The Silent Fire Behind Chronic Disease—and How to Put It Out

Inflammation is the body’s natural way of healing, but when it becomes chronic and hidden, it quietly drives many of today’s most common health problems—heart disease, diabetes, dementia, cancer, autoimmune conditions, and more. Unlike the redness and swelling from a cut or sprain, this “silent inflammation” often goes unnoticed while slowly damaging tissues and speeding up aging. Modern life fuels the fire: processed foods, food additives, pollution, plastics, chronic stress, too much sitting, and poor sleep. The good news is inflammation can be calmed by simple daily choices—eating colorful whole foods like berries, leafy greens, beans, nuts, seeds, and omega-3 rich fish; adding herbs and spices like turmeric and cumin; moving regularly; practicing relaxation; and repairing gut health. Even small shifts, like climbing stairs, eating within a shorter window, or reducing sugar, can make a big difference. By lowering inflammation, the body finds balance again, opening the door to more energy, resilience, and healthy aging. In this episode, I discuss, along with Dr. Shilpa Ravella and Dr. David Furman, why it’s important to be aware of systemic inflammation and how to address it. Dr. Ravella is a gastroenterologist and Assistant Professor of Medicine at Columbia University Medical Center. She is the author of A Silent Fire: The Story of Inflammation, Diet & Disease, which investigates inflammation—the hidden force at the heart of modern disease. Her writing has appeared in The Atlantic, New York Magazine, The Wall Street Journal, TIME, Slate, Discover, and USA Today, among other publications. Dr. David Furman is Associate Professor and Director of the Bioinformatics Core at the Buck Institute for Research on Aging, as well as the Director of the Stanford 1000 Immunomes Project. He obtained his doctoral degree in immunology from the School of Medicine, University of Buenos Aires, Argentina, for his work on cancer immune-surveillance. During his postdoctoral training at the Stanford School of Medicine, Dr. Furman focused on the application of advanced analytics to study the aging of the immune system in humans. He has published nearly thirty scientific articles in top-tier journals such as Cell, Nature Medicine, PNAS, The Lancet, and others. This episode is brought to you by BIOptimizers. Head to bioptimizers.com/hyman and use code HYMAN to save 15%. Full-length episodes can be found here:What Causes Inflammation And How Can You Treat It? The Silent Killer: Inflammation And Chronic Disease How Silent Inflammation Accelerates Aging

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Dr. Mark Hyman?

  Coming up on this episode of the Dr. Hyman Show. And what we know about that is that 95% of chronic disease is caused by the exposome, not the genome, meaning your genes are affected by the exposures that then change the gene's function, which then lead to all these diseases. But it's not the genes that are the problem. It's the exposome that's the major problem.

• 0:21Dr. Mark Hyman?

  Before we jump into today's episode, I want to share a few ways you can go deeper on your health journey. While I wish I could work with everyone one-on-one, there just isn't enough time in the day. So I built several tools to help you take control of your health. If you're looking for guidance, education, and community, check out my private membership, The Hyman Hive, for live Q and As, exclusive content, and direct connection. For real-time lab testing and personalized insights into your biology, visit Function Health. You can also explore my curated doctor trusted supplements and health products at drhyman.com. And if you prefer to listen without any breaks, don't forget you can enjoy every episode of this podcast ad-free with Hyman Plus. Just open Apple Podcasts and tap Try Free to start your seven-day free trial.

• 1:02Dr. Mark Hyman?

  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 site 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 in medical school, rubor dolor corlorum, tumor. Tumor just means swelling, not tumor. No, that'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 rough.

• 1:45Dr. Mark Hyman?

  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's 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,

• 2:29Dr. Mark Hyman?

  obviously autoimmune disease, obviously allergies, asthma, all sorts of gut issues. All of these problems are caused by inflammation, of course. Then the question is, what causes inflammation? We're going to get to that. So 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 you 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.

• 3:14Dr. Mark Hyman?

  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, 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 because it gets inflamed and white blood cells scop up, soup 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.

• 3:58Dr. Mark Hyman?

