How Silent Inflammation Accelerates Aging

Mark Hyman, MD

Dr. Mark Hyman is leading a health revolution—one focused on using food as medicine to support longevity, energy, mental clarity, happiness, and so much more. Mark Hyman, MD is a practicing family physician and an internationally recognized leader, speaker, educator, and advocate in the field of Functional Medicine. He is the founder and director of The UltraWellness Center, Founder and Senior Advisor for the Cleveland Clinic Center for Functional Medicine, a fifteen-time New York Times best-selling author, and Board President for Clinical Affairs for The Institute for Functional Medicine. He is the founder and chairman of the Food Fix Campaign, dedicated to transforming our food and agriculture system through policy.

He is a co-founder and the Chief Medical Officer of Function Health. He is the host of one of the leading health podcasts, The Dr. Hyman Show with 150+ million downloads. Dr. Hyman is a regular medical contributor to several television shows and networks, including CBS This Morning, Today, Good Morning America, The View, Fox, and CNN.

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Full Transcript

Automatically generated. Please forgive any typos or errors in the following transcript. It was generated by a third party and has not been subsequently reviewed by our team.

Introduction:
Coming up on this episode of the Doctor's Farmacy.

Dr. David Furman::
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.

Dr. Mark Hyman:
Welcome to Doctor's Farmacy. I'm Dr. Mark Hyman. That's farmacy with an F, a place for conversations that matter. 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 going to 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 Research on Aging, as well as the director of the Stanford 100 Immunomes Project. We're it deep into what the 100, I mean, sorry, 1,000 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 postdoctoral work at Stanford School of Medicine.
He's basically looking at how we use artificial intelligence and 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 going to talk about called the IH Test, measures your immunological age. 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 going to talk a lot about this.
I do include a lot about this work, about the 1,000 Immunomes 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 going to get deep into this. So welcome, David.

Dr. David Furman::
Thank you so much, Mark, for having me here. Pleasure.

Dr. Mark Hyman:
Yeah. 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 the blood panel and it may be 20, 30, 50, maybe 100 analytes if you're lucky, and he goes, "Oh, you're fine. Everything's fine. Your liver's fine. Your kidney's fine. Your electrolytes are good. Your cholesterol's all right. Okay, good. You're fine," and sends 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.
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 in bioinformatics and artificial intelligence. You were going to take a thousand people ages, I think, nine 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 if were relevant or not, but you were going to 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 published this data and you've developed this test which allows us to measure our immunological age, which is really important, and we're going to talk about why immune age is such an important biomarker of health and aging and it's exciting.
So before we get into the nitty gritty of 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 were thinking very differently than most scientists out there about this process of aging and longevity?

Dr. David Furman::
Yeah. 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. That's the confusion.

Dr. Mark Hyman:
You're a med student dropout. Okay.

Dr. David Furman::
Exactly.

Dr. Mark Hyman:
That counts. That counts. I don't know. You maybe didn't get officially licensed, but you definitely went through medical school. So that's the important part.

Dr. David Furman::
Exactly. I'm not board certified, but exactly. I went to medical school, got my PhD in 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, right? For the most part, what we know about immunology over the past 100 or 150 years comes from animal models, namely mice, right? 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 two billion dollars to make it work to get to the FDA approval. This means that the systems are not working well 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. One thing that we noticed 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.

Dr. Mark Hyman:
Hopefully we're not, hopefully we're not.

Dr. David Furman::
Therefore, the variation in immune systems is huge. It's gigantic. So one way to cope with this huge variants 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. 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. 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 this individuals and we can make this generalizable."

Dr. Mark Hyman:
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 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 want to 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 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 because 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 a weird 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 really finding and looking for, right?

Dr. David Furman::
Exactly. So 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? In this case, we're talking about a type of inflammation that increases with age that we call, exactly as you mentioned, is sterile. That means that these stimuli, that the triggers of inflammation are not infectious and they go back to very multiple things that have to do with how we age, so the quality of air, the quality of water, the nutrition that you know very well-

Dr. Mark Hyman:
Inflammatory diet, right.

