Good Life Project - Groundbreaking Cancer Research: How Common Meds May Change the Game | Matthew D. Park, PhD

Episode Date: February 24, 2025

Could aging immune cells actually be triggering cancer growth? Groundbreaking immunologist Matthew Park reveals surprising research showing our body's own myeloid cells may suppress cancer-killing cells as we get older - and how existing medications could help reset this deadly process. An eye-opening look at a new frontier for preventing and treating cancer through the years.You can find Matthew at: Website | Linkedin | Episode TranscriptIf you LOVED this episode you’ll also love the conversations we had with Tim Spector about eating for health.Check out our offerings & partners: Join My New Writing Project: Awake at the WheelVisit Our Sponsor Page For Great Resources & Discount Codes Hosted on Acast. See acast.com/privacy for more information.

Aging of the immune system is what seems to be the main driving factor for why older folks are more predisposed to cancer. With that in mind though, it gives me hope about how... Matthew Park is a groundbreaking immunologist covering how aging immune cells trigger cancer development. His breakthrough research at Mount Sinai has launched three clinical trials using existing drugs to prevent lung cancer in entirely new ways. There are many lifestyle variables that can modulate the changes to the immune system that happen with age and many of these include. Could what you've been working on have implications for say other age-related diseases like cardiovascular disease or infections?

I'm really glad you brought up this topic because... Do you have business insurance? If not, how would you pay to recover from a cyber attack, fire damage, theft, or a lawsuit? No business or profession is risk-free. Without insurance, your assets are at risk from major financial losses, data breaches, and natural disasters. Get customized coverage today starting at $19 per month at zensurance.com. Be protected. Be Zen.

With the FIZ loyalty program, you get rewarded just for having a mobile plan. You know, for texting and stuff. And if you're not getting rewards like extra data and dollars off with your mobile plan, you're not with Fizz. Switch today. Conditions apply. Details at Fizz.ca. Sonic the Hedgehog 3. Welcome home, my boy. He's now streaming. On Air Mount Plus. He's now streaming on Paramount+. He is much more impressive than the Hedgehog

I fought previously. Dude, I'm standing right here. Sonic the Hedgehog 3, now streaming on Paramount+. It really begins with some of the earlier work that I did at Georgetown. As you mentioned, I went there for undergrad. And the research that I did at Georgetown. As you mentioned, I went there for undergrad, and the research that I had done there was done in collaboration with

the National Institutes of Health, the NIH, and Bethesda, not too far north from Georgetown. And that's where I developed an interest in immunology. Most of my studying had been done on staphylococcus bacterial infections, but the fact that there was this intricate interaction between bacteria and the human immune system was a very apt segue into understanding how the immune system then combats diseases that are not necessarily,

quote unquote, foreign to our body, like bacteria or other pathogens, and namely cancer, because cancer develops from within. With all of that in mind, when I started my graduate studies at the Icahn School of Medicine at Mount Sinai, a lot of the field had begun shifting its attention to understanding why diseases like cancer develop. From the therapeutic aspect of things, this attention would be concerned with prevention as opposed to just treatment of diseases after they've already occurred. So when you think about it from that lens,

one of the main risk factors, one of the strongest risk factors that are documented for cancer is aging. And so given that statistic, we were very interested in shifting gears, taking a step back from necessarily treatment of cancer towards understanding the mechanisms that predispose older individuals to cancer. I mean it's so interesting right because when you hear the conversation around cancer and especially if it's oriented around the prevention side like

what can I do and how early should I be starting and you know what are all the boxes that I can check and so often it's lifestyle oriented you know it's like this is focusing on nutrition and focusing on movement and focusing on stress and not that we're saying the these things aren't important but the notion of aging, this actually came into a conversation with me fairly recently, which I think is one of the reasons I wanna speak to you. I'm of an age where you're like,

hanging out with my doctor for my annual physical, and the sentence tumbles out of their mouth where they're like, you know, what you just said, like the single biggest risk factor for you getting cancer, for anyone getting cancer, is actually age. And you're sort of like, you're moving into a season of life where simply because of your age,

which I can't do anything about in theory, all these things are gonna start to shift. And I got me really curious, which I think for a lot of people when they hear that, I wonder if they associate a sense of almost futility with it. Well, it's like, well, I can't stop the clock. So what am I supposed to do with it? Which kind of brings us to your research.

For sure. I completely relate to that. I mean, I think if you ask anybody, there's always going to be a family member with what we would now classify as an aging-related disease, whether that's cardiovascular disease, whether that's some sort of neurological syndrome. I mean, it's wide-ranging, things that occur with age.

That having been said, the research that was recently published suggests that, well, one, aging of the immune system is what seems to be the main driving factor for why older folks are more predisposed to cancer and why older individuals with cancer are likely to have a worse outcome. With that in mind though, I think it gives me hope about how, or that it's not so futile in that there are many lifestyle variables that can modulate the changes to the immune

system that happen with age. And thereby, by addressing those lifestyle variables, you can deter aging of the immune system, or at least prevent it from accelerating too far. And many of these include, for example, a diet. Because what you eat will impact the shape and composition of your immune system. Obesity is very tightly linked, for example, to the types of immune cells that are produced from your bone marrow.

