How Silent Inflammation Accelerates Aging with Dr. David Furman

Coming up on this episode of the Doctor's Pharmacy. Every single one of the hallmarks of aging are driven by elevated systemic chronic inflammation in the body as a response to multiple triggers that have to do with how we treat our bodies.

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That's Pharmacy with an F, a place for conversations that matter. And if you are wondering about how fast you're aging and if there's a way to test and track it, if there's new science that's telling us how we can identify hidden inflammation that's linked to all the chronic disease of aging. Then you're gonna love this podcast because I am excited to bring to you Dr. David Furman, who is an expert in immunology. He's a physician. He's an associate professor and director of the bioinformatics core at the Buck Institute for aging, for research on aging, as well as the director of the Stanford 100 Immunomes Project. We're gonna get deep into what the 100, I mean, sorry, the 1000 Immunomes Project and what that is. He got his PhD in immunology from School of Medicine, University of Buenos Aires, Argentina. And he also has done post-doctoral work at Stanford School of Medicine. And he's basically looking at how we use artificial intelligence, advanced analytics to study aging of the immune system in humans, which is really an important topic because as you know, inflammation is a huge driver of all the chronic disease of aging. So he's doing some really amazing work and has developed a number of things, including this test which we're gonna talk about called the IH test measures your immunological age. And as you know, I'm all excited about longevity and aging. I've written this new book, Young Forever, which coming out in February, we're gonna talk a lot about this. And I do include a lot about this work about the 1000 Immunes Project in my book. Now, he's got over 30 scientific publications in major journals like Cell, Nature Medicine, Lancet. These are top tier journals.

So he's the real deal and we're gonna get deep into this.

So welcome, David.

Thank you so much, Mark, for having me here.

Yeah, so pleasure. It's great. You are a very unusual physician and scientist because you think in systems and you think about how things relate to one another and you are looking for things that most people often ignore. Often we go to the doctor and we get a checkup and doctor does like the blood panel and it may be 20, 30, 50, maybe a hundred analytes if you're lucky. And he goes, oh, you're fine. Everything's fine. Your liver's fine. Your kidneys fine. Your electrolytes are good. You know, your cholesterol's all right.

And.

Okay, good. You're fine. And send you on your way. And the truth is, they may be missing a whole slew of Clues about your health and your rate of Aging. And you decided you were going to take a very different perspective, which is rather than. look at the tests that we're already doing and try to find what is correlated with aging, you were going to look at the immune system in ways that are only now possible because of advanced analytics and bioinformatics and artificial intelligence. And you were going to take a thousand people ages, I think, 9 to 96 and look at them over 10 years and correlate all kinds of biomarkers from the immune system, over 50 different cytokines and markers that you didn't know were relevant or not, but you were gonna see if they were correlated with aging and age-related disease and how they were important or not. So this is a radically different view. And it's really exciting because you publish this data and you've developed this test, which allows us to measure our immunological age, which is really important. We're gonna talk about why Immune age is such an important biomarker of health and aging. And it's sort of exciting. So before we sort of get into the nitty-gritty of like what you found and what the sciences around this and why the immunology of aging is so important, how did you actually become interested in this? And how did you as a scientist begin to think differently than everybody else? Because you weren't thinking very differently than most scientists out there about this process of aging and longevity.

Thank you for that question. I think it's a very appropriate one. Just first of all, let me correct you. I'm not a physician. I studied medicine for four years, but I dropped out to go to Stanford. So I studied medicine for four years.

You're a med student dropout, okay. Exactly. That kind of counts. That kind of counts. I don't know. You may not got officially licensed, but you definitely went through medical school. So that's the important part.

Board certified, but exactly. I went to medical school, got my PhD, immunotherapy against cancer and then went into Stanford to study immunology in an unbiased fashion. The idea, really, Mark, was to conduct research in humans. For the most part, what we know about immunology over the past 100 or 150 years comes from animal models, namely mice. And the big, big problem there is that things do not translate. Just to give an example, for one drug to be successful, you need about 10 to 15 years of research and around $2 billion to make it work, right, to get to the FDA approval. This means that the systems are not working well, right, and mostly because studies in animals do not translate into humans. So we decided to take a very different approach and start using humans as model organisms, if you will. And one thing that we notice is that the variation that we see in humans is huge. It's just gigantic, right? We are not inbred. We're not in a controlled environment.

Hopefully we're not inbred.