Dr. David Furman::
Exactly, consumption of gluten, sedentarism, 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, right? 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.

Dr. Mark Hyman:
Yeah. So it's almost like the final common pathway, right? When you look at the hallmarks of aging, and I was deep into this in my book, 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 added an extra one, the microbiome, and I think 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 this big mishmash of everything that ends up with lots of inflammation.

Dr. David Furman::
That's absolutely right. Oftentimes, I get asked this question. What goes first? Is it inflammation or is it the other hallmarks of aging? 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 have found that-

Dr. Mark Hyman:
Zombie cells, we call them zombie cells.

Dr. David Furman::
The zombie cells, exactly.

Dr. Mark Hyman:
These cells that don't die and produce all these inflammatory products that go around just creating a wildfire, like a wildfire throughout your body that accelerate aging even more, and then they don't die and they just keep producing, making other cells, zombie cells and it's just a nightmare.

Dr. David Furman::
Exactly. Exactly, but there are ways to cope with that. Obviously, the one thing that we both know, it's a very powerful a method to avoid all these things is just really stop the trigger. All these are triggers that are pushing inflammation upwards.

Dr. Mark Hyman:
Well, this is really an important thing because as I began to do the science investigation and look at these hallmarks of aging and look at the research on longevity, a little more detail, it occurred to me that the researchers in ways 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." My question is, well, what's causing these things? Right? Functional medicine is looking at the cause, the root cause. If hallmarks are the cause of aging, what's the cause of the hallmarks of aging?
Like you said, inflammation is one of the key hallmarks and 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 I want to ask you about that, and then I want to get into how you mapped out a way of looking at this sterile chronic inflammation in a novel way that gives us a chance to see our rate of aging and where we're headed because a lot of the traditional testing doesn't do that. So I think this is a huge contribution to science.
When I saw this, I was so excited. It's like I know that that 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 start with, okay, now we've established that these hallmarks of aging, and by the way, they're all in my book, you're going to read all about them, it's coming out in February, but we're not going to get into all that on 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?

Dr. David Furman::
Exactly.

Dr. Mark Hyman:
That's the key.

Dr. David Furman::
Yeah, yeah, absolutely. So I've been studying social and exposome determinants of inflammation for about 15 years now 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 are causing inflammation. We can-

Dr. Mark Hyman:
What's the exposome? What's in it?

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

Dr. Mark Hyman:
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.

Dr. David Furman::
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. That is something we know. Now, the problem is in some countries, people are dying at the age of 70, 75. That's the average lifespan expectancy. Some countries is 89 or 90 like Monaco or Japan because we figure out ways to extend that period of healthy living, right? So in essence, what we're trying to achieve is to push that 80 to 90 average life expectancy to 120.
Now, tweaking genes is a completely different thing. We're not going to talk about that at this podcast, but I'd like to go to idea of the exposome, back to the root cause of inflammation. So we do know already today that pollutants in the air, that pollutants in water, that-

Dr. Mark Hyman:
Pollution.

Dr. David Furman::
Pollution, exactly. Pollution are drivers of inflammation, imbalances in nutrition such as both the macro and micronutrients, right? These cause inflammation by large. Food additives, go back to the microbiome, things like carboxymethylcellulose 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, gliadin, it's either an-

Dr. Mark Hyman:
Wait, wait, I want to hold on. What you said was very important. You just said that basically when you eat these food additives, things that are in our food that we don't even pay attention to like polysorbate 80, it damages your gut lining and then all the poop and bad 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 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 if you're a hippie and you want to eat granola and you shouldn't eat food additives, they're really damaging to our bodies, right?

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

Dr. Mark Hyman:
Then you were going gluten was the next thing you were going into.

