The Melanie Avalon Biohacking Podcast Episode - #377 - Austin Perlmutter

TRANSCRIPT

Austin Perlmutter
These same pathways we talk about in our book that relate to brain inflammation were being activated by people's need to stay at home, and being socially isolated, and eating junk food, and not exercising, and not getting outside. There's no real break between psychological state and biological state.

They occupy the exact same real estate. They use the exact same chemical pathways. So where most people get their polyphenols from, though, in the United States, the top source, not in terms of total amount, but in terms of the top source or the one food that has the most polyphenols that they're consuming, is going to be coffee.

Melanie Avalon
Welcome to the Melanie Avalon Biohacking Podcast, where we meet the world's top experts to explore the secrets of health, mindset, longevity, and so much more. Are you ready to take charge of your existence and biohack your life? This show is for you. Please keep in mind, we're not dispensing medical advice and are not responsible for any outcomes you may experience from implementing the tactics lying herein. So friends, are you ready to join me? Let's do this.

Welcome back to the Melanie Avalon Biohacking Podcast. Oh my goodness, friends, what an honor it was today to have this incredible conversation with Dr. Austin Perlmutter. You guys are probably very familiar with his dad, Dr. David Perlmutter, who I have had on the show twice before, so it was so nice to connect with Austin. He is The New York Times bestselling co-author of Brain Wash, which he did with Dr. David Perlmutter, and has an incredible company, Big Bold Health. We talk about so many fun rabbit hole tangent topics in today's episode, things like the role of brain inflammation in your health and wellness and the factors that are affecting that, the evolutionary reason for why you don't wanna hang out with people when you're sick, how you can actually measure the inflammatory state of your immune system, what we can learn from epigenetic clocks, the problems with social media, the benefits of polyphenols, including how much of them you actually need to consume and from what sources, why we have anxiety and depression, and so much more.

The show notes for today's episode will be at melanieavalon.com/austinperlmutter. Those show notes will have a full transcript as well as links to everything that we talked about, so definitely check that out. I can't wait to hear what you guys think. Definitely let me know in my Facebook group, IF Biohackers: Intermittent Fasting + Real Foods + Life. Comment something you learned or something that resonated with you on the pinned post to enter to win something that I love, and then check out my Instagram Find Me Friday announcement post, and again, comment there to enter to win something that I love. All right. I think that's all the things. Now without further ado, please enjoy this fabulous conversation with Dr. Austin Perlmutter. Hi, friends. Welcome back to the show. I am so incredibly excited about the conversation I am about to have. It is with somebody who I have been following for quite a while, and I'm actually ... I'm really surprised that I haven't, like, met this individual or had him on the show yet. He really is a legend. I have had his father on the show twice. I am here with Dr. Austin Perlmutter, the son of Dr. David Perlmutter, who came on the show for his book Brain Wash and also Drop Acid, and he actually co-authored Brain Wash with Austin. So Austin is a board-certified internal medicine physician. He is a New York Times bestselling author, a researcher, an educator. He's been on PBS, and Rolling Stone, and Newsweek, and NPR, and all the things.

Melanie Avalon
He's also a managing director at Big Bold Health, which is a food as medicine company focused on helping people rejuvenate health through better immune function. And we were just talking about this right before recording. He's just a wealth of knowledge on so many topics, and in particular, things related to the brain, all of the factors that go into supporting a healthy brain in our modern environment, the role of how muscle relates to the brain, uh, a lot of stuff about food as medicine.

I'm sure we will dive into ... He has a really, really fascinating study that I was looking over all about tartary buckwheat, Himalayan tartary buckwheat, and how it affects epigenetic markers when it comes to aging. Yeah, he's just a wealth of information. I actually was interviewing Ashley Koff earlier this week, and she just randomly actually brought you up, Austin, Dr. Perlmutter. She was talking about how she was fascinated what you were talking about the role of pollution and how it affects our brain. So I was like, "I'm interviewing him on Friday. I'll have to ask him about that." But yeah, so thank you so, so much for everything that you do. I've really been looking forward to this for a long time, and thank you so much for being here.

Austin Perlmutter
Well, it's quite an introduction. There's a lot to live up to, but I'm super excited for the interview as well.

Melanie Avalon
I am too, and like I said, my notes are all over the place 'cause you literally cover so many things. To start things off, so your personal story, did you alway- Okay, so, like, what you're doing today, did you always envision being in this sphere?

Was it influenced by your dad? Like, is that ... Did you inherit the, uh, that gene, or, like, what led you to what you're doing today?

Austin Perlmutter
You know, I've actually been talking with my dad about this a lot lately because he's been talking about how he was influenced by his father, my grandfather, who was a neurosurgeon, and the extent to which, you know, we all have this kind of programming that's handed down. I would definitely say that while it was a subconscious influence, my goal was never to become a doctor, but I always liked the idea of education and trying to understand complex topics and convert them into information that was valuable to other people.

I majored in English in college. I really wanted to be a writer, and so I've had just this remarkable opportunity over the last 10 or so years to be able to combine a lot of my interests and do something within medicine that I didn't even know kind of existed when I first got into it. For a quick background, I'm a conventionally trained internal medicine physician, so I did my MD at University of Miami and then I did my internal medicine residency out in Portland. And the thinking was if you look at the top ... drivers of disease and, and both morbidity and mortality, so disability as well as early death. These are largely preventable problems, so metabolic dysfunction, immune dysfunction leading to cardiovascular disease and diabetes. And my thinking was, if I could understand it well enough, then I could go work with patients and educate them on what they could do differently, and that would provide me with, you know, this remarkable opportunity to help people and also grant me the benefit that comes from understanding a topic really well. And what I found was, which is probably not news to a lot of people listening out there, is that modern medicine does an amazing job preparing us to manage the acute manifestations of chronic diseases, the acute issues that come up each day, and then really there's a lot of drugs or are a lot of drugs that are capable of slowing the rate of decline of preexisting conditions. But what it did not allow me to do, which is the thing that I wanted to do and, and continue to want to do the most, is help to scale education for the general population on what can be done that is evidence-based to decrease their chances of developing these diseases in the first place, and especially as it relates to brain health.

What I found through work with my father, through the work we did writing Brainwash especially, is that there is no more important issue in the world than the state of our brain function. You know, I'm sure you have lots of guests on here who have different degrees of concern about other things, but if you really peel back the curtains and ask yourself consistently, "Why does it matter? Why does it matter?" Whether it's heart disease, even cancer, it matters because it takes away from the only thing that matters, which is our ability to show up and enjoy the years that we have on this earth, and that is fundamentally a reflection of what is happening in our brains.

Austin Perlmutter
So through the research I've done, through the teaching I've done, through the book I wrote with my father, the goal has simply been to help people understand how we can leverage lifestyle modification to prevent brain diseases, sure, but also optimize on the front end so we don't wait until we have the diagnosis in the doctor's office of dementia or depression or something else that we could have helped to prevent using these tools that are, are well-established that just most people don't know about.

Melanie Avalon
Yeah, I, I love all of this so much, especially with the brain part because I think people, you know, will talk about inflammation, like this this nebulous word to kind of be all-encompassing for the, the health problems that we experience. You guys really go into brain inflammation specifically and how it relates to, like, so many things, you know, not just, not just our, you know, cognitive functioning, but our, like, our, our behavior, our, our mental health, our, you know, depression, anxiety.

I think my favorite topic in Brainwash was the role of empathy, for example, and how that's actually a biomarker of brain health, or, like, it relates to it. Yeah, so actually some, some questions, some questions there if we can just, like, dive in.

Austin Perlmutter
Sure.

Melanie Avalon
So first of all, I'm curious, so that book, Brainwash, it came out-- it was during COVID, right? Like, 2020?

Austin Perlmutter
Yep, it launched right in the spring of 2020, so concurrent with the pandemic.

Melanie Avalon
Wow, okay, so if it launched in spring, so you guys weren't anticipa- you were writing it before the pandemic.

Austin Perlmutter
We were. We were. Exactly, exactly. And then, yeah, the, the book went live, and then right after that happened because we were... You know, luckily we were able to do a lot of the podcast tour on the front end. But the book went live and, you know, we had these events scheduled around the country to do various interviews and retreats and the like, and they all got shut down.

