The Hidden Immune Signal Accelerating Aging & the Beta-Glucan That Fixes It | Bob Rountree & Chris D’Adamo
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This is the longevity conversation functional medicine providers need to hear. What struck me in each of these conversations is how deeply functional medicine already holds the answers we’re chasing in longevity science. We don’t need to reach for extremes. The tools we use every day—our frameworks, our lens, our root-cause approach—are longevity medicine.
If you’re a clinician who’s felt unsure about where you fit in this rapidly growing space, I want this episode to remind you: you’re already in it. You’ll hear how leaders in our field are using the functional medicine matrix to slow cognitive decline, decode inflammatory pathways, and reframe aging itself as a process we can impact intelligently and safely.
These interviews are just a glimpse of what’s coming in the Functional Medicine is Longevity Medicine Masterclass™ and I can’t wait to share them with you. Don’t miss what will be an inspiring, high-energy event. Book your free spot here.
Why Functional Medicine Is the Future of Longevity
The longevity conversation is gaining momentum, but much of it is focused on extremes that may not serve our patients or the long game of health. In this special episode, Dr. Kara Fitzgerald invites us to rethink longevity medicine through the lens of functional medicine: a lens grounded in systems biology, clinical wisdom, and real-world outcomes.
You’ll hear from Dr. Bob Rountree on how the functional medicine matrix naturally aligns with the hallmarks of aging, Dr. Dale Bredesen on addressing cognitive decline through network-based thinking, and Dr. Charles Serhan on the discovery of the body’s own inflammation resolution molecules. These excerpts are a preview of what’s to come in the Functional Medicine is Longevity Medicine Masterclass™ and a powerful reminder that functional medicine already offers the tools to support longevity safely and effectively.
In this episode of New Frontiers, learn about:
- Rethinking the Longevity Hype: Explore why chasing lifespan alone can lead clinicians astray and how functional medicine provides the safer, evidence-based tools we need to support longevity, cognition, inflammation, and immune resilience.
- A Systems-Based Approach to Cognitive Decline: Dr. Dale Bredesen reveals how addressing root-cause network insufficiencies can improve cognitive function in early Alzheimer’s patients.
- The Missing Link in Inflammation Management: Dr. Charles Serhan introduces specialized pro-resolving mediators (SPMs) and explains how they guide immune recovery and tissue repair.
- Measuring Biological Age Through Epigenetics: Explore how methylation clocks provide actionable insights for tracking aging and guiding personalized interventions.
- Why Extending Life Isn’t Enough: Dr. Rountree discusses compressing morbidity and how functional practitioners can help patients stay vital into later decades.
- Resolution Biology and the Return to Homeostasis: Learn how the body transitions from inflammation to healing and what nutrients and signals help complete the process.
- Integrating Longevity Principles Into Routine Practice: Discover how to apply aging science without starting from scratch, by building on existing systems-based strategies.
Dr. Kara Fitzgerald: Hi everybody, welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. And today is no exception, but it is a special day because we will be interviewing three of the best minds in functional and a lot more than that. Did you know that functional medicine is longevity medicine? And if you’re a functional medicine provider listening, or if you are an individual working with a functional medicine provider, you know that we’re already bringing it forward. We’re bringing longevity medicine to each and every patient. And we want you to be confident in this fact. We want you to be confident in what you’re doing with this awareness.
Dr. Kara Fitzgerald: And to that end, we want you to be prepared for the road ahead with the tools and knowledge needed. Join us at our Masterclass coming this September 17th through the 19th. I will be bringing 30 of my brilliant colleagues talking to you about the best in functional medicine as longevity medicine. And as always, we will have that delicious connected community chat happening concurrently. Many of these chats will be with the presenters themselves. So if you’ve ever attended one of our platform webinars, you know that we’ve got these good smart dialogues happening clinician to clinician. Often I am there with you in the chat and this will be happening through the course of these three days.
Dr. Kara Fitzgerald: Who’s going to be with me at this incredible Masterclass? Well, right off at the get-go, if you’re thinking Dr. Jeff Bland, you’re absolutely right. He’ll be opening the program with me and he’ll also be closing it. Me, Jeff Bland, Laurie Hoffman, and in between it’s going to be a historic collection of brilliant minds, including Mark Hyman, Dale Bredesen, David Perlmutter, Sara Szal, Helen Messier, Monique Class, Terry Wahls, and Jill Carnahan. Lots and lots of amazing names and all of us will be coming to you through the lens of Functional Medicine IS Longevity Medicine™ to bring you the latest in interventions, in natural products with great science behind them, in new laboratory technology, and just how we’re bringing AI into the conversation as well.
