Inflammation is Aging Your Brain – Dr. Andrew Miller : 643

Yeah, absolutely classic depression caused by a molecule that stimulates the immune system and stimulates inflammation. And so that began this whole notion that inflammation may cause depression in some people.

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Today's guest is someone I've been wanting to interview for a while and someone you might not have known. He is an internationally recognized expert in the way the brain and the immune system work together specifically around stress and depression. He's a vice chair of research in the Department of Psychiatry and Behavioral Sciences at Emory School of Medicine, also the director of behavioral immunology there. And you're saying, that is a mouthful. This is how you behave based on what your immune system does. This idea that the tiny cells in your body, even subcellular things, are driving large behaviors, such as whether you want to punch someone or not, is it is shocking how real that is. So dumb little mitochondria, other little things, they are kind of in charge of things way more than we like to admit to ourselves. And Andrew Miller has researched these underlying mechanisms, including how inflammation can cause depression in humans and other primates. And he did the first clinical trial examining how effective immunotherapy would be in the treatment of depression. More than 250 scholarly publications, numerous awards, and was voted a top doctor in psychiatry for the past 4 years. In other words, a game changer if there ever was such a thing. Dr. Miller, welcome to the show.

Thank you very much, Dave. I'm very pleased to be here.

There are lots of things you can study as a medical doctor. There are lots of things that will make your colleagues really, really pissed off. And one of them is saying exactly what you've said, that the immune system is causing behavioral issues. In fact, there are people who've had their licenses taken away for that. What made you decide to go the high-risk route and start studying this and publicizing it?

Well, it's actually an interesting story. And you're right, I think most of us believe that what we think and feel is driven largely by psychological factors that are going on in our lives, our relationships with other people, and things that happen to us at work and in our various pursuits. But the thing that was fascinating to me and got me started in this area was some work that was going on in the area of cancer. And very early on, there were some of the first immunotherapies. And as I think most of your audience and you know that some of the major changes in cancer treatment have come about through our understanding the immune system and using different types of therapies that target the immune system to treat cancer. Well, these were some of the very earliest treatments that they were using as immunotherapies to treat cancer. What they would do is they would administer these drugs, which are usually molecules that are normally found in the body, so that's how immunotherapies are working with the immune system to help it fight cancer. In this case, they were giving a molecule that is a cytokine, which is one of the many molecules that mediate how the immune system works in the body. Immune cells release cytokines. So they were giving an, a cytokine that induces inflammation to patients to treat their cancers.

Which one was it?

It's interferon alpha. So interferon alpha is an inflammatory cytokine. It's actually one of the first, if not the first, immunotherapy, and at that time being used to treat malignant melanoma and renal cell carcinoma. So It became apparent very early on to the oncologist when they gave this interferon alpha to patients that the patients started becoming depressed. And they were quite concerned because patients were dropping out of treatment and would not continue. No, I don't want to have that, that drug again. I felt miserable. And so eventually they said, we need to get psychiatry involved. And so I was asked to see one of these patients who was receiving interferon alpha. And I expected going into the, to the infusion center where they were infusing these molecules into the veins of these patients, I was expecting to see people sort of covered in a blanket and shivering and looking miserable. And of course, the oncologists don't know anything about depression, so, you know, we'll, we'll, we'll see what's really going on. So I went in and there was a woman sitting there And it probably took every ounce of energy and wherewithal that she had to get prepared for her seeing the psychiatrist, but she was nicely dressed and she sat there and in quite sober fashion told me that she was absolutely depressed, that she had no interest in anything. She had no interest in her family. She had no interest in her husband, her children. She said she loved to cook. She was not cooking. She loved to garden. She was not gardening. She said she couldn't concentrate. Her memory was shot. She wasn't sleeping. She was exhausted all the time. And yes, maybe the thought had— fleeting thought that maybe, is this a way to live your life?

Wow.

Kind of a suicidal type thing. And I looked at her and I said, oh my God, This is someone who looks exactly like someone I would see in my practice who had just lost a child or just had a broken up relationship or had had some other horrible thing happen to them in their, in their lives. And I said, this is real depression. This isn't something that is a sickness or a fever or some type of a medical reaction. This is a purely psychological brain reaction to this, to this drug, to this cytokine, to this inflammatory cell.

But she had cancer. I mean, shouldn't you be depressed if you have cancer?

I asked her that question. I asked her exactly that question. Good question. I said, well, you know, look, you have malignant melanoma. That's not a good cancer. And she says, look, I came to grips with that months ago. Okay, this isn't about cancer. This is about having received this. Uh, well, she tied it to the treatment. She said I felt fine, and then she had tied it to the treatment. And just related to that, which I think is important because this comes up often because our studies did originally focus on cancer patients, and that, that issue came up multiple times in presentations and whatnot. And What I can just say briefly to address that is that we also gave interferon alpha to non-human primates, to rhesus monkeys, and they too became depressed and showed all the features.

These are monkeys who, who weren't already depressed because they were living in a laboratory?

Well, they're not, they're not happy about it, but, but they're not depressed.

I, I understand that they're probably more pissed off, which is probably exactly depressed.

Absolutely. Okay.

And, and a lot of people who succeed in fighting cancer, they are fighting cancer and they are full of fight, right? And you're saying here's a drug that shifts you from that fight response into—

yeah, absolutely classic depression caused by a molecule that stimulates the immune system and stimulates inflammation. And so that began this whole notion that inflammation may cause depression. In some people.

