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

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 genes 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. You might be eating clean, working out, even meditating, but still feel anxious, wired or totally exhausted. The truth is, it's easy to become magnesium deficient in today's fast paced world. Stress screens, sugar, caffeine, caffeine and even workouts, they all deplete your magnesium stores. And magnesium is involved in over 300 processes in your body, from sleep to stress regulation, muscle recovery, heart health and hormone balance. That's why I take Magnesium Breakthrough every night. It's the only supplement I've found with all seven essential forms of magnesium your body needs in one formula. Most magnesium supplements only give you one or two forms. That's not enough to make a difference. If you feel burnout or constantly on edge, your body's likely needing more magnesium. Try Magnesium Breakthrough and feel the difference in your sleep, your mood and your energy. Bioptimizers has increased their discount for my audience. Just go to buyoptimizers.com hyman and use code HYMAN for 15% off your order. 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've 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 Hymenhive for live Q&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@doctor hyman.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 7 day free trial. 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. Rhubar dolor cholor tumor. Tumor just means swelling, not tumor. You know, 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 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 addiction, 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 tack rule. If you're standing on attack, it takes a lot of aspirin to make it feel better, take out the tack. And if you're standing on two tacks, 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 ten tacks. 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 cause. 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, even with cholesterol, if you're. 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's normal, you're no risk. But if your cholesterol is high and your inflammation is not high, you're really not great risk. And the worst is if you have, obviously, both. So inflammation is a real big issue. 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 tests 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. Other patient, I don't know what's wrong. I feel fine. I don't. 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 talked about the hallmarks of aging. One of the key hallmarks is inflammation, or they call it aging itself. Inflamma aging. And what happens with aging is there's this 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 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 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, 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 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 be essential. It'd be the equivalent of curing leukemia or asthma. So it's 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 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. 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 1. 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 age, I age 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 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. You know, if you have a strep throat, I can give you a penicillin. Great, I'll get a cure. But most 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 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, 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 to 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 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 ten 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 I eliminate a lot of things and then you just add back one at a time. And for example, dairy I know cause 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 focused gut repair program because a lot of their imbalanced bacteria are causing inflammation. And lastly takes the right supplements, a multivitamin, fish oil, vitamin D, all help drop inflammation.

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 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, just getting out and moving every day, even if you do it in small bursts, that tends to add up. For example, if you take the train, if you take your bike instead of the train, or if you try to go up the stairs instead of taking the elevator, all of these different things can actually add some exercise in your day, some movement in your day. 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. 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 and the inflammation in the body. And another thing too, I think is to just be mindful of the times at which you're eating. 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 speak to your physician and a nutritionist before or 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 the good stress and also maintain the bad stress that we don't want. And those things, I think are very important for inflammation.

Magnesium is like the body's natural chill switch. It helps regulate stress, sleep, mood, and more. But most people are deficient and most supplements don't give you the full spectrum. That's why I recommend Magnesium Breakthrough, the only formula with all seven forms of magnesium. Feel calmer, sleep better, and give your body what it's missing. Bioptimizers has increased their discount for my audience. Go to bioptimizers.com hyman and use code HYMAN to get 15% off your order today. Yeah, I think that's really important to think about. I think exercise is so key. And I think we, we, we, you know, we, 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 is pretty amazing. And yet, you know, less than 8% of Americans get the recommended exercise. I think 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 help regulate our immune system? Do you have any perspective on that?

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 supplements like curcumin supplements, some of which have been shown to be efficacious in diseases like inflammatory bowel disease, that's a great thing. You can also use curcumin in your cooking, for example. So I think with supplements, as long as you have the data behind them, then that could be something that is potentially beneficial. Depending on your disease process as well.

You know, the things that 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?

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 a wonderful food. You can have frozen berries, for example, just in your freezer and eat them whenever you want. And they're filled with a variety of phytochemicals, including polyphenols. 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 love quinoa. It's one of my favorite grains. And 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.

Yeah, fermentation.

Yeah, fermentation of those grains. So I think that when we are talking about grains in general or certain foods, we really do need to be looking at the nuances. So, you know, if you have a hearty po bread that's fermented and baked in the ancient tradition without any flour, say, that's a very different response in terms of your immune response than a bread that you buy at the supermarket. And so that's something to be very mindful of. And I love beans as well, and lentils. There are dozens of 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 you will need to hear it.

People need to hear this podcast for.

Me, it's for everybody listening.

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 I.

Don'T want you to skip over that feeding your microbiome is so important, right?

It's incredibly important, yes.

And also those polyphenols, which is polyphenols in your discovery. 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.

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 Mana 1 shot monounsaturated fats and just a handful of nuts a day is 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 traditions, you know, the cuisines that my parents and grandparents cook, they're just an array of spices that I can't even. I still have to learn all the names of everything. So. But spices and herbs 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, 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 you know, just like thinking of.