And in particular, those specific immune cells are the ones that we specify in this recent publication as one of the causative factors for tumor development and progression. So I want to circle back around to some of the things that we can think about to do here but let's start a bit more into the research because I really want to understand this better. You know like from the outside looking in from a layman's perspective you know it seems like you've done this research that shows that aging myeloid cells suppress these things called natural killer cell responses that in some way promotes cancer progression.

Talk me through this in sort of everyday language where I can really wrap my head around what is it that you really discovered here. If we start breaking a tumor down, for example, a tumor itself is obviously comprised of the actual cancer cells. Those are the prototypical bad guys that we want to get rid of. But it is also comprised of immune cells that infiltrate the tumor. And these immune cells consist of the classic white blood cells that kill tumor cells. So these are your T cells, your B cells, and NK cells.

And then you've got other immune cells called myeloid cells. You can think of these guys as the first responders to, for example, a viral infection or a bacterial infection. So when you've got a bacterial infection, myeloid cells such as neutrophils or monocytes will be the ones that come to the site of injury and try to clear up. And by cleaning it up, you're hopefully getting rid of as much of the toxins that would otherwise result in worse disease. Interestingly enough, the general consensus is that these myeloid cells, because their

aim is to try to clean things up, dampen inflammation, prevent things from getting worse, we call them immunosuppressive. And one way that they do that is by inhibiting the activity of those tumor-killing cells, the white blood cells, so for example, NK cells. So obviously that presents a problem because in order to kill a tumor, you need those effector white blood cells. But if you've got your immune system also producing these myeloid cells, well, you're kind of self-defeating the mission in a way. So if we break the tumor environment down that way, one objective is to prevent the

infiltration of tumors by these myeloid cells so that we give the opportunity for T cells, B cells, and K cells to do their job and kill tumor cells. Now, if we start incorporating age into all of this, so how does aging influence the composition of the tumor? Well, there's been work done, for example, from the Mournless Lung Tettering showing that perhaps it's the age of the tumor cells themselves, the cancer cells themselves, that makes them more aggressive, for example. Right?

So that was the initial hypothesis, or that was one of the... It's one of the more logical hypotheses. You go straight to looking at the tumor and you try to see if, for example, if the cancer cells or if your cells become cancerous when you're older, perhaps they're more aggressive and that's why you have worse outcome. It turns out that's not the case. If anything, if your cells become cancerous later in life, at least in mice, this hasn't been shown in humans, so we don't know for sure, but at least in mice, if the cells become cancerous later in life, at least in mice, this hasn't been shown in humans,

so we don't know for sure, but at least in mice, if the cells become cancerous later in life, they actually are less fit, so to speak. They're poor at surviving and proliferating. So if anything, those mice that develop cancer later in life, simply just by looking at the age of the cancer cells, they actually develop smaller tumors, which presents a kind of paradox, right? Because again, it wouldn't align with what we're seeing in terms of patients, right? It doesn't align with the fact that older patients have worse outcomes. And so that motivated us to look at the immune system because that's the other half of that environment that we just discussed. And so when we started doing experiments where we're taking the immune system and transplanting

them into young and old mice to see whether by looking at the age of the immune system there's a difference in outcome, we did find that essentially mice with old immune systems, basically with old bone marrow, regardless of whether the receiving mice, the recipient mouse was young or old, developed worse cancer. And so it didn't matter how old the recipients were, if the donor bone marrow was old, then you had worse cancer progression, suggesting that really it's the age of the immune system that determines how quickly your cancer will develop and grow. So that is so fascinating.

So if I wanted to see if I understand this right. So the original hypothesis was that when you're older, that the aggression of the cancer cells was the primary driver of rapid growth and worse outcomes and then what your research is showing that in fact It's probably the opposite that is probably a little bit chiller when it's old in life and that The underlying driver may in fact be the decline in the immune system and its ability to actually Fight the tumor cells as effectively as it did when it was younger.

Exactly. Exactly. And the nuanced point here, or if we just get into more specific detail, is that the reason why an older immune system essentially suppresses your ability to fight off the tumor is because it is it produces more of those myeloid cells and because it produces more of those myeloid cells it does a better job at inhibiting the the NK cells for example the T cells that are assigned to fight and kill off the tumor cells. So when you then transplant effectively a younger immune system into an older physiology, then is what you're doing this or the transplanting an immune state where

the myeloid cells are at a lower level and the white cells and the natural killer cells, the NK cells are at a higher level. So it's just, it's more effective at being aggressive at fighting. And those myeloids, it doesn't have to almost battle, the immune system doesn't have to battle itself on the same level to be effective. Exactly.

That is to say, I wouldn't recommend people starting, you know, going to their PCPs and asking them to save their bone marrow. That isn't necessarily what I'm advocating, but scientifically, or at least in theoretical practice, our data, and we've done the experiments showing that when you take old mice and you give one group old donor bone marrow and you give another group young donor bone marrow. The old mice that receive the young donor bone marrow have a much more superior anti-tumor response and therefore their tumors are much, much smaller. And it really is due to the fact that the immune system in that context is less inclined to produce these immunosuppressive myeloid cells.