But the pro was that the message itself turned out to be incredibly relevant for what was happening during the pandemic. And you know, interesting, we may get to this, but I wrote a, a paper, a peer-reviewed journal article in Frontiers in Neurology specifically on the topics we discussed in that book as to why the pandemic was programming our brains for depression, and not just because of people getting COVID, but rather because these same pathways we talk about in our book that relate to brain inflammation were being activated by people's need to stay at home and being socially isolated and eating junk food and not exercising and not getting outside. So it became kind of a catalyst for a lot of reflection on how do our, our, our, our day-to-day experiences, but certainly things that happen at the level of the pandemic, impact brain health. And the scale effect of that is something that not only are we still experiencing because of the pandemic itself, but we can see the ripple effects of similar large-scale changes in how we operate as a society in the United States and really around the world in terms of what it is doing in a negative fashion to mental health and cognitive health.

Melanie Avalon
I was reviewing my notes from that book, and I, I wasn't even thinking about the fact that you wrote it before the pandemic because it is so perfect for the pandemic situation because it, you know, it talks all about the role of loneliness, like you were talking about, and social media and this, you call it, like, disconnection syndrome. So I'm curious, have-- So actually a few different questions there.

Number one, I would love to know how loneliness and disconnection is actually inflammatory. Like, what, like, what is the actual pathway that that works? Actually, I'll start there. How does that actually work?

Austin Perlmutter
Well, I think before we get into that, I want to just speak to what this topic represents because it is a fundamental disconnection with the way people see brain health, that they look at the brain either as a state of mind, so mental health doesn't exist in the same sphere as, as cognition, that it's not tethered to biology. That's an issue.

But also, as we look at topics like loneliness, people might say, "Oh, well, that's kind of a psychological state. It's maybe even an optional psychological state. How could that impact, for example, a person's risk of developing dementia?" And what you alluded to is, is what we're learning, which is that there's no real break between psychological state and biological state. They occupy the exact same real estate. They use the exact same chemical pathways, which is why there's a lot of overlap between risks, for example, developing dementia versus ... developing depression. There's inflammation in both cases can predispose to higher risk for both of those conditions. Similarly, there's a reason there's an overlap between the development of insulin resistance, type 2 diabetes, and developing dementia and depression because the biology is conserved. So thinking about what it represents in terms of something like loneliness, what research shows is that loneliness, of course, translates to higher risk for developing something like depression. It co-localizes with depression, but also predisposes people to higher risk for dementia, and the pathways that seem to be at play there are, one, stress pathways, so loneliness may translate into higher levels of, of stress molecules, which over time could actually lead to, uh, higher risk for developing dementia. We know that the converse of that, so having social connections, the oxytocin, the stress-mitigating effects of that may actually be protective against dementia. Beyond that, it looks like inflammation is actually influenced by social connections, and there are a number of kind of biologically plausible reasons from an evolutionary perspective why this may be the case. But one that I think is actually kind of cool looks specifically at the microbiome, and a number of studies recently have shown that our microbiome tends to be shared with people that we spend time with, not just the people in our homes, but also in our local communities, and even, it turns out, with our pets. And so we know that the gut microbiome has a lot of a role in kind of mitigating excess inflammation when it's in a state of relative balance. So while that's a little bit of a, a deep cut here, the point here being that just spending time with other people isn't just a good thing because, oh, you feel, you know, happy that you're getting to tell somebody else about your goals or your problems, but you're actually kind of sharing this microbiome and you're programming each other's immune systems and stress pathways in real time. So it gets us to some interesting questions about how we've decided to prioritize in the United States, especially the things that we think are most important in our lives.

Austin Perlmutter
And so much of what I've really kind of been exposed to that is, I think, endemic, especially to the medical culture, is this hyper-productivity version of, "I need to be successful, even if that means trying to kind of get ahead of others and don't worry about them because as long as I've made it out," which is really the medical school vibe, is directly counter to what is most strongly associated with better brain health. So there's kind of a lot to, to look at there in terms of how we've set up society and where there are potential issues.

But to answer your question most directly, all of these psychological states, so loneliness and empathy and, and mental state, for example, whether we're feeling happy or whether we're feeling socially disconnected, not just lonely, but socially disconnected or uninterested in other people, seem to be reflections of the same biology that is influenced by things like exercise and diet. And so all of these things converge onto this really, really interesting concept, which is that everything we're doing is programming our brains for the better or for the worse. And, and really the central theme of Brainwash was simply that when we take back agency over that biology and we start to program our brains for the better, that's probably the single most important thing that we can do with our lives.

Melanie Avalon
This is so, so fascinating. On the, the immune front, and one of-- I'm trying to remember the irony that I'm trying to remember, and we're talking about the brain.

Um, one of the guests I was prepping recently, they were talking about the, the brain... Sorry, social connection and the immune system, and I learned that the part of the im- like, when you're in a group setting, it boosts immunity for, like, viruses and things that are contagious 'cause you would be around people, whereas if you were isolated, it boosts the part of the immune system that would be responding to, like, if you got a cut and fell and were, like, alone in the woods. And, like, even, like, that nuance of the immune system changing based around if you're with people or not, to me is so, so fascinating.

Austin Perlmutter
Well, let, let me sp- let me speak to that because I think one of the best examples of what you're describing is something called sickness behavior, and this, this is a great example because people have all kind of experienced this, which is what happens when you get sick. When you get a flu, when you get a bad cold, people tend to not feel super socially motivated.

Many people feel kind of more depressed, and it's actually been studied that when people are sick, so one thing that happens is you have higher levels of inflammation, which is not necessarily a bad thing. Inflammation is a key part of getting better. It's basically your body responding to a threat. So thinking here of inflammation not just as a response to a pathogen, but basically a part of your body's defense system, where it's revving up these molecules to help to deal with whatever is going wrong. When a person is sick, they start to feel socially disconnected, and what's fascinating is when you inject a healthy human with a molecule called lipopolysaccharide, which some people may remember because it's linked to leaky gut. When you inject a person with lipopolysaccharide, you can induce in a healthy person feelings of depression and social withdrawal simply by increasing inflammation in their bloodstream. So what that kind of tells us is that all of these things floating around in our bloodstream and in our brain, they're not just kind of one-dimensional, meaning inflammation isn't just what some people think of, oh, it's bad because it's linked to X, Y, or Z condition. It is a set of signals. It's actually the immune system is 100-plus different signals in your bloodstream and in your body that are, in essence, fine-tuning not just, you know, the healing of a wound or a fighting off of a bacterium, but your, your brain and the responses that it has in order to best survive. So why would a person who is injected with an inflammatory signal or a person who is sick with an illness feel socially withdrawn? Well, one of the main hypotheses is that that's what's the best thing for the tribe, is to take that person and get them away from others so they don't get infected. The issue is that nowadays the bigger threat is chronic low-grade inflammation, which affects roughly one in three people based on certain data looking at certain inflammatory markers. And why that's an issue- Is because in essence, what your body is intuiting from that data, meaning that inflammation is revved up, is that you are in a state of alarm. And so that's what's been linked to not just worse outcomes in terms of heart disease or in terms of being associated with diabetes and obesity and all these other conditions that we don't really want to get, but it's also linked to not just higher rates of dementia and depression, but also suboptimal brain function. And it makes sense because in essence, what your body is doing is prioritizing its resources to deal with this perception of threat, which is what that inflammation represents. Now, why a person has that low-grade inflammation?

Austin Perlmutter
Well, it may have to do with building of certain unhealthy fat cells and eating an unhealthy diet and taking in perpetually stressful content, not getting enough exercise, all these variables that people are familiar with. But if we were just to take a step back and say, "Well, maybe all of these things that people say the body does wrong or the body's reacting in a poor way," a lot of it just makes sense from an evolutionary perspective if we look at our bodies as perpetually under siege from this perception that there is a danger signal out there in the world.

And so if we can start to quell the degree to which our brains are perceiving danger, that is so powerful in terms of helping them to rebalance themselves, change the neurochemistry, change the neurotransmission towards what we would enjoy but our biology could honestly care less about, which is to enjoy life, to feel happy. There's really no intrinsic motivation for the brain to make us happy. It just wants to keep us alive, and so it will always prioritize that over peace of mind. But that's just not the way most people operate in terms of understanding why they're thinking what they're thinking.

Melanie Avalon
I'm, I'm smiling because I, I'm just thinking about that concept that it, it's actually-- it's really nice that evolution chose, you know, dopamine and hap- and, like, feel-good neurotransmitters as the, uh, method of keeping us alive because it could be... Again, trying to remember where I read this, but in one of the books I was reading, they were talking about the existence of a reptile, for example, and it's kind of the opposite. Like, their entire experience is driven by, I think-- I don't know if it's cortisol or... So basically, like, when they're in the like, because they're cold-blooded, when they're in the, like, the shade, they-- Wait, okay, how does this work?

