Inflammation: impact on aging and disease risk, & how to identify & prevent it (AMA 59 sneak peek)

1. 0:00 – 0:09

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 0:09 – 6:54

   Defining inflammation (and the cultural impact of Napoleon Dynamite)

   1. SPSpeaker0:10

      Peter, welcome to another AMA. How you doing?

   2. PAPeter Attia0:13

      I'm doing especially good today, actually.

   3. SPSpeaker0:16

      Yeah? What's different about today than usual?

   4. PAPeter Attia0:19

      Um, just reflecting on 20 years almost since Napoleon Dynamite came out and just reflecting on what an important contribution that was to mankind.

   5. SPSpeaker0:31

      If you look back at what you learned in medical school compared to what Napoleon Dynamite taught you, which do you use more on a day-to-day basis?

   6. PAPeter Attia0:41

      Um, it depends on the context, but in terms of referencing, probably Napoleon Dynamite.

   7. SPSpeaker0:49

      For today's AMA, we're talking about inflammation, and I'm trying to think. It's been a bit since I've watched Napoleon Dynamite. Do that-- does that get covered in Napoleon Dynamite?

   8. PAPeter Attia0:58

      I mean, I think Tina, the llama that he's got, is on a low-FODMAP diet, if I recall, when he's slapping the food at her. Um, also, I think the talons on those chickens were large, probably due to some of the inflammatory changes in the talons. So yeah, uh, uh, I think, I think indirectly there is a thread of inflammation, um, and other very important ideas in Napoleon Dynamite.

   9. SPSpeaker1:27

      The Venn diagram of Napoleon Dynamite inflammation and what we're talking about today is quite big.

   10. PAPeter Attia1:33

       And I think you know this story, I've told it before, but, [clears throat] um, Bob Montgomery, who is, uh, one of the, you know, legends in the field of transplant surgery, was the head of transplant surgery at Hopkins when I was there, and he was also a huge Napoleon Dynamite fan. So back in 2005, so this was, like, about a year after the movie came out, you know, we still just couldn't get enough of it. I mean... And, and there was a c-- this is back when you listened to CDs, so there was a Napoleon Dynamite CD soundtrack. And it was great 'cause it had, like, 45 tracks on it. So all the songs from the movies, but just as importantly, all, like, millions of little clips of funny, you know, actual sections of the movie. And, uh, you know, as, as is often the case, any, you know, surgeons often are listening to music in the OR, but we only listened to that CD. So for an entire month, that CD never left the operating room, and it was just on repeat. And God bless the nurses who didn't find it as funny as we did. That was, like, just probably a completely annoying thing. But, like, we never stopped laughing at this thing. And I will say this, 'cause people often ask if I tell this story, you know, did it compromise the outcomes? And I will say that there was a, a period of three days when we did 13 kidney transplants. Every one of those patients had a remarkable achievement outcome. And look, 13, you know, it's not uncommon for one of those to have a graph that goes down or something. But... So we, we, we thought that there really should be a clinical trial done where you randomize patients to undergo a kidney transplant with Napoleon Dynamite soundtrack playing versus some other soundtrack, and I wouldn't be surprised if that was done, and it did produce superior outcomes.

   11. SPSpeaker3:25

       To be honest, based on some of the studies we see, it would not be the most ridiculous study-

   12. PAPeter Attia3:29

       [laughs]

   13. SPSpeaker3:30

       ... that has been done. Um, also, Bob Montgomery, he was the person who did the first-

   14. PAPeter Attia3:37

       Yeah, first xeno stuff, yeah

   15. SPSpeaker3:39

       ... pig transplant of a kidney, right?

   16. PAPeter Attia3:39

       Yeah, Bob's up at NYU now. Uh, amazing guy. We should-- I'd love to get Bob on the podcast at, at some point.

   17. SPSpeaker3:47

       Awesome. Well, with that divergence, we are now gonna move into what we're talking about, which is inflammation. And it's a topic that seems to be talked about so much online, so much in different podcasts, different things of that nature, and it is talked about in a variety of ways. It's also one we get asked about a lot, and we haven't covered it in detail before. So what we did is we pulled all the questions that we saw, and what we're gonna hope to cover today is not only what is inflammation, but how do you measure it, how do you know if you have it, and most importantly, and what I think people care about the most, is what you can do about it. And so I think it'd be insanely helpful just to start off with a definition of what is inflammation, how do you define it? Because again, it seems it's defined and talked about in so many different ways that I think we almost need to set the stage early on and just be talking about how are we gonna define it for the conversation today.