And therefore the variation in immune systems is huge. It's gigantic. So one way to cope with this huge variance that we see in human immune systems is by measuring a lot of different things. in an individual or a set of individuals in different cohorts over time. And this is what we know, it's one way to study the immune system and we call that systems biology of immunology. So we use a systems approach. Why for a number of years this wasn't possible? Because of technology. But what we had at Stanford was state-of-the-art technologies including proteomics that measures many, many cytokines and measures other proteins in the blood, and also cellular phenotypes and also many genes that we can measure from individuals. And then the premise was, okay, we're going to be using AI and machine learning to really understand and cope with all this data and try to see if the immune system is able to predict rates of aging in these individuals and we can make this generalizable.

Yeah, it's fascinating because you took a very different approach, which is a systems biology approach. And functional medicine is essentially a clinical model that applies the principles of system biology, which basically hypothesizes that everything is connected, that the body's a system, that you can't just look at one organ or one pathway and try to fix problems. It's sort of whacK-A-Mole medicine. But if we stand back and we go, what is the relationship between these various sort of networks in our body? And the immune network is such a critical aspect of aging, and I wanna get into that in a minute, we can begin to understand things a little bit better. So, in the work that you're doing, you sort of describe a lot of the hallmarks of aging. And inflammation is one of the key hallmarks and is often referred to as inflammaging. In fact, the process of aging itself is a weird process 'cause at one point, at the same time, you're actually getting more sterile inflammation and your immune system isn't working to fight infections. You're also less able to fight cancer and have more autoimmune disease. So, it's kind of a weird kind of mishmash of things happening. But at the end of the day, what happens as we age is we get more inflamed and that's what you're really finding and looking for, right?

Exactly. Here I would like to just pause for a moment and try to make a very important distinction between inflammation as the response to an infection. And that's what we all know as acute inflammation. You cut your finger, it gets red, swollen, warm. All those are signs, cardinal signs of acute inflammation that should be resolved in less than a week or 10 days, right? In this case, We only 20 years ago started to realize that there's other types of inflammation out there, right? The original paper that was published by Franceschi in 2000 talking about this concept of inflammaging points to this reality that there are multiple types of inflammation, right? And in this case, we're talking about a type of inflammation that increases with age, that We call exactly as you mentioned, it's sterile. That means that these stimuli, that the triggers of inflammation are not infectious, right? And they go back to very multiple things that have to do with how we age, right? So the quality of air, the quality of water, the nutrition that you know very well.

The quality of your diet.

Exactly, a consumption of gluten, sedentaryism, sleep quality, the levels of stress, and we can elaborate on this thing extensively for hours. But going back to the hallmarks of aging, that's a really interesting one. Hallmarks of aging are found for the most part in animal models. So we're testing these hallmarks of aging as I speak, mostly using worms and flies and mice. so the classical telomere shortening and genomic instability and disruption in different intracellular communication. All these things are actually driven by systemic chronic inflammation.

Yes. Yes.

And there's more than 5,000 papers showing that every single one of the hallmarks of aging are driven by elevated systemic chronic inflammation in the body as a response to multiple triggers that have to do with how we treat our bodies.

Yeah. So it's almost like the final common pathway, right? When you look at the hallmarks of aging and I was going deep into this in my book, you know, mitochondrial damage changes to our proteins that are damaged, the changes in nutrient sensing pathways around insulin and protein and mTOR and AMPK and all these different pathways, the epigenetic changes, the genomic instability as you mentioned, I sort of added an extra one. microbiome. I think that's degradation of the microbiome, I think could be even an important additional hallmark of aging. But like you said, all of them are worsened and made worse by inflammation. So, the inflammation can both accelerate these, but also these problems can accelerate inflammation. So, for example, disordered nutrient sensing when you have inflammation from eating sugar, then that's going to drive problems with insulin sensing pathways and then you end up with more inflammation. So it's kind of this big mishmash of everything that ends up with lots of inflammation.

That's absolutely right. And oftentimes I get asked this question, what goes first? Is it inflammation or is it the other hallmarks of aging? And it's both, right? As we age, we are exposed to multiple different inflammatory triggers that cause cellular senescence, as you know as well. It's a very important hallmark of aging. We are- Zombie cells.

We call them zombie cells. These cells just don't die. Exactly. And they produce all these inflammatory products that go around just creating a wildfire, like a wildfire throughout your body that accelerate aging even more. It's like, and then they don't die.

And they just keep producing, making other cells zombie cells. It's just a nightmare. Exactly. Exactly. But there are ways to cope with that and obviously, the one thing that we both know is a very powerful method to avoid all these things is to really stop the trigger. All these are triggers that are pushing inflammation upwards.