  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 at not 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, another cytokine test for inflammation, they had a 216% more likely chance of dying in the next four years. So this is no joke. So you might feel fine. The patient, he's like, "I don't know what's wrong. I feel fine. I saw my blood test says, I don't really care.

• 4:39Dr. Mark Hyman?

  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

• 5:21Dr. Mark Hyman?

  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 going to help you and stabilize your blood, blah, blah, blah, and prevent clotting." But it turns out that the recommendations for aspirin were over enthusiastic, 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

• 6:06Dr. Mark Hyman?

  is not good, like GI bleeding. So. You know, if you, if you look at those drugs like aspirin or Advil or Aleve, they're not benign. I mean, they, 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, many, as many people die from taking those drugs as from asthma or leukemia. So imagine if we literally eliminated those drugs, we'd basically essential, it'd be the equivalent of curing leukemia or asthma. So it's not, not a joke. So, you know, statins, for example, even cholesterol drugs like statins like Lipitor, they may not have their main effect by lowering cholesterol. In fact, it may

• 6:50Dr. Mark Hyman?

  be because they actually lower inflammation. That's what they do. It's a side, quote, a side effect of the statin, but actually may be their main effect. So 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 your, 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 one to 10 range, that's usually the hidden inflammation. They're, ideally, it should be less than one. Any higher than that means you're on your way.

• 7:32Dr. Mark Hyman?

  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 by, developed by a professor at Stanford called IAGE, I A G E, meaning immune age. And it really looks at your immunome, 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 attacks, cancer, diabetes, Alzheimer's and so forth. What's so amazing, this test is really not that expensive. It's easy to get and you

• 8:14Dr. Mark Hyman?

  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 kinda 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. You know, 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 and or I'm giving you an immune suppressant. And that's not the answer, unfortunately. So, okay, so let's say you've identified the causes, you've figured out you have inflammation, you know, 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.

• 8:57Dr. Mark Hyman?

  All those colorful plant compounds are anti-inflammatory. All 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,

• 9:37Dr. Mark Hyman?

  it improves your mood, it helps reduce stress. I mean, it's, 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 kinda 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 kinda floated away. It was great. Also, food sensitivities are another big factor.

• 10:20Dr. Mark Hyman?

  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 and 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. Many people would benefit from actually a focused gut repair program because a lot of their imbalanced bacteria are causing inflammation.

• 11:05Dr. Mark Hyman?

  And whilst they take the right supplements, multivitamin, fish oil, vitamin D, all help drop inflammation.

• 11:12Speaker 01

  We know today that exercise actually can dampen inflammation in the body. We have dozens of clinical trials to back this up. And even in the absence of weight loss, the exercise can decrease the amount of immune cells that are infiltrating your fat tissue. And to me, that's an amazing fact because, you know, we're not, we're not just looking at the end result, weight loss, we're actually changing our bodies on a biological level, even if we are not able to see it on the outside. And so just getting out and moving every day, even if you do it in small bursts, that tends to add up. You know, for example, if you, if you take the train, you know, if you take your bike instead of the train, or if you try to go up the stairs instead of taking the elevator,

• 11:54Speaker 01

  all of these different things can actually add some exercise in your day, some movement in your day. And when you think about the Blue Zones books, this is how they incorporated some movement into their days. And I think it's a very seamless way to do it. And nothing wrong with going to the gym and exercising or anything like that. But for most people, it's, it's this difficult thing to begin exercising when they have not done any of it, especially some of my patients who come to me saying, you know, doc, I don't have time to incorporate exercise into my day. And this is something I think that anyone can do just by making some simple lifestyle changes and it can actually dampen the inflammation in the body. And another thing, too, I think, is to just be mindful of the times at which you're eating,

• 12:39Speaker 01

  because fasting has been shown to dampen inflammation in the body, to fortify your body against a variety of diseases. And just something as simple as trying to consume your calories in a 10-hour window, it doesn't have to be anything complicated. And of course, if you have comorbidities, then you should, you know, speak to your physician and a nutritionist before attempting a fasting program. But we do know that stressors like exercise and fasting are good stress in our life, because we have to have a good stress and also maintain the bad stress that we don't want. And those things, I think, are very important for inflammation.