Okay, when they're in the sun, they're warm. They're, like, warming up their blood, but they're, like, susceptible to predators. And then when they go in the shade, they're safe, but they might die from, you know, being cold-blooded. So it's like just basically going back and forth, like, responding to threats, like, your entire life.

Austin Perlmutter
That's also, that's also, let's be honest, what we're doing here. The only thing a human does is basically moves away from pain, and I think that's really something to c-consider here. We like to think about ourselves as so intelligent, having agency, being conscious compared to other animals, but you can in essence break down any behavior as moving away from pain, or if you really want, moving towards pleasure, which is the other side of that equation. Now, because we're so smart as humans, there's a little bit more nuance to it than just saying, "Well, we're trying to escape from a predator," or, you know, not die of, of freezing to death because we're in the shade. We might say we're trying to escape from the pain of having our spouse yelling at us, so we're gonna go cope by eating something unhealthy. Or we might say we're trying to e-escape from the pain of our job, so we're going to go binge on social media. But the reality of it is that if you apply that lens to the equation, which is just like that cold-blooded lizard, all of our responses make sense in terms of moving away from pain, then, then life actually gets a little bit easier to comprehend.

It's not always a fun exercise because all of us want to think of ourselves as, you know, having agency, lack of predeterminism, and, and the ability to, to really modify our decisions is, is kind of key and part and parcel to what it means to be a human. And, and I'm on board with all of that, but I do think if you were to really take a step back and simply ask this question of what is it that drives an individual decision? A lot of people hate their jobs, but they do it because the pain of not doing it is more significant than the pain of doing it. Where we run into issues, though, is that our brains aren't really capable of understanding the difference between a, a pain that we're trying to cope with that is actually something better to respond to in a long-term fashion versus being thoughtful about the future. And so one of the big kind of conversations that we have in the book Brain Wash is how do you kinda rewire and rebalance your brain so that it is invested in the future and to where you get enough bandwidth to consider how you're making decisions? So much of what people do right now is for a short-term fix that, yes, takes us away from pain, but that's only for the moment, and in the aggregate, long term actually creates more psychological and physical pain for us, which is kind of the whole conversation around why chronic disease is such a almost inevitable outcome in the United States. We sacrifice long-term health for short-term pleasure, and this is not coming from the perspective of blaming the individual for making unhealthy choices. It is simply that our society is progressively set up to where those are the choices that become inevitable.

Melanie Avalon
So I'm thinking about this more. Let's use an example. You could have two people, and they-- L-let's put them into an ideal, like, situa- like a vacation situation. So just, like, in a good, good environment. They, they have access to food. They can sleep. They can have fun. Everything's good. I feel like why would some people-- they'd be fine, and they would just wanna exist there, and I don't know what, what, what they would be running away from. Like, everything is taken care of, so they're-- it's, like, all good.

And then you might have an individual who would not like that. Like, they would, they would wanna, like, do more or, like, work, for example. And, like, you were talking earlier about how evolution selects for Certain individuals, or maybe I was going to ask if evolution selected. You were talking earlier about, you know, people who are trying to get ahead and, you know, in business, like do all the things at the expense of others. Wrapping this all into a question, I have always been fascinated why-- for, for me, for example , like I love working, I love like doing things. I-- the idea of going on a vacation is actually not that, like I don't really want to. Like I'd rather not go. So am I-- Are people who are like driven by work, like that's where like the dopamine flood is coming in? Is that also running away from pain? Like, 'cause you were talking earlier abou-about like why we make the decisions we make.

Austin Perlmutter
Well, let's just say right now I forced you to go to a fourteen-day silent retreat, and you didn't have access to your emails, you weren't able to respond to anyone. You would probably feel a lot of stress around that, even though other people might enjoy it a lot, right? So your psychological stress comes from a need perhaps to be productive. A-And I'm just hypo-- this is all hypothetical. I'm not, I guess, talking about you and your psychology. But I will say, for me, I do have some of that. If I'm not being, quote, productive, it creates some angst, some anxiety. And so for me, there is psychological pain associated with not being productive, not feeling like I'm moving towards some sort of a goal.

Whereas for somebody else, they might be completely content to, you know, never work again. And this isn't a value proposition. I don't have any issue with, with either of those. I think the, the question is kind of what are the drivers for an individual? It's, you know, everyone's kind of got their own pathways that could be adaptive or maladaptive, in part driven by their early life experiences and the environment that they find themselves in. What it gets to eventually is kind of this question of how do you define brain health? And clearly, there is one version of this, which is you want your cognitive testing to be as good as possible, right? You want to decrease your chances of developing dementia. And then there's the other version, which is the mental health side, which gets a little bit more nuanced. So most people would say the goal is, you know, if you can help it, not to develop a mental health condition like depression or anxiety. And if you do have one of those conditions, to manage it to allow yourself to be as kind of functional as possible in society. But I think where there's a whole lot of interesting nuance and discussion is all the shades of gray in between. Because I learned in medical training, and I think what is still being taught, since it wasn't that long ago that I finished, is that a lot of these conditions where we tend to have a diagnostic code kind of start there, as opposed to the reality, which is these things tend to come and go and, and they, they brew in different ways and on a given day they may be more intense or less intense. And so just using anxiety as an example, you know, there are textbook criteria for when a person would have generalized anxiety disorder. But every person experiences some degree of anxiety or stress each day, which is basically just the gap between what we're doing and what we think we need to be doing. It's an unmet need, right? And so each person has their version of what that unmet need represents. For some people, it's saying that unmet need is going to continue on until I've made a million dollars or until my face is on a billboard in Times Square or until my spouse says you're amazing. It doesn't matter necessarily what that thing is, but everyone has that unmet need which is where anxiety and stress come from. And so when it gets pathological is where it really interferes with a person's ability to function.

Austin Perlmutter
But there are so many people out there that are, quote, functionally doing great, but internally, you know, they're, they're really struggling. So a lot of the people that I know who are hyper-productive, who have been super successful across a number of domains, when you really talk to them, you understand that that same pathway within their brain that allowed them to be so successful, and I use that I guess in quotes, is, is also hugely detracting from their ability to show up in quality relationships and to kind of be able to relax at all because their brain is always playing out this idea of I could be doing something else that is externally validating or going to drive success.

So kind of, I guess, we're opening up a can of worms here because everyone's got their own unique psyche, but I think that there are some really important things to consider around how our modern world, and especially in the United States, culture is going to index towards normalizing a lot of these mentalities of, of productivity and external validation, even though Americans are by far not the happiest country among comparable countries. The people are not happier in the States than they are in other countries, despite us, you know, having all these very wealthy people and despite everyone being able to, quote, forge their own destiny. So there are a lot of, I guess, side paths that we can go down there. But if you fundamentally get to this question of what is it that is most strongly associated with long life, with good brain health, with good mental health, these are largely not the things that Americans think are the most important priorities. So it's not surprising to me either because of the decisions our government makes or the corporations make or the individuals make in this country that mental health and, and physical health is where it is. It's simply just that we're not designing a culture optimized towards the variables that have been consistently associated with better overall and brain health.

Melanie Avalon
Yeah. And, and also speaking to, you know, all the factors of modern society that are encouraging these states of either anxiety, depression, whatever it may be, this is a completely in the, in the moment hypothesis I'm coming up with but I think you could make the argument that it must be largely environmental because I would assume, I would assume evolution would not select for maintaining at least depression because I don't see how that would-- I don't know how that, you know, that, that does not encourage if you're, if you're withdrawn and depressed and not securing food and not-- that would not be a beneficial trait to pass on.

Anxiety maybe it would be passed on because of the productivity aspect.

Austin Perlmutter
Yeah. It's not just productivity, but, but to go back to, you know, a common example here is if you're living ... couple of tens of thousands of years ago in a cave, and you are a anxious person, you might be more likely to not be sleeping when that predator shows up. So could be super adaptive. Or if you're the anxious person who's perpetually worrying about where the food is gonna come from, you might be the person who figures out, you know, where that, that next source of food is, where other people are willing to be a little bit more complacent. So I think you're right.

