The Root Causes of Inflammation & What You Can Do To Stop It

Coming up on this episode of the Doctor's Pharmacy.

So anything that's sugar and starch drives inflammation, particularly high fructose corn syrup. So the average American eats 152 pounds of sugar and 133 pounds of flour every year.

That's enough to kill most of us pretty quickly.

And it does.

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Hey everyone, it's Dr. Mark here.

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A summary of my favorite and tested products. hi, I'm Dr. Mark Hyman, a practicing.

Physician and proponent of systems medicine, a.

Framework to help you understand the why or the root cause of your symptoms. Welcome to the doctor's pharmacy. Every week I bring on interesting guests to discuss the latest topics in the field of functional medicine and do a deep dive on how these topics pertain to your health. In today's episode, I have some interesting discussions with other experts in the field. So let's just jump right in. What are the causes and drivers of inflammation? Well, basically number one, two and three is diet. And guess what? The number one, two and three in diet thing is sugar, sugar, sugar or the equivalent of sugar, starch, starch, starch. So anything that's sugar and starch drives inflammation, particularly high fructose corn syrup. So that should not be a staple in your diet. Unfortunately, it is. It's about 60% of our calories in America. Soda is the number one source of calories in America, which is terrifying to me. And the average American eats 152 pounds of sugar and 133 pounds of flour every year. That's enough to kill most of us pretty quickly, and it does, which is why we see we're the sickest population in the world and so many people die from diet-related diseases. So it's in sugar, it's in high fructose corn syrup, it's in processed flours and foods. Also, inflammatory fats may be a factor. So lots of refined oils, non-omega-3s, trans fat, which have been ruled not safe to eat by the government, but they're still everywhere in food. I don't know how that works to be honest with you. I guess there's little loopholes that the food industry gets to give them maybe years or decades, but this was 2005, seven years ago. They said, Hey guys, trans fat kills you, not safe to eat, don't use it. But if you go to the grocery store, you can find it everywhere, which is terrifying. I mean, more and more companies are removing it, but it's still there. Also, what else can cause low grade inflammation? Sitting on your butt. Not exercising, exercise is a powerful anti-inflammatory. Not over exercising, not running a marathon, but doing a moderate amount of exercise every day really helps to lower inflammation. Stress, another big cause of inflammation. So, nothing we knew about stress, it's out there, bad things happen, reading the news, I try to stay away from the news, by the way, it's so stressful. Like I figured if something really bad is happening, I'll hear about it. But the key is to find habits and behaviors that reduce your stress response, meditation, yoga, you know, hot and cold therapies, massage, breath work, whatever works for you, try it. But it's got to be a daily practice. I do it every day. Today I worked out, I did a sauna and an ice bath, and that really helped me calm my nervous system. I also deal with toxins. Toxins are also inflammatory. They're called immunotoxins, low levels, pesticides, chemicals, petrochemicals, heavy metals. I encourage you to go to the Environmental Working Group's website, EWG, and find out how to reduce your exposure to food, including fruits and vegetables, animal products, fish, household cleaning products, and even skincare products. I mean, did you know that lead is in a lot of lipsticks? That a lot of skincare products have petrochemicals that get absorbed through your skin and get in your body and cause harm? Yeah, don't be doing that. So also, another source sometimes is latent infections. We might not know we have it, like a virus or tick infection or mold were exposed to. So those all can drive inflammation. And of course, our microbiome is probably one of the biggest sources of inflammation in us. We all have an imbalanced microbiome, mostly from our poor diet, lack of fiber, processed food. So we want to cultivate our inner garden. I've written a lot about this. We created a new product called Gut Food that helps people actually heal their gut and it's like a multivitamin for the gut. So I