• 13:22Dr. Mark Hyman?

  Yeah, I think that's a really important thing about. I think exercise is so key. And I think we, you know, we don't realize how powerful it is as a, as a trigger for all the beneficial things we want to have happen with aging. And it, it works for depression, it works for heart disease, for cancer, for diabetes, for Alzheimer's, you know, for every kind of inflammatory disease. It's pretty amazing. And yet, you know, less than 8% of Americans get the recommended exercise, maybe 20 something, if you take a, like a broader view of what's minimal, but I think most people don't even get close to that. I think, you know, what about the role of supplements, or phytochemicals, or other things that we can be taking to help regulate our immune system? Do you have any perspective on that?

• 14:05Speaker 01

  I mean, I, I do love to tell patients to get their phytochemicals from, from the foods first. So, so I basically, you know, I have my patients eat lots and lots of colorful vegetables. And we know that polyphenols are incredibly important phytochemicals for inflammation. They're antioxidants. They help to tone inflammation down in the body. They are also metabolized by the gut microbiome in part, and more beneficial compounds are created. So I certainly think that polyphenols have a major role. And when I think about supplements, I think it's more the exception than the rule. So when you look at, you know, supplements like curcumin supplements, some of which have been shown to be efficacious in diseases like inflammatory bowel disease.

• 14:48Speaker 01

  You know, that's a great thing. You can also use curcumin in your cooking, for example. So I think with supplements, as long as you you have the data behind them, then that could be something that is potentially beneficial, depending on your disease process as well.

• 15:01Dr. Mark Hyman?

  Yeah, the the things that I I tend to sort of recommend people to eat are certain foods which have anti-inflammatory compounds. So what are your top anti-inflammatory foods that people should be focused on?

• 15:10Speaker 01

  Well, I really love grains. I think kale is one of my favorite grains. It has the immune-modulating potential of our ancestors, our ancestral plants. And it's it's very versatile, very easy to cook. So we want to try to get to foods that are more like those ancestral plants, like scallions instead of onions, for example, because the ancestral iterations are actually much more powerful from an inflammation-damping standpoint. Berries, again, are are a wonderful food. You can have frozen berries, for example, just in your in your freezer and eat them whenever you want. And they're filled with a variety of phytochemicals, including polyphenols.

• 15:53Speaker 01

  And when you think about inflammation, you really want to think about the very, very colorful foods, not just the iceberg lettuce and the bananas. And in my pantry, I have a variety of whole grains. And by whole grains, I mean actually whole. So I I love quinoa. It's one of my favorite grains.

• 16:11Speaker 01

  And I I think it's something that is very easy to use. And, you know, whole intact grains are actually much better for your gut microbiome than processed grains. So that's just something that's a nuance that that can be helpful when it comes to talking about inflammation and also.

• 16:26Dr. Mark Hyman?

  Yeah, fermentation.

• 16:27Speaker 01

  Yeah, fermentation of those grains. So I think that when we are talking about grains in general or certain foods, we really do each be looking at the nuances. So, you know, if you have a hearty bread that's fermented and baked in the ancient tradition without, you know, any flour, say, that's a very different response in in terms of your immune response than a bread that you buy at the supermarket. And and so that's something to be very mindful of. And I love beans as well and lentils. There are dozens of, you know, randomized controlled trials showing that beans can help to dampen inflammation and beans have a good amount of soluble fiber. And you probably know all of this already. So I'm just regurgitating what you already know here. So.

• 17:12Dr. Mark Hyman?

  People need to hear it. People need to hear it. This podcast is for me. It's for everybody listening.

• 17:18Speaker 01

  Yeah, yeah. So the soluble fiber is very important for the gut germs and that's, you know, they metabolize that fiber and salvage calories that way. You make beneficial compounds that go throughout the body and calm the immune system down. And one thing I think that.

• 17:34Dr. Mark Hyman?

  So feeding the youngest, I don't want you to skip over that. Feeding your microbiome is so important, right?