I mean, anxiety, again, there are some underlying conditions that can perhaps drive it to a state of being maladaptive that are, are not so much evolutionarily based. But if you think about the basic idea here, which is just anxiety is concern about the future, and there's, there's something important there, which is that everyone has some degree of anxiety, which is what motivates us to get out of bed in the morning, not just stay put. And then this is a, a, a huge simplification of this, but if you think about depression being a little bit more focused on the past and what's already happened, there's some value to that as well. You know, kind of rumination, which is, is often associated with depression, which is kind of playing over these stories. You know, in, in some ways there is value to thinking about the past to help you to restructure your future in a more adaptive way. A big issue though with each of these things is kind of getting stuck. So you're no longer in the present. You're spending your time in the past. You're, you're hyper-focused on a, a future which maybe in some cases is never going to actually materialize. And I think especially as it relates to the anxiety piece, so much of what we consume each day, you know, you think about the average American consuming 11 plus hours of digital media, four hours a day watching TV, two hours plus on their phones, so much of that is designed to induce anxiety type feelings specifically because, coming back to the point I made before, the brain is not there to make us happy. It's there to keep us alive. So any chance that we have to trade off between something that is, you know, an, an existential threat versus something that is just something to make us happy, our brain is going to focus on the threat, and that threat might look like the news that says the stock market is crashing or that, you know, something terrible happened in another country or that, you know, your local news is saying there's been a string of break-ins somewhere near where you live. The brain can't help itself but to over-focus on that negative news at the expense of our, our mental health. And, you know, not to, to point too much of a finger, but the reality is that news networks know this incredibly well, which is why data show that we wrote about in Brainwash that the news has become progressively more negative over the last few decades. We know that, you know, the bleeds it leads-- if it bleeds, it leads stories.

Austin Perlmutter
There, there's a, a method to that madness, and so much of this entire conversation is simply recognizing that as time goes on, these algorithms are increasingly designed to not just force, you know, this sensationalized negative and otherwise distracting information down our throats, but also just distract us in general as a way that we can cope from the anxiety that we already have. And so what you get at the end of the day are a bunch of people who don't have all that much agency over their mental state, who are, in essence, just consuming mindless content as a way to cope with something that they're, they're unable to get around.

And so that's... it's incredibly problematic.

Melanie Avalon
I do not watch the news at all. I figure if something-- like, if it-- if I need to know something that's happening, it will find its way to me, like through conversations or if there's a zombie apocalypse, I mean, I'll see it outside. So I think I'm like, I, I'm okay with not checking into the news.

However, I'm, I'm gonna, like, on my to-do list after this, I'm gonna work on this because I-- my Instagram feed-- I do think people... Okay, this is a, a tangent, but I will bring it back. I do think-- I know the algorithm is set up to, like you were saying, to be like short clips of things and, you know, it sparks our stress signals and our reward signals, and we just want more, more, more. I'm always curious, like, how much of that is intentional versus how much of it is that the algorithm just keeps giving you what you're watching. So, you know, for my algorithm for the longest time was basically just like Taylor Swift and cats, and it was like a really happy place to be. But I've noticed recently, for example, 'cause I, I had a, a press conference event, so I started following all the news channels on my Instagram and now my f- my main feed is a lot of this stuff that you're talking about. So I, I'm gonna have to like proactively go in and, you know, change that. That was a lot of tangents. You've been using this word perception a lot. So like when the body perceives inflammation or perceives LPS or when we perceive a, a stress state. So what is the actual role of the stress and inflammation itself versus the perception of the stress and the inflammation? 'Cause I know for me historically, I've, I've been like a little bit obsessed with inflammation and even LPS and have had many conversations with my therapist where she's like, "Melanie, everything is not inflammation." I'm like, "But it is." Like, I, I got so, like, worried about inflammation that I think I was stressed about stress. So what is the role of perception in this? Could you be really stressed but be like, "Oh, it's great," like, "It's fine"?

Austin Perlmutter
I think these-- it's this line, I'll just reinforce this, this line that we have between what we think, how we think, and what's happening in our biology, it's not really a line. So our thoughts are a reflection of neurotransmission, of, of neuronal firing rates, and s- similarly so are our decisions. So what's really interesting though is how these things can modify each other. How with biofeedback you can change your state of mind and that changes your biology, or you can make a decision to alter your biology by, for example, eating a certain meal or consuming a certain piece of content, and that will then change your future decisions because you've altered the decision-making engine itself, which is the brain.

Speaking specifically about inflammation and stress, so these are two separate pathways generally, but they do have a good amount of overlap. And so when it comes to stress, you know, again, I'll just define it as stress is an unmet need. So it's basically a, a pressure on the body that needs to be responded to. So you can have kind of like a physical stress, you know, wear and tear from exercise that kind of is creating this, this need for repair, and that's where the stress is going to be-- could also show up as inflammation in your joints because you're putting them too, through too much stress. Or you could have the psychological stress where your brain perceives kind of like you're having this, this unmet need of you're supposed to be planning for your, your test tomorrow and you haven't done that. And so there's a gap, there's a delta between what you're doing at that moment and what your brain perceives needs to be done, and that's a psychological stress. What's interesting though is that when it comes to psychological stress in particular, there's no universal every person who experiences the same thing will have the same degree of psychological stress. Meaning, it's how we perceive the stress that matters in terms of whether it converts into higher levels of cortisol, whether it activates the HPA axis and activates stress hormones throughout our bodies. So a lot of, you know, psychological therapies are around changing how we perceive the world, how we manage stressors such that we can alter the degree to which some of these pathways within our brains and our bodies are activated by environmental stressors. Specific to the inflammation-stress connection, so what's interesting is that stress pathway activation, cortisol, has an anti-inflammatory effect in an acute setting, which is why, you know, if you have inflammation in a joint and you get a, a steroid injection, that can actually decrease inflammation, and so that can improve symptoms. But chronically over time, and the mechanism isn't perfectly known, but it seems like what happens is that chronic stress leads to basically this like dampening of sensitivity of various stress receptors, and therefore, it actually increases chronic inflammation, because in the short run it seems like it actually decreases chronic inflammation.

Austin Perlmutter
So it seems like chronic stress can actually rev up chronic inflammation, and that's what's been seen in a number of studies looking at things like psychological state. Where all of it kind of comes together, though, is how do stress and inflammation influence what happens within your brain? And both stress and inflammation are linked to many of the same conditions. They're not exactly the same.

So for example, higher levels of inflammation predict development of depression. They're also found in schizophrenia and PTSD, but not as much in anxiety. Whereas higher levels of stress molecules, stress hormone activation seems to be more related to anxiety. So there's, there's a lot of kind of molecular pathways that link all of these things, but generally speaking, those are the kind of the main ways in which they interface.

Melanie Avalon
If, so if somebody were to test biomarkers for this, for inflammation, is it really, is it like CRP? Or are there other things as well that we can test?

Austin Perlmutter
It's a great question. So my group right now, we're actually doing a lot of research specifically on this topic because it's one thing to just say, "Oh, you have inflammation and therefore you need to take X, Y or Z product." What inflammation is-- so first of all, it is, it is a necessary and essential and life-saving thing. Inflammation isn't also just one thing, meaning it's not like, well, if you have your white blood cells are at this level, that's what inflammation means in every case. There are different molecular signals that you can look at. There are different thresholds. Usually, when people are talking about inflammation in kind of a clinical setting, some of the things that they will be looking for are C-reactive protein, sedimentation rate or an ESR. They can also look at a white blood cell count. There's mar- there are markers that kind of respond to inflammation like procalcitonin, haptoglobin, fibrinogen, ferritin, prealbu- prealbumin. But you can also look at the actual inflammatory molecules themselves. So beyond just the immune cells, you can look at what are called cytokines. So interleukin six, tumor necrosis factor alpha. These are more expensive labs and they're not typically done, you know, just to see whether a person has inflammation. Usually that's something where it would be a CRP, for example, just looking for levels of inflammation.

But what's really interesting and where we're spending a lot of our time right now is looking at how you can take a white blood cell count, or specifically I should say a complete blood count with a differential which looks at different white blood cells, uh, lymphocytes, leukocytes, neutrophils, eosinophils, et cetera, and calculate from this an index that will help you to understand the degree to which the immune system is revved up and is inflamed. This-- it gets a little bit tricky, you know, in terms of what does this mean for the average person? But there are markers like the systemic immune inflammation index or the SII, systemic immune response index or the SIRI, and that's actually what we're looking at right now in terms of how can we intervene on those markers because it turns out that when you kind of apply some of these calculations, you're able to predict a whole lot of conditions. So these are just to kind of recap here because I know we're getting kind of deep in the wei- in the weeds. If you get a blood cell count, for example, if you go to your primary care doctor's office or if you're in the ER in the hospital, you will get a complete blood cell count, and sometimes you get that with a differential, which means it tells you about the relative makeup of different cells within that complete blood count. If you apply a calculation where you multiply and divide some of those numbers, and this is like, it's literally like an eight to fifteen dollar test. It's super cheap. But if you have that data and you apply this calculation You can actually get some incredibly important information that is predictive of a number of different outcomes.