Now, one of the core tenets in, in the entire body of things that I've written and, uh, uh, and just taught and learned over years is that inflammation is pretty much at the root of most aging. By the way, right now as we're recording this, for the first time in my career as an author, my new book Superhuman about longevity and aging is in its second week on the New York Times bestseller list, which is awesome.

Congratulations.

Thank you. But a big thing is, hey, you better turn down inflammation if you want to live a long time. And the primary cause of inflammation is actually mitochondria, like, because you don't get inflammation without them. And if they're, if they're not functioning, all of the cytokines will affect your mitochondria in some way or another. And in my own path of being much happier and not weighing 300 pounds and all that, turning off Inflammation is a fundamental goal of almost everything I do. What I found though is that anxiety, not just depression, but anxiety is very much tied to biological wellness. If your cells are working, and I have all kinds of theories and certainly you've got all sorts of laboratory stuff there, but for people listening to this, okay, they don't have cancer, they're not injecting cytokines, but they're doing stuff that causes inflammation. Where I'm going with this, is this kind of a binary thing? Either you have enough, you're depressed, or is it, oh, you're a little depressed, you have less bounce today, you're far from depressed, but you're a little bit inflamed, so you're a little bit less effective in your life. Is it linear or is it binary?

[Speaker:DAVE_ASPREY] Well, you know, of course, as a physician, we tend to be more binary about things and we say, well, either you have depression or you don't, and we all know that people have a lot— there's a lot of gray, gray area in between. And I think it is linear. And, and what you're talking about is extremely important because the level of inflammation in your body— and, and we all, as you, as you pointed out, that we all have sources of inflammation, we can get into that, you know, where does inflammation come from if somebody's not injecting it into your arm or you don't have cancer, for example. There are many sources and we can go over them, and you've already touched on some. But I was recently at an aging conference about, you know, what, what are the drivers to people getting older?

Which conference?

This was at Stanford, and the conference was really, uh, it was all about inflammaging. So that is a concept. Inflammaging is one of the hottest topics in immunology right now because we recognize that much of what drives the process of aging in the brain and much of what drives many of the illnesses that eventually do people in are driven by inflammation. So we're talking about cardiovascular disease, we're talking about diabetes, we're talking about cancer, We're talking about neurodegenerative disorders. You're really talking about all of the diseases, all the modern ills that we as a society are grappling with right now. And the thing that's really cool about this is if you go back and you start to say, well, why? You know, where did all this come from? It's interesting if you think about it from an evolutionary perspective. We as human beings are— we're not designed to live in the world we live in now. We were designed to live in a world where there was a very heavy, high pathogen load and we could get attacked by a predator at pretty much any point time. And in order to survive to reproductive age in ancestral times, you needed a really aggressive inflammatory response, a very aggressive immune system to go after all these pathogens that were rife in the environment because there was no sanitation, the water was contaminated, the food was spoiled. There was no way you were going to get around not being exposed to a ton of pathogens. Plus, there was all this wounding that's going on. And what does inflammation do? It's all about fighting pathogens and healing wounds. So, okay, so that's— if, if you're alive today, you're alive because your ancestors had a really aggressive immune system. And I think something that's kind of really an added coolness factor in this when humans migrated out of Africa into Europe and Asia, we actually had to mate with subhuman species to pick up their DNA in order to fight the pathogens that were in Europe and Asia because it was— they could not—

the Neanderthals and Denisovans.

Exactly. So if you go into every you know, Caucasian, every person that's not African, of pure African descent, you will find DNA and from the, the Neanderthals and the Denisovans, and that DNA is sitting in regions of the genome that are responsible for fighting infection.

The reason that that is so fascinating is that I've looked into something called the HLA DR4 genetic subtype, and something that I have, something about a third of people have, that makes you more prone to inflammation. And in fact, my first book I wrote about this. This has a lot to do with toxic mold and Lyme disease sensitivity, environmental sensitivities. And the theory there is that we picked up those genes because we were the people who were the marauders. So in addition to fighting tigers, we had to go to a new village with new bacteria. We had to take our swords or arrows or clubs or whatever the heck we used back then and survive getting cut. So your blood clots quickly and you have a hyper-aggressive immune response. And unfortunately, that means you're very likely to have massive health problems if you live in a building with toxic mold. So that was my, my focus. I've done a documentary on toxic mold. But your work is going beyond just inflammation. Does that mean that people who tend to be more inflamed, that they're also more likely to be anxious, depressed, angry, warlike jerks?

I would think that— I guess the answer to that question If you just look at the data, the answer to that question is yes. Because if you look at—

Thank you.

If you look at individuals, for example, who have autoimmune or inflammatory disorders, these individuals have much higher rates of psychiatric complications, including anxiety, depression. And what's interesting, you say, oh, we can go back to your, if you have cancer, you'd be miserable anyway. So what's, you know, what's this have to do with inflammation? If you take those individuals who have these high rates of depression and anxiety and you treat them with a drug that blocks these cytokines like we were talking about earlier, if you block just those cytokines, the depression scores drop, the anxiety levels drop, and the people feel as if they are new people in terms of their their psychological wellness, their psychological well-being, their mental health.