Well, this is really an important thing because as I begin to do the science investigation and look at these hallmarks of aging and look at the research on longevity, a little more detail. I kind of occurred to me that the researchers in a way are stopping short. They're going, okay, these are the hallmarks of aging. These are the things that go wrong. Let's fix these things. And my question is, what's causing these things? Functional medicine is looking at the cause, the root cause. And if hallmarks are the cause of aging, what's the cause of the hallmarks of aging? And like you said, inflammation is one of the key hallmarks in the final common pathway, but then what's causing the inflammation in the first place that's driving sterile chronic inflammation and causing acceleration of all these hallmarks of aging. So that's really the question. So, you know, I want to, I want to, I want to ask you about that. And I, and then I want to get into how, how you kind of mapped out a way of looking at the sterile chronic inflammation in a novel way that gives us a chance to see our rate of aging and where we're headed, because, because a lot of the traditional testing doesn't do that. and so I think this is a huge contribution to science. And when I saw this, I was so excited. It's like, I know that the people are inflamed and sometimes the normal tests don't show up as inflammation, but then you found all this other stuff. So let's kind of start with, okay, now we've established that, you know, these Hallmarks of Aging. And by the way, they're all in my book. You can read all about them, but it's coming out in February. But, but I want to, we're not going to get into all that. This, this, this, this podcast, but I want to get into the overarching framework of inflammation and what's causing the inflammation. And then we're going to talk about how we identify it and what you've learned about how to identify the right kinds of inflammation that correlate with aging specifically. So take us down the pathway of what we know about the causes because if we know the causes, then we can get to the treatment of the root cause, right? Exactly.

Yeah, yeah, absolutely. 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 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 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, 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 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, 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 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. 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 additives are just not bad because they're, you know, if you're a hippie and you want to eat granola and like that, 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.

And then you were going. Gluten was the next thing you were going into. Exactly. So, or, or plasticizers, Plastics, things that are, are stored in, in Plastics, in plasticizers or, or the plasticizers and. cause 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 gonna go to gluten. Gluten, as you know, is highly inflammatory. Glycine can bind to certain cells in your gut and cause inflammation, increase in leaky gut, et cetera. Then the other one is sedentaryism, as you very well are aware. If we're sitting in a chair, were developing an inflammatory reaction and that it's a perfect 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 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? Paraformaldehyde 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 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 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? Hey everyone, it's Dr. Mark. Now something I get more and more excited about every year is personalized medicine. Now when I began practicing functional medicine over 20 years ago, it was clear to me we have to look at how unique each body is. Now with technology advancing in amazing ways, we can truly take that concept to the next level. One of the tools that I recently discovered that can help us all do this from home is InsideTracker. Founded in 2009 by top scientists in aging, genetics, and biometric data from MIT, Tufts, and Harvard, InsideTracker is a personalized health and wellness platform like no other. It's purpose-built to help you live a longer, more productive life. Their cutting-edge technology analyzes your blood, DNA, your lifestyle to give you highly personalized recommendations. Then using the app, you can track your progress every day. Inside Tracker tells you what to do and why so your health goals are clear and actionable and most importantly based on exactly what your body needs. And now you can connect Inside Tracker with your Apple Watch to unlock deeper, more precise insights into your health. With real-time exercise, resting heart rate and sleep data synced with your Inside Tracker plan, you can truly wear your health on your sleeve. My team took InsideTracker for a spin and really loved it. They discovered some important things about their health that led them to stop procrastinating when it comes to certain parts of their health, like, for example, finally taking a vitamin D supplement after seeing they were deficient, or eating more iron-rich foods due to low ferritin and hemoglobin, and making an effort to embrace stress reduction techniques after seeing high cortisol levels. Now, health is not black and white. Your wellness plan shouldn't be either. If you're curious about getting your own health program dialed in to your unique needs, I highly recommend checking out Inside Tracker. Right now, they're offering my community 20% off at inside tracker.com/DrHyman. That's I-N-S-I-D-E-T-R-A-C-K-E-R dot com slash Dr. Hyman. And you'll see the discount code in your cart. Now, let's get back to this week's episode of the Dr. Dr. Peter's Pharmacy. 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 if you screw it up.

I doubt you will. So similar to the concept of exposome, the end in the word som, accounts for the totality of it. 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 the Thousand 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, hs-CRP, sedimentation rate, that you can go to the doctor and have those are very 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 CRP- I tell people.

That it's not very sensitive. It's not very sensitive.

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 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?