Austin Perlmutter
And there's actually some really interesting data suggesting that based on these numbers, you can predict people's chances of dying early, the speed with which they're aging, their variables around dementia and stroke risk, heart risk. So a little bit complicated, but what I would float for you is, yes, you're right, CRP, you can look at LPS binding protein and other markers like that.

But where I think the research is going is really starting to understand that it's not just elevated or low or normal, but rather in the context of a larger picture that you're getting a sense as to what a person's inflammatory burden is, and also you start to understand what are some of the drivers of that inflammation.

Melanie Avalon
So the way that the, that the, that it's calculated or being developed, do they look at people in known disease states and what their, what their immune system looks like and then create all of the algorithms from that based on that?

Austin Perlmutter
The, the majority of the research to date pools large data sets to look at the correlations between this lab, so let's just say the systemic immune inflammation index or SII, which is platelets times neutrophils divided by lymphocytes, if you're somebody who's out there trying to do the actual math. And based on that number, you can predict outcomes for a number of things. So the chances that you're gonna have a good outcome if you get cancer, the chances that you're gonna have a good outcome if you have a stroke. But also it is predictive of general chances that you will survive to a certain time, meaning if the score is higher, your chances of living longer is lower, and also if your score is higher, your rate of biological aging may be faster, meaning that your cells are aging more rapidly.

And so where that research has been to date is in essence being predictive. So this is not a diagnostic test which tells you if this is high, this is what is causing it. It's also not to date really been something where if this is high, here's what you do to lower this, but that's what we're looking at right now in our clinical work, which is how can we intervene on these, these labs, the SII, the SIRI using nutritional intervention, because we know that when they are lower, that is associated with better health outcomes. So it's, it's in essence a very cheap immune test for inflammation that very few people are using, but it has a very strong predictive value for certain conditions. And where we are taking this research is to say, "Well, what are the nutrients most strongly associated with higher or lower levels? How do we help people to integrate that lab into a larger conversation around immunometabolism?" So not just looking at labs like CRP and interleukins and the SII or the white cell count, but also how does this mesh with something like an elevated fasting insulin or an elevated hemoglobin A1C or an elevated LDL level? Because kind of the core premise of all this research is that there are these two systems, the immune system and metabolism, and they kind of weave together and are probably the two strongest predictors of risk for a host of different diseases when we account for the fact that metabolically, I think the latest data is somewhere between eighty-eight and ninety-two percent of American adults with some aspect of cardiometabolic dysfunction. And then when we look at the immune system, so lots of people with bonafide immune system issues, allergies, autoimmunity, et cetera. But starting to get more granular in terms of understanding how some of these labs, these low-grade inflammatory labs are predisposing people to disease, even if they never get a diagnosis of an immune condition. So it i- it's kind of it's a map. It's a comprehensive ses- uh, sense as to what's happening within the body, and this is largely being validated right now by a lot of publications that have come out in the last decade, in essence showing how you can understand how your immune cells work based on their metabolism, and you can see how the immune system alters metabolic function.

Austin Perlmutter
And so it's, it's blurring the lines between these systems we used to think was immunology and metabolic state to better conceptualizing how, especially through lifestyle and now a lot of, you know, GLP-1s and other medications are capable of intervening on this and hopefully slowing the progression of and potentially even preventing some of the most, you know, destructive conditions of our day.

Melanie Avalon
Wow. Okay.

And when you say for that number, like lower and higher, does-- is that correlating to a reduced immune system activity and increased immune system activity, or is it more nuanced than that?

Austin Perlmutter
It's, it's a little more nuanced than that because the way that these labs are calculated, just to kind of go through, so the, the systemic immune inflammation index or the SII, it looks at platelets, so that's kind of a-- it's a part of the immune system involved in clotting, but also in inflammatory signaling, multiplied by neutrophils, and neutrophils are part of the innate immune system, the rapid-acting immune system. They're involved in oxidative stress mitigation. Well, specifically, they actually create oxidative stress to kill off microbes. And then you divide that by your lymphocytes. And so your lymphocytes, thinking about T cells, B cells, more of the slower or adaptive immune system. So if the score is higher, what it kind of tells you is there's more of an acute thing going on relative to this slower adaptive immune system capacity.

But just to give context for why it's not as straightforward as simply saying, "Oh, well, if it's high inflammation and therefore bad and we know what's happening," it goes up in pregnancy. We know that pregnancy is an inflammatory state, but that's not necessarily problematic. That's a natural transition in how the immune system is functioning. So we've got to be cautious with these things to put them into the context of what is happening with an individual so that it isn't just, well, this is high or low and therefore problematic. It has to, it has to be contextualized, which is why we're trying to be cautious here- And not simply saying as, as is often the case, that these are these binary systems which, you know, you have inflammation, you don't, you have gut issues or you don't. It's, it's-- it requires a couple steps further in, in understanding what an individual's biology is doing.

Melanie Avalon
So does something like rapamycin individually act on one part of that, like one a- arm of that immune system?

Austin Perlmutter
Yeah, I mean, I think that's a little different. So with rapamycin, we're starting to get to, you know, AMP kinase pathways, mTOR inhibition, which certainly interfaces here in terms of this immunometabolic arc. But what does that do long term? I mean, granted, it's kinda used as a form of immunosuppressant. I don't know that there's a ton of data specifically looking at what that does to these various indices.

You know, 'cause the other, the other kind of built-in question with this, talking about any of these more advanced anti-aging therapies like pulse rapamycin, is are they a good plan for the average person? And I think with rapamycin in particular, you know, you may have a different perspective on this than I do, but I don't think we've seen a whole lot of human clinical data indicating that it's of value to the average person just yet.

Melanie Avalon
I, I feel like it's just not-- I just don't see many people, like, testing it or trying it. I've, I've wanted to out of curiosity. I I probably will at some point.

Okay, you mentioned the effects of all of that on the speed of aging. So when you say that, is that determined by people's just, like, mortality stats, or is that actually something epigenetic that it's speaking to?

Austin Perlmutter
I guess a couple of things here. So when we're talking about these immune scores and what they mean in terms of rates of biological aging, mechanistically, I don't know that we, they really know exactly why that's the case. A lot of epigenetics work, which is the basis for a lot of biological aging testing, is, is not necessarily getting us to the point of knowing exactly how mechanistically different things work in terms of biological aging. There's still a lot of hypothesis testing.

What was shown in this study that I'm referencing here is that having higher scores on these tests correlated with higher rates of aging on certain epigenetic biological age clocks. So that, that's just kind of the first phase of, of this understanding. And, and granted, it's already kind of a well-known, I guess, variable that people who have higher levels of inflammation may be aging more rapidly throughout multiple parts of their bodies. There's actually a term for this, which is called inflammaging, which is how as we get older, we tend to have more chronic low-grade inflammation, and that's been associated with more rapid overall aging, more early mortality or people dying earlier, as well as aging at a cellular level. So chronic inflammation seems to age the body, and so we're able to pick up some of those variables in these biological age clocks, these epigenetic clocks. What is interesting though, just to kind of go to what we have seen from an interventional perspective, so there was a study called the DIRECT Plus GreenMed study. It was published first a few years back, I think a little over five years ago, and it was an eighteen-month interventional trial where they used a group of people who were based in a, a military base and actually it was a, sorry, a nuclear power plant in Israel. And what they did here is they had a couple of different arms. So they had a healthy diet group, then they had a Mediterranean diet group where people were given about four hundred and forty extra milligrams of polyphenols, which are these plant molecules, per day. This is, again, over the course of eighteen months. And then they had this GreenMed therapy group where they were given twelve hundred and forty milligrams of extra polyphenols. So these were polyphenols that came from walnuts and green tea and a plant called duckweed. So what made this study really interesting is it was an intervention first. A lot of these studies are not interventional, they're observational. What they showed is that there were changes in epigenetics at the end of this period that correlated with the amount of kind of polyphenol intake that people had in these different groups. But when they really dialed in to see kinda what the value add was from this, they showed that the high polyphenol group had about double the rate of visceral fat loss as the other group. They also found, which was maybe most interesting to me, that the group that consumed the highest amount of polyphenols had a slowing of the shrinkage of the hippocampus, the memory center of the brain, and this was correlated with changes in blood sugar measurements in particular.