That is one of the most powerful things in 700 episodes that I've heard someone say just straight up in one sentence. In my own path, when I got over time control of all the different inflammatory cytokines that I had problems with, and it was more than just a couple, cause I had a lot of inflammation. I stopped being a jerk. My anxiety levels dropped. My performance at everything I did went up. My energy levels went up. And I like to think I'm generally a nice person the vast majority of the time. And if I do something that causes inflammation, I see a change in my happiness levels. And it's very noticeable on even sometimes a half hour basis. I can see a shift in my energy levels. And it's not just mitochondrial, like, oh, I have energy, I could run faster, my VO2 max is slightly better. It's I care more or I care less about everything. And I am not depressed. I'm very far from depressed. But for me, it's very linear. And I think it's that way for most people. Is it that way for most people, or just the third of us who have the extra Neanderthal, I will invade your village and take your food even if it's spoiled, James?

Well, I think this is something that we're struggling with because we— it's very clear that if you have high levels of inflammation, that the inflammation through a series of processes that have a lot to do with what you're alluding to, which is metabolism, that metabolism, especially even within the immune cells themselves, leads to the release of these cytokines, these inflammatory cytokines, which we know can get into the brain, and they get into brain regions that are relevant to behavior. And they go to a couple of brain regions. They go to one brain region that are subcortical brain regions that are involved in reward processing. So your motivation, and they go to a region of the brain that's involved in your perception of threat. So when you talk about being irritable and maybe a little aggressive, you see things more as threatening. So your likelihood to interpret something that's going on in your environment and in an interpersonal interaction, you'd see it as more threatening as it might otherwise be. So that's clear to us. It's clear that if you have significant inflammation, there are two things your body wants to do. Number one, it wants to shut down, to shunt energy resources to wound healing and fighting infection. Second thing you need to do if you're infected or wounded, and these are evolutionarily derived, we think, behaviors, is you need to be on hyper alert status. You need to be looking for trouble in the environment because that trouble could be an animal coming to finish off the job. They wounded you to start with and now they're looking for you to, to ultimately have you for lunch. And so there is a certain vulnerability that comes with being sick or wounded and so you need to be on alert. That you may be attacked because of that. That's— so those are the things that— those behaviors are the behaviors we think feed into the psychiatric disorders per se. Okay, so depression, anxiety. But let's go back to the linear. What if you just had a little bit of inflammation, you know, a little above normal? Does that impact behavior? And the answer, we think, and we're testing this now, is yes, that the decision-making process is influenced in such a way that you begin to discount things that take more effort. So if you're thinking about going to the gym, you go, "Well, you know, I'd rather just kind of get my..." my goodies by sitting on the couch and watching TV instead of going to all the trouble to go to the gym. And it may show up in that you're just kind of not as motivated to go and do these other things. Maybe you're a little fatigued. So there are lower levels of symptoms that ultimately impact our decision-making. Am I gonna go to the store and buy a series of healthy foods that I'm then gonna have to bring home and cook, or am I going to go to one of the local fast food places and get something that is simple, easy, and quick? So I'm—

and inflammatory—

and feeds the fire. Yes, absolutely. I mean, it feeds on itself, really. I mean, if you think about it. So yes, to answer your question, I think it And this is the kind of thing that we're now sort of working into some of our research studies is cognitive neuroscience, where we can begin to see how people make decisions. And there's a process of discounting, as if I say I'm going to give you a dollar now or $5 in 2 weeks. 2 weeks, you'd probably say, look, I'll take the dollar now and wait 2 weeks for $5. So you're discounting by virtue of the time factor. We think inflammation affects those decisions so that even if the payoff is bigger and bigger and bigger, the person will still take the immediate reward because they don't want to wait. They're not willing to put in the time and energy for the, for the, for the big win in the future that may require some work as well.

One of the things that didn't make it into, uh, into Superhuman, my anti-aging book, is the idea that as we age, we pick up slow-growing bacteria, things like Mycoplasma, uh, things like Bartonella, uh, things that really aren't gonna do anything for 20 or 30 years, but the longer you live, the more you're exposed to them. And these bacteria actually make cytokines specifically to cause cellular destruction so they can use the parts of the cells as their own either fuel or building blocks to make more of themselves. And that, I believe, I just didn't have enough evidence to put it in the book, but I believe some of the things that happen as we age are coming from those those guys. My personal experience, I had, I had the toxic mold exposure and Lyme disease and a bunch of other things, so I really dug in on the bacterial side of things. I take a stack of herbs. This is actually something I've never talked about on the show, but herbs that come from all around the world that I know based on lab testing, in addition to the studies, that turn down all the inflammatory pathways that I have. When I take those, I don't I don't get sick very often, and I perform really well. And if I don't take them for a while, I start to degrade, right? And it's literally managing cytokines. Do you believe that these subclinical bacterial infections that are common but really don't make you that sick, are those common? Are those relevant to what you're studying?

I think that they likely are. It's not an area that I study and there's not a lot of literature on it. What there is a growing, rapidly growing literature on is on the microbiome. And those are all the bacteria that are basically in the body and in the gut and the skin and in pretty much all the parts of your body. And what we understand now is that the microbiome, especially in the gut, is playing a huge role in dictating exactly how the immune system functions. That is now expanding to viruses. I am sure it will expand to parasites and other, other various infectious or commensal organisms. Organisms that are kind of along for the ride. We just are— it's just now the tip of the iceberg. We really have not dug down deep enough. But what is very clear is that infections and the microbiome are playing a huge role on your level of inflammation in your body. And part of it is related to how the microbiome regulates the immune cells as well as leaking into your circulation through a leaky gut based largely on your diet and other factors such as stress. These can all lead to leaky gut and microbial products from your gut will leak into the circulation and activate immune cells to then release inflammatory molecules that then can affect your brain.