It all starts very upstream because the myeloid cells, the white blood cells, they all come from a stem cell in the bone marrow. And so there are more detailed nuances about how does aging then influence those stem cells and why is it that aging influence those stem cells and why is it that aging of those stem cells makes them more inclined to produce myeloid cells over the white blood cells. So, there's that kind of additional level of detail involved, but in terms of the outcome, it's the fact that there's less myeloid cells because the immune system is younger.

I mean, that's so interesting. So, we can trace it really back to stem cells, which actually explains something interesting. I was talking actually to a physician who specializes in regenerative medicine and there's a lot of work trying to understand like how can they use stem cells in different ways to potentially regenerate tissue that's been damaged or issued or injured in some way. And this particular physician was also a researcher, practiced in research outside of the United States. And what he was telling me was that, you know, because of the regulatory sort of situation in the U.S., that there's a big restriction on what you can do with stem cells

and what kind of stem cells that you can use. But outside of the U.S., there's a big restriction on what you can do with stem cells and what kind of stem cells that you can use. But outside of the US, there's more freedom to use different cells in research. And that, you know, if, and he was kind of saying, one of the things he was saying was that if you have an opportunity to explore the use of stem cells and you are older than in your 40s, it's actually probably much more efficient and effective to use some form

of other stem cells, not your own, because it'll be much more effective at differentiating into the desired tissue. And so it was an interesting sort of like, carler to what you're saying in a weird way. So I wonder if in the same way, like the stem cells here that then are the source fuel for what you're saying eventually become immune tissue, that maybe they differentiate in a different way into the myeloid or the white and the NK cells that just makes it a better balance based on age. Exactly.

I mean, it's interesting that you mentioned that because it is one area of research that I am now focusing on now that this publication is out to try to understand why aging of hematopoietic stem cells, so these guys are the ones that will give rise to white blood cells and myeloid cells over at the expense of white blood cells. What is going on at the genetic, you know, epigenetic level that rewires them so to speak, that makes them older and, you know, is there a way to, you know, rejuvenate them and reprogram them so that your hematopoietic output, your immunological output from your bone marrow is Reverted back to the way it was when you were younger in a way It sounds a little bit like a holy grail type of thing. It would be very cool if it were for short. Yeah. Yeah, right more to come on that and We'll be right back after a word from our sponsors And we'll be right back after a word from our sponsors. standing right here. Sonic the Hedgehog 3 now streaming on Paramount Plus. Do you have business insurance? If not, how would you pay to recover from a cyber attack, fire damage, theft, or a

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So, somebody is listening or watching along with this, right? And they're probably wondering, you know, is bone marrow or is something much more, a much more intensive intervention the only path here? And in fact, this is where your research gets really fascinating too. If I understand it correctly, your team effectively repurposed existing medications like anakina and even sort of like just allergy medications as a way to potentially block inflammation pathways as almost like a more mainstream approach

to see if we can modulate this in a way just using things that are already out there in the market. So take me deeper into this because I think this is really interesting. Well, so in terms of high-level principles, the idea is that, you know, when we think of inflammation, we think of it as a good thing because inflammation is what will typically fight off infection, so on and so forth. But in terms, but in the cancer context, inflammation can be quite damaging because the proteins that are involved in the inflammatory process oftentimes will tell the bone marrow to turn

out more myeloid cells. Again, this is all in that classic context of an infection, right? What we found was that the myeloid cells that end up in tumors, so we specifically study lung cancer, we show that this can occur for other cancer types as well like colorectal or pancreatic cancer, but specifically in lung cancer we found that myeloid cells contribute to inflammation, they start producing these proteins that we find are being sensed by the bone marrow. So there's this communication that's occurring between these immunosuppressive myeloid cells and tumors

that is then telling hematopoietic stem cells in the bone marrow, hey, we actually need more myeloid cells despite the fact that the tumor is growing. Right, so it's actually worsening the condition by the signaling. Exactly. It's this feedback loop that is so counterproductive to our body's hope to be rid of the cancer. One of those proteins is a molecule called IL1. We found that therefore if you block IL1, you would prevent hematopoietic stem cells from recognizing this bizarre protein

that shouldn't be produced that is actually contributing to this pathologic feedback loop and by blocking it, we tell the hematopoietic stem cells, hey, you guys need to reset yourselves. You don't need to produce more myeloid cells. We need to let the white blood cells in the tumor actually do its thing and kill off the tumor cells. And so by then disrupting that feedback loop, we're preventing this massive accumulation

of myeloid cells and the drug that does, that blocks IL-1 is a drug called anakinrin, as you mentioned, which is a drug that has been FDA approved already for autoimmune conditions like rheumatoid arthritis. In that disease as well, IL-1 plays a major role in ramping up pathologic inflammation. We also mentioned our study on allergy medications. We found that in addition to IL-1, another protein called IL-4 is produced in the bone marrow. And it also tells the stem cells, hey, produce more,