   18. PAPeter Attia4:41

       As you know, and just for the listeners, I, I was almost hesitant to do this AMA because I just hate buzzwords, and inflammation is just such a buzzword that gets thrown around so much with no meaning. Um, so on the one hand, I felt the tug of doing this as sort of a, a, a public service announcement, and on the other hand, I was like, "Oh, my God, it's just, you know, you're-- we're actually gonna have to do a lot of heavy lifting to get people to really understand what we're talking about." And ultimately, we've decided to do that because I do think it is important, and I wanna make sure people have a very clear understanding of what, what, what they're talking about and what is often, you know, misconstrued in sort of popular circles. So, um, so let's define inflammation. So inflammation is a biological response of the immune system to defend against some sort of stimulus, uh, usually harmful, but not always, and to eliminate the cause of injury. Um, now look, uh, it, you know, as is often stated, of course, inflammation is not always bad, right? So oftentimes inflammation is essential. It is the, you know, the fundamental issue for tissue repair, for the clearance of infectious pathogens, um, and obviously the immune response plays a very important role in that. Um- You know, in medical school, I think the first thing you learn about on this front is the acute inflammatory response. There's a mnemonic for what happens when you are experiencing acute inflammation, and it deals-- I, I can't remember the mnemonic, but of course, it talks about how things get red, things get swollen, things get sore, all of those things. Um, and that of course results, um, from both the injury, but also-- and/or the infection, and also the response of the body. Um, and then of course there's something, um, that is more chronic in its nature. And truthfully, that's really where we're gonna spend our time today, um, because I don't really think there's much to talk about as far as acute inflammation that goes well. So if acute inflammation goes unresolved and becomes chronic, then we should talk about that. Um, but again, what we're here to really talk about today is the maladaptive side of inflammation.

3. 6:54 – 10:27

   Acute vs chronic inflammation

   1. SPSpeaker6:54

      I think just early on, it'd be also really important just to maybe double-click on the difference between acute and chronic inflammation. Again, you spoke about it a little bit there, but do you maybe just kinda wanna walk people through that, again, with the idea that we're gonna focus mainly on the chronic aspect today?

   2. PAPeter Attia7:09

      Yeah. So again, everybody-- anybody who's had a mosquito bite or who's cut themself, uh, knows what acute inflammation is. Um, so again, if- think about a mosquito bite, right? It's gonna be warm. It's gonna be painful. It's gonna be swollen. You might even have loss of function. Um, and, and again, this is actually in-- for the most part, a very important, um, aspect of, of healing the insult or inflammation. Um, w-w-what we're here to talk about is chronic inflammation, um, which again, can be, you know, something that lasts from months into years. Um, and here you don't have-- This is a very important point. You don't tend to have the same physical signs or symptoms, the redness, the swelling, the pain, the obvious things. And so oftentimes we think of this as low-grade inflammation. Um, and again, um, it's, it's often asymptomatic, although we'll get into some examples of maybe where it, where it's not, for example, when it's diet induced. Um, but why we talk about this, of course, is the role that this plays in disease and ultimately in life.

   3. SPSpeaker8:22

      And what do we know about why acute inflammation can be good but then it becomes bad in the sense of chronic inflammation once that acute trigger's gone?

   4. PAPeter Attia8:34

      Well, you know, as I said, so a-acute inflammation is essential to, to heal the body. So we, we, we have, um, an innate immune system that is able to react immediately with soluble antibodies to harmful, uh, infectious pathogens, as one example. Um, if you have injury, tissue is damaged, so d-damaged tissue needs to be cleared. All of these things have to happen really, really quickly and very efficiently. Um, and y-you know, we, we... You know, anything that inhibits that process, by the way, is often quite deleterious, right? So people who have, um, shortcomings in their immune system, especially for that type of acute stuff, are going to, to have significant problems, and there are, of course, certain disease states that do that. Um, it's when inflammation becomes more chronic, um, even after the acute problem has resolved or sometimes when it lingers, that it becomes maladaptive and the balance tips against the organism or the host, which is us. So, um, you know, a prolonged immune activation can lead to a persistent release of inflammatory cytokines or mediators. We're gonna talk about a bunch of those here. And, and that can also damage healthy tissue. Um, we're gonna talk about something that I think people loosely understand, which is the relationship between chronic inflammation and poor metabolic health. So, um, in-inflammation really becomes chronic once it's persisted for several months, uh, but it can persist for much longer than that. And we definitely see patients who show up and you can tell based on even their biomarkers, which we'll also discuss the utility of biomarkers and the futility of biomarkers in times, that, hey, they've been in a state of low-grade inflammation for a decade. Um, and, and th-there's, there's simply no scenario by which I can imagine that being a good thing.