• 17:38Speaker 01

  It's incredibly important. Yes.

• 17:40Dr. Mark Hyman?

  And also those polyphenols, which is your discovery.

• 17:43Speaker 01

  Yep.

• 17:43Dr. Mark Hyman?

  So they, they're not just eating fiber, but they're eating all the colorful plant compounds that can improve their, their bacterial content in there.

• 17:51Speaker 01

  And they're also eating some fat, like healthy fats from nuts and seeds. That's another food that I prescribe for patients. All those healthy mono one shot, mono unsaturated fats and just a handful of nuts a day is a great thing to add into the diet. And then something I think that people tend to forget about are just spices and herbs. I mean, there are so many different spices you can use and, and in my family's tradition, you know, the cuisines that my parents and grandparents cook, they're just an array of spices that I can't even, I have, I still have to learn all the names of everything. So, um, but spices and herbs are, are just filled with polyphenols and just very, very beneficial nutrients. You know, you look at something like cumin, which has salicylic acid in it.

• 18:35Speaker 01

  You're actually getting kind of some anti-inflammatory potential from that, which also helps to resolve inflammation. Because aspirin is one of the few medications that actually not only dampens, but also resolves inflammation and, um, you know, just like, uh, thinking of things like.

• 18:51Dr. Mark Hyman?

  A lot of you were talking during COVID about using black cumin seed oil, like as a, like cumin seeds are a really different kind of cumin. And it's a very powerful immune modulator and anti-inflammatory, potentially antiviral. Yeah. So these, these spices and herbs, we, we sort of neglect, you know, we use a lot of salt, a lot of sugar, a lot of processed refined oils to kind of make food taste good. And we don't actually use the spices and then you don't really need that much of those other things when you actually have a yummy spicy. I mean, diet, I mean, I love to cook Indian food at home. I actually make it scratch stuff. So like, I actually get the actual spices. I grind them. I get the peppers.

• 19:28Speaker 01

  That's wonderful.

• 19:28Dr. Mark Hyman?

  Yeah. And it's like, oh, it's so good. It's like, and, and it's

• 19:32Speaker 01

  It's a lot of hard work. It's a lot of hard work.

• 19:34Dr. Mark Hyman?

  Uh, well, I have, I have a little like, you know, I have a little like a brawn like thing. It's just like, I just pushed the button and go

• 19:43Dr. Mark Hyman?

  But it's, it's, it's so more to start to include these in your diet on a regular basis.

• 19:47Speaker 01

  Absolutely. And the one thing I want to mention, the last thing is also seaweed, because I love seaweed and it's just kind of like a superfood in some ways. And you can find fibers in seaweed that you don't find in terrestrial plants. And

• 19:58Dr. Mark Hyman?

  Yeah, tell us about that.

• 20:00Speaker 01

  And the goal is just to have a diverse array of, you know, some of these plants. And we know that simply by increasing the diversity of plant foods in the diet, that can actually predict lower inflammation. So not, it's not just about the quantity, but also the diversity. So just kind of thinking about all these different types of foods that you can get, I think could be pretty useful.

• 20:19Speaker 02

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

• 20:42Dr. Mark Hyman?

  What's the exposome? Like, what's, what's

• 20:45Speaker 02

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

• 20:59Dr. Mark Hyman?

  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 then change the gene's 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.

• 21:18Speaker 02

  That's exactly right. I, I would like to get at that in a moment. Um, we have the genome, everybody, you and I, and everybody in this business world, to be able to live 120, 130 years.

• 21:34Speaker 02

  At least, right? That is something we know. Now, the problem is, in some countries, people are dying at the age of seventy, seventy-five. That's the average lifespan expectancy. Some countries is eighty-nine or ninety, 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 eighty to ninety average life expectancy to a hundred and twenty. 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 the idea of the exposome.

• 22:15Dr. Mark Hyman?

  Yeah.

• 22:16Speaker 02

  Back to the root cause of inflammation. So, we do know already today that pollutants in the air, that pollutants in water.

• 22:27Dr. Mark Hyman?

  Pollution.

