly. That's what we're trying to learn.

Yeah, I think his argument was, again, getting back to the notion of a hormone That's true. And ultimately leading to more functional mitochondria, enhancing autophagy, enhancing mitochondrial biogenesis. But let's go back for just a moment and talk about one of the, I think, pathways I'm sure that you'd like to talk about, the NRF2 pathway. And, you know, this is a— I'll let you explain what it all does, what the downstream activation pathways are from activating NRF2. But primarily, we know that polyphenols activate the NRF2 pathway, but we know that it is also quite responsive as a regulator to increased oxidative stress in the body. I mean, that's what it seems to do, and that, you know, the polyphenols activate this pathway as well. So in that regard, if polyphenols are pro-oxidant, it might— that might be one of the mechanisms by which NRF2 is dissociated from the key protein and then does all the cool things that

Yeah, I think that is interesting. So, there are kind of a couple of key pathways at the level of a cell that polyphenols seem to influence, NRF2 being one. They seem to potentially suppress the inflammasome. They seem to act on mTOR and AMP kinase. And again, mostly this is mechanistic at a cellular level, right? So, if you're looking at NRF2 expression, you're probably going to be looking at a cellular level. Cell-level study as opposed to a human study. And I think this is really a great opportunity to highlight, you know, one of the key pieces of what we're trying to do with this research, which is it is amazing to get excited about individual pathways. So I'm sure I could say polyphenols augment autophagy because they have this positive effect through antioxidant pathways, NRF2, mTOR, etc. And so if you consume polyphenols, you will remove older dying cells, you will clean up the cells that are not efficient. We don't know if that happens in humans. What we do know happens is that at scale, when people consume diets higher in polyphenols, they have better health, they have better brain health in particular. What we're starting to see through some of these interventional data points is that when people consume polyphenols, polyphenol interventions, it seems to beneficially augment cognition in a short amount of time, meaning over the course of minutes potentially after an intervention, and then in kind of a middle-range amount of time, it seems to be protective against certain aspects of brain dysfunction. So, coming back to this study I mentioned before, this GreenMed Direct Plus study, the 18-month study showing a slowing of brain atrophy. If you really drill down to the level of the cell, you can go down any of the pathways you want to. You can go Krebs cycle, you can go mitochondrial oxidation, you can go mTOR AMP kinase, and there's data for all of those. We've been a little bit more focused, again, trying to move away from this purely antioxidant pathway towards the immunometabolic component, and And so, I know we've spoken about this a little bit before, but where polyphenols have kind of emerged as exciting in the research in just the last decade or so is through the longevity pathways associated with molecules, or I should say associated with channels like the AMP kinase, mTOR kind of bifurcation. And again, we've moved away from just resveratrol being the golden child of this, but why this is exciting is if you look at Yeah. So if you look at the longevity research right now, what you'll see is that we're talking about molecules called senotherapeutics. So these are molecules that target aging at the level of the cell, and some of these are purely pharmaceutical. So some of these are potent molecules, some of these are chemotherapeutics. But polyphenols like quercetin as an example, or luteolin, fisetin, or fisetin— what I want to just describe here Yeah. Is yes, antioxidant, yes, NRF2, yes, inflammasome, yes, mTOR and AMP kinase, yes, metabolic and immune pathways otherwise. That's really interesting for the people who want to know the specifics. What I think we need to focus on right now is for a person listening to this podcast, right, who has been told this thing, which is that it's all about calories in versus calories out. Next level in, it's about your macronutrients. You need to get enough protein, don't eat that many carbs. Next level in, it's about getting magnesium, making sure you get your B vitamins. We don't want to lose the magic of what nature provides, and nature isn't providing a very specific dose of polyphenols so that you can get a very specific activation of NRF2. What it's trying to do is give you a set of signals so that your body can best respond to the environment around you. And I think to that point, you know, one of the takeaways I want to make sure people leave with is to say, as you're going out and making dietary choices Consider diversifying the amount of polyphenol-rich foods. Our friend Deanna Minich talks about this often, but the rainbow, the idea of consuming a range of colors in the fruits and the vegetables that you consume, is an amazing way to make sure not only that you're getting more polyphenols, but that you're getting a good range of polyphenols so that your cells are being exposed to a whole set of signals that can help to promote health. Colors in foods, tastes in foods, especially bitter tastes in foods, are signals that they are rich in polyphenols. This is why we talk about why coffee is bitter, dark chocolate is bitter, and our goal is to move away from a culture in which we've, you know, said bland and sweet are kind of the major signals we want to pursue and readdress this fact that we have co-evolved with these molecules and with plants to be able to internalize those signals to promote health. So polyphenols are a great instance of that.