So 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 are 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 7,000 proteins in the blood, 3,500 metabolites, and it becomes much more normal. It has normalized with time.

So, when you did the 1,000 Immunomes Project, Were you measuring how many analyze? 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 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 as 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 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 this 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, 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 they're 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 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 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.

We can-- you- can do a selfie of me, whatever, 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 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 an 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 downwards. So in other words, they have an inflammatory age that is beneficial according to their age. Then we find that those 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's two diseases. And then you add up up to 10 diseases. So, 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. Wow. So 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. In 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 cytokine 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 a very different set of proteins that are coming up as being the most predictive. And then we went ahead and looked at we had a number of different cardiovascular phenotyping measurements in these individuals and were able to correlate CXCL9 with cardiovascular aging, with cardiovascular health. And then we went ahead and continued this study to look for mechanisms and to explain other morbidities. And we published that last year in.

2021. so basically this, this I age biomarkers. And, and as I understand, there's like, there's a smaller panel on 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, and then there's others that are an expanded one. Maybe it's seven or eight. I don't remember the number, but there, there's not an infinite number of these. And, 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 key 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 cells produced. The endothelium is the cells that.

Are.

Making up your vessels, right?

The lining of your blood vessels.

Exactly, your blood vessels, lining of your blood vessels. And those cells can become inflammatory. So when you, as 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? Or 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, right? CXCL-12. 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 of tubes that you need. 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 siRNA, we can restore completely the function of those cells.

Exactly. Amazing. So really it opens the door to a different set of therapeutics because before it was very hard to measure metrics that gave us a predictive sense of the rate of aging. There's DNA methylation clocks, which are really important. I've talked about them before in the podcast, but they're essentially looking at your epigenetics and how your genes change and the marks on your genes change and how that correlates with longevity and aging and your biological age. For example, I had my DNA methylation test done and I'm 63 this month, but I'm actually 43 according to my biological age, which makes me happy. So then, then I think the immune age is a little bit different. because it sort of looks at a different kind of component of aging, which is not just epigenetic changes, but the immune changes, which may, who knows, may be more important. And what's really important as we start to look at the science of longevity is we need biomarkers or we need metrics to say, oh, if we do this, this gets better. In other words, if I eat better, do these markers change? Or if I take this vitamin or this herb, does it get better? If I do a sauna, does to fix this problem or whatever it is that we're doing is, do I take stem cells? Is it going to make it better? So we need metrics to sort of look at the interventions that are, are going to control. And so I know you've done a lot of work and you're doing now a couple of clinical trials actually using some interventions that are designed to modify these biomarkers that you've identified, and that hopefully will then sort of lead down the road to avoiding some of these age related diseases. Or even treating it?

Right, I think what you're bringing is twofold, right? You're talking about ways to evaluate interventional procedures. It could be dietary, it could be other lifestyle procedures. We need those surrogate markers of aging. Inflammatory age is one. Epigenetic aging is another one. This now metabolic metabolomics clock, there's a number of clocks out there that will ultimately help address the question, is this intervention helping for the aging process? That's one question. Now, a very different one is, are these biomarkers or clocks, can they be used to identify interventions? Not interventions that we know could help, like a better quality of sleep or not interventions that we know are anti-inflammatory, like a better diet, but interventions that can actually reverse the clock because you're targeting those biomarkers. So for example, if you do that with the epigenetic clock, that's very difficult. And why is it difficult? Because we understand very little about how to change epigenetic landscapes. That's very difficult. Now, with the inflammatory age, it's much easier because we just measure proteins. so I take the way we have building this and then let me expand this a little bit in this idea. We take these five biomarkers, one of them being CXCL9, the other one eotaxin, gamma interferon, other biomarkers that you can find in blood, and then we use again artificial intelligence and machine learning to from the literature, hundreds of thousands of compounds that are able to interact with these biomarkers. And then I would ask the algorithm to pull, to take the compounds that are likely to change that in vivo.

Right? Yeah.

And so that's the basis of the two clinical studies that we have been running. The first one, we identify a compound that is able to decrease your inflammatory age by about two and a half years. in two weeks.

Wow.

That's very rapid, very, very quickly.

What is that compound?

That's a compound that's included in a hot breakfast that I cannot really disclose at the moment because this is a collaboration with a corporate partner. What I could tell you though is our own clinical trial in a thousand individuals in which we tested different grass approved compounds. So these are generally recognized as safe by the FDA. So we can take drugs, we can take bioactive compounds, and we can take also a number of different mapping compounds to food and food ingredients, right? So things like manganese chloride, beta-carotene, iron, other vitamins, p-cresol, quercetin, things that are readily available available as a direct to consumer LTC. Yeah, it was interesting because when I.