Dr. David Furman::
Exactly or plasticizers, plastics, things that are stored in plastics in plasticizers or the plasticizers and plus the resin, makeup plastic, and there's S leeching, and there's a leeching of plasticizers that go into our foods and those are hormone disruptors that also cause inflammation longterm.
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 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 perfect correlation between the time-

Dr. Mark Hyman:
Wait, I'm going to get up. I'm going to get up.

Dr. David Furman::
The time sitting in a chair and mortality, there's almost a perfect correlation between those two. Sleep quality, there's disruption in our circadian rhythm. Social stress, there's a very, very compelling evidence that individuals that are exposed chronically to social stress, social isolation, they develop inflammation, they have more cardiovascular disease, and death. Obviously, other chemicals that we're exposed to that are surrounding us, just to give you a good example, formaldehyde, paraformaldehyde, that serves as a glue for plywood that is often used in furniture and cabinetry.

Dr. Mark Hyman:
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. 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? 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 immune ... Well, why don't you define the immunome? You're the expert. I'll probably screw it up, but it-

Dr. David Furman::
Yeah. I doubt you will, but similar to the concept of exposome, and the word some accounts for the totality of it. So when we talk about 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 1,000 Immunomes Project, which it's a project that, as you mentioned, lasted for about now 15 years. We just got another source of funding from NIH, 15 million dollars, to continue the study for the next five years.

Dr. Mark Hyman:
Amazing. Amazing.

Dr. David Furman::
We've been monitoring these individuals, their immunome, and basically, we're focusing 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, HSCRP, 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 the immunome-

Dr. Mark Hyman:
It's helpful, but it's not very sensitive, it's not very sensitive.

Dr. David Furman::
It's not very sensitive as a measure for systemic chronic inflammation, exactly, and that's where this whole idea of discovering new biomarkers but looking at the immune system in an unbiased fashion comes into play, and that's what we did. So what we are using is not only technology that help us measure all these things, but also computational analytical tools that are rather novel including AIML, machine learning, to be able to cope with the data and to derive metrics that are simplified, that take us hundreds of thousand parameters. Now, we have a metric that can be used in the clinic, right? That's-

Dr. Mark Hyman:
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?

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

Dr. Mark Hyman:
So when you did the 1,000 Immunomes Project, were you measuring how many analytes because I remember reading the paper and there were 50 cytokines that you looked at, but was there a lot of other stuff you also measured besides those 50?

Dr. David Furman::
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. 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. 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.

Dr. Mark Hyman:
So in a way, this is something that's never been possible before because you have this convergence of the framework of systems biology, understanding the bodies and network where there's these dynamic interactions of thousands and thousands of maybe trillions of chemical reactions every minute. 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. So as a doctor, I'm so excited because it's always been really clear to me that we're missing stuff, that we do an exam and we do lab tests pretty much like we've been doing for the last a hundred years without a change.

Dr. David Furman::
Yeah, exactly.

Dr. Mark Hyman:
It's like, "Come on, guys, there's more going on here," and we get stuck in the way we do things, but you're blowing the lid off it. What you did was then correlate, things that would be hard for the average scientist in this lab with graphs and maps and things to figure out, correlate which of these analytes and proteins and cytokines and biomarkers were correlated with different diseases and the rate of aging. So to explain what you found as you begin to unpack the extraordinary amount of data and what were the nuggets that you came up with in terms of identifying the things that we should be looking at, and there're honestly things I never even heard of as a doctor that I don't even remember.

Dr. David Furman::
Sure.

Dr. Mark Hyman:
Maybe they taught me at medical school, but I don't even think we knew about it then. So it's so exciting, but like, "Oh, there's this cool thing that is so different that I never even heard about that maybe 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?

Dr. David Furman::
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. So we can predict the age of individuals by just a selfie. That's easy. We can predict-

Dr. Mark Hyman:
Come on. You do a selfie of me, whatever, how old do I look?