4. 10:27 – 18:53

   The connection between chronic inflammation, aging, and age-related diseases

   1. SPSpeaker10:27

      You mentioned it there, but I think it'd also be worth touching on again, which is what is the connection between chronic inflammation, aging, age-related disease that makes that ongoing inflammation so dangerous to people and something that they should really try and be aware of if it's affecting them?

   2. PAPeter Attia10:46

      Well, we've, we've certainly talked a lot on the podcast about these hallmarks of aging, these cellular hallmarks of aging, and we talk about them both as things that occur as we age. We also talk about them, by the way, as targets for geroprotection. So we talk about geroprotective drugs are drugs that don't target specific diseases, but instead target these cellular mechanisms. So when you think about these, again, you know, decreased, um, nutrient sensing, cellular sy-senescence, genomic instability, um, epigenetic remodeling or epigenetic, uh, change, uh, we know that inflammation or low-grade inflammation is actually one of those things. So, um, out of the gate, we just recognize this as something that happens more with aging. We also understand that the association between chronic inflammation and the four horsemen, right? So the atherosclerotic diseases, cancer, neurodegenerative diseases, and metabolic diseases, uh, is incredibly high. Now, um, you, you know, I, I, I, I can just cite a couple of examples, right? So I, I don't think we will go into all the detail here because it's, it's one of those things that is so reproducible that I think, you know, quoting even one study might be sufficient. So here I'll kind of quote from one observational study that looked at, you know, a hundred and sixty thousand participants, um- And it asked the question, if they had a high degree of inflammation as measured by just two biomarkers, C-reactive protein and serum albumin, so high C-reactive protein, low serum albumin, it asked the question, what was their relationship to all-cause mortality or disease-specific mortality? Now, again, people have heard me talk about all-cause mortality before. You know, something that increases all-cause mortality by 20% is a pretty big deal. And yet, if you look at people with very high C-reactive protein, and again, it had to be darn high, right, above 10 milligrams per liter, their hazard ratio for all-cause mortality is 2.71, meaning they have 171% increase in the risk of all-cause mortality, meaning at any given year, they have 171% increase in the risk of death from any cause relative to someone with a low CRP. When it comes to cancer mortality, that hazard ratio is 3.16, cardiovascular mortality 2.33, and cerebrovascular mortality 2.17. So in other words, for every one of these things, there's more than a doubling in the risk of all-cause mortality. Now, does that mean that inflammation is causing that? No. But again, when you look at epidemiology and it's so consistently finding these things and the magnitude of these findings is so significant, it becomes very difficult to dismiss them. And therefore, I think it is generally regarded, and I tend to regard this as also true, that there is a causal relationship between inflammation and disease. And again, why do I harp on this? Because when things are causal, they are targets of therapy, right? When things are associative but not causal, well, it's great to know that, but it doesn't mean it's a target for therapy. But if you believe, as I do, that high inflammation plays a causal role in these diseases, then reducing inflammation should therefore reduce the risk of those things. And again, I think that's true not just of those diseases, but I think it's true in diseases that extend to them, you know, or diseases that extend from them, such as, you know, NAFLD, which we're starting to talk about more and more. Now, of course, one other way that one could go about trying to understand the role of causality here would be to try to effectively treat inflammation and see if by proxy you reduced the incidence of any of these conditions. And there's not a huge amount of literature here. There's a little bit, and I'll point to one trial called the CANTOS trial that tested a monoclonal antibody against interleukin-1 beta. So the monoclonal antibody, the name of which is irrelevant, but it's canakinumab, was used to do what's called a secondary prevention trial in patients with significant ASCVD. So took 10,000 patients who had previously suffered heart attacks. So we're talking about people who are, you know, very, very high risk for a subsequent event and who had a CRP, and this is an HSCRP. We'll kind of use those terms interchangeably, but HSCRP, highly sensitive C-reactive protein is what we typically use. They had an HSCRP above two milligrams per liter. Normal is kind of below one, just for reference. And they were randomized to either a placebo or a dose escalation of this antibody. And they were treated, I believe, every three months for a period of about four years. Okay. So what did they find when they did this study? They actually found that at a median follow-up of just under four years, the incidence of MACE, major adverse cardiac events, so remember non-fatal MI, stroke, or death from either of those things, was lower in the treatment group than in the placebo group. And it was, you know, actually didn't really seem to be that dose dependent. There was a little bit of a reduction or a little bit of an improvement by dose. And this was not true in the 50 milligram. I think it was only true in the two higher doses, and there was really no difference between them. The point is when they reduced CRP in response to this drug, they reduced events. Now, I will say this. The reduction was not enormous, right? So it was, you know, it was a reasonable reduction. I believe it was about a 15% relative reduction in the two higher dose groups. The lower dose did not reach statistical significance. And I think you could argue, look, given the size of the problem, a 15% relative reduction was reasonable. However, the drug was never approved because those patients went on to experience a higher incidence of infections and even very serious infections called sepsis. So this is a bit of an interesting study in that it's a cool proof of principle that says if you target inflammation, at least this one very, very narrow component of inflammation, which is interleukin-1 beta, you could reduce MACE in a very susceptible population. The drawback was, oh, and by the way, you made them less robust against an infection. And, you know, truthfully, I think that's a cautionary tale, right? I think what that says to me is, well, several things, but perhaps most important is be very careful of how you target inflammation and holistic, as much as I hate that word, holistic ways to target inflammation, which is really what we're going to talk about in this podcast, are probably the better way to go as opposed to pharmacologic hammers that really get at, you know, in this case, one kind of isolated pathway. I have to be honest with you as well. I'm a little surprised this trial showed any benefit at all. I didn't expect it to because of the redundancy within the human immune system. In other words, if you target IL-1, it's like big deal. You've still got IL-6, IL-11. You've still got all these other cytokines. So in that sense, I'm actually kind of surprised it worked. But notwithstanding that, um, I, I think th- that, to me at least, does bolster the claim that there's causality on this side.