Looked at your clinical trial, it's listed on clinicaltrials.gov, the compounds that you had identified to regulate inflammation, I was a little surprised by some of them, like iron bisglycinate, magnesium chloride, vitamin D2, guar gum, you've got a broccoli extract in there, indole-3-carbinol, methionine, biotin, caffeine, lutein, beta-carotene. So, I'm like, this is an interesting cocktail. I'm like, how did they come up with this? And, I guess it was because you used the literature to determine which of these compounds may have mechanistic actions that regulate these pathways of inflammation, right?

Exactly. That's exactly right. And, you can take drugs to be able to repurpose drugs, and that's not in our business here. Or, we can take bioactive compounds that are readily available and also found in so you're absolutely right. Yeah.

It's amazing. So, so these trials are not completed yet. You're still, they're still underway. So we're gonna find out more. But, but, you know, you, you have, you know, on the, on the website for Oedipus help, which is the company that's sort of behind the IH test. And by the way, is this available, this test now clinically yet or not yet?

It's not available yet. And the reason is to make this available to the public, we need a couple of milestones, right? One is to finish a trial, be able to add our claims, and preliminary results are looking really interesting, very, very good. So I'm very happy for that. And we also need a CLIA accreditation. And this is particularly for labs that are taking clinical samples. So we cannot go to market quite yet until we have a CLIA certification in our laps. So that's part of the ongoing process in the market. Yeah. So I know we had lunch right.

As COVID was starting in March of 2020. And you were telling me about this and I was like, wait a minute, it's two plus years ago already. Let's go. I'm waiting, I'm waiting, I'm waiting. I'm being patient here. But it's exciting. I think it'll come around soon. And then we'll be able to, you know, then as an individual, you can go, you know, geez, I want to change my diet or I'm gonna take these supplements for a few months and I'm gonna check my test and I'm gonna repeat it and see how it looks. Right. And so we'll be able to sort of on a end of one basis determine what works and what doesn't for us. And I think as a doctor, it's very exciting to me because then I have a metric to use with my patients to determine, you know, is what I'm doing working or not on things that actually really matter.

Right.

So we do things that are, we do our, that already, like, oh, we change our diet and improve our cholesterol, or we change our improve our blood pressure. We see a reduction in CRP or inflammation, and we can do that already. But I think this is going to be a much more profound marker because what you're saying is based on this huge data analytics and thousands and thousands of biomarkers, you're actually finding the things that are maybe the most important.

Right, and it's important that you mention the fact that you as a physician that can use this to evaluate how your patients are doing, right, and how effective your interventions of your favorite interventions for a particular patient will work. And so on that angle, I would like to say that we really need to educate primary care physicians and other health care providers about the power of inflammation, about the power of our test. For now, it's a test that is out of pocket and it will come out as out of pocket test. And the reason for that is that we have a long way to get FDA approval. And why is that? Because aging is not considered a disease. Inflammation is not considered yet. Inflammation is also not considered a disease. So we have a risk factor for multimorbidity, which is also not a disease. How can you go to the FDA and explain these folks that this needs to be reimbursed? and everybody should have access to this. So that's a completely different story, but we do have to map inflammatory age as a risk factor for a particular indication for a particular disease, and that's one way to go FDA and get that approval.