If you're listening to this and asking yourself, well, Well, seriously, I'm probably not someone who's affected by this. It's starting to sound like you are affected by this. And interestingly, think about that time you were hungover and when you were really drunk, you ate a bucket of fries and some pizza and you woke up the next morning. How did you feel? Okay, you just turned on massive inflammation through aldehyde and trans fats and God knows what else you did that night. That was not a good day, right? We can all feel that. That's inflammation, right? So this is just to get over that little skepticism, say, hey, actually I have at least one case in my own life where this happens. Or you felt really crappy after the flu and it wasn't just the symptoms, you, you're dragging. That's— this is at least how I picture these things. Are those good examples of, of things that most people have experienced?

Yes, I think I think that especially the flu, I think most people have experienced pretty much what inflammation does in stark relief. I think that that's sort of a dramatic example, though. Those moments when you have the flu where you literally cannot move, even though you want to move, you can't move. And it's almost like a paralysis. And you hear people with Lyme disease and some of these other infectious illnesses will describe exactly the same thing. And as I said, this is a grand design to shut us down when we are— when we're infected, because we really need to shunt those energy resources to fueling the immune system.

I'm just blown away to hear you say this, especially given what you're studying, your background, and that this is entering the field of hard science and medicine so that we can start looking at people who have anxiety and depression and say, all right, do you have an infection? Do you have inflammation? And are there parts of your brain that aren't necessarily structured right or aren't working? But even if they're not working, is it because of inflammation? And so I'm a fan of Dr. Daniel Amen's work with SPECT scans and fMRI looking at the brain. Dave Asprey, my own brain, we did the radioactive marker injections and all and found big parts of my PFC that just had no metabolic activity. Sorry, for people listening, PFC is prefrontal cortex, the logic part in the front of the brain. His determination was, look, you had environmental toxins from mold most likely, maybe mercury or something else that were inhibiting activity there. Now, are you seeing, or are your colleagues seeing specific regions of the brain? You mentioned subcortical, but are there other spots that get hit by inflammation more than others that would affect our behavior in other ways?

Yes. So that's, um, much of the work that, that we've done, and there are other investigators that have found very, very similar results. It's all of us going at the issue a little bit differently. So we know these findings are relatively reproducible across different inflammatory stimuli and across different laboratories. And what we find is that yes, there are effects in the prefrontal cortex, and yes, we see a decrease in activity, metabolic activity in the prefrontal cortex. Frontal cortex. We also see activation of threat-related regions in the brain, including regions that may not be relevant to your audience, but maybe some—

the dorsal amygdala, or— well, that's—

yes, the amygdala for sure, the hippocampus, the dorsal anterior cingulate cortex. These are all in the insula. These are all brain regions that form circuits, and much of what we do in psychiatry now is about circuitry, what different brain regions talking to one another, leading to behavioral phenomena, and that circuit that involves the amygdala and the insula and the hippocampus, dorsal anterior cingulate cortex, is the anxiety circuit. So we see this activation of the anxiety circuitry. We also see, and I alluded to this previously, effects on reward circuitry. So that includes both subcortical regions, the striatum, and cortical regions, the ventromedial prefrontal cortex. So in those prefrontal cortex regions, what you see is you see an increased activity in the anxiety circuits and you see a decreased activity in the reward circuitry. And the And the amazing thing is you see a linear correlation between the activity in these circuits and the amount of inflammation in your body as measured by C-reactive protein, which you can, which you can go to your doctor right now and get measured.

In fact, there are 3 lab tests that I have recommended since the very beginning of, of writing my first book, my blog post, it's homocysteine, C-reactive protein, and Lp-PLA2. And the first two are because inflammation matters, and the third one is because everyone's afraid that cholesterol is going to damage their arteries. And if there is damage to arteries, the third one goes up. And if you just have those three numbers, magically you're going to know if you have inflammation. If you have inflammation, it's your job to figure out what it is and what to do about it. Now here's a question for you. Who, uh, or not who, what would be the best single anti-inflammatory compound you've come across that might make people feel better?

That's a tough one. And I think that's the, um, right now that's the holy grail in medicine. We recognize that inflammation is driving these diseases. But yet, strangely enough, we do not have any drug at this point that blocks inflammation in a way that doesn't leave one pretty vulnerable to infection. So the drugs that are used for people with autoimmune and inflammatory disorders, those are great drugs. And we actually are giving those drugs to patients with depression right now. And these are drugs that block certain inflammatory cytokines. They're very potent anti-inflammatory agents. And if you have a bad inflammatory disease, that's great because you'll feel much better. But if you're someone who has middling and semi-high levels of inflammation without a frank inflammatory disease, then the risks of having a serious infection are greater than the benefits that you would receive from blocking inflammation. So right now there is not a drug. We recommend a couple of things that we do. We recommend obviously the lifestyle factors that contribute to inflammation. You've alluded to some, some of which you've struggled with yourself. Obesity, obese, hands down, obesity is the biggest offender. Fat cells grow at a very rapid rate. And when they grow, they outstrip their oxygen supply, their blood supply, and they die. And anytime there's tissue damage or destruction, it's a wound as far as the immune system is concerned. It's not quibbling, is this good, bad, whatever? And the immune system, the cells enter fat tissue, they release a ton of cytokine. And if you go into fat tissue and you biopsy it, you'll see a ton of these inflammatory cells. The macrophages will be there and they'll be activated. So obesity is clearly the number one offender. Then you start looking at stress as being a major offender, especially early trauma. Early childhood stress appears really have lingering influences on how the immune system is regulated and biases towards inflammation.