encourage you to check it out, www.gutfood.com so really tending your inner garden is so important because There's actually a phenomena called metabolic endotoxemia. This is a phenomena that is resulting from bad bugs that produce these toxic compounds called endotoxins that get absorbed through your gut lining into your bloodstream and then activate your immune system. Like, for example, these lipopolysaccharides, which are these little endotoxins. And then your immune system gets activated, triggers inflammation, and there's all the downstream causes consequences of that. For example, high levels of TNF-alpha, one of the inflammatory molecules, it triggers insulin resistance. So literally not even by changing your diet, you can become pre-diabetic just by the toxic bacteria in your gut. That's why they call it metabolic endotoxemia. So what is inflammation? What's the big deal? Why does it become so dangerous? Well, inflammation is a natural part of your body's function. It's essential. Yes, you cut yourself. What happens? The white blood cells gather. They come to the side to rescue. They create swelling. They bring all kinds of healing factors. And what you see is redness and swelling and pain and heat. That is the classic sign of inflammation in the body. We used to call that medical score. Rubor, dolor, calor, and tumor. Tumor just means swelling, not tumor, you know. it's anyway Latin, whatever. But the key is that it's this normal process that happens as a result of dealing with problems that go wrong. But here's the rub. In the past, most of what we had to deal with was acute things that caused inflammation like a cut or an infection. But today our modern lifestyle is driving so much hidden inflammation, systemic chronic inflammation, silent inflammation. It's a silent killer and it turns out that it's not the kind of inflammation that we are familiar with, like a sprained ankle or a sore throat or something that's an obvious kind of inflammation, the kind that's good. The kind that we're talking about is the kind that's bad and that leads to almost every known disease of aging, heart disease, cancer, diabetes, Alzheimer's, not to mention things like ADD, depression, obviously autoimmune disease, obviously allergies, asthma, all sorts of gut issues. All these problems are caused by inflammation. Of course, then the question is, what causes inflammation? We're going to get to that. From a functional medicine perspective, I don't care that you're inflamed. I care about why you're inflamed. I don't want to give you an immune suppressant, an anti-inflammatory drug, a pile of aspirin. I want to find out what the cause is and get rid of it. In functional medicine, there's a simple rule and it's this, it's called the TAC rule. If you're standing on a TAC, it takes a lot of aspirin to make it feel better. Take out the TAC. And if you're standing on two TACs, taking one out doesn't make you 50% better, so get rid of both of them. Okay? And all of them, maybe there's five or 10 TACs, and that's the secret of functional medicine. It's a method of investigating the body as a system looking for root causes and getting the body back in balance. All right, so what is the deal with this inflammation? I mean, I think, you know, when I was in medical school, heart disease was a plumbing problem, you know, it was clogged arteries. We now know that it's an inflammation problem, that the reason your cholesterol becomes an issue is 'cause it gets inflamed and white blood cells sop up the cholesterol and stick it in the arteries causing plaque. Same thing happens in the brain. Alzheimer's is inflammation in the brain, all those plaques in the brain, come from inflammation. So cancer also is a disease of inflammation. And when you, for example, look at various studies, even with cholesterol, if your inflammation level is high but your cholesterol is also high, you're at high risk. But if your cholesterol is normal and your inflammation is normal, you're no risk. But if your cholesterol is high and your inflammation is not high, you're really not at great risk. And the worst is if you have obviously both. So inflammation is a real big issue. They did a study of an elderly population. They found that if their CRP was high, which is a blood test for inflammation, and interleukin 6 and other cytokine test for inflammation, they had a 260 more likely chance of dying in the next four years. So this is no joke. So you might feel fine. The patient, I don't know what's wrong.