Dr. David Furman::
You can also take any blood biomarker and predict the age. Prediction of age is easy because things change with age. That's not the complicated part. The interesting part is once you take this immune biomarkers and try to predict the age of individuals. So in essence, you're 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 downwards. So in other words, they have an inflammatory age that is beneficial according to their age. Then we find that with higher inflammatory age according to their age are at risk for developing multi-morbidity. That's the first finding, and multi-morbidity-

Dr. Mark Hyman:
Multi-morbidity is what?

Dr. David Furman::
Multi-morbidity 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 to 10 diseases. 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 identify is a biomarker from blood that is focused in the immune system, that is able to predict multiple diseases simultaneously. So this is multi-morbidity, that concept. 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 they're independent enough, and you take a grip strength, and the time up and go, different functional measurements in individuals, and we're able to predict with inflammatory age seven years before it happens who's going to become frail.

Dr. Mark Hyman:
Wow.

Dr. David Furman::
So that's another big discovery that we did that we published last year in Nature Aging. There are 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? Markers that are usually coming up in the inflammatory reaction against pathogens, that's easy to measure, interleukin 6, TNF alpha, interleukin one beta. Those are well-established canonical markers for acute inflammation.

Dr. Mark Hyman:
Those are cytokines like we talked about with the cytokines storm with covid. So those are the typical cytokines, right.

Dr. David Furman::
Exactly, 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. 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 continued this study to look for mechanisms and to explain other morbidities, and we published that last year in 2021.

Dr. Mark Hyman:
So basically, with this IH biomarkers, and as I understand, there's a smaller panel and expanded panel. So out of these thousands and thousands of things, you found four key ones that you can measure now on a blood test. 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. In those 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?

Dr. David Furman::
Correct. So the understanding of these diseases is very poor as we know. Otherwise, we wouldn't suffer from those. 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? 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 cell produced-

Dr. Mark Hyman:
What's that?

Dr. David Furman::
The endothelium is the cells that are making up your vessels, right?

Dr. Mark Hyman:
They're lining your blood vessels.

Dr. David Furman::
Exactly, your blood vessels, lining up your blood vessels, and those cells can become inflammatory. So as one 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.

Dr. Mark Hyman:
So what are these cytokines and chemokines? What are they doing? How are they accelerating aging? Are they the cause of heart disease? Are they the cause of dementia? Are they just correlated with them?

Dr. David Furman::
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're putting 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.
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, we block CXCL9 by introducing what we call silencing of the protein, in this case we use an shRNA, we can restore completely-

Dr. Mark Hyman:
The function.

Dr. David Furman::
... the function of those cells. Exactly. Yeah.

Dr. Mark Hyman:
Yeah. 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 on the podcast, but they're essentially looking at your epigenetics and how your genes change and the marks on your genes changing and how that correlates with longevity and aging and your biological agent. 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.
Then I think the immune age is a little bit different because it looks at a different component of aging, which is not just epigenetic changes, but the immune changes, which, who knows, maybe more important. 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 it fix this problem or whatever it is that we're doing? Do I take stem cells? Is it going to make it better?
So we need metrics to look at the interventions that are going to control. 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 lead down the road to avoiding some of these age-related diseases or even treating them.

Dr. David Furman::
Yes, 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. There's now a 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? Non-interventions that we know could help better quality of sleep or non-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. 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, right? So I take the way we have building this and let me expand this a little bit and this idea. We take these five biomarker, one of them being CXCL9, the other one EO toxin, [inaudible 00:39:52] other biomarkers that you can find in blood, and then we use, again, artificial intelligence and machine learning to pull from the literature hundreds of thousands of compounds that are able to interact with these biomarkers. Then I would ask the algorithm to pull, to take the compounds that are likely to change that in vivo, right? 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.

Dr. Mark Hyman:
Wow.

Dr. David Furman::
That's very rapid, very, very quickly.

Dr. Mark Hyman:
What is that compound?