Austin Perlmutter
They also found changes related to things like the immune system in the people who were consuming the highest amount of these polyphenols. So to kind of put all that into the context here of what we're discussing, it seems like certain interventional data are now telling us that we're able to modify epigenetic expression, and that then leads to changes in some of these biological age clocks, which could potentially get us closer to what a lot of people want, which is slowing the rate of aging, not just systemically, but at the level of an organ like the brain.

But when we looked at that data or when the data was published showing that slowing of the brain's memory center was correlated with better cognition through just a dietary intervention, that's where it starts to get very interesting, because now we're going from hypothetical mechanism to actionable information in people with, in this case, a diet rich in these plant-based molecules. So there's still, yeah, there's still a lot of aspects of what epigenetics and biological aging actually mean, how it translates to things like the immune system, but they're all interwoven. And so our kind of hypothesis here is if we can intervene on the immune system to target age-related changes like immunosenescence, inflammaging, then that should lead to benefits across the body. One of those may be a slowing of some of these age clocks, these biological age clocks as measured through epigenetics. So kind of a lot to, uh, to untangle there in terms of the value set for the average person. But I do wanna highlight again, when they did eighteen months of a nutritional intervention with a high polyphenol diet, they were able to show changes in epigenetics and visceral fat, as well as those benefits to shrinkage of the brain. And I think that's something that is worthy of, you know, putting into the camp of, well- This is an intervention. It's something that people can use right now.

Melanie Avalon
Okay. I love, I love this topic, and it's a good, it's a good bridge to your study on the tartary buckwheat powder. So some questions here.

So these age clocks. So I've done-- I was just looking it up. So I had on the CEO of TruDiagnostic, and they have a, they have a test that includes-- I don't know how to say these all. One of them is in your study, the omic-omic-omic age.

Austin Perlmutter
Omic age. Yes. This, this Matt, Matt Dawson?

Melanie Avalon
Yes. Yeah. He's great. He's actually coming back in a few weeks. So that one, and then theirs also includes the duned-dunedin or PACE? PACE.

Austin Perlmutter
Yeah, DunedinPACE.

Melanie Avalon
Okay. These names. A-and then Symphony Age, um, are the three. Actually, when I had him on last time, it was such a moment because I had my results, and he said they were some of the-- for one of them, he said they were some of the best he'd seen, which made me very happy.

But the buckwheat powder study, which you did, and I also have thoughts and comments about the one that you just talked about, but for that one, so you did PhenoAge. Say it again. Omic, Omic Age?

Austin Perlmutter
Yeah. So the, the main ones that they're looking at now, which we didn't do all of them, but right now DunedinPACE, PhenoAge, GrimAge are kind of some of the, the core ones. And just, you, you probably went through all this with Dr. Dawson, but just so listeners know, because this, this is a technical thing. The way all of this works is every person on their DNA has these methyl groups, and methyl groups are basically, it's a carbon with some hydrogens, and the methyl groups can either be on or they can be off on these specific sites on the DNA called CpG sites. Those are just kind of the nucleotides that they're bound to. And if it is on or off, it changes the degree to which a gene is expressed. So it's not necessarily a binary to where a gene is on or off, but it can change like a dimmer switch, the degree to which a gene is expressed. And why that matters is because up until very recently, it was kind of nature versus nurture. You had certain genes, and then you had certain environmental effects, and those were the two things that influenced your health outcomes. But with epigenetics, it turns out that your day-to-day choices can influence the degree to which your genes are expressed, which means you have this incredible blurring of this concept of nature and nurture to where you are able to actually influence your gene expression.

And so epigenetics has kind of been tethered to biological aging for a long time because-- well, actually not a long time, about a decade or so, because when you use these methylation marks on DNA, you can basically run an algorithm that tells you, one, what is that person's likely age in years? So if you took the right DNA algorithm using this epigenetic chip, it could tell you, without me knowing how old you were, "Here's chances are how old you are." But then researchers said, "Well, what can we do to take that one step further and not just say, 'Well, how old is this person?' Because that's cool, but we could always just ask them for their age. But what are their chances of having certain age-related conditions beyond even what we would guess based on how many years they had in terms of their bi-- or their chronological age or their age in birthdays?" And since then, some of these more advanced epigenetic algorithms, these are these age clocks, have in essence been able to say, "Let's forget about how old this person is in terms of birthdays. Let's ask the question of how old their body looks and how old their cells are, and that may actually better allow us to predict their lifespan than simply knowing how many birthdays they have had." And so again, there's, there's a bunch of different algorithms, these age clocks that you've mentioned, that have differing degrees of kind of what they tell you, the specifics of what they tell you. And the one that we were looking at in particular in our study was one called the PhenoAge clock, which is interesting because it seems to correlate more strongly with immune cell aging than some of the other age clocks.

Austin Perlmutter
And in our study, what we were looking at was the effects of a polyphenol-rich concentrate. So just quick aside here, polyphenols are a group of chemicals found naturally in plants. There's about eight thousand plus of them. Research shows that people who consume more polyphenols tend to have better health outcomes, live longer, better brain health.

Uh, polyphenols are, are high in the so-called blue zone diets, longevity type diets, and we have been working with a plant called Himalayan tartary buckwheat, which is a non-grain seed that turns out to be very high in certain polyphenols called rutin and quercetin. So we had a concentrate of this. We did it for ninety days in people to look at the changes in their epigenetics over that time. We didn't mess with anything else. And what we showed was almost nine hundred different places on the genome where these epigenetic sites were modified at a statistically significant level. And when we really dialed in to understand, well, what does this represent, we were able to find that there were a number of pathways, gene pathways that were significantly modified in terms of their statistical significance and also the degree to which they were modified. And so these were involved in things like immune cell function, metabolic function, brain cell function, and they're a little esoteric in terms of their names. So there's the COP nine signal zone, there's the ceramide kinase pathway. But the goal of the whole study was, in essence, it was a pilot study, hypothesis testing, which is to see could we find evidence beyond just chance that when you took people and gave them a concentrate of these nutrients found in this plant, this Himalayan tartary buckwheat, that it would change their epigenetic expression, and this would relate to things like immune cell function. And so we had, you know, still to this day, some of the, the only data showing that this type of thing is even possible. And where we're at now is we're just wrapping up an eight hundred and fifty person randomized controlled trial with a placebo looking at the effect of a tartary buckwheat sprout powder on epigenetics, cognition, and other brain health metrics. So Again, I, I know I've, I've gone on here for a moment, but the, the question that I feel like we all need to be asking ourselves is so really interesting that now we can understand that our cells age at a different rate as our birthdays, that our organs age at a different rate than our birthdays, and that organ aging relates directly to our chances of developing issues with those organs. What can we do about this? And so much of the, the kind of public understanding has been around well, yeah, there's these pharmaceuticals. We look at things like rapamycin, uh, and its effect on mTOR and immune cell pathways. But what can we do from kind of a nutritional perspective to help to slow that rate of aging and to hopefully then lead to some organ-specific benefits, which is really exactly where we're at right now with this research.

Melanie Avalon
Okay, I have some, some questions about the study that you conducted. First of all, how did you... I've-- this is something I've thought about for a long time because I feel like there are quite a few different longevity-related food-based supplements out there, like food-derived things that w- like people talk about as, you know, being really great for anti-aging or health or whatever it may be.

So whether it's like fisetin, strawberries, spermidine, like I'm always wondering there's so many foods out there and so many polyphenols. How do we even... like, how did you select specifically Himalayan tartary buckwheat pow-powder and, yeah, like why that one?

Austin Perlmutter
And I will just tell you my bias here is that when we're looking at these longevity pathways, like I don't take high doses of individual molecules in hopes that that's going to fix it for me because I just don't think the data are there yet. What we see across the board is that people who eat certain types of diets that are minimally processed, rich in plant nutrients, those are the people who at this time have the highest chances of making it to a hundred plus. As much as there are aspects of, you know, the biohacking world that I think are wonderful, it's still kind of this unspoken truth, which is that there are no data showing that any sort of supplement extends lifespan in humans, uh, in healthy humans.