I feel fine.

I saw my blood test says, I don't really care. I feel fine. Why should I change what I'm doing? I'm like, well, if you don't change what you're doing, it might not go well for you. Now, there's no guarantees that's true, but it's likely true. So, the real concern isn't our response to an injury or an acute infection or something like that, but this chronic smoldering inflammation that slowly destroys our organs and our ability to function and leads to rapid aging. In fact, I just finished my book on aging called Young Forever, and they talk about the hallmarks of aging. One of the key hallmarks is inflammation, or they call it aging itself, inflammaging. And what happens with aging is there's runaway inflammation that just degrades your whole body. So understanding what inflammation is, how to diagnose it, and how to deal with it and get rid of it is so essential if you want to be healthy. Now, what's the problem with the treatments we use? Why not just take Advil or aspirin or take a steroid like prednisone? Well, they're fine for acute problems, but when things are in this slow smoldering state, they really don't work. In fact, the new data on aspirin was pretty scary about heart disease. Oh, it's gonna help you and stabilize your blood, blah, blah, blah, and prevent clotting. But it turns out that the recommendations for aspirin were overenthusiastic and that there are certain patients who should be on aspirin, but very few compared to the, you know, universal statement that everybody should take an aspirin to prevent heart disease. No, because it causes strokes and it causes bleeding, which is not good, like GI bleeding. So, you know, if you look at those drugs like aspirin or Advil or Aleve, they're not benign. I mean, they really helpful when you need them, but they can cause terrible gut issues. I had gastritis, for example, after taking them for a broken arm. And many, many people die. In fact, as many people die from taking those drugs as from asthma or leukemia. So imagine if we literally eliminated those drugs, we'd basically be essential. it'd be the equivalent of curing leukemia or asthma. So it's not a joke. So statins, for example, even cholesterol drugs like statins like Lipitor, they may not have their main effect by lowering cholesterol. In fact, it may be because they actually lower inflammation. That's what they do. It's a side effect of the statin, but actually may be their main effect. How do you know if you have inflammation? Is there a way to test for it? Is there a blood test? Well, there are and there are more and more coming. So the most common one that people do is called C-reactive protein. It's high sensitivity C-reactive protein. It's something your doctor can order. It's on any lab panel you can get. And you can also see that as a sign of hidden inflammation. Now, if it's super high, it could be infection. But if it's in the sort of 1 to 10 range, that's usually the hidden inflammation. Ideally, it should be less than one. any higher than that means you're on your way. Now, there are other blood tests you can check cytokines, sed rate and so forth may not be as helpful, but there's a new test developed by a professor at Stanford called I-Ag, I-A-G-E, meaning immune age. And it really looks at your immune, which are 50 different cytokines, many of which you've never heard of. They're molecules that are regulating immunity inflammation that he was able to correlate by using artificial intelligence with disease. So he found there really there were about four that highly correlated with your risk of heart attack, cancer, diabetes, Alzheimer's and so forth. What's so amazing is this test is really not that expensive, it's easy to get and you can track it over time and then the good news is you can change things and change your inflammation. Anyway, enough with that. So, you know, the reason we really don't track this is because doctors just kind of are not thinking about the root causes of disease. They're like, okay, what's your symptom? What are you suffering from? Okay, let me find the drug that best matches that. If you have a strep throat and I can give you penicillin, great, I'll get a cure. But most of the time I'm just managing symptoms or I'm giving you an immune suppressant and that's not the answer, unfortunately. So let's say you've identified the causes, you figured out you have inflammation, how do you live an anti-inflammatory lifestyle? it's the same old stuff. I hate to say it, but it's eat real food, lots of phytochemicals, all those colorful plant compounds are anti-inflammatory all the, the phytochemicals in food are so powerful for reducing inflammation. Also, you know, just real, whole, unrefined, unprocessed foods, not lots of sugar and starch, not, no trans fats, no, no refined oils, and get lots of those phytonutrients. Good fats are really important, too. Avocados. olive oil, extra virgin olive oil ideally, omega-3 fats, things like sardines, herring, sable, wild salmon, they're all really rich in omega-3 fats and they're very healthy for you. Exercise, lots of research on exercise can reduce inflammation, it supports your immune system, it strengthens your heart, it corrects insulin resistance and improves your mood, it helps reduce stress. I mean, it's one of those miracle therapies that can really do so much for you at so many levels. Practice active relaxation, which sounds like a contradiction or an oxymoron, but no, you have to actively relax. It's not, I don't mean sitting watching TV drinking a beer. I mean meditating, doing yoga, deep breathing, getting a massage, doing something where your body just kind of hits down into the parasympathetic state and calms your nervous system. Hot bath, I love that. Last night I was a little, had a very busy day. lots going on and I just took a hot bath with Epsom salt and I just kind of floated away. It was great. Also, food sensitivities are another big factor. You might not know this, but a lot of hidden inflammation can come from not allergies, but food sensitivities, things like gluten, dairy, and certain things that people react to that they may not know they react to. So, I often recommend an elimination diet, like the 10-day detox diet that I've created to help people reduce their overall level of inflammation and then you can add back foods to see what's really the problem. So maybe eliminate a lot of things and then you just add back one at a time. And for example, dairy I know causes inflammation. If I have dairy, I get pimples, my skin's weird, I get congestion, so I don't eat dairy. Although I do manage to tolerate goat and sheep, okay. Healing your gut, you know, doing a gut repair program, that's why we've created gut food, that's so important. And I think many people would benefit from actually a focused gut repair program because a lot of their imbalanced bacteria are causing inflammation. And lastly, take it takes the right supplements, a multivitamin, fish oil, vitamin D all help. Are you tired of sleeping hotter than you'd like?