you need to turn out more myeloid cells. So it's this miscommunication that's happening here. The allergy medication, Dupilumab, also commonly known as Dupixent, blocks IL-4 signaling. So it prevents the stem cells from sensing IL-4 signaling. So it prevents the stem cells from sensing IL-4 and being told that it needs to produce more myeloid cells. So in those ways, we found that essentially a rheumatoid arthritis drug and an allergy medication, dopilumab, which is commonly used to treat eczema and things like that, can

be effective in preventing the generation and this accumulation of bad myeloid cells that prevent our white blood cells from killing tumor cells. Which is, I mean, pretty incredible if that then scales into human beings, you know, in clinical experiences. How does this, you know, so effectively you're saying there is maybe the potential, and again, early in the research, but there is maybe the potential in understanding these pathways to use some approved readily available medications in a sort of like a different and off-label use for potentially cancer, to fight cancer, which would be pretty incredible.

Because I would imagine that the side effects, and tell me, maybe I'm completely wrong here, that the side effects of just the two classes of medications that you just talked about are probably much more dealable than those that we classically associate with many of the ways that cancer is treated now. Yes, very true. I mean one of the mainstays of mainstay treatments, for example lung cancer, is for example a class of drugs that we call immune checkpoint blockade molecules, these antibodies.

And the name is not so important but the point being that one of their major side effects are basically auto-inflammatory events that occur. We call them immune-related adverse events. So these can manifest as for example a rash or heart disease or there's a variety of them that come up only because in our attempt to revitalize the immune system, we accidentally tip it over too far and the immune system gets too activated, too excited, and that can also cause a variety of problems. But as you mentioned, you know, Dupilumab and Anakinra are already FDA approved for

different diseases. Their safety and tolerability have already been well profiled. And so, we have been at Mount Sinai, the early phase trials unit led by Dr. Tom Maron is responsible for designing and implementing early phase clinical trials actually going on right now where we are giving Dupilimab and Anakinra to patients with late stage cancer who, for lack of better words, you know, did not respond to existing modes of, you know, therapy. What we've been fortunate to see is response in some of these patients where the intervention

of Dupilumab and Anakinra has successfully reset the bone marrow and has reached the stem cells and said to them, you need to stop producing these bad myeloid cells. So we're very excited for those patients who have been responding to these interventions. What we are very keen on moving on towards now is seeing whether we can use an akin rail or a duplium map or at least other drugs like them to prevent cancer from even occurring. And so the kind of patients we would be, you know, hoping to help manage are those that are at high risk for developing lung cancer, for example. So these are current smokers, for example,

who come in for a lung cancer screening, and on their x-ray, we see these nodules in their lungs. And typically, the kinds of nodules we would see on an x-ray, we see these nodules in their lungs. And typically, the kinds of nodules we would see on an x-ray scan are indicative of pre-cancerous lesions that have the potential, for example, the potential to become full-blown frank cancer. And we're interested in seeing whether we can prevent that transition from happening because it's usually those myeloid cells that prompt pre-cancerous lesions to become full-blown cancer. Yeah, I mean, that would be so incredible. I mean, on both counts, the fact that you're seeing in just early data, you know, results

in people who have been non-responsive to other treatments and are late in the disease and like this is actually doing something for them. And then the notion that like what if you could catch people with very early sort of warning signs that this might be coming and have them then be able to give them something that's fairly straightforward as a way to prevent it. I mean, it's incredibly hopeful on many different levels.

I mean, part of my curiosity here also is, effectively what you're doing is, it sounds like, and I'm gonna just completely butcher this with layman terms, but you're trying to tamp down one part of the immune system so that the other part, you're not juicing the other part, but you're basically just letting it do what it would naturally do if it wasn't being hindered by the part of the immune system that is basically

stopping it from working against cancer. What's happening, and I tend to look at the human body as a fairly elegant system. There's pretty much a reason for everything that goes on, and things do go haywire, right? But if this is just how the immune system, how a quote, healthy functioning immune system tends to work, what's happening here that the signals are getting crossed in this way so consistently in this disease presentation? Is this just the way that it's supposed to be? Is there an error or a glitch somewhere in the system that's causing this? I think, well, it depends on who you ask.

I have been taught the evolution perspective where immunologists, evolutionary biologists alike will argue that cancer, that our bodies have not evolved fully to combat cancer. It has evolved well enough to handle and manage diseases that are caused by infections, for example. But if we think about, for example, just human lifespan over the past few centuries, it's extended significantly thanks to antibiotics and so on and so forth. But the human lifespan would, very early on in human development, would not have even had the opportunity to see something like cancer only because the human lifespan was

45 at some point, you know. So now that- You just literally wouldn't live long enough to experience it. Exactly. Yeah. That's exactly the point. And so now that, you decades, now the immune system,

now we have to just help educate the immune system to handle something where the enemy is not from outside but from within, where time gives the opportunity for mutations to occur, and those mutations are the basis for why healthy normal cells that have been doing just fine up until the sixth decade of life, for example, suddenly becomes the precursor to such a devastating disease. Again, I mean, this is all supported by epidemiological data showing that really the frequency of cancer diagnosis really peaks at that sixth decade of life, which explains why when our lifespan was only up until the fourth or fifth decade, we just weren't. We, our bodies just did not feel the need to somehow evolve a cancer-fighting immune

response. Yeah, I mean, it is pretty amazing, you know, that this notion that we have extended lifespan so dramatically in the last five or six decades through medicine, through technology, through better information, that really our immune systems haven't caught up with the speed at which we've been able to extend our lives to figure out how to make our bodies function as older beings in a way where they're still efficient and effective and healthy on the level where they were when they were younger. Exactly.

