Inflammaging: Brian Andonian, Sara LaHue, Joe Hippensteel

Eric 00:11

Welcome to the GeriPal Podcast. This is Eric Widera.

Alex 00:12

This is Alex Smith.

Eric 00:13

Alex, we’re going to be talking about inflammaging…inflammation, and aging. I’m not 100 sure what it is, but our guests do. Who are our guests?

Alex 00:23

Our guests today are Brian Andonian, who is a rheumatologist and geroscientist at Duke. Brian, welcome to the GeriPal Podcast.

Brian 00:30

Hi, thanks for having.

Alex 00:32

And Sara LaHue, who is a neurologist and geroscientist at UCSF. Sara, welcome to GeriPal.

Sara 00:39

Hi, good to see you.

Alex 00:40

And Joe Hippensteel, who is a pulmonary and critical care physician and geroscientist at the University of Colorado. Joe, welcome to GeriPal.

Joe 00:48

Hi, thanks for having me.

Eric 00:50

So I’m excited to learn about inflammaging. But before we do, we always have a song request for Alex. Sara, do you have the song request for Alex?

Sara 01:00

You know, so there was a lot of, I think, internal debate over what the song should be, but finally settled on We Didn’t Start the Fire by Billy Joel.

Eric 01:07

Why did you pick we didn’t start the fire?

Sara 01:11

Just trying to think about setting up this conversation, talking about inflammation and aging. And I think the line always burning. Since the world’s been turning, it’s a bit like chaotic low grade inflammations. So I think it’ll set a. Set us off on the right note.

Alex 01:27

And also, the three of you didn’t start the fire. You’re not responsible for the inflammation. You study it.

Brian 01:33

We’re trying to put it out. Exactly.

Alex 01:36

And there’s that.

Sara 01:36

Great. We’re the firefighters.

Alex 01:38

You’re the firefighters. There we go. And there’s a great documentary, I think, about Billy Joel I haven’t seen yet, but I’ve heard is quite good. Oh, I gotta see it. Okay, here we go.

Alex 01:48

(singing)

Eric 02:34

Now you got to do that with, like. But all the words are like, prostaglandin IL6.

Brian 02:41

Yeah, I was half expecting that.

Alex 02:43

Cellular senescence. At the end.

Eric 02:47

At the end of the show. We’ll see. Well, let’s start off. I tried to actually do some background research on inflammaging before we got on this podcast. I failed miserably because I tried to listen to a bunch of podcasts and videos about it, but the only thing I found was, like, people trying to hawk me skincare products and, like, vitamins to prevent inflammation. So there’s, like, a lot of, like, skincare podcasts that talk about inflammaging.

Um, so unfortunately, I failed. We did get a good article, which I. I read, which I’ll put up on the show notes. But would anybody be willing to give me, like, a one or two liner on what. How should I think what inflammation is?

Brian 03:32

Who wants to start.

Joe 03:34

Yeah, hunting to Brian. I think Brian’s the.

Brian 03:36

Leave it to the rheumatologist to talk about inflammation. Well, I mean, inflammation is inflammatory. Aging is really just referring to chronic and progressive inflammation that’s related to aging, but then is linked to aging associated diseases. So there’s other ways we can talk about it if you guys want to jump in, but that’s the basic principle behind it.

Eric 03:58

So aging associated diseases, that’s a lot of diseases, right? Like, pretty much most diseases increase as you age, whether it be, you know, dementias, Alzheimer’s disease, diabetes, cancers. Is that ever.

Brian 04:15

Like, we’re spanning everything. Yeah, I think. I think you’re right.

Eric 04:18

Yeah. Osteoarthritis, like, you name it.

Sara 04:22

And I think that’s one of the goals of the work that we’re doing here. And Brian, I’ll turn it back to you, but I think just to set off the conversation around why it’s important that this is a transdisciplinary framework that we pose, because we are coming from different medical subspecialties, and we encompassed nine medical subspecialties in our paper. Certainly we’re not incorporating everyone, and there are definitely some areas that I wish we could have incorporated and hope to in the future.

But, you know, but we often will talk about this topic within our own little silo, you know, within neurology or within rheumatology, et cetera. And so I think, you know, understanding how this might affect diseases more broadly and maybe a more generalized way is a way to bring. To bring this topic, I think, you know, together to try to. To try to approach these conditions in maybe a more unified way instead of a more of like a whack a mole approach, specialty by specialty.

Alex 05:22

That’s kind of what geroscience is. In your paper you call geroscience the study of shared mechanisms of aging related diseases. And it seems that inflamma aging may be one of the, if not the organizing principles of geroscience. Is that fair to say? Does anybody want to claim that? Bold statement.

Joe 05:42

I. I mean, I think inflammaging is one of. I think it’s the 12 pillars. Somebody can correct me if there’s 12, but it’s one of the pillars.

Brian 05:48

14 or 15 now, they just keep growing. But so many.

Alex 05:52

That’s too many pillars. I feel like one of you should stand up. I’m baiting you here.

Eric 05:56

This is the most important.

Alex 05:57

This is it. This is the central organizing principle of.

Brian 06:00

Pillar of inflammation that we’re.

Sara 06:02

Yeah, well, I think also they’re hallmarks. Right. So at least maybe we can. But yeah, there are a lot.