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How exactly do you know that you're inflamed? And I think there are a lot of things that are coming up these days. For example, in cardiology clinics, Doctors might test you for something called C-reactive protein, high sensitivity C-reactive protein. And that's a marker of inflammation in the body. It's made in the liver in response to areas of inflammation. And there are a variety of other markers as well, but some of the problems with these tests is that they may not be that specific. So, if you have elevated C-reactive protein, you may have that elevation from the cold you have and you cannot be sure where it's coming from in your body, how long it's been there for. But, you know, there are new markers being developed. There are inflammatory signatures, for example. There was a Stanford study a couple of years ago on aging and an inflammatory signature comprised of several markers that can help to predict healthy aging. And, you know, there are so many different things that are in the works, I think, from tests like CAT scans and MRIs that can pick up inflammation around blood vessels, for example, and predict which plaques are most likely to rupture. So those are some of the things. And one of the proxies for being inflamed that we can all look at when we go to our primary care physician's office is just things like high blood sugar or diabetes. If you have prediabetes or diabetes, you are most likely to have some amount of inflammation in the body because high blood sugar does tend to create inflammation. And if you have that belly fat, for example, then you also know that you most likely have some level of inflammation in the body because we know that the belly fat is a marker for the fat that wraps around your internal abdominal organs.

Yeah, I mean, by the way, that fat is a source of a lot of inflammation. because it's not just, you know, the belly fat is not just holding up your pants. It's actually a very active immune hormonal organ that's spewing out all kinds of inflammatory signals if you get this excess belly fat. And I think most people don't realize that. If you have a big belly, you've got a smoldering fire inside of you. And, and that is really important to understand. And the reason we get the big belly is because of what we're eating. So, you know, let's talk about you know, you know, the, some of the things you were talking about, like, how do we know? Right. So we can do a CRP, but it's not very specific. It doesn't tell us why it, you know, there are other markers. We mentioned Stanford research. I think that was David Furman's work on the Thousand Immunomes Project, where he looked at cytokines or inflammatory markers in a thousand people from little kids to old people. And he found they were like things that we probably never heard about in medical school, these cytokines that we don't test for in a normal lab result, but that actually are probably more predictive and more correlated with various age-related diseases than other markers that we actually do measure, right? So we're kind of learning about how to test for this. And you mentioned high resolution scans, imaging tests. Now, for example, with Alzheimer's, we know that Alzheimer's is an inflammation in the brain. We can see through various MRI and high technology scans we can see inflammation in the brain. We can see, for example, in new AI driven heart scans, we can see inflamed plaque where rather than just looking at O and angiogram or, you know, even calcium score, which gives you a rough idea of the calcified plaque doesn't tell you how inflamed your plaque is. So we're getting more and more sophisticated. But, you know, are there, are there tests that we should all be doing to check for inflammation? And are there tests that help us figure out the why? Like, what is the why? behind why we're so inflamed?

I think that's certainly a tough question for sure. And I think it's also very specialty dependent. For example, in my own practice, I tend to see inflammation all throughout the intestinal tract. And so depending on what sorts of symptoms a patient comes in with, I may do endoscopic testing. I may do an upper endoscopy and a colonoscopy. And I may catch microscopic inflammation in the intestines as well through that way. And there are also stool tests that we do in our practice to measure inflammation. like lactoferrin, which is one of the stool tests. And these are very situation dependent. And again, if you go to your physician in general, you're unlikely to be told, hey, let's just check you for inflammation and then let's try to treat it. And we're not quite there yet, but I think we're getting there. And I think one of the interesting things, too, with testing is that, you know, perhaps we should be measuring inflammatory responses to challenges. rather than just like a baseline snapshot of inflammation. I think that's something that could be very interesting as well because we want to know that the immune system is doing its job when it should be and not overreacting as well. So I think there are a lot of great things that will come up in the future regarding testing and hopefully we'll see more and more specific markers and we'll see more trials in this space. But I think when we go to our physician's office, in the modern age, we have some proxies that can tell us if we're inflamed and we have specialty specific diagnostic tools that we can use as well. Interesting.

So you mentioned sort of a challenging the immune system.

Can you talk more about that?

Because we know, for example, if you want to check for diabetes, you do a glucose tolerance test where you give people a bunch of sugar and see what happens to their blood sugar. Or if you want to check someone's heart, you don't just check an EKG, you put them on a stress test or do a stress echo to stress their system. Tell us what you're talking about. I think this is a really interesting concept of how do we test our immune system's function? Are we overreacting or underreacting?