Register at FunctionalMedicineIsLongevityMedicine.com. And yes, this three-day virtual conference is free. Now back to the podcast.
Dr. Kara Fitzgerald: Our first excerpt is with Dr. Bob Rountree. He’s been in functional medicine for a long time and likely you’re familiar with his work. He’s going to be talking to you about how he’s bringing these longevity principles into his own clinical practice. Have a listen.
Dr. Kara Fitzgeral: Dr. Roundtree it is great to be with you yet again.
Dr. Bob Rountree: Yet again.
Dr. Kara Fitzgerald: Only we get to talk in a fun context today. Today I get to pick your brain. I always learn from you and have my entire career, and of course alongside you in the immune module (at IFM) for the last decade plus.
Dr. Bob Rountree: So many years of getting younger, right?
Kara Fitzgerald: Yeah, so many. Now we’re going to find out how you do it. You are the clinician’s clinician. I think that among all of us faculty at IFM, people really turn to you for what you’re doing in practice, and how you’re vetting products, and what you’re thinking about in the larger space. You have our ears. You have the ears of the educators. And then of course, all the people attending and being trained are paying attention to you.
Dr. Bob Rountree: That’s a little scary to hear actually.
Dr. Kara Fitzgerald: Yeah, no pressure, no pressure. So here we are in this massive longevity conversation. The name of this masterclass is Functional Medicine is Longevity Medicine. This longevity conversation has just blown up. And I’m curious your perspective, you know, just being in our world for a long time. From your vantage point what’s going on here, and how do you think about it, and how are you incorporating it in your practice? Has it changed your thinking? Anyway, I’ve thrown out a lot. I’m gonna zip it.
Dr. Bob Rountree: Well, oh boy. Aging. I first gave a presentation, I think, at an AIC, (IFM’s Annual International Conference) with Jeffrey Bland on aging, like 15, 20 years ago. I mean, a long time ago. And we just outlined all the different processes involved, which basically reiterates what you’re saying. Functional medicine is longevity medicine. If you’re walking around the matrix and looking at all the imbalances that can occur, it’s amazing how that overlaps with the ‘pillars of aging’, right? I don’t remember when that article came out. Was that like 10 years ago?
Dr. Kara Fitzgerald: Yes. The hallmarks. Yes.
Dr. Bob Rountree: Yeah, the pillars of aging and those have gotten more and more, but they’re still basically very similar to the functional medicine matrix. So I’ve been looking at those processes all along. And academically, you’ve got Steven Austad and people like that who’ve been in the background doing this research for a long time. But all of a sudden it’s a big social media thing. And it’s kind of interesting to me because it’s not like there’s some bit of new information out there that we didn’t already know about that we weren’t already talking about, but suddenly it became the thing.
Dr. Bob Rountree: And what’s really struck me about it more than anything else is how many people in their 40s are obsessed with this? Or their 50s. How old is Bryan Johnson? I have no idea, but suddenly you’ve got these younger individuals that are saying, whatever you do, don’t die. I’m going, wait, you haven’t really had to confront the things that you’ll confront when you get to be sixty. And then seventy. So somehow I became an elder.
Dr. Kara Fitzgerald: Yes, I know. It happens.
Dr. Bob Rountree: You just wake up every day and you’re a little bit older and it kind of confers a different perspective entirely. So it’s just a bit odd, I think, this explosion in interest. And I’m not sure exactly what sparked it. Again, it wasn’t like suddenly they discovered the Klotho gene and now everybody’s obsessed with it for that reason. Or suddenly people started thinking about metformin or rapamycin and saying, hey, this new research is now making us obsessed with longevity. That stuff has just been moving along for years.
Dr. Bob Rountree: It could be that Peter Attia has given it a certain level of legitimacy by saying here’s the research, and doing it in a really calm manner. So I do appreciate the work that Peter has done because he’s so non sensationalist. Some people might disagree. Some people might say he’s sensationalist, but I think he’s very careful at looking at the data. Here’s the research. So when he talks about longevity medicine it’s a whole different ballgame than if you only took this magic pill then you’ll never die.
Dr. Kara Fitzgerald: Right, right. And they have always been there. There’s always been the group of individuals who were all about escape velocity. And some scientists with good reputations are talking about this idea of escape velocity. So, that is you shave a year off, you reverse bio-age every year forever.
Dr. Bob Rountree: Yep. Let’s compress morbidity. I mean, when did Fries come out with that? Like, ages ago.
Dr. Kara Fitzgerald: Yes, that’s right. That’s right.
Dr. Bob Rountree: That’s not a new concept, this idea of compressing morbidity. It’s like, okay, great, health span is important. Sure, we’ve been saying that for a long time.