Even how you're born.

Yeah, absolutely.

And that was my first book. Yeah, but it was a fertility book.

And the more we learn about it, there's a lot of in utero stuff that's going on as well. So some of this you may not have a whole lot of control over, although there are We are learning a lot about the changes that occur to your genome, the epigenetic changes. I don't know that that's come up. And those are changes where the environment influences how the genes work. So even if you have a certain genetic predisposition, uh, the, uh, the environment can influence how those genes are expressed. And we've learned about that. So I think there'll be some treatments along those lines, but stress can cause chronic inflammation. And then we talked about the, the gut and the dysbiosis. Infections can obviously cause inflammation. And of course, there are a ton of things we do to people in my world, in medicine, where we do surgery and we do radiation, chemotherapy, the kinds of treatments that people get for cancer and whatnot. In terms of medications, um, this is an area that I'm actively working on right now, but I'm not targeting inflammation. I'm going downstream of inflammation and targeting the molecules that inflammation is screwing up in your brain. And one of the molecules that seems to be a number one target is dopamine. So think about dopamine. Dopamine is your get up and— if you don't have dopamine, you might as well cash it in. I mean, that's Parkinson's. You have no dopamine, you can't move, you're— of course, Parkinson's disease, very high rates of depression, lack of motivation, no dopamine. That's pretty much it. That's, you know, and so what we do is, and this is how I treat my own patients, is that if they have increased inflammation, we we will work with medications that are targeting dopamine as their main mechanism of action. So that would be— there are certain antidepressants, bupropion being one of them, stimulants, other drugs that directly activate dopamine receptors, pramipexole being one of those. We're even giving some of the Parkinson drugs to patients with increased inflammation and this kind of, uh, loss of motivation, anhedonia we call it, and depression, fatigue, and so on and so forth.

You're sensitizing their dopamine receptors basically, where they'll be more responsive to smaller stimuli.

Yes.

That's mind-blowing. Uh, what about nicotine? Oral nicotine, nicotine patches for Alzheimer's?

Yes, it's— there's not a lot of work in terms of the impact of inflammation on nicotine, other than to say that nicotine binds to nicotinic receptors in immune cells and actually shuts off inflammation. So how that all works, and I mean, Obviously, acetylcholine has other effects that are probably more dramatic in the brain that you're talking about, but in terms of the effects of inflammation on the brain and the neurotransmitter systems there, there's not been a lot of work on what's happening with acetylcholine.

What, what about the other natural compounds, things like fish oil, things like turmeric, turmeric, and like full disclosure, I make a fish egg oil thing. My turmeric formula includes some of the Chinese herbs that I use for inflammation, not all of them, but some of them. And there's like this long list, way longer, green tea extracts, resveratrol, you know, that David Sinclair has been studying. And I mean, the list is hundreds of compounds that you can buy at the vitamin store. Is there any efficacy, any research, just your general thoughts on that path?

I think there's a lot of interest at this point, and there are studies underway that the, the National Institute of Health is, is very interested in determining which of these compounds actually have biologic activity, and much of the interest is related related to inflammation. Um, the data is, um, not entirely clear yet because there are multiple issues around dosing. There are multiple issues around the quality of the compound.

Oh yeah.

And in order for us to study, uh, these, um, various, uh, food supplements, if you will, They— you— this all has to be run through the FDA. So in order to do these kinds of studies, you have to get a supplier who's willing to give all of the details from the actual growing of an herb, for example, and what contaminants might be introduced in the process of growing them. It's really quite, quite detailed, and there are no there are not many suppliers who are willing to give you that information or even have that information. So that really blocks us as a, as a, as a society from getting access to good quality supplements that may in fact have major impacts on, impact on our health. And so that, that's kind of just one of those things that we don't have a lot of control over, and so you're kind of a catch-as-catch-can when you go to the vitamin store or the health food store and you buy this and that and the other thing. We just don't know. The fish oil, there is better data with fish oil. There are some studies that suggest that it has anti-inflammatory effects and potentially anti-depressant suppressant effects. That's an active area of investigation, but they're using, again, highly purified, you know, really high-quality stuff.

And it has to be— it has to be standardized. Yeah, absolutely. It's the same thing people say, oh, I, my— I hear this from functional medicine doctors a lot. I told my patients to take this specific brand of whichever this was, and then they went to some store and they bought the $6 version, and then they came in with pimples and no positive effects, and they told me they were doing what I said. And unfortunately, having dug in on the supply chains and stuff like that, a good indicator of the quality of your supplement is the cost, because it costs more to make the good stuff. However, unethical companies can also raise their price to make it look good, and you're like, ah, How do you crack that code? I found it frustrating as well, so I'm with you. There are some studies of single ingredients, but quite often they're out of India or somewhere, but we do our best. I feel like the worst that's going to happen for most of these natural food-based things— look, if you try taking broccoli extract or turmeric or whatever the thing is and you feel way better and your joints don't hurt and you sleep better or whatever, that happens. Good for you, keep doing that. And if nothing happens, maybe don't do that. And it just, it seems like the risk is relatively low, so it might be worth experimenting. But, um, I know if I hadn't experimented, I wouldn't be where I am today. But also I'm a corner case because I had all the bad stuff.