Yeah, I think it can be as simple as injecting a molecule like lipopolysaccharide and trying to figure out what the immune system's response is. Is the immune system one, responding appropriately? And two, is it overreacting? Are we having too much inflammation to a stressor? And I think that could tell us more than perhaps just a snapshot of the blood markers that we have currently. And this is something that I think maybe that we will see in the future.

Yeah. Now, we've all heard about the cytokine storm from COVID and cytokines are basically the messenger molecules of your immune system. And a lot of the, you know, work by David Furman, things we're measuring like CRP, KF Alpha, IL-6 cytokines, they're just, they're just the, the symptoms of inflammation. They're not the cause. They're the body's response to something that's irritating it. Right. So my, my question is, you know, is, is, you know, why always, why is the immune system pissed off in the first place? Right. It's easy to measure. Look at, you know, you can look at scans, you can look at a colonoscopy, you can look at CRP, you can look at all these other biomarkers, but it's not going to tell you the why. And so, you know, my joke always is that a functional medicine doctor is really an inflamologist. Like, I'm an inflamologist. I think I, I, like, made it my life's to understand inflammation, to understand what causes it, how to actually remove the causes, and how to get the body's own immune system to calm down and to reduce the inflammation naturally. So can you talk a little bit about, from your perspective, what do you see as the main drivers of this epidemic of inflammation and inflammaging, which we talk a lot about?

I think, first of all, that this idea that all of these disorders share a deep biological link from heart disease and cancer to some cases of depression and neurodegenerative disorders, that lengthening inflammation, it forces us to look at all of these things and really try to figure out what these root causes are. And it forces us also to look at patients and to treat patients not only from specialty perspectives, but also holistically in some ways as well. And a lot of what is causing this low-level chronic silent inflammation today is our environment, our dietary habits, our lifestyle. And we know that chronic inflammatory disorders. And when I talk about chronic inflammatory disorders, I'm talking, you know, not just about rheumatoid arthritis and inflammatory bowel disease, but all of these different modern diseases because these are inflammatory disorders. And so we know that our lifestyle factors play a very, very important part.

So talk more about, you know, specifically, what is it about our diet that's driving the inflammation? And then I want to get into potentially exploring other causes that may not be immediately obvious to people that are driving inflammation.

Sure.

Because your book is really Silent Fire talks about diet as a big driver of inflammation.

Exactly.

So what are we talking about here?

There are so many different factors and I think one of the biggest ones is the Western diet. And this type of diet is loaded with an excess amount of sugar, salt, inappropriate fats, processed foods, processed meats. refined carbohydrates. And the problem with this Western diet is that our immune system actually tends to respond to it as it would a germ. You know, your immune system tries and tries to kind of fix things in your body, and it realizing that keeps getting these hits, you know, maybe three times a day or six times a day, however many times a day you'll have a meal. And when we are eating this Western type of diet, we're also starving our gut microbes of their most beneficial nutrient, which is fiber. And fiber can manipulate all arms of the immune system, from the innate immune system to the adaptive immune system. And it's an incredibly powerful, powerful nutrient that we need to be eating more of. But 95% of Americans today do not meet the recommended daily allowances of fiber. 28 grams for females and 38, I think, for males. So we are really starving that microbiome. Then the microbes change their behaviors, causing inflammation. They'll inch closer to the mucosa. They will create more inflammatory molecules like lipopolysaccharide. Those molecules will go out into the bloodstream, causing body-wide inflammation. So it's changing, you know, who the microbes are, the species in your gut, and also what their behaviors are. So the Western diet, one of the biggest losses is also the fact that we are depriving our bodies and our guts and our gut microbes of their most essential nutrient. So diet is certainly a very big component of creating this low-grade inflammation. And I would also say that the.

Other main- Not just a lack of fiber though, right? It's probably other things in our diet.

Right. Plenty of other things. And, you know, the other thing too, I would say, is that we tend to think of foods as dampening or creating inflammation, but there's also a reversal going on. This whole process by which inflammation tends to die down in the body is not a passive process. It's an active process and immune cells like macrophages and neutrophils will secrete new mediators. And we need to feed that process. And so we need to eat healthy fats like omega-3s. And I think that's something that we don't do enough of. nearly enough of. So that potential to resolve inflammation in our bodies, we need to really be able to create those molecules. And that also comes from diet because the precursors of these lipid signaling molecules are actually omega-3s, which we find in a variety of foods.