It's such a mess though because traditional medicine is so hyper specialized and reductionist, and it doesn't understand that if it's like a unified field theory, right, of medicine. If you understand inflammation, you understand so much about what goes wrong with our bodies and any, really almost any disease. And it's such a key phenomena. I mean, and it's such a misunderstood and inadequately understood phenomena that the doctors don't know how to identify inflammation properly. They don't know how to treat inflammation properly. They don't know what to do from a lifestyle perspective. And they go, oh, just take Advil. you know, I remember one study that came out a while ago where they're like, oh, in Alzheimer's is inflammation in the brain. So they did a big study where they gave everybody Advil. And I'm like, oh, that's not gonna work. It's like, you know, we, we got to find out the cause of the inflammation. And so from a functional medicine perspective, it's, it's the things you talked about. It's sedentary lifestyle, it's inflammatory diet, it's chronic stress, it's environmental toxins, it's allergens, it's microbes, it's the gut microbiome, all these things, which we actually ability to control. And it's also the lack of things, right? So, you know, I hear from Argentina and, you know, the world's quite different down there and the foods are different and people live in a more sort of closer to land way. And like when I came back from Sardinia and Ikaria in Greece and in Italy, I mean, these people were eating these foods that were so rich in phytochemicals and in these compounds that are anti-inflammatory. they didn't even know they were doing it, right? They don't know that they have this wild sage tea every day for breakfast because that's what's growing in their field, you know, that it's full of these catechins that in fact modify NF-Kappa B and regulate gene expression of inflammatory cytokines and blah, blah, blah. They don't know any of that. They just drink the stuff because it tastes good. So, you know, but we've gotten so far away from that and, and yet, you know, what's exciting is, you know, you're starting to kind of look at these interventions, which are relatively low cost, which are relatively accessible to most people. Like it's what you eat, it's how much exercise, it's how you sleep, it's how you manage stress, it's including some phytochemicals in your diet, maybe a few supplements. And these are the kinds of things that you're looking at because when you, I think you realize, and it's exciting to me to kind of hear the way you're thinking about it is that it's not like we're gonna find the drug to, you know, change your immune age. You know, it's like that just, that's just not a sensible way to think about it because it's not one pathway. There's all these inputs that you have to modify in order to actually allow yourself to age well and to not only, you know, prevent disease, but to reverse your biological age.

So the good example that you have given on taking Advil to combat inflammation Alzheimer's is a poster child. It's perfect because not only this will not work, but also you would wipe out your microbiome and in the long term Advil will cause probably more chronic inflammation.

So it is not just- Yeah, exactly. And why are we- Leaning.

But the hope here is that more and more primary care physicians and functional medicine physicians are realizing the importance of inflammation, the important part of using this systems approach. We can't treat one disease. You're going to have another disease. What happens if currently you stop today, you cure cancer in the entire population worldwide? You only extend the lifespan of the humanity by one and a half years. We know that because you have all the diseases, and that's where it's important.

So the war on cancer doesn't make sense, right? The moonshot for cancer, it should be the moonshot for the root causes of disease, right?

Of many diseases, exactly. And we know now that that's possible. And let me tell you something really interesting that's happening in France. I'm collaborating with a group in Toulouse and the WHO very recently in July of this year, have accepted, has included in the ICD-11, the classification for diseases, a decline in intrinsic capacity as a disease. It's not aging, right? Because we can't talk about aging as a disease that causes a lot of social and political issues. And I think we're talking now about the decline in intrinsic capacity. It would be something similar to aging, right? But that's very good news because if we now can map or correlate inflammation with that decline in intrinsic capacity, we can present this to the FDA and make it available for everybody, right? And so the French system is really interesting what's happening. Bruno Vella is at the University of Toulouse, he's assembling around 500 people in the university hospital and he developed an app that tracks functional domains of aging, namely vision, audition, mobility, et cetera. And what happens if he already has 25 or 30,000 individuals that have been filling up this questionnaire in an app, what happens with there is a slight decrease in some of these functional domains of aging. Red flag calls a nurse, nurse comes in, she makes sure that the input is correct and that person gets derived to a primary care physician. They're not sick yet. That's not an indication. They're starting to decline in their capacity of their organs and systems. So that's where the whole system, healthcare systems are actually going through. I think the idea of doing functional organ specific decline is where everything and everybody should be focused on. We now have a clock of different organs, that's a completely separate story, but we're trying to define from a single drop of blood how how or where you mark, where are you in terms of your internal organs? Is it your liver maybe going a little bit off? Maybe my cardiovascular system is off as opposed to my liver. So everything is pointing to functional and to personalized precision health using these different domains.

So the IH test is going to help us map that, Right, and that's exactly right. Do you think you're gonna be adding more biomarkers to that test or is there gonna be another kind of framework to look at biological aging, you know, as you start to learn more 'cause you're constantly learning, right?

So aside from the product that we have, inflammatory age, which is these five core proteins, we're measuring on the back thousands of them, right? So imagine we don't have a very large population ethnically diverse so far, right? So the study was run at Stanford, Palo Alto individuals, very specific population there, and we're expanding this to African Americans, to Indians, to Japanese population. So more biomarkers will be added for absolutely no question about it.

You know, one of the things I thought was passing about your study was that you had a bunch of people who got very old, like there were like 19 people who got to 99 or more. What did you learn from that group?