Joe 06:09

There’s a. There’s a Venn diagram between all these things. But I think inflammation may affect a lot of these and maybe interlinked. And I think one thing that’s kind of interesting about the work that we put out, which is a little distinct, is not only thinking about chronic disease states like rheumatologic conditions and the development of Alzheimer’s, which is obviously slow onset, but we’ve also reframed this. Both Sara and I work a lot in the acute setting where we’re taking care of people.

I take care of people in the icu, Sara on that neuro ICU and on the wards as well. And one of the things is that thinking about inflamma aging as a predisposition for acute conditions too. So while we think about it as driving the development of chronic conditions, it can also potentially lead to the acute conditions that we see like sepsis. ARDs may have impact how people recover from things like traumatic brain injury. And then those diseases can actually feed back and it becomes a closed loop. Right. Where you have an acute condition that can then propagate inflammation. So we’ve sort of reframe this, even broadening that. That understanding of inflammation.

Alex 07:11

Yeah, I was kind of shocked when I read the the through your article, which is terrific. And we’ll have a link to it again in our show. Notes about all of the conditions like. Cause you start off with the chronic ones. And I’m like, okay, inflammation involved in type 2 diabetes. I can see that Rheumatoid arthritis, of course. Right. Inflammatory bowel disease. Well, it’s in the name. Right. Inflammatory. Inflammatory skin disease. Also in the name. Multiple myeloma, chronic kidney disease.

But then you get to acute conditions, TBI, traumatic brain injury. It’s like what ARDs? Well, I guess I’ve heard a little bit about sepsis. Okay, I’m starting to see it. But that, the idea that inflammation, which I think of this as like chronic smoldering, ongoing inflammatory state or imbalance, I think as you said in your article, between inflammation and anti. Inflammation at a cellular and biologic level, I think about that as chronic. So this idea that it could be involved in acute injury as well, I think is revolutionary.

Sara 08:10

Well, I think this is a way for us to think about how people might recover after injury too. And thinking about how, you know, they’re, you know, unfortunately, after having an acute illness, you know, or an acute trauma, people are going to have difficulties, different, different successes in terms of how they recover. And certainly older age is going to be a risk factor for not recovering as, as well or as fully as someone who’s younger. And so really understanding what it is about age that might, you know, that might make older people not recover as well, you know, is I think, a key question to figuring out really how do we target our recovery efforts?

Brian 08:49

For folks, it really highlights the importance of the immune system across all of these diseases. I’m a rheumatologist, I deal with chronic inflammatory diseases. But we appreciate that it’s really not just our diseases where inflammation and immune dysfunction in general contributes. So in my mind, perhaps it’s not inflammation, it’s not our immune system just not working properly.

Eric 09:10

Well, can you describe that? Like, what happens with aging in the immune system and inflammation? Like, do we have a good idea of that?

Brian 09:18

Well, for one thing, we talked about the hallmarks of aging. One of the hallmarks is senescence, but rather it’s really about our inability to senescence.

Eric 09:26

Again, I’m trying to think back to. Oh, we had John Newman on our podcast back in 2019 talking about science.

Alex 09:32

Song request who Wants to Live Forever by Queen Good choice.

Eric 09:36

Don’t tell John, but I’m going to ask you this question. What’s senescence again?

Brian 09:41

So senescence is the idea that the cells just stop growing and proliferating. But this is a normal process. Actually, in my mind, if you have damage to your cells in your body, they become senescent and then they send out all these molecules, cytokines and proteases, and all these Things to really be cleared because when the cell’s not working, you want your immune system to come and target it and take it away.

Eric 10:04

You don’t want to turn to a malignant cancerous cell by continuing to. Yeah, so.

Brian 10:09

So senescence is really a normal process. It’s rather probably the inability to clear the senescent cells which our immune system is key in that. So when we talk about senescence, it’s really more our immune system not clearing or getting rid of the cells that are signaling to the immune system to get rid of me. And when these signals keep happening, then that’s gonna trigger inflammation just throughout the body if that’s not taken care of.

Eric 10:33

And does that happen with aging?

Brian 10:36

We know that with aging we get more damage to our cells, we get more accumulation of senescent cells. And ideally we would clear those cells more. But in fact we just get worse at clearing the cells cause our immune system stops functioning as well as we’d like it to. So yes, this is something that we see. I think maybe we should hold a step back and say this is really biologic aging. Not necessarily just the number like chronologic ages based on your birth date. This is biologic aging, like how your cells are actually functioning, which is related to your age.

Alex 11:07

So biologic aging is how your cells are functioning, which is related to your age. Biologic aging. One determinant of biologic age, you’re saying, is the inflammatory state of the body, its ability to that balance between clearing, between pro inflammation factors and clearing those senescent cells and, and the in inflammation out of your body, which is a function of the immune system. This is me trying to restate it as a non clinical, you know, bencher clinic translational researcher for our audience.

Sara 11:40

And I think this is something that we end up seeing with patients pretty frequently where you know, you’re looking at the chart and you’re expecting to see someone of a, of a particular age based on their birth date. And then, you know, they may seem functionally way younger than what you might expect for that age. And so understanding what that disconnect is, is getting at that difference between the chronological age or what your, you know, what your driver’s license says versus what this biological age might represent.

Brian 12:09

There was all the skincare products come into play the, the skin ages and they’re trying to, to treat the skin aging, which is a, I guess a form of biological aging.