Yeah.

I mean, these are called the eicosanoids, right?

This is what we learned in medical school. These pathways of regulating cytokines, inflammation, and they're highly regulated by the fats in our body, particularly the omega-3 fats. I want to loop back to what you earlier talked about because I think it's really important. I don't want to skip over it, which is the role of the microbiome. And as a gastroenterologist, I think this is your area, which is the microbiome plays a huge role in regulating our immune system. And most people don't know that 70% of our immune system or 60% of anything you're talking to is in our gut. And it's because it's the first place where we interact with the outside world, right? We put all this pounds of foreign stuff on our mouth every day and it goes down there and has to be sorted through. And then you've got all those bacteria and bugs and poop in there and it you know, you have to lay in the right stuff, but keep out all the bad stuff. And when we get a problem with the microbiome, we tend to get damage to the gut and more inflammation. So can you kind of walk us through that whole story of what we're doing to damage our microbiome besides just not eating fiber and what changes happen in our microbiome and how that starts to up ramp the inflammation cycle in our body?

Right.

So, so, so when you look at the microbiome, when you see, for example, a mouse who grows in a sterile bubble with no microbiome, no germs on that mouse whatsoever. You find that this mouse actually tends to develop all kinds of abnormalities, like a deformed heart and lungs and a shrunken brain. So microbes actually train our immune system. They help our immune systems to develop. Our microbes are having conversations with our immune cells at all hours of the day. And this is a process that begins even before we're born. and once we're born, of course, and all throughout life. So we need to be having those essential conversations. And how do we foster those conversations? And again, it comes down to lifestyle. What kinds of foods are we eating? I had mentioned fiber, but there's so many other foods that are great for the gut microbiome because we know also that a lot of the fats that we eat can make their way, some of them can make their way down into the colon. And we have that proportion of fats, for example, being metabolized. And we know that, you know, there are spices and herbs and all of these wonderful foods with polyphenols, which are amazing compounds for the gut microbiome, because again, some of those make their way down and are metabolized by the microbiome. So it's not just about the fiber, but all of these amazing nutrients that we find in foods. And what we know today, too, is that a dysbiotic microbiome or a microbiome that is an imbalance is very often an inflammatory one. So when you have microbial dysbiosis, when you're eating a poor diet and not exercising, you know, stressed out and not getting enough sleep or social connections, and you have a dysbiotic microbiome, we do know that you most likely have low-level chronic inflammation coursing through the body in those states. So our microbiome is incredibly important for the inflammation picture as a whole. And our immune system shapes the microbiome as well. We know that microbes do so much in the body, from digesting nutrients we cannot digest to changing gene expression to modulating the inflammatory response.

I've been studying social and exposome determinants of inflammation for about 15 years now, right? And the type of data that it's out there point very clearly to things that most of us know. However, there are certain aspects of the exposome that we do not know.

What's the exposome?

What's an exposome?

Yeah, yeah, yeah. So it's the totality of biological, chemical, and social exposures that a person suffers throughout the life course.

And what we know about that is that 95 of chronic disease is caused by the exposome, not the genome, meaning your genes are, are affected by the exposures that didn't change the genes function, which then lead to all these diseases. But it's not the genes that, that are the problem. It's the exposome. That's the major problem for most of us.

That's exactly right. I, I would like to get at that in a moment. We have the genome, everybody, you and I and everybody in this world, to be able to live 120, 130 years. at least, right? That is something we know. Now, the problem is in some countries, people are dying at the age of 70, 75, that's the average lifespan expectancy. Some countries is 89 or 90, like Monaco or Japan, because we figure out ways to extend that period of healthy living, right? So in essence, what we're trying to achieve is to push that 80 to 90 average life expectancy to 120. Now tweaking genes is a completely different thing. We're not going to talk about that at this podcast, but I'd like to go to idea of the exposome. Back to the root cause of inflammation. So we do know already today that pollutants in the air, that pollutants in water, pollution, that pollution, exactly, pollution are drivers of inflammation. Imbalances in nutrition, such as both the macro and micronutrients, right? These cause inflammation by large. Food additives go back to the microbiome. Things like carboxymethyl cellulose or polysorbate 80 that will wipe out your microbiome and will cause inflammation because the mucin layer in your lining of your gut will get very thin and then you're going to have translocation of different antigens to your periphery and you're going to develop an inflammatory reaction. Gluten, you know, gliadin, it's a- Wait.