So there's just a centenarian group that we obtained in collaboration with the University of Bologna in Italy. So they get to be centenarians, right? A lot of fish, a lot of walking, good quality of lives. And so what we learned was that pasta bolognese, right? I would avoid that one. but what we did learn when we did the, in that population we measured 1300 proteins and we derived inflammatory age and we compared with older adults 70 to 80 years old and it turns out that their inflammatory age in this very older individual centenarians, I'm saying, It's very, very low as compared to the calendar age. So on average, 40 years below their calendar age. That means that for a- so assuming.

That when you look at their I age test, they were 40 years younger. So if they were 100, they were like 60.

On average, there's some individuals that is closer to their own age and some of them, there's one outlier very interesting liar, super healthy. He's never seen a doctor, 105 year old. He looks like a 25 year old kid. So we're talking about 80 years below it's got his.

Oh, you mean not he looks like it. His bloodwork looked like he was 25.

Exactly. Yeah.

It's like maybe he got a birthday wrong there.

No, no, no, no, no, no, no. I'm referring to his inflammatory age. was 80 years below his calendar age. And he's doing extremely well and still alive.

Incredible. And so you found basically that were there anything unique about these people besides their lower levels of these inflammatory compounds in the IH study?

Not in our study. We didn't look in detail, but we know that the microbiome of centenarians is very particular. that the immune system is also particular with very high levels of CD4 naive cells, which usually they exhaust with time. So it looks like they do have.

A.

Constellation of biomarkers that are associated with immune system function that looks much younger than their chronological age.

Wow. Wow. That's quite amazing. And were there any characteristics of their lifestyle, their habits, what they did that were different besides living in Bologna? Were these women all in Bologna, right? Or were they all?

Yeah, we couldn't have access to additional information. This is a correlation that we just had the samples, the blood samples, and we run our studies. And what we do see though is that when you do metabolomics, Metabolomics measures around 4,000 metabolites from blood that can inform what you're eating actually, right? So the quality of the nutrition. We do see that they have... Yes, we did.

What did you find?

Well, we do see a very favorable phenotype in the metabolomics. So the metabolomics clock that we built is actually much more beneficial also in these individuals that in younger counterparts that are still older, like so 70 to 80 years old.

So, so this metabolomic clock is a measurement of the metabolites in the blood that are related to what they're eating or related to what?

Yeah, so it's yet another clock of aging. So you take metabolomics in large cohorts and you're trying to predict a chronological age and after you do so, you look which metabolites are more informative. And then you map that back to foods, yes. So we can actually predict what you were eating yesterday, say, based on that metabolic clock.

And did you see any things that they were eating that were unique or different in that group?

Mostly fish derivatives.

Yeah, fish derivatives. Interesting. Yeah.

Yeah. Not surprisingly, no.

Well, Omega-3 fats and, you know, selenium.

Iodine, all those things. Yeah.

Interesting. I mean, I, I did my metabolomics once, and I, it was shocking, actually. And, and it made me change everything. So I, I found that I had these oxidized byproducts of olive oil because at the time, this was years ago, I was using olive oil to cook, like, not just on my salad dressing. And they were basically oxidized, damaged olive oil compounds, which, I think, olive oil is healthy. but when you heat it up to high temperature, it oxidizes. So I was actually harming myself by having cooked olive oil. And I didn't notice that, you know? Completely. Yeah, so it was interesting. So I think what's so exciting is that, you know, people listening, there's this whole new world emerging in medicine that you're really not getting in the clinic that is able to sort of look at massive amounts of data from things that, you know, we never even looked at at all in medicine clinically. I mean, there are thousands and thousands of pounds in our blood, you know, tens of thousands of genes that are doing all sorts of things. Our epigenetics, our immune system, our microbiome. I mean, that's a whole nother can of worms of what's in there, which is even far greater than our own genome. There's probably a hundred to four, 400 times the amount of genes in our microbiome than there are our own genes. So they're all producing proteins and metabolites. We're absorbing them. They're doing stuff. It's like. It's like this incredible. poles, ecosystem, soup. And so, what's exciting about people like David and Dr. Fuhrman, I mean, is that they're actually able to start to make sense of all this kind of stuff that has been hidden below the surface and now is becoming revealed and guiding us into ways of changing our practice of medicine, our diagnostics, and our ability to change our therapies and then measure how our therapies are working in ways that are much more relevant than what we're doing today. Would you say that's fair?

It's absolutely fair. And we owe this to technology. Technology has enabled all these to happen. We can now measure what we measure because we have advances in technology. We also have advances in computing power. And that's very, very important. When 10 or 15 years ago, just to run a script that may involve a thousand people, and 50,000 features, it could take a day. Now it's taking milliseconds. So both at the analytical standpoint in terms of lab, but also at the computational standpoint, technology has evolved and we're using that at large to try to resolve this issue of information that drives aging. So we know that today we have mapped that out and we're continuing to do do so. Yeah.