Would it be fair to say that the new recommended dietary guidelines for Americans Are going to shift the recommendation more towards a diet that has higher levels of polyphenols?

I'd say yes and no. So there are aspects of the new dietary guidelines that I'm in favor of. I think the most significant of those is they've done a great job with a marketing campaign around food, around eating more real whole food, and I'm a huge proponent of this. But moving to some of their recommendations, which is a reintroduction of higher levels of saturated fat-containing products Moving steak to the top left corner, I don't think that Americans suffer from a lack of eating red meat. I don't actually think that increasing the amount of standardized red meat consumed by an average American is going to be a value-add for their health. One of the things that's been rightfully criticized is that one of the best sources of plant-based protein and also many polyphenols as well as fiber, legumes, right? So why are we not prioritizing those given that they're an excellent source of so many of the things that we're looking for? Yeah, there are plenty of additional things to discuss around the dietary guidelines, but what I really do like around, you know, the premise of it is let's make a big deal about Americans or really anybody not only eating more real minimally processed foods, but can we actually do something to increase the chances that they have access And I think that the kind of cop-out with a lot of this is to say, well, we the government, or we as doctors, have told you that these are the types of foods that you should be eating because they're healthy, but then we've set up a system where purchasing those foods and maintaining access to them is harder by the day. So I think that's, you know, obviously a little bit more of a political conversation, but I am in favor of the idea of advocating for and making more accessible Hey everyone, we're

going to get right back to the podcast, but I have an important message for you. If you're caring for somebody with Alzheimer's, any other form of dementia, or even what we call mild cognitive impairment, or maybe you've received one of these diagnoses yourself, or if you're focused on preventing cognitive decline, I want to speak directly to you for just a moment about some serious research that's going on looking at what we call 40 Hz light and sound simulation. We've been actually talking about that on the program. Here's the challenge. Not all 40 hertz light devices are the same. Most use what's called stroboscopic light. And that's the type of light that flashes, then you can see the flashing. And that can cause nausea, it can cause headaches. And if you can't tolerate that, you won't use it. So, there is a company called OptoCeutics. They've solved this problem with a patented technology that still gives you the 40 hertz light flashing, but through light that looks and feels It's the device I actually have on my desk when I'm working. And that's why this company sees a 94% adherence rate and significant improvements across various metrics, including mood, energy, focus, sleep, and memory. And the light is called the Evy light, E-V-Y. You can use it as I do when you're working on your computer, when you're reading, when you're watching TV, eating breakfast, whatever. It becomes really part of your day, not just another burden. It's kind of passive in the background. So, I recommend giving it a try for 90 days. And if you and your family don't see value in it, then you can return the device for a full refund. They cover the shipping both ways. And this is a device that really is risk-free in terms of getting involved with 40-hertz stimulation. Important information. Let's get right back to our podcast.

So, tell us what's the hidden ingredient in coffee that people should know about?

Coffee is wonderful for a number of reasons. It's one of my favorite beverages. Partially it's because of the caffeine, but the thing that people need to understand is that coffee is an incredibly rich source in brain-active polyphenols. These are plant nutrients that may have a number of beneficial effects on everything from dementia prevention to stroke risk, and it's one of the reasons why I drink a cup of coffee every day.