I mean, it's a very interesting idea. There's interesting anecdotes to support this. So for example, if we take a look at a few of the immune cells that are in our bodies, for example, there's a type of immune cell called a dendritic cell. There's different varieties of dendritic cells in our bodies. But if you look at those different subsets

and you start to wonder why those different subsets even evolved, some would argue that those different subsets arose because our bodies started to realize that bacterial infections weren't the only things that our bodies could contract and die from, that viral infections could cause just as bad or even worse disease, perhaps even chronic disease. And so some of those dendritic cells, cell subsets that exist, we think, is because they were designed to fight off viral infections, because the existing ones were incapable of accommodating the types of toxins and antigens that are produced by viruses that bacteria just don't.

So I think there are different ways of looking at the immune system and coming to the same conclusion. So if we zoom the lens out from discoveries, and we look at potential broader implications here. So you're now working on clinical trials to test these findings of the human being and shared this really promising early results. What are some of the most exciting possibilities for potentially translating this research into real-world cancer

prevention or treatment strategies? Like you said a lot of these trials are very early in their development but the hope is that these interventions might prove to be effective prevention modalities and I think that would be the chart on top for cancer therapeutics in that we can identify high-risk individuals and prevent them from developing full-blown cancer. That of course highlights the ongoing challenge of identifying what are biomarkers for high-risk individuals. So that will always, that continues to remain a major research objective. But that having been said, I think one of the following areas of research that deserves significant attention are some of the other co-variables that are also linked to aging

and are also linked to increased cancer risk and worse outcome. And so, for example, there is a condition called clonal hematopoiesis. It's essentially a blood disorder. Except I would, I think the statistic is that nearly 30% of individuals over 70, or at least 65, will develop clonal hematopoiesis simply because of age. And it is caused by a collection of mutations, again, that just naturally occur with time. And these mutations, it almost sounds too good to be true, but these mutations also

promote the immune system produce more myeloid cells. So you can imagine that if you've got these mutations in the stem cells, so I should specify these are mutations that your stem cells start to accumulate with just age, and these mutations promote stem cells to become more inclined to produce more myelid cells, you could imagine the potential catastrophe that results from when you've, you know, you're a smoker and you've also just started developing pre-cancerous nodules in your lungs, you've got clonal hematopoiesis because you're 70 plus years old. I mean, it's not going to add up to a very optimistic outcome for you because of the fact that your

immune system is set so poorly. And so one of the active areas of research in the lab right now is also about how can we combat clonal hematopoiesis? Is there a way to counter the effects of these mutations? Of course, there's different ways of combating the formation of these actual mutations, you know, gene therapy, there's all different kinds of things that geneticists are trying to do. But let's say that the mutations have already occurred and you already have clonal hematopoiesis,

is there a way that we can then intervene before you get actual cancer to reduce the potentially damaging effects of clonal hematopoiesis and try to, again, reduce the output, the production of these bad myeloid cells? It just so happens that one of the mutations that causes clonal hematopoiesis is also one of these mutations, it reduces the expression of a protein that is responsible for organizing your genome. So one could argue that a lack of organization of your genome is the impact that aging has on your stem cells that promotes the production of myeloid cells. It just so happens that we also find that with age, this protein, even if it's not mutated,

the levels of this protein go down and it's called DNN T3A. So it begs the question, why does the level of this protein just naturally decline with age even in the absence of this mutation, right? So there's a good number of question marks that we're trying to finagle here that we're trying to untangle, whether it's the effect of just mutations naturally arising or aging.

And so these are the next few areas of interest for us, at least on the side of hematopoiesis, which is the catch-all term that we use to describe the production of immune cells. Got it. Yeah. Do the... I know you've been focusing on lung cancer. Do the mechanisms that we're talking about here, I mean, can you generalize broadly to a wide variety of different types of cancers? It's really more focused on this one type. Two pieces of data that we included in our recent publication

dealt with seeing whether anakinra as a therapeutic intervention is also able to reduce the progression of colorectal and It is also able to reduce the progression of colorectal and pancreatic cancer. And our data shows that blocking IL-1 using anakinra does just that. It reduces the progression of colorectal and pancreatic cancer. Now, we have other folks in the laboratory whose primary focus is just looking at colorectal cancer and just looking at pancreatic cancer. The data that we've been collecting since the publication suggests that the mechanism