• 22:28Speaker 02

  Pollution, exactly, pollution, are drivers of inflammation. Imbalances in nutrition, such as both macro and micronutrients, right? These cause inflammation by large. Food additives go back to the microbiome, things like oxymethyl cellulose or polysorbate eighty 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.

• 23:11Dr. Mark Hyman?

  Wait, 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 eighty, 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 additives are just not bad because they're, you know, if you're a hippie and you want to eat granola and like this, you shouldn't eat food additives. They're really damaging to our bodies, right?

• 23:47Speaker 02

  Your microbiome, yeah, exactly. They're causing this concept of dysbiosis, right, in your gut.

• 23:55Dr. Mark Hyman?

  Then you were going gluten was the next thing you were going into.

• 23:57Speaker 02

  Exactly. So our plasticizers, plastics, things that are stored in plastics, in plasticizers, or the plasticizers and plus the resin make a plastic and there's leaching, right? And there's a leaching 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. Glyadin can bind to certain cells in your gut and cause inflammation, increasing leaky gut, etc. The other word is sedentarism, as you very well are aware. If we're sitting in a chair, we're developing an inflammatory reaction and that it's a perfect correlation between the touch.

• 24:44Speaker 02

  The time sitting in a chair and mortality, there's almost a perfect correlation between those two. Sleep quality, disruption in our circadian rhythm. Social stress, and 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.

• 25:14Speaker 02

  And obviously, other chemicals that we're exposed to that are surrounding us. Just even a good example, formaldehyde, right? Par formaldehyde that serves as a glue for plywood that is often used in furniture and, you know, cabinetry.

• 25:33Dr. Mark Hyman?

  So those are, 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 combatted inflammation. So just as there's an inflammatory lifestyle, there's an anti-inflammatory lifestyle, right? 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 immunome.

• 26:17Dr. Mark Hyman?

  And for those that don't know what that is, it's basically the sort of immune. Well, why don't you define the immunome? You're the expert. I don't know, I'm probably screw it up.

• 26:28Speaker 02

  I doubt you will. But so similar to the concept of exposome, the end and the word somme accounts for the totality of it. So when we talk about the immunome, 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 Thousand Immunomes Project, which is a project that, as you mentioned, lasted for about now 15

• 27:09Speaker 02

  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 it 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, HCRP, sedimentation rate, that you can go to the doctor and have those are very poor predictors of any type of condition, right? CRP, just to give an example, is predictive of cardiovascular

• 27:53Speaker 02

  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

• 28:05Dr. Mark Hyman?

  It's helpful, but it's not very sensitive. It's not very sensitive.

• 28:08Speaker 02

  It's not very sensitive as a measure for systemic 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,

• 28:32Speaker 02

  That help us measure all these things, but also computational analytical tools that are rather novel, including AI ML, right, machine learning, to be able to cope with the data and to derive metrics that are simplified, that that that that take us hundreds of thousands of programs. Now we have a metric that can be used in the clinic, right?

• 28:58Dr. Mark Hyman?

  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?

• 29:03Speaker 02

  That's exactly right. That's exactly right. But the the the

• 29:08Speaker 02

  the medicine and the clinical medicine also research is changing. So there's a now a lot of different groups across the world. Here in the US is very popular to do transcriptomics, proteomics, and we're measuring seven thousand proteins in the blood, thirty five hundred metabolites, and it becomes much more

• 29:32Speaker 02

  normal, has, you know, it has normalized with time.

• 29:36Dr. Mark Hyman?

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

• 29:50Speaker 02

  Right, so we measured the expression of genes, and these are roughly fifteen thousand 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 twenty five different cell types. And we also measure metabolites. And the fifty proteins that we measured across these different years, this is a panel that was expanded now. We were currently measuring seven thousand proteins from individuals. Making sense of that is the is the challenge here. And it's really a beautiful system that this company has started,

• 30:35Speaker 02

  I would say maybe ten years ago or so, in which they can now analyze seven thousand proteins. There are other companies analyzing thirty five or four thousand proteins. And we're we're measuring all these things to see how those contribute to rates of aging.