I want to hold on. What you said was very important. You just said that basically when you eat these food additives, things that are in our food that we don't even pay attention to like polysorbate 80, it damages your gut lining. and then all the poop and bad, like in food particles that are partially digested leak across that and your immune system is right under the lining of your gut and then your immune system goes, Hey, what's this bad foreign stuff? And it starts creating this inflammation. So that's why it's bad. So food add-ins are just not bad 'cause they're, you know, if you're a hippie and you want to eat granola and like that, you shouldn't eat food add-ins.

They're really damaging to our bodies, right? Your microbiome. Yeah, exactly.

They're causing this concept of dysbiosis.

Right in your gut.

And then you were going gluten was the next thing you were going into.

Exactly. So, or plasticizers, plastics, things that are stored in plastics, in plasticizers or the plasticizers and plus the resin make a plastic and there's leeching, right? And there's a leeching of plasticizers that go into our foods. And those are hormone disruptors that also cause inflammation long term. I was going to go to gluten. Gluten, as you know, is highly inflammatory. Gliadin can bind to certain cells your gut and cause inflammation, increase in leaky gut, et cetera. The other one is sedentaryism, as you very well are aware. If we're sitting in a chair, we're developing an inflammatory reaction and that is a correlation between the time. The time sitting in a chair and mortality, there's almost a perfect correlation between those two. Sleep quality, there's disruption in our circadian rhythm, social stress, There's a very, very compelling evidence that individuals that are exposed chronically to social stress, social isolation, they develop inflammation, they have more cardiovascular disease, elevated rates of and death. And obviously other chemicals that we're exposed to that are surrounding us, just giving an example, formaldehyde, right? paraldehyde that serves as a glue for plywood that is often used in furniture and cabinetry.

So, those are important things. So, basically, it's environmental toxins, it's social stresses, it's inflammatory foods like sugar, it's food additives, and even other environmental toxins you didn't even mention like heavy metals, not just plastics. We're exposed to all this stuff. and that, and our gut microbiome becomes disturbed because of a lot of these things, and that even creates worse inflammation. So we're in this inflammatory environment, which historically we really didn't have throughout evolution. And, and the truth is we did a lot of things that naturally combated inflammation. So just as there's an inflammatory lifestyle, there's an anti-inflammatory lifestyle. Right. And, and so the beauty of your work, and I want to get into this in a minute, is that you've been able to map out the changes in the immune and for those who don't know what that is, it's basically the sort of immune, well, why don't you define the immune? You're the expert. I don't mind him probably screw it up.

I doubt you will. But so similar to the concept of exposome, the end and the word som accounts for the totality of it. So when we talk about the immune, we talk about all the cells, the proteins, and the genes that are in your immune system that are able to communicate between them, right? And so orchestrate an immune response. So we're talking about hundreds of thousands of different parameters that can be measured from blood, and that's what we did in 1000 Immunomes Project, which is a project that, as you mentioned, lasted for about now 15 years. we just got another source of funding from NIH, $15 million to continue the study for the next five years. And we've been monitoring these individuals, their immunome. And basically we focus in blood, so we take cells, genes, proteins in the blood. And as you mentioned before, the biomarkers that are currently existing for what we believe is inflammation such as CRP, hs-CRP, sedimentation rate, that you can go to and have those are very poor predictors of any type of condition, right? CRP, just to give an example, is predictive of cardiovascular events with a power of 0.6. The area under the curve when you're trying to predict cardiovascular events is almost close to random chance, right?

So in studying the immune system, it's not very sensitive. It's not very sensitive.

It's not very sensitive as a measure for systemic chronic inflammation exactly. And that's where this whole idea of discovering new biomarkers but looking at the immune system in an unbiased fashion comes into play. And that's what we did.

So.

What we are using is not only technology that help us measure all these things, but also computational analytical tools that are rather novel, including AIML, right, machine learning, to be able to cope with the data and to derive metrics that are simplified, that take us hundreds of thousands of parameters, now we have a metric that can be used in the clinic, right?

It's like finding a needle in the haystack, you know, and it's a way of doing that, which is very hard to do in medicine. right?