Dr. Kara Fitzgerald: Yes.That’s right. Yeah. And we’ve known for a long time that health span stinks in most countries.
Dr. Bob Rountree: Yeah, we can keep you alive. You might be on life support, but we’ll keep you alive till you’re a supercentenarian.
Dr. Kara Fitzgerald: Yeah. What about the whole idea of biological age? Was that kind of the catnip that allowed it to blow up? This idea of biological age versus chronological age and then…
Dr. Bob Rountree: I think having a way to come up with a number, you know, having these clocks that are reproducible clocks, that not just one lab can do, but multiple labs can have their own version of the clocks. That was something because, as you know, the debate has long been going on about aging as to whether it is an underlying process that influences all these other processes.
Dr. Kara Fitzgerald: Yes, and what do you think about that?
Dr. Bob Rountree: Okay. I think there’s something to it. Yeah, I mean, it’s always interesting to me when they interview these supercentenarians and they say, what did you do? Well, you know, I made sure I got up and had a cigar every morning and, you know, a glass of whiskey, that sort of thing. So clearly there is this group of people that have something going on genetically that influences all these other chronic degenerative diseases, the heart disease, cancer, neurodegenerative disorders. There is some underlying influence. Is there a program that is built into it that says, okay, at some point, your cells are gonna hit the Hayflick limit and you’re done? And if we could overcome that, we’d be like a naked mole-rat. You live forever. The females never have menopause. Like naked mole-rats.
Dr. Kara Fitzgerald: So all right, what do I want to say about that? Interesting to me is the fact that these biological age clocks, well, a mammalian clock has been identified. They’re using DNA methylation so they’re looking at CpG sites. There’s a collection of CpG sites across mammals and then an iteration has identified life expectancy. So they’re able to map that out. None of the interventions that they’ve tried to manipulate it have actually worked. But one of the things that these authors, [Steven] Horvath being one of them, who’ve mapped out this mammalian age clock have said is that there might be what they call a pseudo program because it’s consistent across mammals. And they’ve been able to actually identify life expectancy using this tool. I think that’s pretty cool. In my mind, that’s an argument towards there being some kind of a program phenomenon on the aging journey.
Dr. Bob Rountree: Right. So is the program an active program that’s turned off in some people? An active program that says, again, you’re going to reach your limit and then it gets turned off? Or is it the other way around? Is it like…
Dr. Kara Fitzgerald: You know, my understanding is there’s not an obvious gene pattern for some of these supercentenarians.
Dr. Bob Rountree: At least once you get away from worms, from C. elegans and some of these simpler models.
Dr. Kara Fitzgerald: Well, you know, speaking of C. elegans, I was chatting with a postdoc from Matt Kaeberlein’s lab and so I’m going to ask Matt Kaeberlein this. She said that when they did caloric restriction, which classically makes C. elegans live a lot longer, if food was in the vicinity, if they had an awareness of food, it just slashed that benefit. Isn’t that wild? Slashed it. Like, they can’t have any conscious awareness of it. And I want to ask him what he thinks about that. You know, we have conscious awareness of food all the time.
Dr. Bob Rountree: Yeah. Well, I can’t remember the name of the experiment they did in Arizona that Roy Walford was in.
Dr. Kara Fitzgerald: Yeah, the biosphere.
Dr. Bob Rountree: Yeah, the Biosphere 2 or something. I was a big fan of Roy Walford’s when that book came out. Again, that kind of started me on this journey of being really interested in aging.
Dr. Kara Fitzgerald: Did it?
Dr. Bob Rountree: Oh yeah. I mean, I thought, okay, this guy is a giant in the field and he appeared to get healthier as a result of almost starving to death in that place because they ran out of food, and they didn’t have enough oxygen, and there were all kinds of problems. They come out and they’re all gaunt and everything. But a lot of their markers at the time, and they didn’t have the methylation panels available, but a lot of other markers looked good. But then, Valter Longo points out later, because Valter was one of his students, pointed out that well, Roy didn’t do so well in the years that came after that. So he looked better initially and all that severe calorie restriction appeared to be beneficial, but maybe it didn’t pay off.
Dr. Kara Fitzgerald: That’s right. That’s right. And I think that they’ve demonstrated that in monkeys. All right. You’re the clinicians’ clinician. That’s how we started this.
Dr. Bob Rountree: I don’t treat macaques, though, either. I treat people, macaques.