Eric 12:19

And again, don’t tell John Newman this, cause I’m going to refer back to his. We’ll have A link to John’s podcast. But I, I know some people talk about, you know, especially here in the Bay Area, measuring biological aging. Aging. Are there measures of biological aging that I can sen. Or should I do that at all?

Joe 12:40

Yeah. So I think there’s, I’ll let Brian and Sara also comment on this for sure. But there’s the sasp, the senescence associated profile that you can look at. Just a panel of biomarkers that you can certainly send and probably a send out lab, but you can get a general sense of where people live that I think includes IL6, CRP and a couple others. And there’s a bunch of different scores that have been developed including I think immune age is one which is in our, in that the, the work that we put together. So there are ways to define this and I think as one of the take homes when I was, when we were working on this together.

And one of the things that I, I think is really interesting is the idea of defining, you know, an inflammation score for somebody so that when they walk into, to their TBI to sepsis to ARDs or in the hospital or they’re developing diabetes, maybe this might be a node that can actually be impacted. But if we don’t have that information, we can never figure it out. There’s some really cool studies going on in the US as well as in the UK and elsewhere in the world. The UK Biobank that starts to do this and we can do this in a prospective observational study. Big study. But to do this clinically we really need that information up front. I think it’s a really nice, interesting place to really leverage the idea behind implementing to improve outcomes.

Alex 13:56

Is this the equivalent of sending out estrogen receptor status on a breast cancer or you know, specific tumor markers for lung cancer, for example? This is more of the, the overall inflammatory state of the person at the time they sustain the injury or developing the chronic condition.

Brian 14:17

Well, it’s a big thing that we talk about in the paper is that we just don’t have great measures as Joe said. So I think there’s a lot of interest in ongoing study looking at how just we measure this because if we step back and look at inflammaging the concept, it was based on some pretty basic associations, like seeing that the C reactive protein, a common, what we call inflammatory marker, is elevated in so many different chronic conditions. So the question was, oh, there’s this inflammatory marker that’s elevated, it must be related to these diseases. And that’s really just a really high level of how we started thinking about it, but that marker in and of itself was just not good enough to give us a lot of good data. And kind of what Joe’s thinking about, like prognosticating how well someone will do after a given injury or insult.

Alex 15:03

Yeah, I’m trying to get a sense of where the state of the field is now because I remember when CRP was like all over the place. Remember that for like, is this heart failure? And then you’d send a CRP and you’d be like, is this helpful or not helpful? How helpful is this? You know, and some of these markers that early on seemed to intuitively make sense turned out to be kind of non specific and not as helpful as we’d once hoped. It sounds like there’s still, there’s tremendous promise here, but in terms of a clinical send out lab that it’s useful clinically at this time, it sounds like.

Eric 15:37

We shouldn’t be, I should not be checking Alex’s panel, his telomere lengths and his.

Sara 15:44

Or should I. I would say there’s a lot of excitement. I feel very excited about the promise of this field, but I think I’m, you know, I, and maybe I differ from my, my counterparts here, but I think that there’s still a lot to be done to better understand how to interpret these tests appropriately and how to know. Yeah, just really what do you do about it, what it means for an individual, what you do about it. And I think this gets back to, I think some of the fundamental challenges just of the kind of research that we’re talking about, you know, more broadly, which is, you know, we’re really interested in understanding these biological mechanisms that are underlying age. And you know, and there are, I think, a lot of challenges with even just studying older adults in research and you know, ensuring that we’re being more inclusive about people, inclusive of people when we’re enrolling them in research studies, really trying to get, you know, a wide array of ages.

You know, I love when I get to enroll someone who’s, you know, 90 or even 100. You know, that’s, that’s, that’s really exciting for me to be able to, to think about, you know, being able to study really, you know, people on the farther ends of the age spectrum, but then also thinking about the other kinds of medical conditions that someone might come to a research study with, you know, so Joe and I are, are really focused on people who have, you know, acute medical problems. You know, multiple organ systems are not working very well, but oftentimes those are the kinds of people who are not getting enrolled in research. Right. The ideal REST participant is going to be someone who’s otherwise fairly healthy who can come to outpatient appointments, get their longitudinal follow up. But that’s not really representative of someone who has multiple chronic medical problems.

Alex 17:28

I wonder if we could just drill down with each of you for a moment and talk about if you could each pick one condition that exemplifies that you are particularly interested. Maybe starting with Joe, I don’t know if for you as pulmonary critical care. Is that lung disease, is that sepsis? What, what would it be for you and how would you explain the role of inflammation in that condition?

Joe 17:48

Yeah, I think so. My, my sort of pet project is to improve critical illness outcomes in general. So I think that includes ARDs, sepsis, traumatic brain injury, whatever it might be.

Alex 17:59

Right.

Joe 17:59

And where inflammation can play into this is trying to understand. I think what we don’t do well is understand what people come in with to then that dictates sort of how you do in the long run. And we’re not very sophisticated in the way that we do our outcome studies at this point. And one of the principles that I think can guide us is thinking about inflammation both on the front end and the back end of critical illness survivorship. And so that’s, I would say critical illness is my disease.

Eric 18:24

What would that look like?

Joe 18:26

So here I think this is where like say 50 years from now, maybe this would be the idea would be you. Everybody has a risk profile that’s like, like your lipid panel.