that I'm describing in lung cancer may not actually be the case. That for example, in colorectal cancer, myeloid cells that produce IL-1 is being sensed just within the tumor microenvironment, just within the tumor and you've got these tissue cells called fibroblasts, which are essentially cells that maintain the structural integrity of the tissue. So the structural integrity of the colonic tissue, for example, is picking up the IL-1, not the bone marrow, but just locally within the colon tissue itself. And these fibroblasts are then reacting to that IL-1 and releasing other proteins that

tell the bone marrow, that tell the myeloid cells to come in and suppress the immune system even further. So there's other nonimmune cells at play as well that we think are contributing to the reasons why IL-1 myeloid cells are pathogenic and pro-tumorogenic in, for example, colorectal cancer. Yeah, and that's so fascinating. So there's probably a reasonable argument to be made that would say that excess amounts of these myeloid cells may well be implicated in the immune systems and aging immune systems'

inability to effectively fight a wide variety of cancers, but each individual type of cancer and the environment that it shows up in may really change the nature of what the effect of intervention is to try and tamp down these myeloid cells based on how unique that situation is. So like, you know, the substances that you're using now in the context of lung cancer may not be the right ones. So maybe it's a matter of like looking at and examining like are there different things or different ways that we can create the same sort of end result of tamping down these cells but in a different

way. Does that make sense? It totally does. I think what's reassuring is that anakinra has a very strong effect in terms of reducing the progression of colorectal tumors. So I think the phenotype, the desired effect of blocking these myeloid cellus is fortunately shared between different tumor types. Now the question is if the underlying reasons for why it's so effective is slightly different between tumor types. Could there be the possibility that we could take advantage or leverage a different protein that is coincidentally being produced at the same time in colorectal cancer that is not

being produced in lung cancer? And then can we combine therapies to yield an even more desirable reduction in tumor load, for example, are the possibilities for missed opportunities that we want to take advantage of. And so I think for that reason alone, there's all the more reason to delve into, for example, different tumor types and see whether there are other proteins, for example, that are still subtly prompting myeloid cells to come in and do their bad deeds. And so then when we combine therapies, we could hopefully eliminate tumors altogether. Yeah.

I mean, that would be pretty incredible. And we'll be right back after a word from our sponsors. plan. You're not with Fizz. Switch today. Conditions apply. Details at Fizz.ca. Do you have business insurance? If not, how would you pay to recover from a cyber attack, fire damage, theft, or a lawsuit? No business or profession is risk-free. Without insurance, your assets are at risk from major financial losses, data breaches, and natural disasters. Get customized coverage today starting at $19 per month at zensurance.com. Be protected. Be Zen.

Sonic the Hedgehog 3 is now streaming on Paramount Plus. He is much more impressive than the hedgehog I fought previously. Dude, I'm standing right here. Sonic the Hedgehog 3, now streaming on Paramount Plus. You've mentioned that your findings could also have implications potentially across a number of different types of cancer. What about when we move beyond the realm of cancer? Could what you've been working on have implications for say other age related diseases like cardiovascular disease or infections or anything else?

I'm really glad you brought up this topic because that is also a new area of research that we are expanding into. So generally speaking, molecules like IL-1, this protein that I've been talking to you about, that anakinra is supposed to block, it's part of a broader collection of proteins that folks in the aging field have described very well up until now and are known to contribute to the aging of tissue cells. And the term for that is called it is senescence. And we found that senescence of tissue cells, whether they're epithelial cells,

whether they're you know fibroblasts, whatever they may be, contributes to organ dysfunction. So senescence of for example the epithelial tissues of your lungs prevents them from efficient gas exchange, which is obviously a prime function of the lungs and if you can't do that then you've got you know quote unquote lung failure, right? If the cardiomyocytes in your heart become senescent and they're less able to contract and expand then that contributes to the dysfunction of the heart. And the same principles apply to for example the liver, the skin, so on and so forth, even

the brain, right? And so a significant amount of research in the aging field, right, you know, if we step outside the immune space has been focused on how do we remove senescent cells. We think that if we take the same kinds of drugs, antikin, and so on and so forth, that block these proteins, if we apply them in just the convex agent, we could prevent this accumulation of those bad proteins and prevent senescence from afflicting too many other cells and thereby protecting us from organ dysfunction. So that's one area of focus that we have.

Now you mentioned other aging-related diseases like cardiovascular disease, there's neurodegenerative disease, all of these sorts of things that we are all too familiar with, whether it's Alzheimer's, dementia, hypertension, so on and so forth. There's an increasing amount of literature showing that myeloid cells are one of the driving causes of for example atherosclerosis for hypertension, for heart failure, for dementia. I mean, there is a list of papers I could share with you that have shown that if you prevent these pathogenic myeloid cells from accumulating in the heart,

from accumulating in the liver, from accumulating alongside the endothelial cells that make up the blood vessel, then you can prevent the negative outcomes of atherosclerosis, of hypertension, neurodegenerative disease, so on and so forth. So it sounds as though because I'm... It sounds as though that because my favorite cell type are myeloid cells that I'm making all of this up, but it comes all full circle and that if you can prevent this pathogenic expansion of myeloid cells that are being produced by the stem cells in your bone marrow that theoretically you could alleviate a lot of the detrimental effects of these other aging-related diseases. Now, it just so happens that one of the kind of correlates to this is that the functioning