Dr. Kara Fitzgerald: That’s awesome. We could go down a rabbit hole, but I want to circle back. So first of all, amen to functional medicine being longevity medicine and to just leaning into the matrix, leaning into our tools, the vantage from which we need to be thinking and acting. With that, I want to ask you about labs, any new labs that you’re thinking about? Are you using those clocks, for example? Or are you measuring Klotho…
Dr. Kara Fitzgerald: That was Bob Rountree showing us how he is bringing the longevity lens into his functional medicine practice. It’s definitely not replacing functional medicine, obviously, but it’s enhancing what he’s already doing. Now we’re going to hear from Dr. Dale Bredesen. He is the former head of Buck Institute for Research on Aging. He’s an internationally recognized neurologist and the creator of the ReCODE Protocol, a systems-based approach for preventing and reversing cognitive decline. Take a listen.
Dr. Kara Fitzgerald: Dr. Bredesen, it’s wonderful to be with you again. You’re a mentor, you’re an inspiration, you’re a leader in the field of functional medicine and beyond. You’ve been a mentor to me, you’ve supported me in my own research as you have many other clinicians and scientists. You have brought forward a model for studying individualized medicine in a very structured and rigorously scientific way using your ReCODE protocol. And you’ve done this despite sustaining some pretty extraordinary pushback from the greater medical community. I think most importantly you’ve brought inspiration to humans, those of us walking the journey of Alzheimer’s, either as a family member or as an individual with the condition. So you are just an extraordinary human who we in functional medicine embrace deeply. And I want to hear just a little bit about this journey for you, and just where we are today in terms of the evidence for Alzheimer’s and cognitive impairment.
Dr. Dale Bredesen: Thank you so much, Kara. It’s always great to talk to you. Love your work and we’re very excited about what you’re doing. So briefly, I was interested in using a model of cancer. There was such a good model where you could study cancer in a dish from dozens of years ago and we wanted to apply that. When I very first got started with my lab in 1989 at UCLA, we wanted to develop neurodegeneration in a dish. The big problem being that it’s easier to study cells that are proliferating because you can pick them out, rather than cells that are disappearing. That’s much harder. So we wanted to understand what we could do. So for thirty years it was all about what’s the best understanding? What’s the fundamental nature of the process?
Dr. Dale Bredesen: As you know, it’s been about: this is a herpes of the brain, this is reactive oxygen species, this is type 3 diabetes, this is amyloid, it’s tau, it’s prions. It just goes on and on and on. But nothing had ever really given a good response when you actually go after these things. And so we actually did develop drug candidates and we’ve got some very exciting ones now. But ultimately we went from, “Okay, what’s the best understanding?” to, “Wait a minute, we’re seeing a picture now.” We’re seeing that if you step back and look at this, what you see is a beautiful network and it’s a network insufficiency.
Dr. Dale Bredesen: And here’s what’s amazing to me, Kara. If you look at evolution – and you know what’s happened with evolution, and you know about antagonistic pleiotropy, which is the leading evolutionary theory of aging – because we select as organisms repeatedly for performance over durability, we get these amazing performing brains. I mean, you can store more in your brain than in over 2,000 home computers. It’s remarkable. You have more amplification ability when you go from thought to maximal muscle contraction than you do when you stomp down on your car’s accelerator. That’s how impressive these systems are. So no big surprise, they have Achilles’ heels. They’re not perfect. And with aging and with changes in all the things that we’ve talked about, changing in inflammation, and changing in blood flow, and oxygenation, and all these things, you can start to lose function. You get a network downsizing. And when you lose the neuroplasticity one, you get Alzheimer’s. When you lose the amplification one, you get ALS. When you lose the motor modulation one, you get Parkinson’s. And so we then changed over to what’s the best outcome.
Dr. Dale Bredesen: Initially, we started with a drug, this was back in 2011. And as we were planning the first clinical trial I was sitting in my office and I realized, wait a minute, what about the other pieces of the network? We’re not addressing that with this drug. So I thought, let’s add this or let’s add this. And of course, after about two or three adds the light bulb went off. Like, wait a minute, we have to address all the pieces of the network that are insufficient. And of course I knew nothing about functional medicine at that time and so I started realizing, okay, this is basically what functional medicine is about. What I loved about it was studying the molecular details the way we did for 30 years and all the test tube research brought us to the same place that others had come from very different backgrounds and so it really showed me that this is the thing that’s working.
Dr. Dale Bredesen: And of course, we started seeing people get better and better. The very first person who ever got better, someone I saw in April of 2012, is now walking across the United States from coast to coast. You can see her on judywalks.com and she’s already in Texas. She’s amazing. She’s now 81. We’ve seen it now in thousands of people, just people getting better. And of course, it’s not 100%. So that’s basically how we got here. And there’s so much more to do, but this is still a very exciting time. We’re seeing things that we just haven’t seen before.