Sara 18:37

Right.

Joe 18:38

That we have available because people have good primary care.

Eric 18:41

Maybe inflammating risk panel that then maybe allows you.

Brian 18:44

Right.

Joe 18:45

We are then taking. The way that we’re doing it in critical illness now is we’re saying time zero. We’re going to stratify you by inflammation status. Some other, you know, your bicarbonate and we’re going to say you’re group one, group two, group three, group two should get this treatment. And maybe we’re going to start using this moving forward to actually pinpoint people. You can imagine that’d be more valuable if you knew what was what people were like before they came into the hospital. Unfortunately in critical illness we can’t do that yet. But, but I think that’s maybe a place that could be a really interesting way to extend the idea of inflammaging to actually improve these acute and sort of longer term outcomes.

Alex 19:19

Right. You can’t do it yet because you don’t know who’s going to develop critical illness. But if you had like population level data about every patient got an inflammatory panel once they hit age 65, then you might have some baseline to work with or something like that, I think.

Joe 19:34

I’m not an endocrinologist. I hate to be a little flippant, but it’s kind of like the low, low T score. Right. Like a low testosterone score is probably something I don’t care about. But. But like you said, the her positivity of breast cancer. Certainly I do. And so sure, we’re going down that second path, not the first path.

Alex 19:51

Yeah.

Eric 19:52

So let me ask you this, Joe, before we move on is does inflammaging change how you practice right now at all?

Joe 19:59

I would say not in my clinical practice. I. I’m a basic translational researcher, so I try to apply these principles to that part of the world. But. But right now, I don’t think I use it directly. There are good trials that have worn out that, you know, inflammation itself is important in critical illness. No doubt.

Alex 20:18

Yeah.

Joe 20:19

Maybe if we clearly define who we should be targeting with their inflammatory state, we can do better. Like in Covid, for example.

Alex 20:28

And before we move on again, we had a terrific podcast with Wes Ely, who wrote this book, Every Deep drawn breath and talked about the amazing book, says Sara. Like, development of post. Like discovery of post ICU syndrome and completely revolutionized the way that we care for patients with critical illness. And when you talk about, like, the before and the after, like the after, to me, like, are you talking about post ICU syndrome and. And how the role of inflammation might be involved in that?

Joe 20:58

Oh, yeah, absolutely. I mean, I think that’s the. The simplest way to describe it is pics. Pics associated outcomes are. Or pics outcomes are probably there’s some interaction with inflammaging, no doubt, like how people were before and how they develop afterwards. So I think affected by inflammation, undoubtedly.

Alex 21:17

Great. All right, Sara, you’re on the hot seat. What is it for you? TBI delirium? There are so many. You said mentioned stroke. Yeah. Dementia. If you had to pick one paradigmatic condition in neurology for our listeners and talked about the role of inflammation, what would that be?

Sara 21:35

Yeah, well, you mentioned traumatic brain injury earlier, so I might as well go down that rabbit hole. And also I think it provides maybe a different lens from what Joe and Brian talk about. So just because I think this gives us an opportunity to think about not just acute medical illness, but also just what the impact of trauma is on the body for a person and how that might relate to the kinds of mechanisms we’re talking about. So as you’re saying, as a neurologist, there are a lot of conditions that I see that could potentially benefit from the work that we’re doing. But traumatic brain injury, especially for older adults, is becoming unfortunately more and more common.

When we think about the group that is the fastest growing group in terms of risk of head injury, that’s going to be older adults. And oftentimes we’ll say years, terms that are thankfully becoming out of favor. But using terms like mild traumatic brain injury to indicate that, you know, maybe this person doesn’t need ICU level care, you know, maybe they could actually even just go home from the emergency department because it was a mild injury, you know, but we know that, that even with, you know, with it being mild, there can still be important long term side effects from, from getting, you know, from that, from a head injury, from, you know, headache to cognitive changes and long term thinking about the impact on cognitive health.

So I think getting back to how inflammation and inflammaging relates to this, you can just imagine that in the setting of a trauma, there’s going to be an acute inflammatory response. You see that if you’re hitting your thumb with a hammer, immediately you’re starting to get swelling and redness. And pain associated with that. You’ve got this acute inflammatory response. That’s an important response. But in the setting of a head injury, and if, you know, again, we’re talking about maybe with older age, the response is maybe not working as you’re hoping it will, you can have more of an abnormal response such that it might go into overdrive and that can lead to more tissue damage and potentially relate to worse recovery down the line. So that’s just one example that we end up seeing.

Eric 23:54

So with tbi, do you, I mean, I, I love that analogy of like hitting your thumb, your thumb turns red, like there’s an inflammatory response. With tbi, like do we see that in the brain? Like there is a lot of inflammation in the brain when that happens or is it systemic throughout the entire body?

Sara 24:11

Yeah, that’s a great question. So, so there is inflammation that you can see on, on, on head imaging. Depending on how severe it is, you can think about it like how you might get a bruise with the hammer. Right. You can similarly get a bruise involving brain tissue. You can even get bleeding that’s, you know, more frank bleeding that’s associated with it too. So this is something where you, you can see this more acute inflammatory response and maybe even bruising. But I’ll say that this is one of the limitations of studying traumatic brain injury in people, which is, you know, ideally you want to look at the tissue, and that’s not, that’s not going to be as easy when you’re talking about people. And so much of the research that I at least end up citing in our article is coming more from animal models, at least at this point. And that’s really giving us a better understanding of that kind of acute process.