How do we know right off the bat if our olive oil is rich in polyphenols?

When you drink an olive oil, what you want to be looking for is how does it taste, and specifically, does it have a little bit of a bite? When you consume an extra virgin olive oil that's rich in polyphenols, you actually want that to have a little bit of an aftertaste, specifically that bite, that freshness that tells you there's something very interesting going on in this food. Most olive oils can be a little bit more on the fence, and as many people know, about half of the olive oils that are on the market are So, as you're looking for that olive oil that is rich in polyphenols, it should taste bright, it should taste peppery, it should taste very plant-forward, and if you're not getting those notes, you should consider finding a different source.

Milk chocolate, dark chocolate, what's best?

So, a recent study actually found that when they compared a polyphenol-rich chocolate versus a low-polyphenol chocolate, there were some associations with improved cognition in the group that consumed the higher polyphenol-rich chocolate in comparison to the lower polyphenol-rich chocolate. Why would we even talk about polyphenols where polyphenols are a very interesting set of molecules that are about 4 to 5 times more concentrated in dark chocolate compared to milk chocolate? So I would say if you're going to be consuming chocolate, shoot for about 70% or higher cocoa content, and that'll ensure that you're getting the right types of polyphenols that you want.

Dr. Austin Perlmutter, this has been, you know, a revelation, I think, for our viewers to learn about the importance of dark chocolate. That there's so much going on in their food. I mean, you know, you talk about, you characterize it as dark matter, but you know, there's so much focus on how much protein I should be eating each day, and I'm gonna boost my protein with a supplement. But I think you're getting us away from the idea of supplementing and the idea of really eating foods that are rich in a variety of chemicals well beyond polyphenols. What's it gonna take, do you think, to get this messaging out so people can begin to rethink The idea of, you know, that we don't— we should stop scientizing our food and really just, you know, settle back and eat whole foods.

A message I would put out for everybody as of right now is that despite the fact that we have this hundreds of billions of dollars each year going into longevity, wellness— I think the longevity industry plus wellness is now a multi-trillion-dollar valuation— the best studied way to live a long and healthy life, specifically around brain health, has nothing to do with supplementation, and it certainly has nothing to do with any sort of fancy gadget. It's specifically to do the basics well. And as it relates to food, one of the things that we lose as we start moving towards more supplements, more customized and kind of broken-down food, is the nutrients that have been provided by nature. So the places around the world where people tend to live the longest, have the lowest rates of dementia, tend to be healthiest, are the places where people eat a regular diet that is made of a diversity of primarily plant-based foods, exercise with regularity, engage in and communication with friends and family, something that many people now might struggle with. And as we look specifically at what we should be doing around food, I am 100% invested in trying to understand exactly why it is that certain foods can be so beneficial to our health and especially our brain health. But you need to understand that right now, your best chance at preventing dementia is going to be on your plate. It's going to be in the steps you take around each day, exercising, the connections you make with each person in your life, the sleep quality that you get. And so I would incredibly highly advocate for a person to say, what steps can I take to create a more balanced diet? And including more polyphenols, polyphenol-rich plant-based foods is an amazing way to take advantage of all the research we've been discussing today.

Wow, Austin, thank you. Uh, thank you for sharing your wisdom. It always, uh, is very enlightening for me. And, uh, how proud could I be? You know, this is— I, I appreciate your time.

Thanks so

Well, we learned a lot today about polyphenols, and, you know, there's a lot of changes that can happen to our diets to increase the levels of these really important molecules in our diets to really bring about improvement in our health through the mechanisms, not just of reducing inflammation and enhancing our antioxidant functionality, but as we learned today from Dr. Austin Perlmutter, to actually change our gene expression through what's called epigenetic modification. Modulation, changing how our genes express, something that's relatively new, but you know, it's been going on an awful long time, as long as humans have been eating these polyphenols. That's exciting. Thank you for joining us today here on The Empowering Neurologist. I'm Dr. David Perlmutter, and we will be back soon. Bye for now.