And so where we're coming into this conversation is to say how do we look at the benefits that certain people are getting from eating a diet rich in polyphenols? And then if we were to say what are good model, I guess in this case, plants that could help to potentially recapitulate some of those value propositions, what are some of the plants that are highest in those, in those molecules? And we settled on this tartary buckwheat or Himalayan tartary buckwheat specifically because it is one of the richest plants in terms of its phytonutrient or phytochemical composition, and I should just say so polyphenols are a form of phytonutrient or phytochemical. But the reason we knew that to be the case was one, there was preexisting data showing that tartary buckwheat was probably the, the top food source of this molecule called rutin. Rutin is kind of a, uh, a very closely related molecule to quercetin, the difference just being a sugar group. But then what we did is we've been working with a university lab, uh, in Utah and in essence running various forms of buckwheat through complex polyphenolic analysis. And so what we found was, first of all, that tartary buckwheat in general compared to common buckwheat can have up to several hundred times more of certain polyphenols. But when you sprout the tartary buckwheat, it actually increases the concentration of polyphenols in general by about threefold. And interestingly, the other piece of this puzzle is most polyphenols cannot be absorbed by humans, which is why if you think about all these supplements and things people are taking, you have to be aware that all of them are pretty much going to, unless there's, there's, you know, some very specific exceptions, make it to the large intestine without being digested, without being absorbed. So what makes a real food a bit different from just consuming a high-dose quercetin supplement is that one, you're getting not just the one polyphenol, but a whole host of polyphenols with it. And two, what you're starting to see is that it comes with variables like fiber, minerals, vitamins that can influence the microbiome.

Austin Perlmutter
And, you know, to that end, it turns out that probably one of the most important aspects of what polyphenols do to our physiology is not that they're absorbed and directly bind to and influence our cells, but rather that they influence the microbiome and can actually be converted by the microbes into various metabolites of those polyphenols which may then have immune and metabolic effects. So the short answer to your question is we looked at a whole bunch of different foods. We found one that was exceptionally high in these nutrients that were already linked to longevity from a dietary perspective. We did detailed analysis to find out exactly what nutrients were in it and then we sprouted it to further increase the nutrient capacity. And the goal here is, is not to prove out that it's a single molecule fixing anything, but rather to take this concept of food as medicine and legitimize it a bit where it's not just, well, you know, food has some nutrients and vitamins and minerals, but rather no, actually food is capable of influencing epigenetics, influencing cognition at people at scale.

So that's where we're, we're at right now in that research. We have, we have our first publication that you mentioned. Hopefully by the time many people are listening to this we'll be well on our way to our next large publication and we also have, as I said, been working with this research group in Utah that has submitted a manuscript specifically looking at the phytochemical makeup of different forms of tartary buckwheat. But the goal throughout all of this is to take this field of food as medicine and show people that it's not just this binary where you have drugs and you have food and they operate through different channels, but rather there are these conserved pathways through the immune system, through metabolism, through the gut microbiome that we're capable of intervening on with real food.

Melanie Avalon
Speaking of food as medicine and getting the polyphenols from food, do you know what the role is of Getting a higher variety of polyphenols in, but maybe a lower quantity. So maybe you're eating a lot of different types of fruits and vegetables and polyphenol-rich food sources, but not massive amounts compared to... So like me, for example, I don't eat a wide variety, but I eat a shocking large quantity of, like, blueberries.

What's the role of variety versus just quantity?

Austin Perlmutter
Yeah, I mean, first, blueberries are great. So let's just, let's just say that.

Blueberries are great. There are certain foods that are high in polyphenols that seem like they just have their own value. So olive oil is another example. You know, olive oil has its own polyphenol set. It's what gives good olive oil that nice peppery flavor, and olive oil has kind of been independently studied in terms of its benefit to a number of health outcomes. There's a great study from a couple of years ago in the Journal of the American Medical Association showing that people who consume around seven grams of olive oil a day compared to people who did not had a 28% decrease in risk of dementia-associated death, even when they controlled for other foods. So there, there are some foods, blueberries are, again, as you said, a good example, that we have some additional data on beyond just saying they're a good source of polyphenols. And there's some data on when you drill down different forms of polyphenols in these great foods. So blueberries are rich in a group of polyphenols called anthocyanins. Uh, they're what give them that deep blue color. And so those may have cardiovascular and neurological benefit, which is a little different than other groups of polyphenols. By and large, though, a lot of people talk about this idea of nutrient diversity, being able to activate all these different pathways by giving your body not just different foods, but seasonal foods, locally grown foods. I have not seen as much data specifically for that in terms of health outcomes as I have for, you know, just kind of general composition of how much, for example, polyphenols people are consuming in terms of dementia risk, et cetera. But what we're seeing from studies like the one I just mentioned with the GreenMed study was those polyphenols seem to preferentially come from walnuts, green tea, and then this duckweed. So those might be foods to look into because there's a bit more data on them. The recommendation I tend to make for people when I'm doing lectures is polyphenols tend to come, as does fiber, from consumption of a minimally processed plant-forward diet. And so huge difference here between saying, you know, you're eating a, a half a cup or a cup of blueberries versus a highly processed blueberry snack. There are a lot of people who will say, "You know, it's exactly this. You have to eat exactly this many almonds. You need to have exactly this many grams of fiber a day." I think for the average person, and maybe the average person may not be listening, they probably gave up on me a long time ago because of how technical this got. But for the average person, the best data are simply starting with consuming less ultra-processed foods and eating a more minimally processed diet.

And if you do that, you're actually going to find that your polyphenol consumption, that your fiber consumption, that your micronutrient consumption should go up alongside it. I think where people get derailed is they start hearing about some of these nutrients, and then it all becomes a competition.

Austin Perlmutter
So if I'm here talking about polyphenols which come from minimally processed plant-based sources, you know, I might tell people cloves are the most concentrated source of polyphenols in the diet, and people say, "Well, great. I'm on a carnivore diet. My goal is to get four thousand grams," I use that facetiously, no one should get that, "but four thousand grams of protein a day, and so I'm just gonna sprinkle a bunch of cloves on my protein to get my polyphenols." And that's just not how this works.

It isn't trying to distill it down to an exact science of how many milligrams or grams of polyphenols to get. It is more a function of these may be carrying a specific signal from a whole minimally processed plant-based food in conjunction with the matrix that comes from the fiber and other nutrients bound up with that food. So just one more point on this. The average American consumes around eight hundred to a thousand milligrams of polyphenols a day. This research that, you know, I've been citing with this DIRECT Plus med or DIRECT Plus study, they increased that to an additional twelve hundred milligrams, right, on top of what people would be eating in a, a typical diet. So where most people get their polyphenols from, though, in the United States, the top source, not in terms of total amount, but in terms of the top source or the one food that has the most polyphenols that they're consuming, is going to be coffee.

And so then you could say, "Well, that's great because there's data on coffee." But then you have to look at what people are consuming with their coffee. And I have seen, as I'm sure you have, that when people say coffee drink, that often means a... I don't know if we're allowed to blame brands here, but I will. A Starbucks mocha Frappa sugar disaster, right? So is consuming that Starbucks beverage going to be good for you because you're getting those polyphenols? I would say the answer is no, right?

In aggregate, it's actually detracting from a person's health. So that's why I feel like this is all kind of for me to be able to say that it isn't about just optimizing towards a specific milligram amount, even though there are some data around that. It's trying to optimize towards a diet where that milligram amount becomes inevitable because it's part and parcel of the food that you're eating.

Melanie Avalon
I was selfishly hoping you were going to say coffee. I just I just launched a high antioxidant organic coffee line, so I'm, like, all about the coffee science.

Austin Perlmutter
Disclaimer on my end, I had no idea. This is, this isn't a pitch for that, but I am a huge, huge fan of coffee.

Melanie Avalon
Okay. Well, good.

I'll have to send you some. But I agree so much about the, the Starbucks example, which, yes, we can, we can name the things. And I won't bring up this tangent, but I also think that actually happens with alcohol, too, where maybe it gets... Like, I feel like there's a big difference between, like, an organic low-alcohol red wine and a high sugar, you know, cocktail at the bar. But- That's a whole tangent. What was the purpose in the study, the one, the first one that you did with the buckwheat, on comparing it to vegans and omnivores?

Austin Perlmutter
So we did that in our study because one of our collaborators, actually the, the True Diagnostic team, had just before our paper put out this publication where they were looking at the impact of a interventional study here with either an omnivore or a vegan diet. And so for those wondering, if you go to Netflix, you can actually look up, they did a documentary on this study because it was somewhat controversial because what they showed was a relative benefit in terms of biological aging in people who were, did a, a vegan diet as opposed to an omnivorous diet.