And, and, and one thing that, that you should be aware of, and you may be aware of, and I don't know what your thoughts are on this, but there are efforts, and we got into this with the, uh, with the curcumin molecule where you can actually— the chemist will take the curcumin and make it more bioavailable, more potent. And so you're taking the natural compounds and creating drugs that are, for all intents and purposes, the same thing but are now being produced. You're using chemistry to make the natural world even better. So I know that wanders out into a little bit of maybe dangerous territory, but no, it's not dangerous at all.

I mean, Delivery systems of supplements are important. Like, we make a liposomal glutathione because liposomes are little balls of fat that can carry drugs past— or drugs or natural compounds— past the lining of the gut. And the, the curcumin formula, we use a standardized extract called BCM-95 with clinical studies that shows it goes up. But we pair it with Brain Octane oil, which is the caprylic acid-based C8 MCT that's part of Bulletproof Coffee because we know that that oil also affects how things are absorbed. And we add some other compounds more from the Chinese herb side of things. And end of the day, the effectiveness of the delivery system, we know that it matters. And I have studies on the BCM-95, but the other things I'm doing, I believe they're going to work. So I only talk about the effectiveness I can prove. But I'm doing other stuff in there and things that are known to be safe and I believe likely to be effective. But it's, it's, it's not—

you're doing your own chemistry at this point.

But yeah, yeah, you have to. But your work talks about— and by the way, thanks for going there on the fish oil and all that stuff. I know for MDs sometimes I I can be, you know, like if I say good or bad things, it's almost like you talked about a vaccine or something like, you know, it can be polarizing and I'm not trying to be polarizing there. Um, you, it's not just dopamine though. It's also glutamate and glutamate is a very interesting compound in the brain because it's tied to migraines. If you have excess glutamate, uh, you can definitely get problems there. But there are also some issues around autism. It's not— it's issues with aging, but it's also necessary. And people who are depressed and feel like crap, you give them glutamine, which is an amino acid, magically their gut lining heals and their brain also can turn on in about 10 minutes. They get less depressed, at least in my experience, not being qualified to diagnose depression. So talk to me about glutamate, glutamine, inflammation, and depression?

Okay, so this is the second sort of downstream target of inflammation that we've had a lot of interest in. And we saw this very early on with those patients who were getting the inflammatory cytokine interferon alpha for treating medical illnesses. And we saw that glutamate was going up in the brain. This fit very well with the larger basic science data that shows that if you treat cells, typically astrocytes, which are the molecules that contain, kind of control the levels of glutamate in the synapse, that inflammatory cytokines disrupt the ability of astrocytes to control glutamate. Glutamate is extremely important. It is the major excitatory neurotransmitter in the brain and critical to brain function. The problem is, is that glutamate, even in just minor increases, is toxic. It's excitotoxic. So whenever you have something that's excitatory, the the bleeding into being excitotoxic is something that can occur at very low concentrations. And so it's—

Does that mean MSG is bad for us?

I'm not sure about that, but clearly too much glutamate is. And so when there is excessive glutamate, it can spill out of the synapse And that leads to chaotic signaling in the brain. It leads to the death of cells, and it leads to premature or accelerated aging in the brain. So it's killing the sort of the white matter tracks in your brain, and the white matter tracks in your brain are the highways along which your the signals go from one series of neurons to the next. So if you destroy the highways, everything slows down, and then you're starting to talk about degenerative disorders associated with, like, Alzheimer's and dementia and those types of things. So the effects of inflammation on glutamate seem to be much more of a destructive nature than the effects on dopamine, which seem much more functional in nature. There are functional consequences, as I said, with too much glutamate because it does cause this chaotic signaling in the brain. And when there's a loss of coherence in signaling in the brain, it kind of screws everything up. And so that, that's when you start to invoke diseases where there's really broken brains, like autism and schizophrenia and these kinds of disorders. We have started to test treatments that target glutamate to treat potentially depression, to treat some of the consequences of chemotherapy like a chemo brain, which we think is an inflammation-related phenomenon. And of course, they're already using drugs that block glutamate to treat dementia unrelated to inflammation, although we think they'd be most effective in individuals who had high inflammation. So there's a whole evolving glutamate story.

Is there anything someone listening who maybe is dealing with inflammation or maybe even knows that they're sensitive to higher levels of glutamate? That they might want to consider? Lifestyle, pharmaceutical, uh, not that you're going to prescribe over the air, that's not what I'm talking about, but just like areas of focus.

I, you know, I think that at this point, um, it— from the data that we have, it's a little premature to go targeting, uh, glutamate as we were talking about with dopamine. I think the best thing to do at this point is to try to get the inflammation down. And so that would include exercise and some of the sort of yoga, meditation, all of these types of strategies increase parasympathetic tone, and the parasympathetic nervous system has been shown to reduce inflammation. So much so that there's actually a treatment, which I think is really cool, where they stimulate the parasympathetic nervous system nerve outflow pathways, and it will treat arthritis and throughout the body. Yes, it's, it's the vagus nerve. Uh, yeah, and it's an electroceutical. It's— they call it electroceuticals. Very cool. And they're stimulating—

got a couple.