Dr. Kara Fitzgerald: It’s so extraordinary and indeed it is very exciting, back in 2011, you putting those pieces together coming, you know, from a Petri dish. And Jeff and all of our functional medicine mentors, you know, we’re putting it together from a different but similar perspective. And of course the systems biology people were building that as well and here we are unified. In functional medicine we’re always talking about the idea of being able to research personalized medicine, but it seemed very difficult coming from a reductionistic model.
Dr. Dale Bredesen: Yes.
Dr. Kara Fitzgerald: You’ve gotten some pushback for your extraordinary expansive thinking. Any comments on that?
Dr. Dale Bredesen: Yeah. So, here’s the issue. When you try to take a model that’s been there for a long time, you’re going to do one thing, and you’re going to check that one thing, and then you’re going to have a placebo control, and then you’re going to use a drug, et cetera. Now you’re suddenly saying, number one, I want to use a protocol, so it’s not one change. And that’s actually why we got turned down in 2012. Our first trial got turned down multiple times starting in 2011. Number two, it’s not a drug that’s going to give you a hundred billion dollars on the other end and so nobody wants to put the money in to show that this actually works. So now you’ve got that as a second problem. And then the third problem is you’re fighting against the powers that be that are already taking advantage of these things.
Dr. Dale Bredesen: This is why Machiavelli said the hardest thing to do is change the existing structure. Whether it be a political structure or whether it be pharmaceutical structure or medical structure, the hardest thing to do is to change that because everybody who is doing well, who is profiting from the current status will fight against it. And the ones who are waiting to see if it’s going to improve are just waiting on the sideline to see, well, I don’t want to jump in and get knocked down. So it is very difficult. And as you know, we’ve had the recent New York Times article. We provided the reporter with 12 different people, doctors and patients, who had all witnessed, or had it happened to them, or experienced cognitive improvement. There’s no question, objective improvement, documented improvement, published improvement. She ignored all of it and just said, this is alternative medicine. It’s hokey, no one believes in it, which is just crazy.
Dr. Dale Bredesen: So this is the world we live in. Again, as you said, it’s the patients who are seeing the outcomes. To go from hopeless to hopeful is so exciting. We know there’s still a long way to go and we’re adapting this now to macular degeneration, to Lewy body disease, to ALS, to Parkinson’s, to frontotemporal dementia, all these things. So I’m very excited that the potential is so great and I think bringing now targeted drugs with these systems biology, and precision medicine, and functional medicine protocols is what’s going to be the most powerful of all.
Dr. Kara Fitzgerald: Yes, I absolutely agree. And certainly, those of us working as clinicians in this space using the ReCODE model, or variations of your original core program, have seen remarkable turnaround. And it fits in very close alignment with our training and with our thinking. I was just doing a little bit of a tour of some of the publications and you’re at least number six, maybe number seven now, starting with case studies – I’ve published many, many case studies and I think they’re essential to move science forward – to clinical trials and you continue to work in this arena. Where are we at with regard to the evidence behind ReCODE?
Dr. Dale Bredesen: Yeah, that’s such a good point. And it’s very important for all of us to get these out there and to show that, yes, here’s where you start. Because there are a lot of people that need what we’re doing and doctors aren’t aware of it, patients aren’t aware of it, and so people literally are dying needlessly. We also want to get people to come in earlier. As you said, we started with the first couple of people, case reports, first 10, then we had 100 documented improvements.Then we went to a proof of concept trial and that was published in 2022. And then of course, Dr. Heather Sandison published her own trial doing very much the same thing, getting very much the same results. I mean, it’s almost like you could take the papers and they’re pretty similar.
Dr. Dale Bredesen: So I think that is confirmatory. We’re not just out here thinking something that nobody else is seeing. Other people are seeing it. And pretty much anyone who’s done this seriously sees the same thing. You see improvements where they weren’t before. So now we are almost done with a randomized controlled trial, and of course, that’s the next step. So we have a group that is being treated by the standard of care for Alzheimer’s disease and a group that’s being treated with this personalized, functional medicine type of approach. And I’m really thrilled to work with some outstanding physicians, Dr. Kat Toups, Dr. Ann Hathaway, Dr. Kristine Burke, Dr. Craig Tanio, Dr. Nate Bergman and Dr. David Haase.
Dr. Dale Bredesen: And so we’re seeing these remarkable results and it’s very interesting. The people who are on the standard of care, just as you’d imagine, are going down, down, down with their cognitive testing. The people that are on the protocol are going up, up, up, and there’s already a statistically significant difference between the two groups. It will be completed October 31st, so it should be published next year by the time we get all the data, get it reviewed, and all that sort of stuff. But that’s the next step. And then I think the following step to that, there are a couple of directions that I’m interested in going next. So one is, these are just….