Dr. David Furman::
That's a compound that included in a hot breakfast. 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. So things like manganese, chloride, betacarotene, iron, other vitamins, [inaudible 00:41:27] quercetin, things that are readily available as a direct to consumer OTC.

Dr. Mark Hyman:
Yeah. 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 bisglycinate, magnesium chloride, vitamin D2, guar gum. You've got a broccoli extract in there, indole-3-carbinol, methionine, biotin, caffeine, lutein, zinc, betacarotene. So I'm like, "This is an interesting cocktail." I'm like, "How do they come up with this?" 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?

Dr. David Furman::
Exactly. That's exactly right. 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 foods. So you're absolutely right, yeah.

Dr. Mark Hyman:
It's amazing. So these trials are not completed yet. They're still underway, so we're going to find out more, but you have on the website for Edifice Health, which is the company that's behind the IH test, and by the way, is this available, this test now clinically yet or not yet?

Dr. David Furman::
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. 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 clear certification in our labs. So that's part of the undergoing process in the market.

Dr. Mark Hyman:
Yeah. So I know we had lunch as COVID was starting in March of 2020, and you were telling me about this and I was like, "Wait a minute. That'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 then as an individual, you can go, "Jeez, I'm going to change my diet," or, "I'm going to take these supplements for a few months and I'm going to check my test and I'm going to repeat it and see how it looks," right?
So we'll be able to, on n-of-1 basis, determine what works and what doesn't for us. I think as a doctor, it's very exciting to me because then I have a metric to use with my patients to determine is what I'm doing working or not on things that actually really matter. So we do things that are already like, "Oh, we change our diet and improve our cholesterol," or, "We change our diet and improve our blood pressure. We see our 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.

Dr. David Furman::
Right, and it's important that you mentioned the fact that you as a physician that can use this to evaluate how your patients are doing and how effective your interventions of your favorite interventions for a particular patient will work. So on that angle, I would like to say that we really need to educate primary care physicians and other healthcare 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. The reason for that is that we have a long way to get FDA approval. Why is that? Because aging is not considered a disease.

Dr. Mark Hyman:
Not yet.

Dr. David Furman::
Inflammation is not considered ... Not yet. Inflammation is also not considered a disease. So we have a risk factor for multi-morbidity, 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? Yeah. 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.

Dr. Mark Hyman:
Yeah, it's such a mess though because traditional medicine is so hyper-specialized and reductionist and it doesn't understand that if you ... It's like a unified field theory of medicine. If you understand inflammation, you understand so much about what goes wrong with our bodies and really almost any disease. It's such a key phenomena, I mean, and it's such a misunderstood and inadequately understood phenomena that 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."
I remember one study that came out a while ago where they're like, "Oh, Alzheimer's is inflammation of the brain," so they did a big study where they gave everybody Advil, and I'm like, "Well, that's not going to work." It's like we got to found out the cause of the inflammation. So from a functional medicine perspective, 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 have ability to control, and it's also the lack of things, right?
So I hear from Argentina and the world's quite different down there, and the foods are different, and the people live in a more closer to land way. When I came back from Sardinia and Icaria in Greece, 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 if they have this wild sage tea every day for breakfast because that's what's growing in their field, that it's full of these catechins that, in fact modify, NF-kappa B and regulate gene expression of inflammatory cytokines, and blabbity blah. They don't know any of that. They just drink the stuff because it tastes good.
We've gotten so far away from that, and yet what what's exciting is you're starting to look at these interventions which are relatively low cost, which are relatively accessible to most people. 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. These are the kinds of things that you're looking at because I think you realize, and it's exciting to me to hear the way you're thinking about it, is that it's not like we're going to find the drug to change your immune age. 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 prevent disease, but to reverse your biological age.

Dr. David Furman::
So the good example that you have given, taking Advil to combat inflammation for 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's not just-

Dr. Mark Hyman:
Well, kidney failure, and leaky gut, and ulcers leading.