Yeah, they're stimulating the vagus, and it's FDA approved. They've done the clinical trials, the FDA said good enough, and you could get your rheumatoid arthritis, uh, treated with stimulating your vagus nerve, and it's stimulating it going down from, from the, from the brain down.

Stephen Porges, the, the father of polyvagal theory, has been on the show, and we talked about just how profoundly important that is for inflammation. Uh, and I mean, I've done weird stuff. I've also put, uh, 5%, uh, xylocaine or lidocaine on the vagus nerve in the the bottom of the left ear canal to lower inflammation. At least for me, it seems to work in a way that you wouldn't expect, but you could see as an MD, why it might make sense. I'm not injecting it. It's just like an ointment or actually a water-based liquid works best. So we talked about glutamate. We talked about dopamine and we haven't talked about the big gun anti-inflammatories that we all know about— ibuprofen, naproxen, aspirin. I mean, if I'm feeling depressed and a little bloated, should I just pop some of these things and not worry about a little bleeding in my gut?

Well, that, that's, I think, the, uh, a, a question that we haven't quite resolved yet. There is a paper that just came out with patients with bipolar disorder and depression, and they use celecoxib, which is a COX-2 inhibitor, which is along the lines of these, these anti-inflammatory drugs. And, and they found a significant benefit of the addition of this celecoxib to, to, to the treatment, to standard antidepressant treatment. The problem is, is that we— what we understand about inflammation and psychiatric disease is that the psychiatric diseases that we study, let's take depression for example, not every depressed patient has increased inflammation. It really only occurs in about 30% of depressed individuals. So this only applies to about 30%. The trials that have been done using drugs like you know, Motrin or ibuprofen or these kinds of aspirin, whatever. All these trials have treated everybody, and they don't split people out. They don't split people out with a— you would, you would think they'd do this study the right way, but they have not. And I've unfortunately, or unfortunately, have been a sort of a very outspoken advocate for doing the trials the right way so that we can actually get the kind of information that would help people make a decision. Should I take an aspirin along with my antidepressant if I'm inflamed, or, or a Motrin, or any of these other drugs? But none of the trials that have been done have split out the patients into those with high and low inflammation.

Not only that, when I hear 30%, there's two groups that have high inflammation that both are 30%. One are the people with methylation inflammation pathway disorders in MTHFR, and people listening to this have probably seen me writing about that and whatever else. That's a third of us. So they're going to have inflammation. And the other third is HLA-DR4, the people who have the things I talked about earlier that make you more susceptible to Lyme disease, mold toxins, and probably metals as well. And if you have both of those things, you're probably depressed and you're probably inflamed. But we can test for those to look for it, and you can also just test for the presence of cytokines. Which is what, it's a $50 or less test to see how inflamed someone is? Or would you just use CRP?

CRP would be, yeah.

And that's like a $10 test. Okay. Now there's other big limitations to the body of research that you and I both rely on. Most of it's done on white males because going back through 1950, there's a preponderance of young white males walking around universities and you can use them as guinea pigs for free. I mean, this is just how it's been. And now education is much more, uh, as much more even that we have a mix of men and women, and we still don't have like a mix of, at least in most schools, that matches the genetics of the planet. So, you know, Southeast Asians or Africans or, uh, you know, indigenous people might not be well represented. Do your results work the same, or your findings, do they apply apply to women and men in different races and different ages?

Yeah, uh, yes. So most of— in depression, there's an overrepresentation of women. So most of the patients that, you know, 65% of the patients in our studies are women. And we do see that the women are showing similar responses, uh, as men. And in fact, there's some data to suggest that women may be more sensitive to the effects of inflammation than men. That's something that we're very interested in and going after.

It's obvious. It's called love handles. I'm not even joking. That is one of the easiest ways to know if you're inflamed. Do you have love handles today that weren't there yesterday? And do women get love handles more easily than men? They actually do. And as someone who's a professional at growing my own love handles, I know this. So like, yes.

And, and, and the other question, the other issue is the, the, the ethnic and racial mix of our samples. We're in, we're in Atlanta, Georgia, so we're a city that has almost 50/50, uh, Black and white. And so we have a very nice representation of both African Americans and, and Caucasians in our samples. And we do see similar, uh, similar results.

So it isn't a difference.

We haven't seen that, you know, the thing that was interesting is that You see these very high rates of depression in women, and so people say, well, maybe there's a biological piece to this. When we did our early interferon studies, we found that women seem to be as sensitive. So our data is not consistent with some of the other data, but we had a fairly large sample, over 100 patients, and receiving this interferon alpha. And the women developed depression the same as the men. There was no difference. So we at the time were writing, and so we'll see how this all falls out, but we at the time were writing that, that inflammation was an equal opportunity phenomenon, that it really was affecting both sexes similarly.

I don't think that inflammation is equal opportunity from a from a racial perspective. I mean, we see more diabetes, which is an inflammatory disease, um, amongst African Americans than we do from Caucasians. And it might be economic because of food quality, but I think there's also something to do with sun exposure, vitamin D levels, because higher melanin in your skin means you need more vitamin D. And none of us gets enough vitamin D right now because we're all indoors all the time, which could be a part of it. And like, we'll tease that out. I don't know if, if you have any more data on that, but inflammation affects all of us. I don't know that it affects every— yeah, when you sort out the economic stuff, who knows?