Alex 25:04

And I’m going to ask Eric’s question that he asked to Joe. Are you using the inflammation concept in your clinical practice of caring for older adults who experience traumatic brain injury?

Sara 25:16

So I think it’s something that I definitely pay attention to. And I’ll say that at least when thinking about some of these more general markers like ESR and crp, granted, again, this is a much more general marker, but even those have been associated with worse outcomes in the traumatic brain injury literature. So I think there is a lot of support for getting, drilling down into more specific kinds of markers. Um, and that’s one of the areas that I, that I focus my attention on. But I think like I said earlier, it’s a little too early for clinical prime time in terms of some of those more sophisticated, you know, epigenetic risk scores or proteomic scores or things like that.

Alex 25:58

All right, moving on to Brian.

Eric 25:59

Yeah.

Alex 26:00

Okay, Brian, are you going to pick rheumatoid arthritis? Because that’s the obvious one, or are you going to pick another rheumatologic condition?

Brian 26:09

Well, here’s the thing. I think in rheumatology all of our diseases are really hallmarked by chronic inflammation. So I think you could look across the board, think of lupus, even psoriatic arthritis, rheumatoid arthritis, all of these have components of inflammaging, driving them. And we know that even looking at lupus and rheumatoid arthritis, that these so called hallmarks of aging, things like mitochondrial dysfunction and senescence and, you know, telomere abnormalities, these, these also are seen in our patients. And so it makes me think that inflammation is really the end result of all these other problems that are driving multiple diseases. They’re manifesting as say, rheumatoid arthritis, based on your genetics and your environmental exposure. So I’m going to say pretty broadly that rheumatic diseases is kind of a cluster of conditions. RA or rheumatoid arthritis being the, the classic one is a good way to look at it.

Alex 27:04

I think we’re gonna finally get a yes here. When I ask, do you think about inflammaging therapeutically or diagnostically in your clinical practice?

Brian 27:14

Yeah. So the answer is absolutely. I wish I had more to offer though because we already talked about perhaps inflammation is the end result of a lot of other things that are going on. And right now in rheumatology we have all these therapies and actually the geroscience world is interested in using these therapies. Think of things like TNF inhibitors, IL1 inhibitors, other anti inflammatories to try to treat other conditions. The problem is that these have a lot of side effects. They cause our immune suppression, lead to infections. So when I’m seeing my patients have these issues with that, I think we need better therapies and perhaps it’s really targeting this other stuff. My background also is really in exercise and lifestyle medicine. So I really think about how other things like exercise, lifestyle can really target all these other pathways that might end up actually improving inflammation. So absolutely am thinking about it. I also wish we had a little better therapies, but that’s what’s exciting about this field.

Alex 28:13

That is a terrific segue. All right, do you have a question for Brian or can we segue?

Eric 28:17

Uh, go ahead, segue.

Alex 28:18

So Eric started off saying like he searched, you know, searched for inflammaging and podcasts. And what did he find?

Eric 28:25

Skincare products. Vitamins.

Alex 28:28

Yes.

Eric 28:28

People trying to hawk stuff.

Joe 28:30

Right.

Eric 28:31

Like yeah.

Alex 28:32

So in the non FDA regulated market there is tremendous interest from consumers. There’s tremendous amount of direct to consumer, you know, selling of these products.

Eric 28:45

Probably more people know what inflammation. Inflammation is than doctors.

Alex 28:50

Than doctors. Yeah, that’s probably true. So there’s a tremendous imbalance here between what I’m hearing from you all about the state of diagnostics, the science and the treatments and where the public is in terms of consuming these products and where industry is in terms of marketing these products. I wonder, do you have reflections on that or what’s, what’s happening here that’s driving this?

Brian 29:15

Yeah, I got plenty of thoughts. I’m curious everyone’s ideas here in general. I’m concerned that the wellness space in general is amplifying some potentially great ideas. But just before we have the evidence. So they’re, they’re not, they’re not that they’re wrong, it’s just that we have, we don’t have the evidence to support them yet. So that’s my general thought.

Eric 29:36

And some of them are feel a little bit more benign. Some of Them are just like what you were saying, like figuring out healthy diet, less highly processed stuff, more stuff that looks like the food that it grew from, less meat, more vegetables, lose weight, exercise. Maybe we don’t need a whole lot of evidence because we have other lines of evidence that those are helpful. Would you agree with that, with your background, Brian?

Brian 30:03

Yeah, I think, I think there’s plenty of evidence to suggest healthy diet and exercise can really target even those individual hallmarks of aging and help in this space of inflamma aging. But then we’re getting into kind of the natural, naturalceuticals or your, your supplements. And yeah, I think there is potential. Again, I definitely want to hear Sara’s thoughts about senolytics, because I think that’s a huge topic. But within the idea of we can help get rid of these senescent cells through different interventions, there’s all these therapies, I think, of these flavonoids like quercetin and fisetin that are sold as supplements. But we also find these in all sorts of natural fruits and vegetables. Right. Like, it’s so odd to hear a.

Eric 30:47

Podcast talking about don’t eat processed food. And then they’re trying to sen processed vitamins like these. Like, why don’t you just eat the food?