Things like a lot of people were talking during COVID about using black cumin seed oil like as a. Black cumin seeds are 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 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, 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.

Oh, that's wonderful.

Yeah. And it's like, oh, it's so good. It's like. And, and it's a lot of hard work.

It's a lot of hard work.

Well, I have, I have a little, you know, I have a little like brawn like thing. It's just like I just pushed a button and goes. But it's, it's it's so more to start including these in your diet on a regular basis.

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

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

What's, what's in it?

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 then change the genes 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 for most of us.

That's exactly right. 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. 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, at this podcast, but I'd like to go to idea of the exposure.

Yeah.

Back to the root cause of inflammation. So we do know 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 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 linen 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.

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

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

Exactly. So our plasticizers, plastics, things that are stored in plasticizers, or the plasticizers and plus the resin make a plastic. And there's leaching, 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. Gliadin can bind to certain cells in your gut and cause inflammat inflammation, increasing, leaky gut, et cetera. The other one is sedentarism, as you very well are aware. If we're sitting in a chair, we're developing an inflammatory reaction, and that is a. 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. 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 and death, and obviously other chemicals that we're exposed to that are surrounding us. Just even an example, formaldehyde, right? Paraformaldehyde that serves as a glue for plywood that is often used in furniture and, you know, cabinetry.

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, 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, which historically we really didn't have throughout evolution. 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 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. And for those who don't know what that is, it's basically the, the sort of immune. Well, why don't you define the immunome? You're the expert. I don't probably screw it up, but.

I doubt you will. But so similar to the concept of exposome and the word som 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 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 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 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 it's helpful, but it's not very sensitive. It's not very sensitive.

It's not very sensitive. As a measure for systemic ranking 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. 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 AI ML machine learning, to be able to cope with the data and to derive metrics that are simplified, that take us hundreds of thousand hours. Now we have a metric that can be used in the clinic.

So it's like finding a needle in the haystack. 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 are also. Research is changing, so there's now a lot of different groups across the world. Here in the US is very popular to do transcriptomics, proteomics. And we're measuring 7,000 proteins in the blood, 3,500 metabolites, and it becomes much more normal. Has, you know, has normalized with time. Yeah.

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

Right. So we measure 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. And 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 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 is 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 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. We do an exam and we do lab tests pretty much like we've been doing for the last hundred years without a change.

Exactly.

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 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 sort of. 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. 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 on our blood work, right?

Yeah. So that's a. That's a great segue for what I wanted to discuss with regards to how this 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.

Come on, you do a selfie of me. How old do I look?

You can also take any blood biomarker. 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 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 and inflammation as Our source 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, we see those that are deviated upwards versus those that are protected, deviated downward. 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 multimorbit.

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. Right. We looked at frailty in individuals. So frailty is measured by asking individuals whether or not their independent enough. And you take the, you know, the grip strength 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 felt.

Wow.

So that's, that's another big discovery that we did that we published last year in Nature aging and also CXCL9. As you just mentioned, one of the most important contributors of inflammatory age of this new metric is a chemokine that is part of the immune system proteins in the blood that has not been identified before as a marker of systemic chronic inflammation. Right. And markers that are usually coming up in the inflammatory reaction against pathogens that's Easy to measure. Interleukin 6 TNF alpha, interleukin 1 beta. Those are well established canonical markers for acute inflammation.

Those are cytokines like we talked about with the cytokines storm with COVID So those are. Yeah, those are the typical cytokines.

Right, exactly. And those allow for cell to cell communication. In this case, we're talking about very different set of proteins that are coming up as being the most predictive. And then we went ahead and looked at a number of different cardiovascular phenotyping measurements in these individuals and were able to correlate CXCL9 with cardiovascular aging, with cardiovascular health. Then we went ahead and continue this study to look for mechanisms and to explain other morbidities. And we published that last year in 2021.

So basically this I age biomarkers and as I understand there's like, there's a smaller panel and expanded panel. 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 then 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 chronic diseases and whether it's dementia or heart disease or cancer or diabetes. These are all inflammatory diseases, right?

Correct. So 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 five. It's a core, five biomarkers, including this one, CXCL9, that is, by the way, largely produced by your endothelium. So it's not just immune produce. The endothelium is the, the cells that are, that are making up your vessels. Right.

The lining your blood vessels.

The light. Exactly. Your, your blood vessels lining up your blood vessels and that those cells can become inflammatory. So when you, when you ask you, when you get older 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.

And so what are these cytokines and chemokines? What are they doing? 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?

That's a very, that's a great question. It's a little bit of a loaded question. 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, CXCL9. When we take CXCL9 and incubate, that means that we put 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 production 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 the body. So when we now block, let's say block, right, we block CXCL9 by introducing what we call silencing of the protein. In this case, we use an shrna. We can restore completely that the function.

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