Dr. David Furman::
Exactly, 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, right? We can't treat one disease. You are 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, right? We know that because you have all the diseases and that's where it's important. Things are changing, though.

Dr. Mark Hyman:
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?

Dr. David Furman::
Of many diseases, exactly, and we know now that that's possible. Let me tell you something really interesting that's happening in France. I mean, 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.

Dr. Mark Hyman:
Not aging.

Dr. David Furman::
It's not aging right because we can't talk about aging as a disease that causes a lot of social and political issues. I think we're talking now about the decline in intrinsic capacity. It would be something similar to aging, 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?
So the French system, it's really interesting what happened. Bruno Vella is at the University of Toulouse. He's assembling around 500 people in the Gerontopole University Hospital. He developed an app that tracks functional domains of aging, mainly vision, audition, mobility, et cetera. What happens, he already have 25 or 30 thousand individuals that have been filling up this questionnaires in the app. What happens, there's 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 healthcare systems are actually going to. 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 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.

Dr. Mark Hyman:
So the IH test is going to help us map that, right?

Dr. David Furman::
That's exactly right.

Dr. Mark Hyman:
Do you think you're going to be adding more biomarkers to that test or is there going to be another framework to look at biological aging as you start to learn more because you're constantly learning, right?

Dr. David Furman::
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, absolutely, no question about it.

Dr. Mark Hyman:
One of the things I thought was fascinating about your study was that you had a bunch of people who got very old. There were 19 people who got to 99 or more. What did you learn from that group?

Dr. David Furman::
So this is a centenarian group that we obtain in collaboration with University of Bologna in Italy. So they get to be centenarians, right? A lot of fish, started walking, good quality of lives. So what we learned was that-

Dr. Mark Hyman:
The pasta bolognese, right?

Dr. David Furman::
I would avoid that one, really, but what we did learn when we did in that population, we measure 1,300 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.

Dr. Mark Hyman:
Really?

Dr. David Furman::
So on average, 40 years below their calendar age. That means that for a 105-

Dr. Mark Hyman:
Wow. So assuming when you look at their IH test, they were 40 years younger. So if they were a hundred, they were like 60.

Dr. David Furman::
Exactly, on average.

Dr. Mark Hyman:
Wow.

Dr. David Furman::
There's some individuals that is closer to their own age and some of them ... There's one outlier, very interesting outlier, super healthy. He's never seen a doctor, 105-year-old. He looks like a 25-year-old kid.

Dr. Mark Hyman:
No.

Dr. David Furman::
So we're talking about 80 years below his calendar age.

Dr. Mark Hyman:
Oh, you mean not he looks like, his blood work looked like he was 25.

Dr. David Furman::
Exactly. Yeah.

Dr. Mark Hyman:
It's like maybe you got a birthday wrong there.

Dr. David Furman::
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.

Dr. Mark Hyman:
Incredible. So you found basically that ... Were there anything unique about these people besides their lower levels of these inflammatory compounds in the IH study?

Dr. David Furman::
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 a 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.

Dr. Mark Hyman:
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 all in Bologna, right? Were already all-

Dr. David Furman::
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. What we do see though is that when you do metabolomics, and 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-

Dr. Mark Hyman:
Yeah. Oh, you did that?

Dr. David Furman::
Yes, we did.

Dr. Mark Hyman:
Yeah. What did you find?

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

Dr. Mark Hyman:
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?

Dr. David Furman::
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. After you do so, you look at 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 metabolomic clock.

Dr. Mark Hyman:
Yeah, and did you see any things that they were eating that were unique or different in that group?

Dr. David Furman::
Mostly fish derivatives.

Dr. Mark Hyman:
Yeah, fish derivatives. Interesting. Yeah.

Dr. David Furman::
Yeah, not surprising though.

Dr. Mark Hyman:
No. Well, omega-3 fats and selenium, and iodine, and protein.