of your tissues is also dependent on a class of myeloid cells, a group of myeloid cells that instead of being produced by your bone marrow are found in your tissues starting at birth. So during fetal development, so we're talking way before you're born, as the embryo grows and as the fetus develops, these myeloid cells are produced and they are seeded, they are deposited in the tissues that will eventually become your lungs, that will become your brain, that will become your soul and so forth. And you need these tissue resident macrophages. It's a very specific term, but you need these tissue resident myeloid cells in order for

your lungs to properly function. For example, these tissue resident myeloid cells are important for helping your epithelial cells engage in gas exchange to get rid of that carbon dioxide, bring in that oxygen. It's important, for example, brain function because the tissue resident myeloid cells in the brain are important for clearing away dead nerve cells so that the brain has the space and the cleanliness to engage in neuronal signaling, electrical signaling. The same applies for the liver. You need tissue-resistant myeloid cells to help with the detoxification process and clearance

of pathogens. And there's a specific name for each one. The tissue resident myeloid cells in the lungs are called alveolar macrophages. You've got KUFAR cells in the liver and microglia in the brain. And they're everywhere, even in your skin. Again, they're different from the bad myeloid cells that we've been discussing because they're not from your bone marrow. They are present in your organs ever since birth. What we discovered and also reported in the paper, or not just us, but other folks as well, is that with age, you lose these tissue resident myeloid cells. And we suspect that it's because of this loss that, for example, lung function becomes increasingly compromised with age.

Liver function becomes increasingly compromised with age. That brain function and the onset of things like dementia or other neurodegenerative diseases becomes more present with age. So then the question is, can we somehow intervene and repopulate these tissue resident myeloid cells in the lungs, in the liver, in the brain, in the skin? And there's a growing area of research. There was a very interesting study from New York University, NYU, where they were showing that you could, on a very micro scale, repopulate the tissue resident myeloid cells in the skin and prevent the breakdown of blood vessels in the skin. We are currently working on repopulating

the alveolar macrophages, the tissue resident myeloid cells of the lungs to see if we can rescue lung function in old mice and hope that it reinvigorates gas exchange. Now, apart from just whether your lung function improves, the application of this kind of research extends to something as simple as a viral infection. Your alveolar macrophages are essential for fighting off bacterial and viral infections in the lungs.

So this applies to something as common as the flu. It's been shown that if you remove alveolar macrophages, you will do poorly against a simple flu infection, very poorly. So having more alveolar macrophages is good for you and will likely help you fight off the flu infection, for example, which makes sense because older folks do much worse when faced with bacterial infections and flu infections, viral infections. And so this is the kind of new area of research that we are expanding into, which again is

still all very much connected with the published research that motivated this conversation and that this is all part of the ageing immune system. These are all still immune cells that are becoming dysfunctional with age that for whatever reason are dying away, are wasting away, and are contributing to the dysfunction of our organs with time. It's so fascinating, right? And it also sounds like there's a bit of a balancing act that kind of has to happen along the way because on the one hand you're trying to

tamp down one type of this same cell because Yeah, it's stopping the immune system from doing things like fighting cancer but the other hand there's a version of this same type of cell that's resident in different tissues, which is Absolutely critical to their healthy functioning. So it's like you you're I would imagine there's this dance of like, how do we create, how do we find interventions or substances or therapies that affect the ones that we want to suppress while not only not having the same effect on the ones that we want, but actually, you know, like, how can we actually grow or regrow the ones that are just diminishing

with age over time, which is from a research standpoint, it's got to be quite a dance. It is, we think, the challenge that will, you know, become the highlight of aging research, this balancing act between helping the myelod cells that are residing in tissues while as you said dampening down the myelod cells that are being produced by the bone marrow. This is as you might expect a very puzzling challenge but also a very a hopeful problem for lack of better words, only because we are starting to get a better idea of what the problem is, when in fact prior to this,

I don't think we had a very clear understanding of what exactly is the problem, what exactly is the underlying pathology that makes aging so clinically undesirable when it comes to our risk for developing different diseases and so on and so forth. So for somebody who is following along in their head saying this sounds incredible, really hopeful the research that's going on now is phenomenal, that you're a human clinical child with some of these things showing really good

interesting early results. And somebody's just listening to this saying, like, I'm moving into the, you know, the second, third half of my life. Is there anything that I can do now or think about doing now that might help support any of the mechanisms that we're talking about? It's a very good question. I personally would not be able to tell you what to do. I don't have the personal life experience for it. But from just purely a research perspective, from a basic science perspective, I think there is a good amount of literature that specifically supports exercise is one thing. Exercise has a positive effect on preserving your tissue resident macrophages, on dampening

that bad production of myeloid cells from the bone marrow. Sleep. We have a very strong group of researchers at the Icahn School of Medicine at Mount Sinai who are dedicated to understanding the balance that interplay between sleep and immune cell production and their research shows that perturbed sleep, poor sleep has a very negative impact on the immune system and the pathologic production of myeloid cells is one of those consequences. So sleep and of course diet as I mentioned before, high fat diets that contribute to