That's exactly right. That's exactly right. But the medicine and the clinical medicine also research is changing. So there's now a lot of different groups across the world. Here in the US, it's very popular to do transcriptomics, proteomics, and we're measuring 7,000 proteins in the blood, 3,500 metabolites, and it becomes becomes much more normal. He has normalized with time.

So, when you did the Thousand Immunomes Project, were you measuring how many analyzed? Because I remember reading the paper and there were like 50 cytokines that you looked at. But was there a lot of other stuff you also measured besides those 50? Right.

So, we measured the expression of genes and these are roughly 15,000 genes. that we measure from a drop of blood, basically. We also measure cells that are circulating in the body, and these are immunological cells, around 25 different cell types. And we also measure metabolites. And the 50 proteins that we measured across these different years, this is a panel that was expanded now. We're currently measuring 7,000 proteins from individuals. I'm making sense of that is the challenge here. And it's really a beautiful system that this company has started, I would say maybe 10 years ago or so, in which they can now analyze 7,000 proteins. There are other companies analyzing 35 or 4,000 proteins, and we're measuring all these things to see how those contribute to rates of aging.

So, so in a way, this is something that's never been possible before because you have this convergence of the framework of systems biology, understanding the body's a network where there's these Dynamic interactions of thousands and thousands and maybe trillions of chemical reactions every minute. And you can measure through Advanced Technologies, thousands and thousands of proteins, the expression of thousands of genes, the analytics that help you process that data, which is so hard with bioinformatics and, you know, computational tools like AI and machine learning, which really didn't exist before. And so, as a doctor, I'm so excited because it's always been really clear to me that we're missing stuff that we, you know, we, you know, we, we do an exam and we do lab tests pretty much like we've been doing for the last 100 years without a change. You know, it's like, come on, guys, there's more going on here and we get stuck in the way we do things, but you're blowing the lid off it. And what you did was then correlate things that would be hard for the average scientist in this lab with graphs and maps and things to figure out, correlate which of these analytes and proteins and cytokines and biomarkers were correlated with different diseases and the rate of aging. so to sort of explain what you found as you begin to sort of unpack the extraordinary amount of data and what were the kind of nuggets that you came up with in terms of identifying the things that we should be looking at. And there are honestly things I never even heard of as a doctor that I don't even remember. Maybe they taught me medical school, but I don't even think we knew about it then. So it's like, it's so exciting of like, oh, there's this cool thing that that is so different that I never even heard about that may be actually more relevant than anything else I've figured out, like CXCL9, which is a chemokine. Well, I never heard of that, but that may be more important than anything else we're measuring on our blood work, right?

Yeah. So, that's a great segue for what I wanted to discuss with regards to how the inflammatory age metric that we build is predictive of diseases, right? So we can predict the age of individuals by just a selfie. That's easy.

We can-- Come on. Give me a selfie of me. How old do I look?

You can also take any blood biomarker and predict the age. Age prediction of age is easy because things change with age. That's not the complicated part. The interesting part is once you take these immune biomarkers and try to predict the age of individuals, so you, in essence, are generating a clock, a biological clock, a new clock of aging. And this is an inflammatory clock because we're looking at the immune system and inflammation as our source of data. So we build that inflammatory clock that is able to accurately predict the age of individuals. nothing very fancy. Now when we adjust for age, that means that for a given age group, we see those that are deviated upwards versus those that are protected, deviated downwards. So in other words, they have an inflammatory age that is beneficial according to their age. Then we find that those that with higher inflammatory age according to their age, are at risk for developing multimorbidity. That's the first finding.

And multimorbidity is what?

Multimorbidity is defined as the sum of multiple diseases, in this case, non-communicable diseases of aging. So say someone could have a musculoskeletal condition, that's one disease. If that person also suffers from cardiovascular conditions or some events in the cardiovascular system that that's two diseases. And then you add up to 10 diseases. And this is very common, as you know well, in the US and also in other parts of the world, after the age of 65, we're suffering from around eight to 10 diseases, and we're taking about 14 to 15 different medications. So it's huge. It's huge. So what we're trying to here identify is a biomarker from blood that is focusing the immune system that is able to predict multiple diseases simultaneously. So this is multimorbidity, that concept. And then we went ahead and did a whole slew of different studies. We looked at frailty in individuals. So frailty is measured by asking individuals whether or not they're independent enough and you take the, you know, the grip strength and the time up and go, different functional measurements in individuals and we're able to predict with the inflammatory age seven years before it happens who's going to become frail.

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