Dr. David Furman::
Exactly, all those are there.

Dr. Mark Hyman:
Yeah. Interesting. I mean, I did my metabolomics once and it was shocking, actually, and it made me change everything. 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, not just on my salad dressing. 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.

Dr. David Furman::
Completely, yeah.

Dr. Mark Hyman:
So it was interesting. So I think what's so exciting is that people listening, there's this whole new world emerging in medicine that you're really not getting in the clinic that is able to look at massive amounts of data from things that we never even looked at all in medicine clinically. I mean, there are thousands and thousands of compounds in our blood, 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 another can of worms of what's in there, which is even far greater than our own genome. There's probably a hundred to four hundred times the amount of genes in our microbiome than there are own genes.
So they're all producing proteins and metabolites. We're absorbing them, they're doing stuff. It's like this incredible ecosystem soup. So what's exciting about people like David and Dr. Furman, I mean, is that they're actually able to start to make sense of all this 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?

Dr. David Furman::
It's absolutely fair, and we owe these to technology. Technology has enabled all this 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. 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 continue to do so.

Dr. Mark Hyman:
Yeah. So what are you most excited about that's coming up for you? What are the things that you're seeing on the horizon that you're really excited and out of bed in the morning?

Dr. David Furman::
Yeah. Well, I mentioned this transition from a highly reactive, disease-centered vision of governments and not-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 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, obviously.

Dr. Mark Hyman:
That's so exciting. It just reminds me of this patient I had years ago. We came in, his blood sugar was 110, which is pretty much in the almost diabetic stage, pre-diabetic. Diabetes is 126. I said, "Gee, did you see your doctor about this?" What did he say? He says, "Well, yeah," he said, "He saw it," and I said, "What'd he say?" He said, "Well, he said watch it until it gets to be diabetes and then we'll treat it with a medication." I was like, "Oh, God!"
I think this is the opposite of that. It's like before even you have a symptom, before even a disease manifest, before even you can pick it up on most lab work, we're going to be able to almost like Star Trek, use a tricorder and figure out what's going on, run it through these incredible computational abilities that are emerging, we haven't even seen yet like quantum computing, 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 trillions of reactions. 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're doing at Stanford, there's a lot of other people doing this in other domains in medicine, and it's all coming together.
So the medicine that we see today is really, I would say it's like we're going to look back and go, "God, this is bloodletting or leeches," and I think we're in this incredible moment and I'm excited to see about your work with the 1,000 Immunomes 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 this is an exciting moment where there's billions of dollars pouring into longevity science where it was a neglected stepchild of medicines like, "Why study aging? It's inevitable. So who cares? Let's study cancer. Let's study heart disease," but aging, one of the things that was shocking is if you're 30 years old and you're a smoker and you smoke three packs a day of cigarettes, your risk of cancer is 50 times less than if you're 75 years old and don't smoke, right? Something like that where the idea, I mean, I'm just making up numbers here, but I think the idea is that the aging itself is such a bigger risk factor for all these diseases that we're missing the point of 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 going to 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 and about the 1,000 Immunomes Project, and you can read their research, little technical sometimes, but they've got a really great interface to learn more about what they're doing.
I hope you've enjoyed this podcast because I did, and I think it's a very exciting moment in medicine. David, hope we continue to collaborate and talk. For those of you listening to this podcast and you'd love to share with your friends and family, we'd bet they'd love to hear about how to regulate their inflammation, subscribe wherever you get your podcast, and we'll see you next time on the Doctor's Farmacy.

Closing:
Hi, everyone. I hope you enjoyed this week's episode. Just a reminder that this podcast is for educational purposes only. This podcast is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. If you're looking for help in your journey, seek out a qualified medical practitioner. If you're looking for a functional medicine practitioner, you can visit ifm.org and search there Find A Practitioner database. It's important that you have someone in your corner who's trained, who's a licensed healthcare practitioner, and can help you make changes, especially when it comes to your health.