Dr. Kara Fitzgerald: That was Dr. Dale Bredesen illustrating how a multimodal root-cause approach can yield real measurable improvements in cognitive health.
Dr. Kara Fitzgerald: And now we turn to Dr. Charles Serhan, Harvard researcher and scientist who discovered and characterized specialized pro-resolving lipid mediators, or SPMs for short. These are the body’s own inflammation resolution molecules derived from omega-3 fatty acids with applications in everything from neurodegeneration to skin health. Take a listen to Dr. Serhan.
Dr. Kara Fitzgerald: Dr. Serhan, it is such an honor to get to be with you again and just learn some of the amazing science that you and your team are up to and just do another dive into the incredible world of specialized pro-resolving lipid mediators.
Dr. Charles Serhan: Well, I just want to thank you so much, Dr. Fitzgerald, for the opportunity to talk with you today and tell you and your audience about some of the things we’ve been digging up.
Dr. Kara Fitzgerald: Cool. But you know what, before we do, I want to do an intro and I was thinking a little bit in preparation about analogies. How to capture the impact of the discovery that you made. And people are probably aware, hopefully by now, that there’s this incredible observatory, the Vera Rubin Observatory was launched and two days ago these extraordinary pictures of the universe are coming out. I think in the first few hours 2,000 new stars were identified and this will go on and on.
Dr. Kara Fitzgerald: And I look at the fact that you discovered and have been characterizing now for, well you can tell me how many years, discovering more of these pro-resolving lipid mediators. And their actions, and how we make them, and what they do, and their essentiality in our immune system, and our inflammatory response, and cleaning up our inflammatory response, and in brain health, and heart health, and in skin, and liver, and in the body complete. These are key fundamental players and this is your discovery. It’s as extraordinary as this new insight into the universe that is upon us recently with the Vera Rubin Observatory. I’m not understating this.
Dr. Kara Fitzgerald: I absolutely think you will be awarded the Nobel for this discovery. You just have to be because it’s essential to physiology, to who we are, understanding and just characterizing all of the science you’ve done. So with that introduction, I want you to tell us about pro-resolving lipid mediators, where they come from, and I would like to hear a little bit about your discovery of this extraordinary universe.
Dr. Charles Serhan: Well, I have to start by saying we all stand on the shoulders of giants. I love your analogy with the universe and having a great scope and you can see more because it does relate to how we discovered these molecules. In my case, I had extraordinary clinician scientists as mentors. Gerald Weissman, an inflammation rheumatologist, top in the field and teacher of mine. Aaron Marcus at Cornell in hematology and oncology learning about platelets and coagulation. And then of course, Bengt Samuelsson. I learned structural elucidation with him and he did the biosynthesis and structural elucidation of the prostaglandins and leukotrienes. So I was destined to put that all together with the grace of God and ask the right questions.
Dr. Charles Serhan: And as a scientist, especially biomedical scientist, you don’t really know if you’re on the right track until many years later. You ask questions and ask nature to give you the answers. So how we came upon the specialized pro-resolving mediators is by pondering the question of what is endogenous anti-inflammation? Now, why would we be thinking about that? Well, if we do a thought experiment, like Einstein would do, and just think of the pimple and that little pustule that forms on your skin. And if you’re healthy and don’t have any other insults along the way, it will resolve. It’ll just go away on its own. So that first response of the white blood cells is self-limited. And I remember in the pathology textbook, the acute inflammatory response, the initial recruitment of neutrophils into the response, and then they go away. And so we started to ask, where do they go?
Dr. Charles Serhan: And so we set up a very simple model like that little pustule where on the back of a mouse where leukocytes come in response to an immunological stimulus and then we could study pus. So we started to do an interrogation of pus for the proteomics at the time, the cellular components, and of course the lipid components. And that’s where we saw these unusual structures. And then it was our mission to figure out what do they do? And it turns out that those initial molecules stop and limit the neutrophilic infiltration, which is very important because that’s what leads to collateral tissue damage and the propagation of inflammation. And they do something else that’s pretty astonishing. They stimulate efferocytosis. And efferocytosis is carried out by macrophages, and it is the process of taking away dead cells and debris. And this acute inflammatory response is the body’s initial response, it’s the first ring at the doorbell of an intruder, a bacteria, a virus. And I was very interested and my group’s mission was to figure out what’s happening there.
Dr. Charles Serhan: And it was already known that the prostaglandins and leukotrienes play an important role in that initial phase. But when the leukocytes reach a maxima [maximum levels] and they start to come down, we found that there’s a lipid mediator class switch – the lipids change in their structure according to the cellular dynamics. There’s a very dynamic process there in minutes to hours. It then goes to produce a whole host of pro-resolving mediators to get us back to a new level of homeostasis. So that’s basically it in a nutshell. They differ from the traditional anti-inflammatories because an anti-inflammatory blocks the initial prostaglandin or the cytokines that are produced, like anti-TNF therapies. The pro-resolving mediators are made by the body and they stimulate this efferocytosis, the clearance of dead cells and debris. And that’s a critical process in every tissue and organ in the body.