So what are you most excited about that's coming up for you? What are the things that you're, you're seeing on the horizon that get you really excited and out of bed in the morning?

Yeah. Well, I mentioned this transition, right, from a highly reactive, disease centered vision of governments and non-for-profit organizations and the whole industry and academics to a much more proactive, a much more preventative, a much more functionally related healthcare system. That is something that I think I'm personally feel like I'm involved in this. I'm taking part of this change and I'm very excited for this huge change that is very positive for humanity.

That's so exciting. It just reminds me of this patient I had years ago, we came in, his blood sugar was like 110, which is pretty much in the almost diabetic stage, like pre-diabetic diabetes is like 126. And I said, gee, did you see your doctor about this? And what did he say? And he says, well, yeah, he said, he saw it. And he said, I said, what do you say? He said, well, he said, watch it until it gets to be, you know, diabetes, and then we'll treat it with a medication. And I was like, and I think this is the opposite of that. It's like before even you have a symptom, before even a disease manifests, before even you, you can pick it up on most lab work, we're going to be, you know, able to almost like sort of Star Trek, use a tricorder and kind of figure out what's going on, run it through, you know, this incredible computational abilities that are emerging, not that we haven't even seen yet, like quantum computing. cooking, which allows us to just crunch enormous amounts of data. I mean, each one of us human beings has literally gigabytes, terabytes of data in us, literally all the time, like trillions of reactions. And it's just beyond the capacity of the human mind to even start to process or think about. But when you start to combine these technologies with emerging science of systems biology, and the work that, you know, you're doing at Stanford. And, you know, there's a lot of other people doing this in other domains and in, in medicine, and it's all coming together. So the medicine that we see today is really, I would say it's, it's like, you know, we're gonna look back and go, God, this is like bloodletting or leeches, you know? And, and I think, I think we're, we're in this incredible moment, and I, I'm excited to see about your work with the 100,000 aminos project, the IH test, which is coming online, hopefully. soon, and also with the kinds of interventions you're now doing to see what modifies your immunological age. Because, you know, this is kind of an exciting moment where there's, like, billions of dollars pouring into longevity science, where there's, you know, it was kind of a neglected stepchild of medicines. Like, why study aging? It's inevitable. So what? Who cares? Like, you know, let's study cancer. Let's study heart disease. But aging, you know, one of the things that was shocking is like, if you're like 30 years old and you're a smoker and you smoke three packs a day of cigarettes, your risk of cancer is like 50 times less than if you're like 75 years old and don't smoke, right? Something like that. Where the idea, I mean, I'm kind of, you know, just making up numbers here, but I think the idea is that you're, the aging itself is such a bigger risk factor for all these diseases that we're kind of missing the point of of like studying aging. So you're studying aging and a lot of other people are doing this. It's an exciting moment. So thank you so much, David, for your work and at Stanford, we're gonna keep track of it. I'll probably have you back on the podcast to talk about what's next and happening in your horizon. Everybody listening, you can check out more of their work at their website, it's edificehealth.com, and there's information there about the IH test about the 100,000 Immunes Project, and you can read their research, you know, kind of a little technical sometimes, but they've got a really great interface to sort of learn more about what they're doing. And I hope you've enjoyed this podcast because I did, and I think it's a very exciting moment in medicine. And David, I hope we continue to collaborate and talk. And for those of you who listen to this podcast and you love to share with your friends and family, but they'd love to hear about how to regulate their inflammation. subscribing to every get your podcast, and we'll see you next time on the doctor's Pharmacy. Hey, everybody, it's Dr. Hyman. Thanks for tuning into the doctor's Pharmacy. I hope you're loving this podcast. It's one of my favorite things to do and introduce to you all the experts that I know and I love and that I've learned so much from. And I want to tell you about something else I'm doing, which is called Mark's picks. It's my weekly newsletter, and in it I my favorite stuff from foods to supplements to gadgets to tools to enhance your health. It's all the cool stuff that I use and that my team uses to optimize and enhance our health. And I'd love you to sign up for the weekly newsletter. I'll only send it to you once a week on Fridays. Nothing else, I promise. And all you have to do is go to drhyman.com/pix to sign up. That's drhyman.com/pix, P-I-C-K-S. and sign up for the newsletter and I'll share with you my favorite stuff that I use to enhance my health and get healthier and better and live younger longer. Hi everyone.

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