When you start to sort out the economic stuff, it— things do change. There are some differences though, and it has to do with stress. So there, there are— we— some of our studies are done on in the inner city hospitals in Atlanta, which are are probably 75% to 80% African American. And in these populations, you see extremely high rates of early life trauma and then chronic stress as well. And the PTSD levels in these populations are higher than the PTSD levels that military personnel coming back from Iraq and Afghanistan. There also is all the, the racial bias that is in our society that everybody just kind of— and that's chronically there, that would not be there for someone who was white. So there is a kind of a low-level discrimination that causes stress, and you can measure this, and we have, and it is related in part to some of the physiologic changes that we see.

Well, the idea here is to build the environment around us so that it supports our biology. Which means that we don't have unnatural stressors. And so we all have access to the things that are actually food instead of things that look like food and you can't eat and things like that. It's gonna take some big work, but it's cool 'cause it's gonna take a little bit of time. And if we can all live for a couple hundred years, we'll have time to do it. I'm very fascinated, if you can't tell, by your research and directly and scientifically in detail tying together what's going on inside, you know, inside of our inflammatory pathways, inside of our cells and the way we show up in the world. I have intuited and figured this out in my own life and I've shared the things that have been best practices for me and it is actually relaxing invigorating to read through your research. You go, I always thought that was the case and I could show people how to do it, but you've told us the why for a lot of this in a way that, as far as I can see, no one else has ever done. And I think it's truly groundbreaking and very meaningful for what it, what it means to be a human being. So I'm, I'm grateful that you've done that. Um, and I have one final question for you. Uh, I mentioned my book on longevity and I've been very public I'm planning to live to at least 180. And because I know I've seen someone do 120, uh, so I'll take that. And I'm counting on guys like you and many of the other people I've interviewed, and some of whom I've become friends with, they're going to do 50% better over the next 100 years than we could do today. So that's why my number is 180. What's your number? How long can you live?

Well, I don't know about myself. My genetics are pretty good. My mother's almost 100, so and there's all— we have a strong family history of longevity. I think that there are some intriguing studies targeting the inflammation, inflammaging, that we were talking about before. And metformin is the one that is the— there's a metformin trial that's going on right now to see if they can extend lifespan in humans. It's already been shown in just about every other species that's been looked at. And they've even done this in worms where you give the worms metformin and then they live, you know, long periods of time.

And so the company that did the, the worm and the mouse study was called Biomarker Pharmaceuticals back in the early 2000s. I started taking metformin based on those studies.

So maybe you will live to 180. You'll be ahead of the curve.

I quit for other reasons. So I'm really curious what the latest study says. I, I'm going back and forth. It's a hot topic.

It is. And whether metformin is the, the right one, but metformin targets the metabolism that drives the inflammation. So as you get older, your metabolism changes and that change in metabolism becomes pro-inflammatory in nature. And if you can block those metabolic pathways that drive the inflammation, then you block the inflammaging. And so that's where I think people are sort of going in terms of the, you know, how can you live to 180? That's where they're going. And so I think if this trial that they're doing now, which they actually had to crowdfund— they could, they could not get any of the governmental agencies to fund it, so I think they crowdsourced it. Uh, I know they crowdsourced it, and And the study has started. Be a good one to get into.

Are you taking metformin?

Uh, not yet. We've, my wife and I have discussed it, but we have not, we have not gone that, that route yet.

Just don't, don't take it when you exercise because it undoes the benefits of exercise. Oh, I see. Okay. The, the current thinking from a group of top anti-aging people I talked to and just my own interpretation, probably 2 or 3 times a week it might be worth it, but every day I think the, the risks outweigh the benefits. Not taking it all, maybe you miss out on something, but the, the daily thing I was doing before does suppress mitochondrial function in a way that maybe isn't good. But we, we will, and we'll tease this.

And you can, you can have metabolic, you know, disruptions that'll land you in the emergency room as well. So there's that, that, that, there's that little problem if you don't have diabetes. Obviously have diabetes, that's a different story. And I'm not recommending metformin for anyone to take. Be careful about that one.

Speaking of not having diabetes, I'm waving my continuous glucose monitor results at you. I don't have diabetes. I just, I've tracked my blood sugar, but it's 5.1 and just, it kind of hangs out there at 5.1. You multiply times 18 to get the US number, but it's around 90.

Oh, that's great.

That's where you want to keep it. So I feel like we are going to get there and the diabetes, high blood sugar, inflammation connection, which you have now said, "Oh, there's your anxiety, there's your depression," and maybe not full-blown clinical diagnostic, but moving in that direction. Absolutely. Thanks for your work. I'm fascinated by it and I plan to continue following it. For people who are are just turned on and excited by this, there is a URL you can go to. It's behavioralimmunology.com. You can tell that's set up for high-end traffic conversion and marketing. Behavioralimmunology.com. It's at Emory University where a lot of this information is and where you're teaching. I got to tell you, if you're you're looking for what you want to study, uh, and you know, you're in high school, you're in university looking for your PhD or something like that, you should look at this kind of stuff. Interpersonal neurobiology and behavioral immunology are areas of decades' worth of fascinating work. Like, we're nowhere near done here, and these are going to rewrite what we know about ourselves. So fascinating work.

Thank you.

Thank you very much for having me.

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