• 30:51Dr. Mark Hyman?

  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 bodies and network, where there's this 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 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,

• 31:33Dr. Mark Hyman?

  you know, we, we do an exam and we do lab tests, pretty much like we've been doing for the last hundred years without a change. You know, it's like, come on, guys, there's like more going on here. And we get stuck in the way we do things, but you're kind of blowing the lid off it. And, and what you did was, was then correlate things that would be hard for the average, you know, scientist in his lab, like, you know, 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, so to sort of explain what you found as you begin to start unpacked the extraordinary amount of data and what were the kind of nuggets that you came up with in terms of

• 32:19Dr. Mark Hyman?

  identifying the things that we should be looking at. And they're honestly things I never even heard of as a doctor that I don't even remember. Maybe they, 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, that may be actually more, more relevant than anything else I've figured out, like, you know, CXCL9, which is a chemokine. Well, I never heard of that, but that may be more important than anything else we're measuring under blood work, right?

• 32:51Speaker 02

  Yeah, um, so that's a, that's a great segue for what I wanted to discuss

• 32:58Speaker 02

  with regards to how this inflammatory age metric that we build is predictive of diseases, right? And so we can, we can predict the age of individuals by just a selfie. That's easy. Um, we can. Come on, you go selfie of me, how old do I look?

• 33:20Speaker 02

  Um, you can also take any blood biomarker, predict the age, age prediction of age is easy because things change with age. Um, that's not the, the, the complicated part. The interesting part is, once you take this immune biomarkers and try to predict the age of individuals, so you, in essence, are you 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 inflammation. Um, as our, as our, um, as our source of, of data. So we build that inflammatory clock that is able to accurately predict the age of individual, nothing very fancy. Now, when we adjust for age, that means that for a given age group,

• 34:05Speaker 02

  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, with higher inflammatory age, according to their age, are at risk for developing multimorbidity. That's the first finding. And multimorbidity is what? Multimorbidity, um, is defined as the sum of multiple diseases, in this case, noncommunicable diseases of aging. So say someone could have a musculoskeletal condition, that's one disease.

• 34:47Speaker 02

  If that person also suffers from cardiovascular conditions or some events in the cardiovascular, uh, uh, system, that's two diseases. Uh, and, and you, you, you add up, um, up to 10 diseases. So, uh, and this is very. Common as you know well in the US and also in other parts of the world. After the age of sixty five, we're suffering from around eight to ten diseases and we're taking about fourteen to fifteen different medications. So it's it's it's huge, it's huge. So what we're trying to hear identify is a biomarker from blood. That is focusing the immune system that is able to predict multiple multiple diseases simultaneously.

• 35:30Speaker 02

  So this is um multimorbidity, that concept. And then we went ahead and did a whole slew of different studies, right? We we looked at frailty in individuals, so frailty is measured. Um, uh, by uh, asking individuals whether or not they're uh independent enough. And you take the, you know, the grip strength and and and that 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.

• 36:06Dr. Mark Hyman?

  Wow.

• 36:07Speaker 02

  So that's that's another big um discovery that we did that we published last year in Nature Aging. And also CXCL nine, as you just mentioned, one of the uh most important contributors. Of uh inflammatory age of this new metric is a chemokine. That uh is is part of the immune system proteins in the blood. And that has not been um identified before as a marker of systemic chronic inflammation, right? Um, and it's markers that are usually coming up in the inflammatory reaction against pathogens. That's easy to measure, interleukin six, TNF alpha, interleukin one beta.

• 36:52Speaker 02

  Those are well established canonical markers for acute inflammation.

• 36:55Dr. Mark Hyman?

  Those are cytokines like we talked about with the cytokines formed with COVID. So those are, yeah, those are the typical cytokines, right?

• 37:01Speaker 02

  Exactly. And those allow for cell to cell communication. In this case, we're talking about a very different um set of proteins that are coming up as being the most predictive. Uh, and then we went ahead and looked at a a number of different cardiovascular um phenotyping. Uh, uh, uh, measurements in in these individuals and were able to correlate CXCL nine with cardiovascular aging, with cardiovascular health.