Alex 30:55

Food. Sara, any thoughts?

Sara 30:58

Sometimes people. Yeah, I mean, I think that, you know, to that point, some, some people don’t have easy access to, you know, to even just the healthy fruits and vegetables that we.

Eric 31:09

Yeah, but the $300 vitamin they’re trying to hawk is probably not that.

Sara 31:13

What is, it’s not the same kind of.

Eric 31:15

Yeah. Brian brought up Synette.

Alex 31:20

Sara, help us out here. What’s a senolytic?

Sara 31:22

Yeah, so this is getting back to what Brian said earlier in terms of senescence. So these cells stop dividing and they can end up secreting these products that then just lead to this feed forward cycle of inflammation. And so there are drugs that can target, target that process and work to remove these senescent cells, thereby also removing that inflammation that’s associated with them. And so these, these drugs are being studied in many clinical trials. And in terms of neurology, this is, I think, an exciting area when we think about different kinds of dementia like Alzheimer’s disease. And this is work that’s being done in early, early phase one, phase two clinical trials presently. So again, it’s, it’s, it’s still a bit early to, you know, to be able to report on what will ultimately see, you know, in human subjects down the road. But I think that at least these early clinical trials are definitely promising.

Alex 32:17

Yeah. And this gets to this sort of central tension that, that John Newman talked about on our prior podcast about these anti aging products. Right. Anti aging products. And like the who wants to live forever? You know, like, as a, as a geriatrician, John was very focused on, you know, I worry about some of these products in the oldest old and the frailest frail. And certainly if we can help prevent some of the morbidity associated with conditions associated with aging, I’m sure that would be very popular with the public. Any. Have you, have you encountered this tension sort of in your own research and thinking about this and the patients you care for?

Sara 33:02

I mean, look, I’m speaking with you from San Francisco, right. So this is, I feel like ground zero for a lot of the things that you’re talking about being in Silicon Valley. But I think, you know, like, like what you’re identifying, it’s really coming from a, you know, an intense desire that people have to be able to. To not just live longer, but live better longer. And so I think that, you know, that as scientists, we’re hearing that and share a similar desire and are working towards that, but really want to be able to show the evidence for both that a thing works and also that it’s not going to cause harm.

Right. Because I think that ends up being one of the challenges, like what Brian was saying earlier, that you have side effects from a lot of these drugs that are going to be impacting your immune system. And so for a lot of these supplements, as an example, you know, there’s not a lot of regulation around what’s actually in them. You know, there was a recent report that came out just around lead exposure and protein supplements, for example. Exactly. So I think that, you know, when there is lack of regulation around what’s actually in, you know, in the item, then, you know, then there ends up being other challenges that come up from.

Joe 34:24

That one comment, just like kind of integrating these couple ideas. I think the biomedical structure in the US in general, and I think most of the Western Europe and elsewhere is we’re disease focused, right. Where we want to fix RA, we want to fix ARDs, we want to fix sepsis. I think geriatrics is kind of a unique place and geroscience in general is a unique place where you’re taking, let’s take a population of people and try to make them better. I think when you move to the end of health, lifestyle modification and nutraceuticals kind of fall into this like you can impact a lot of people with lifestyle modification and all sorts of diseases. There’s almost this void where inflammation kind of lives, where we might have an impact on everybody if we were able to study everybody.

Sara 35:07

Right.

Joe 35:07

We can do that with heart failure, we can do that with the Framingham heart study. But maybe reframing some of this as we need to integrate and this is maybe that disciplinary approach that we’re talking about in this paper is the way to go. And, and maybe there should be some funds that are filtered towards that.

Eric 35:22

Joe, I guess the question for you and I, I’m struggling with this. Is it as you chronologically age, you’re having more immune dysfunction that causes inflammation, low grade inflammation, which causes kind of accelerated aging? Or is it that you have these diseases that cause inflammation? Like you get a tbi, you develop diabetes, that causes the inflammation which worsens aging. Like which is coming first, the aging or the inflammation? Or is it just a cycle and there’s no.

Joe 35:58

Yeah, I think there’s, there’s Venn diagram, there’s a lot of interconnection. I, I think I’ve been working we weirdly on a pediatric study recently and sort of at the other end of the spectrum. And one of the things I think that these big data approaches that we have now, you can think of exposome meaning what are you exposed to in the world. You can think of genomics things, the genes that you have in your body. Then you can think of all the different exposures that are biomedical.

Sara 36:24

Right.

Joe 36:24

Like you end up in the hospital, you have a monopoliosis when you’re 18. These things all interplay. We don’t understand it well enough. But I think if you. It’s very easy to conceptualize as coronary artery disease. I should put a stent in and give them some aspirin. Yeah, Infil aging is like this lofty concept of maybe we need to cut this off before those things even present. That said, some of this is inevitable. Injuries happen, genetics happen, exposures happen, and there are social determinants of health that sort of are certainly upstream of all this. But I think it is this interesting interplay and complex situation that now we’re starting to get big data in Silicon Valley and elsewhere to be able to maybe figure some of this stuff out.

Eric 37:06

I guess another question that I have is, are there things, things that we can do now or like what things that you’re excited about around potential interventions for inflammation? Whether it be. I think with John, we talk about like metformin, ketone bodies and intermittent fasting. You know, rapamycin.