5. 18:53 – 24:00

   The impact of inflammation on metabolic health

   1. SPSpeaker18:53

      Last kind of question on background is when we hear inflammation talked about, we often hear it talked about in the context of obesity, fat mass, metabolic health. What do we know about the relationship between metabolic health and inflammation?

   2. PAPeter Attia19:09

      Well, there's a very clear relationship between inflammation and excess adiposity that, um, lives outside of the sub-Q space. So when you look at even small amounts of ep- ectopic and visceral fat, that appears to promote far more inflammation than sub-Q fat. So sub-Q fat is the fat none of us like because we see it in the mirror. It's the fat that, um, you know, exists under the skin and, you know, obviously has whatever aesthetic components it has. Um, but it's, it's, it's the visceral fat, it's the organ fat that we don't see that's really driving the inflammatory response we want to avoid. And, and that's why there's such an association, a strong association between obesity and chronic disease. It's really less about the sub-Q fat. It's just that the more sub-Q fat you have, the more likely you are to have these, um, other stores of fat. So, um, the, you know... And, and that, that relationship's not one-to-one, so that's why we have sometimes the obesity paradox, where we have people who are obese, but their risk of disease seems to be normal. Those tend to be people that don't have these, um, ectopic and visceral stores. And conversely, you have, you know, lean people who at least on the outside look lean, but on the inside they're quite fat, and lo and behold, their risk of disease is much higher, as is their inflammation.

   3. SPSpeaker20:33

      Moving now from kind of that background section to what people are probably curious on now is do I have inflammation? Am I at risk for inflammation? So what do we know about someone's ability to understand if they have inflammation that they are dealing with, not on the acute sense, but again, on the chronic sense?

   4. PAPeter Attia20:53

      Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member. It's extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. So if you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. Premium membership includes several benefits. First, comprehensive podcast show notes that detail every topic, paper, person, and thing that we discuss in each episode. And the word on the street is nobody's show notes rival ours. Second, monthly Ask Me Anything or AMA episodes. These episodes are comprised of detailed responses to subscriber questions, typically focused on a single topic, and are designed to offer a great deal of clarity and detail on topics of special interest to our members. You'll also get access to the show notes for these episodes, of course. Third, delivery of our premium newsletter, which is put together by our dedicated team of research analysts. This newsletter covers a wide range of topics related to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our private podcast feed that provides you with access to every episode, including AMAs, sans the spiel you're listening to now and in your regular podcast feed. Fifth, the Qualies, an additional member-only podcast we put together that serves as a highlight reel featuring the best excerpts from previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and listen to each one of them. And finally, other benefits that are added along the way. If you want to learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can also find me on YouTube, Instagram, and Twitter, all with the handle PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up-to-date and active list of all disclosures. [outro music]

Episode duration: 24:00