Dr. Kara Fitzgerald: And they’re right there in the same immune cells. They just, as you said– important, underlined, exclamation point– they class switch. So from the most exquisitely potent pro-inflammatory compounds, the eicosanoids and the prostaglandins, there’s this switch in those same cells to this cascade of potently anti-inflammatory things doing all this cleanup work that’s tissue-specific. So if it’s in the brain, it’s going to be behaving differently than if it’s in the skin or in the liver. Is that right?
Dr. Charles Serhan: Yes, two subtle points. One is the summoning of the leukocytes. So leukocytes and neutrophils travel in the bloodstream, as your audience knows, but they have to get to the interstitium. They have to go past the endothelial cells. The process is called diapedesis and two very important arachidonic acid products play a role there. The endothelial cells have to open up, this causes a little edema, and that’s governed by prostaglandins. And then the chemotactic and diapedesis, leukotriene B4, the white cells smell and move along that chemotactic gradient till they get to the site where they have to do phagocytosis and kill and destroy bacteria.This happens from head to toe, the identical repertoire in this initial response. Moving to the resolution, that’s when we see the utilization of other partly unsaturated fatty acids, EPA and DHA, the marine oils, to produce the resolvins for bringing us back to this homeostatic function. I consider their role to be more of a biosynthetic resilience in good health.
Dr. Kara Fitzgerald: Yeah. I just want to color a couple of things in and then correct me. We want to understand the lipids involved. I know most folks listening here understand that arachidonic acid is, of course, the polyunsaturated six in the polyunsaturated six family. And it’s the pro-inflammatory substrate that will then be converted to the eicosanoids, the prostaglandin and the leukotriene. So that’s arachidonic and that’s often why we, as clinicians, are trying to turn the volume down to some extent on omega-6 fatty acids. We essentially need some of this arachidonic acid because it allows us to have a robust and essential immune response. It also is essential in the class switch journey, as you have taught, with the lipoxin.
Dr. Kara Fitzgerald: So it’s the first step in allowing us to move into the resolution phase. And the resolution phase, as you just pointed out, these players are essential because they’re coming from our omega-3 fatty acids. This is why we need to have our membranes packed with DHA, EPA, DPA, and who knows what else? I’m imagining that you’re going to be continuing to discover other fatty acid substrates.
Dr. Charles Serhan: That’s right. Yeah.
Dr. Kara Fitzgerald: Yes, so we need the omega-6s, we need to have arachidonic. Arachidonic is essential for initiating the class switch and the cleanup, but if we don’t have the cleanup substrates, if we don’t have the ingredients, we’re not going to be doing a heck of a lot of efficient cleanup. But this is a really important reason why we need to be balanced in our fatty acids in the body.
Dr. Charles Serhan: Oh, that’s such an important point. Thank you. It’s exactly right. We need the arachidonic acid also in coagulation. It is essential as well. It’s really the balance between the N6 versus the N3 and we have little to no capacity to make them ourselves. So this is all based on what we take in in our nutrition. I think the other point about the switch that’s really important to point out is that this is a programmed, active response by the body. And earlier people thought that there was just a passive dilution of all the chemokines and cytokines that were elaborated to bring in leukocytes to do their function within the tissue. And that’s not at all the case. This is a very well orchestrated program. And this should be obvious to us because the early textbooks in immunology make the point that nutrition is essential to have the immune system operate at full capacity.
Dr. Kara Fitzgerald: Yeah, yeah, it’s extraordinary. And we’ve run into pretty profound complications given that, by and large, we’re a world deficient in adequate omega-3 fatty acids in the lipid membranes. And so inflammation, this very active intentional inflammation resolution—
Dr. Charles Serhan: Well, I have to tell you one important point. What we’ve seen emerge in recent years from data, now from many laboratories in addition to our own, is that the lion’s share of EPA and DHA that get converted to the specialized pro-resolving mediators, the resolvins and the protectins and the maresins, come from free fatty acids in circulation. So we don’t have to go through that esterification step into the phospholipids, at least in the acute inflammatory response.
Dr. Kara Fitzgerald: Very interesting.
Dr. Charles Serhan: In other tissues that I’m very excited about, like the vagus nerve, electrical stimulation of vagus nerve, it appears that the DHA is coming from the membrane phospholipid pool. That’s very interesting. In the M2 macrophages, they’re the reparative macrophages, they need to carry DHA in their plasma membrane to mobilize it and produce pro-resolving mediators in addition to their job in efferocytosis. As they carry out efferocytosis, they’re making more SPMs.