Brian 37:31

I think this comes up.

Sara 37:33

Yeah.

Eric 37:34

What, what are you excited about? And is there anything you’re thinking? It’s, it’s. This is, this is looking pretty good. Brian, you’re gonna say something.

Brian 37:42

Who wants to take it? I mean, I already mentioned I’m early in the lifestyle space. I think there’s a lot of potential nutritional interventions that have a lot of potential benefit. You already mentioned the idea of intermittent fasting or really caloric restriction is where that comes from. We have a lot of data and preclinical models saying that it’s reducing the amount of calories you take in and could lead to a longer lifespan.

Eric 38:07

Does it reduce inflammation?

Brian 38:09

There’s some data actually in humans. The calorie study is what I think of looking at people who did a low lower calorie diet over the course of two years. Their clock of aging or their biological aging didn’t age as fast in compared to the group who didn’t. But then they also showed some signs of lower inflammation. And I think we’re still learning more, but there seems to be a tie to inflammation even in that group. So I, I think diet has a lot of potential. Exercise, we could also talk about that. There’s a ton of benefit there. Um, one thing I’m really hopeful for is understanding how exercise works because we know that people who are fit and who exercise have better functioning immune systems. But the question is why?

It’s not intuitive to most of us to understand what are the connections between exercise and immune function. Um, so there’s studies like Motor Pack or the Molecular Transducers of Physical Activity Consortium trying to understand through multi ohmic analysis what are the connecting pathways between our muscle and our immune system and our liver and our fat tissue. I think if we understand those mechanisms, we actually could say, hey, there’s an exercise pill or exercise memetic. Or we could augment these pathways to like get the benefits of exercise easier. I, I think that’s the promise that I’m particularly excited about.

Eric 39:23

Oh, that’s wonderful. I could take a pill and I can sit on my chair and exercise.

Brian 39:27

That’s why I say augment. I think, I think I can help you exercise more or that’s greater. Never, never want to recommend.

Eric 39:35

Sara.

Alex 39:36

What?

Eric 39:36

Are you excited? Oh, Alex, you’re gonna say something.

Alex 39:38

I was gonna say as an endurance athlete, I think that. Correct me, this is my consult. This is great. I believe that endurance athletes have always like a low grade state of inflammation from like the constant exercise and pounding and I wonder like why is that, that you know, are, am I making, am I less healthy if I’m an endurance athlete or am I more healthy? Probably the cardiovascular benefits outweigh the, the inflammatory state that I’m inducing in my body chronically.

Brian 40:08

I think it’s all about the recovery because you’re right, an acute bout of exercise will cause inflammation to go up, but really should be temporary. Like if you’re, then you’re after that, you really should have more of an anti inflammatory response. Potentially doing that multiple times throughout the weeks and months and years, that just boosts the way your immune system functions. But if you don’t allow your body to recover, you can kind of maybe build up more, more inflammation. So inflammation can be a sign of over training is an interesting thing to think about.

Alex 40:36

That’s good. I’ll take that advice. So today is my rest and eat pastries day. But I shouldn’t have too many pastries because I need to caloric restrict.

Eric 40:45

Okay, Sara, what are you excited about?

Sara 40:47

I mean, I think that really gets to a point, I think to the point that it really depends on what the, what the dose is. Right. So I mean any, virtually anything can be toxic if you take enough of it. Like water and. Like water. Exactly. And so you know, just like with some of the supplements we’re talking about, sure. If you have a vitamin deficiency, you know, it can be transformative to be able to identify that and target it with particular supplements, you know, but if you’re just taking things in excess, be it exercise or various vitamins, then you can run into problems that way. So yes, I think keeping in mind moderation in some ways is important here.

Alex 41:32

And Sara, like blue sky ten years from now, inflammaging has made it. What does that look like? What is the success story? What is the best possible future in which we’ve made tremendous advances in inflammaging?

Eric 41:47

Eric has a new skincare product line that he’s selling on Jerry Val Skincare. What do you think, Sara?

Sara 41:56

Yeah, I guess there are a couple of directions that this can go. You know, I would love to see better recovery after injury is a big focus of my work now with traumatic brain injury. But that’s also with a lot of other injuries that I’ve studied in older adults, like starting out with hip fracture. Right. That is something that really is a life changing traumatic event for a lot of older adults. And I think being able to improve recovery by addressing some of these mechanisms I think could be hugely Transformative. But I also think getting back to what Joe said earlier in terms of we have an opportunity to not just treat disease, but also think about how to enable people to live more healthfully longer and trying to, in terms of preventative medicine, target these kinds of pathways before we even get to the point where then they’re developing all these chronic diseases.

Eric 42:47

Okay.

Alex 42:48

Well, yeah, and just to reiterate something that Brian said earlier and that Sara just said, like the inflammation developed evolutionarily for a reason. Right. So it probably serves an important purpose. And so like Brian was saying with, you know, as a rheumatology, they use these immune modulators that, you know, turn off the immune system. Well, that can have devastating consequences. Right. Because it’s there for a reason. And if we just, you know, try to get rid of the inflammation itself without thinking of the adverse consequences, then there are likely to be some unintended consequences.

Eric 43:24

We don’t take the NSAID or the steroid every day.

Alex 43:26

Yeah, exactly. Yeah.

Sara 43:28

So this is, again, where we’re moderation and trying to target if this is as best as possible.