What we were trying to see and why we talked about it in our paper was are there overlaps in the pathways that are modified by those diets compared to what we found in people who were having the polyphenol supplement, uh, or the concentrate? Because, you know, it's one thing to say, "Well, we found that people who did this thing had a slowing of their aging rate," but what we really want to do is understand mechanistically what's happening here. So that's kind of been a challenge with epigenetics, which is you find some very interesting data, but the next phase is to say, "How does this happen? Why is it that when a person changes their diet for a couple of months they start to think clearer or they start to generally feel better or they start to lose weight?" It's not enough to simply say it happens if you're a researcher because what you want to see is a mechanism. And granted, at the extreme end of that, then you get, you know, these drug targets. So a GLP-1 agonist works really well because this mechanism has been increasingly well established whereby GLP-1 agonism leads to changes in appetite, leads to changes in insulin sensitivity. And therefore, if you give a person a drug that increases the agonism by a thousandfold over what's naturally found in their bodies, they're going to get some physiological effects. But at the level of what we're doing with this nutritional research, what we're trying to see is how does food actually influence physiology? And there's this theme I've been talking about for the last several months, which is that as it relates to nutrition, humans have a whole lot of hubris in thinking that just because we have some additional data, now all of a sudden we understand what's in our food. If you look at the last 100 or so years of nutrition, I mean, first of all, we just discovered vitamins in the last 100 or so years, but there's always this idea that we have somehow understood the most important aspects of what's in our food. So we know that caffeine in coffee leads to some stimulation. So is a caffeine pill the same thing as a cup of coffee in terms of its health benefit? The answer is no because caffeine is not coffee. Caffeine is in coffee along with other variables like the polyphenol antioxidants. Similarly, if we were to say, "Well, you know, there's a loaf of white bread, and we've stripped away all the fiber, we've stripped away a lot of the vitamins, but we've gone ahead and injected, enriched it in some of these vitamins and minerals.

Austin Perlmutter
Is that equivalent to really eating whole grains?" And again, the answer is no because there are somewhere in the neighborhood of 140,000 different chemicals found in our food. And I use chemicals here not in a negative way, but in a chemistry way, which is to say that our food is just loaded with data. And the more of it that we take away through various forms of processing, the more we lose out on the opportunity to, you know, do what our bodies were evolved to do, which is to benefit from all those signals coming in.

So the reason we looked at that data set was because the omnivore and the vegan diets showed specific patterns of DNA methylation that were different from each other, but they turned out also to be a bit different from what we found. So that's why in this, this study that we're running right now, we're going to be retesting epigenetics to see is there a specific signal linked to consumption of a certain polyphenol kind of mixture that comes from this plant, tartary buckwheat. Because if we can start to do that, then we can start to show how different food differentially influences our health. And just at, as a very base level, what that does is starts to break down this divide which has historically been a huge issue that connects conventional medicine, integrated medicine, alternative medicine, functional medicine, all these different groups, which is that for conventional medicine, food generally exists at the level of calories, at the level of nutrient deficiencies, at the level of glycemic management, specifically for people with diabetes. But in many of these other groups, food is seen as this matrix, all these different molecules, all these different potential values to our health, but that perspective still needs to be grounded in good data. And so that's what we're trying to show now, which is how does food actually influence physiology? So it's not just saying, "Well, polyphenols are antioxidants, and therefore they're good." That's not quite right. If a person takes high doses of antioxidant vitamins, it decreases their chances of having optimal health. So we're trying to look at these mechanisms beyond that, and it's, it's nuanced, but it's important.

Melanie Avalon
So for like Big Bold Health, how many supplements do you guys have there?

Austin Perlmutter
Big Bold Health has, well, so I should say really like two kind of core product lines. The one is around tartary buckwheat, and the other one's around omegas, both of them kind of predicated on the idea that the less processing, the better as it relates to trying to maintain the nutrient integrity of the food.

So right now what we're doing mainly is focusing on the tartary buckwheat, and so we're studying right now in this large clinical study a sprouted Himalayan tartary buckwheat. The intervention is literally just a food, 18 grams a day for a three-month period of the sprouted powder. And that's also what we're studying with this manuscript that's been submitted for, uh, review of the actual polyphenols. And depending on, you know, what polyphenols we're looking at, we've actually seen between 70s to over 100 different molecules found in this plant. So- There's, there's a lot of, of science in the background. We actually did a, a small study a couple years ago where we looked at the changes in the polyphenols in the tartary buckwheat when we treated the seed with microbes and fungi because as it turns out, which is something that I certainly didn't learn in medical school, the microbiome of the soil has a lot to do with the nutrient capacity of the plant. So by inoculating the seed with various microbes that then get kind of integrated into that soil, we can actually see changes in the polyphenols, specifically root and concentration in the seed from the plant that has grown from that inoculated initial seed, which is... It's crazy stuff.

Melanie Avalon
Wow. I'm staring at my hydroponic plants and thinking how they're missing out on the soil, I guess. It's a... Is it a, a drink then? You, you mix it into a drink?

Austin Perlmutter
That's what we're doing for this clinical study. It's the easiest way.

You put it into a smoothie or another beverage, but a lot of people will, you know, will bake with it, will put it in savory dishes. There's lots of recipes on the website if people are interested in that. And the... What's cool about the, the sprout powder compared to the flour, so the, the plant itself, as you might expect, because it's super high in polyphenols, is a bit bitter, but when you sprout it, you actually increase certain molecules that are anti-bittering, so the sprout powder has kind of a nutty flavor as opposed to the flour, which is still great, but for some people it's a little bit more bitter.

Melanie Avalon
Nice. Okay. Well, this has been absolutely amazing, and yeah, we only barely scratched the surface on all the things. We didn't even get to ayahuasca.

Next time. I'm very curious about that. But thank you so much for everything that you do. Is there anything else that you wanted to draw attention to listeners? How can they get the, the buckwheat powder, all the other things, follow your work? Are you writing another book, question mark?

Austin Perlmutter
At some point, yeah. I really appreciate this conversation.

If people are interested to keep learning more, there's other research that I'm involved in that you mentioned with ayahuasca. We're looking at how ayahuasca influences the microbiome, epigenetics, the immune system, and how that could potentially help to understand, us to understand how it works on depression, which I think is super cool, just the general concept of how psychedelics are capable of benefiting people's mental state for years after a single dose. That's a, I feel like, an important question for us to be addressing as a society. I'm also doing a lot of work now on kind of links between cognition and air quality, so for people who are interested in that, they can learn more about that. If you, basically, if you go to my website, it's austinperlmutter.com, there's a, a more than I care to admit, but there's, there are a lot of blogs, podcasts, et cetera. And then on the Big Bold Health side, we're gonna be doing more with this research, so if you go to the Big Bold Health YouTube or to the website, you'll be able to learn more about what we're publishing there. And depending on when people listen to this, I'll be probably at some sort of a, a wellness, longevity, or health conference near you in the coming months. So if people want to meet me in person, you can always sign up for my newsletter. It's on my website, austinperlmutter.com, and I keep people in the loop on where I'm gonna be and what I'll be talking about.

Melanie Avalon
Amazing. Will you be at Eudaimonia this year?

Austin Perlmutter
I will be at Eudaimonia this year.

Melanie Avalon
Okay. I should be too, so that's exciting.

The very, very last question, it's so easy, I promise, and it's just because I realize more and more each day how important mindset is, so I always ask the guests what is something that you're grateful for?

Austin Perlmutter
I'm grateful for the ability to, to see where my edges are and to be able to, hopefully, increasingly as, as time has gone on, be able to, to hold that a little bit longer. It's still an, an ongoing challenge, but not to immediately identify with the defensive version of myself that says that something must be wrong because it's uncomfortable or feels different.

So I'm very grateful that I've been able to expand that a bit over the last years. I'm super grateful to my wife for helping me to do that, and, um, we are, we're moving into a new phase of life. We have a, a daughter on the way, and I'm just hoping to continue to expand that part of me because I know I'm gonna be challenged in a way that is, is super intense and more than has ever been before.

Melanie Avalon
Oh my goodness, congratulations. That's incredible. If everybody could take the pause in between you know, the things that we experience and the reaction, that would just be a game changer. So thank you so much for all that you do.

This was absolutely fascinating, so enlightening. You're helping so many people. Keep on keeping on, and yeah, hopefully see you at Eudaimonia.

Austin Perlmutter
Fantastic. Thanks so much for having me.

Melanie Avalon
Thank you. Bye.

Thank you so much for listening to the Melonie Avalon Biohacking Podcast. For more information and resources, you can check out my book, What, When, Wine, as well as my supplement line, Avalonex. Please visit melonieavalon.com to learn more about today's guest, and always feel free to contact me at contact@melonieavalon.com. And always remember, you got this.