Dr. Kara Fitzgerald: Yeah, just locally they have the enzymes right there.
Dr. Charles Serhan: That’s right. So you have these two different systems that are emerging.
Dr. Kara Fitzgerald: It’s very interesting.
Dr. Charles Serhan: One is in reproductive biology, which is astounding. There’s such cool… Our first look there was in breast milk. Breast milk is very high in resolvin production. It was known to be a site for EPA and DHA deposition. But recent studies on the lacrimal gland in the eye show that the lacrimal gland makes the SPMs and then in age they are reduced. The conjunctiva of the eye makes SPMs. This system is under cholinergic stimulation. This is not triggered by an invader like the acute inflammatory response. This is another level of physiology that we’re really excited about.
Dr. Kara Fitzgerald: What are the implications in that we’re losing our reservoir as we age?
Dr. Charles Serhan: Well, I see it more as losing the capacity. The reservoir I think of as the substrates. The substrates might be available, but they’re just not efficiently converted. And so the enzymes might be lost. Yeah, that’s something that needs to get studied in more detail. We did find though that in the mouse models, the aged mice that were known to have excessive inflammatory responses, we noted in there that they also have a loss of resolution mediators. And so there’s no control over their inflammatory response. They can’t counterregulate. So that is an area that I hope will progress. We have now been using aged cells. Senescent cells, are cleaned up by resolvin-stimulated M2 macrophages.
Dr. Kara Fitzgerald: Amazing. Wow.
Dr. Charles Serhan: And that work is going on in the heart by groups around the world. And we continue to look at this in the spleen, because the spleen is the organ that clears aged red blood cells. Red blood cells circulate for about 120 days but then they have to be cleared out so you can get new bone marrow stimulation and new red cells appearing. And those aged, senescent, red cells are cleared by an EPA-derived resolvin E4 stimulating the macrophages. So there is a physiologic role, a percolation going on of resolvins and SPMs in and apart from this challenge scenario which we first came in on.
Dr. Kara Fitzgerald: It’s just so interesting. It’s so fascinating to me. I want to say, just thinking about senescent cells, of course…
Dr. Kara Fitzgerald: That was Dr. Charles Serhan giving us a glimpse into the frontier of inflammation resolution science. These were just three excerpts from the 30 speakers you’ll hear in our Functional Medicine IS Longevity Medicine™ online masterclass. Again, it’s live, it’s free, it’s packed with clinical pearls you can use immediately in your practice. Head over to FunctionalMedicineIsLongevityMedicine.com to register and join us in what’s to be a real historic event.
Dr. Bob Rountree is a board-certified family physician with over 40 years of experience integrating conventional medicine with nutritional science, botanical medicine, and mind-body therapies. Based in Boulder, Colorado, he offers personalized consulting at Boulder Wellcare, where he specializes in complex chronic conditions and root-cause resolution. A recognized leader in the field, Dr. Rountree is also the coauthor of several books on integrative and functional medicine.
Follow on Instagram: @wellcaremedicare
Full bio: www.ifm.org/educator/robert-rountree
Dr. Dale Bredesen is a neurologist and senior director of Precision Brain Health at Pacific Neuroscience Institute®, known for pioneering the ReCODE Protocol™ to prevent and reverse symptoms of cognitive decline. He’s also Chief Scientific Officer at Apollo Health, a medical information company, where his decades of research have reshaped our understanding of Alzheimer’s and age-related brain health. He’s the author of several bestselling books, including The End of Alzheimer’s and The Ageless Brain, and holds over 30 patents related to neurodegenerative disease.
Follow on Instagram: @drdalebredesen
Website: www.apollohealthco.com
Dr. Charles Serhan is the Simon Gelman Professor of Anaesthesia at Harvard Medical School and Director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women’s Hospital. A leading figure in inflammation resolution, Dr. Serhan discovered the specialized pro-resolving mediators (SPMs) and has authored groundbreaking work on their role in immune recovery and tissue repair.
He has received numerous awards, including the NIH MERIT Award and the 2023 CPPA Award from Northeastern University for his visionary work on SPMs. He is a Highly Cited Researcher in Immunology, with an h-index of 192 and over 125,000 citations.
Learn more about his research at serhanlab.bwh.harvard.edu
Join Dr. Kara Fitzgerald and leading experts LIVE on Sept 17–19, 2025 for a free virtual Masterclass on redefining healthcare & longevity through the lens of science-backed, systems-based approach. Register now: www.functionalmedicineislongevitymedicine.com
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