Eric 43:33

So, Joe, what are you most excited about?

Joe 43:37

The skincare products for Sure.

Eric 43:39

J Pal skincare products coming soon.

Brian 43:42

Yeah, let me know on that one.

Joe 43:44

I mean, I think, you know, I like to think about this as I still use the same labs that have probably been used for 60 years, 70 years in the ICU, that we get to a point where these things, you know, the sasp, this senescence associated with profile actually matter for patient care. I think there are some things that are working, like looking at IL6 levels and maybe using tocilizumab in the ICU. But thinking about this inflammation concept and actually being able to do something actionable with it would be really fun and exciting and I think really is maybe the. The forefront of where we’re, where we’re going with, with all this stuff, so.

Eric 44:22

Okay. Alex, can I ask a lightning round question?

Alex 44:24

Yeah, go for it. Yep.

Eric 44:25

Because I think probably all of our listeners want to know, like, so you. I’m sold on this idea that there is inflammaging, that it’s complicated and you just can’t. Like, you don’t want to shut off the immune system, but this low grade chronic inflammation is bad for the body and it, you know, worsens biological age. Did I get that everybody kind of agreement with that? Yeah. Is there anything that you do, because I asked, in a clinical practice, is there anything you do differently? Is there anything you do differently in your own lives knowing that There is this concept of inflammaging.

There’s a low grade chronic inflammation that probably worsens your biological aging parameters, but also importantly maybe puts you at risk for increasing disability later on in life. Okay, Brian, I’m going to start off with you. Anything that you’re doing different, except for the GeriPal skincare products, say I.

Brian 45:20

Need the skincare products. But yeah, I mean I still go back to trying to understand how we can prevent this because that’s, I think that’s the promise of geroscience. What can we do to prevent it? To me thinking about lifestyle changes, exercising, sleeping well, having the right diet, trying to minimize stress, putting it all together to me is what, what can be beneficial?

Eric 45:40

Do you do calorie restriction?

Brian 45:42

I do some intermittent fasting. Um, I think about how that can be really beneficial. I think we miss out on resistance training. Most of us I think aren’t trying to build enough strength and muscle strength and muscle size is really, really impactful for preventing chronic diseases. I think we think about exercise as just you’re running, walking with the aerobic stuff. But so many of my patients miss out on the great benefits of resistance or muscle building type exercise. So that’s something I try to focus on more these days because I know it’s so beneficial for anything related to aging.

Eric 46:18

I have a lot of resistance to exercise. Joe, how about you? Is there anything you’re doing different?

Joe 46:25

I think, I think, agree with Brian. I think exercise, these lifestyle modifications, the things that we kind of know are healthy are the best right now. Brush my teeth every day and floss my teeth once a day.

Alex 46:35

Oh yeah, that’s good too, right?

Eric 46:37

So good oral care.

Alex 46:38

Yeah, yeah. Because the mouth is in under in diseases of the mouth are major contributor to systemic inflammation. I think.

Brian 46:46

Yeah.

Sara 46:47

Potentially important for dementia too. Yeah.

Eric 46:49

Sara, are you doing anything different?

Sara 46:51

Yeah, I, I think about this a lot, I think in my personal life. So totally agree with Brian in terms of resistance training. So love weightlifting. Definitely something that I think is important as one is getting older to maintain muscle mass and. Yeah. And also dietary changes. Intermittent fasting.

Eric 47:10

Do you do intermittent fasting too?

Sara 47:12

I do, yeah.

Eric 47:13

Joe, do you do it? Is this a 3 out of 3?

Joe 47:17

I inadvertently intermittently fast when I’m in clinical service.

Alex 47:20

There you go. Yeah, I see you. One last question.

Alex 47:27

What is clinstar, Sara?

Sara 47:29

Oh, well, I think I’ll also just say mindfulness and I think that in meditation practices is also a growing area.

Eric 47:37

And is that because chronic stress can cause slow grain inflammation?

Alex 47:41

Exactly.

Sara 47:41

So thinking about other ways of addressing stress in that manner. But yeah. So ClinStar, that’s how we all came together. It’s an amazing resource for people who are interested in aging research. IT is an NIA funded organization. ClinSTAR, the acronym is Clinician Scientist, Transdisciplinary Aging Research or ClinSTAR. We’ve all worked really closely with Andrea Sherman, who’s one of the program officers, senior program officer there. And this is an organization that helps both with grant funding like gemstar. I personally benefited from GEMSTAR and also interest groups. So I helped to found the Delirium one. And then this is one that’s coming out of the inflammating and inflammatory interest group. So really recommend everyone check out ClinStar.

Eric 48:29

How do you check it out?

Sara 48:31

Hopefully you’ll include the link to the website.

Alex 48:33

There you go. We will.

Joe 48:35

Good.

Eric 48:36

I heard you. Clintstar also has a theme song. Is that right?

Alex 48:39

(singing)

Eric 49:27

Very nice!

Eric 49:34

Brian, Joe, Sara, thanks for being on this podcast. Learned a ton. Love the concept of inflammaging. Great work that you’re doing.

Brian 49:42

Yeah, it’s great being here.

Sara 49:43

Thank you so much for having us.

Joe 49:44

Thank you so much for having us.

Eric 49:45

And thank you to all of our listeners for your continued support.

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