obesity and cardiovascular disease, the underlying basis is this bad production of myeloid cells. So if you control the diet, I think that would be extremely helpful as well. Ultimately, it's those main three things that will, at least for the time being, are very well supported in a way keeping your immune system younger. Of course there's many other dietary supplements that have a lot of popularity and it's not without good reason for sure. So you know there's supplements called spermidine that people take. I know that in the aging field a lot of folks have discussed metformin which is a diabetes

medication or arapamycin and so on and so forth and there is foundational research to support a lot of those kinds of interventions, a lot of those kinds of day-to-day metabolic interventions. I think given our also, we also have an interest in those medications as well. We are also doing research on how, for example, those medications might be influencing immune cell production and those myeloid cells that we've been discussing. And while we don't have any solid data to make any concrete proposals, I think my suggestion would be to listen to your body and see what kind of, I wouldn't say clinical, but what kind of positive effects you seem to feel from interventions that you think are worth your time and energy for sure.

I want to ask you one more question along the lines of nutrition because this is a topic that is sort of like a topic to George come up a lot. I have experimented with it and it's this notion of fasting and fastings and the effects on apoptosis and cells in essence and potentially cancer prevention. Are you aware of any research that would speak to the impact of either like pure fasting, intermittent fasting on myeloid cells? So it's a very interesting question. My mentor, Dr. Miran Miraj, she leads the laboratory in which I'm in at Mount Sinai.

She was, I think, arguably one of the first few researchers who published on the effects of fasting on immune cells, namely myeloid cells. And what she showed was that fasting indeed reduces the production and output of myeloid cells from the bone marrow. And it's an intricate communication that exists between the liver and the bone marrow. And if anything, her paper on this particular subject is one of the earlier reasons why I wanted to learn from her and get her mentorship on immunology. So it was a very personal reason for me to join. There have been a number of studies since then,

and I would argue probably prior also, and not to give too much credit, not to give everyone credit as much as possible, but there have been a number of other studies that support the fact that there is a direct impact of intermittent fasting, long-term fasting on myeloid cell production. That having been said, I think there were a number of recent studies that might have

put a few caveats, a few asterisk marks here and there. I can't remember off the top of my head as to what those warning labels were, but it definitely seems as though there may be a desired effect of fasting on myeloid cell production. So it is quite relevant to the conversation here. Yeah, so fascinating. Well, I mean, I've enjoyed learning and I'm excited for the research to come as well. It sounds like, you know, there's between your lab and others, there's a lot that, you know, may well unfold, especially in the context of human beings and human trials over the

next five to ten years. The potential for it to potentially change the way that we approach both treatment and prevention is just super exciting. It must be pretty cool to be in the middle of all of that just as as a human being and a researcher on your side. I find it extremely rewarding. I think, well, I will say one of the reasons that I chose to come to Mount Sinai as a scientist, as a researcher, was that we are very dedicated to not just doing the basic science, but keeping in mind all the way through why we're doing this. At the end of the day, this is for patients. As thrilling as the pure science is intellectually, academically, the justification for using

taxpayer dollars to fund this kind of research is so that we can bring it back to those who actually need it. And I think that is exemplified by the translational mindset that Mount Sinai has in terms of making sure that what we find in the lab can be brought to clinical trials for proper testing so that if it works, it can definitely reach those who need it. And so it's not, I will say, I don't think it is quite common that, for example, my research on anakinra, my colleagues' research on Dupilium-AP, that all of these findings could be so quickly brought to the clinical trial setting in a manner that is safe, that is thorough. And so with the right setting, with the right support system, this kind of translational,

the true translational research is possible. So to see our current findings hopefully presenting possible solutions for patients with cancer is personally rewarding and I hope fulfilling for the years to come for sure. Yeah, no, it's fantastic. So I always round these conversations out with the same question in the context of this container of good life project. If I offer up the phrase to live a good life, what comes up? Well, that's a very deep question. I really like this question to live a good life. I would say that to live a good life is to listen to your body, to understand or to be informed of why you may not feel good, but

also why you do feel good. And knowledge is power. So hopefully living with information and being conscientious will lead to living a good life. Thank you. Before you leave, if you loved this episode, safe bet you'll also love the conversation that we had with Tim Spector about eating for health. You'll find a link to Tim's episode in the show notes. This episode of Good Life Project was produced by executive producers Lindsay Fox and me, Jonathan Fields.

Editing help by Troy Young, Christopher Carter crafted our theme music, and special thanks to Shelly Adele Bliss for her research on this episode. And of course, if you haven't already done so, please go ahead and follow Good Life Project in your favorite listening app or on YouTube too. If you found this conversation interesting or valuable and inspiring,

chances are you did because you're still listening here. Do me a personal favor, a second favor, share it with just one person. I mean if you want to share it with more that's awesome too, but just one person even, then invite them to talk with you about what you've both discovered, to reconnect and explore ideas that really matter, because that's how we all come alive together. Until next time, I'm Jonathan Fields, signing off for with Fizz. Switch today. Conditions apply.

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