• 37:28Speaker 02

  And then we went ahead and continued the study to look for mechanisms and to explain other morbidities and we published that last year in 2021.

• 37:41Dr. Mark Hyman?

  So basically, this eye age biomarkers, and as I understand, there's like, there's a smaller panel and expanded panels. So out of these thousands and thousands of things, you found like four key ones that you can measure now on a blood test. And there's others that are an expanded one, maybe it's seven or eight, I don't remember the number, but there's not an infinite number of these. And in those kind of biomarkers, you're able to identify the rate of aging and also the risk of product diseases and whether it's dementia, or heart disease, or cancer, or diabetes, these are all inflammatory diseases, right?

• 38:19Speaker 02

  Correct. So the the the understanding of these diseases is very poor, as we know, otherwise we wouldn't suffer from those. And so only as I mentioned at the beginning of this conversation, 20 years ago, we started looking at the immune system as a major root cause of these diseases. And we are just starting to derive the biomarkers. This is rather new, right? And you're absolutely right. From looking at this extended panel of cytokines and proteins in the blood, we identify key five, it's a core five biomarkers,

• 38:59Speaker 02

  including this one CXCL9, that is, by the way, largely produced by your endothelium. So it's not just immune cells produce.

• 39:09Dr. Mark Hyman?

  What's that?

• 39:10Speaker 02

  The endothelium is the the cells that are that are making up your vessels, right?

• 39:18Dr. Mark Hyman?

  The lining of your blood vessels.

• 39:20Speaker 02

  The line, exactly, your blood vessels, lining of your blood vessels. And that those cells can become inflammatory.

• 39:28Speaker 02

  So when you, when you, as you are going to get older and, and we treat our bodies in different ways, those cells become senescence and they start producing CXCL9 and then you have all these downstream effects that we just mentioned a few minutes ago.

• 39:44Dr. Mark Hyman?

  Hmm. And so what are these, these, these cytokines and chemokines, what, what are they doing? Like, how are they accelerating aging? And are they the cause of heart disease? Are they the cause of dementia? You know, are they just correlated with them?

• 39:59Speaker 02

  Um, that's a very, uh, that's a great question. It's a little bit of a loaded question.

• 40:08Speaker 02

  And, and I'm saying that because we would need a lot of mechanistic studies to demonstrate the relationship between every one of these proteins and the causal inference in tissues and degradation of organs. We did that for a single one, right? CXCL9. When we take CXCL9 and incubate, that means that we are, we're putting in, in a petri dish and we start growing cells in the presence of CXCL9, these endothelial cells are completely dysfunctional. They don't respond well to acetylcholine. They don't contract. They don't have the

• 40:52Speaker 02

  production of, of, of tubes that you need. So these are completely dysfunctional endothelial cells. And then we also see that cardiomyocytes, which are the cells that are in our heart, are suffering from the presence of CXCL9 in, in, in, in the body. So when, when we now block, let's say block, right? We block CXCL9 by introducing what we call silencing of, of, of the protein. In this case, we use an SHRNA, we can restore completely that part of the, the, the, the function of those cells.

• 41:33Dr. Mark Hyman?

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• 42:17Dr. Mark Hyman?

  If you love this podcast, please share it with someone else you think would also enjoy it. You can find me on all social media channels at Dr. Mark Hyman. Please reach out. I'd love to hear your comments and questions. Don't forget to rate, review, and subscribe to the Dr. Hyman Show wherever you get your podcasts. And don't forget to check out my YouTube channel at Dr. Mark Hyman for video versions of this podcast and more. Thank you so much again for tuning in. We'll see you next time on the Dr. Hyman Show. This podcast is separate from my clinical practice at the Ultra Wellness Center, my work at Cleveland Clinic, and Function Health, where I am Chief Medical Officer. This podcast represents my opinions and my guests' opinions. Neither myself nor the podcast endorses the views or statements of my guests. This podcast is for educational purposes only and is not a substitute for professional care by a doctor or other qualified medical

• 43:01Dr. Mark Hyman?

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