The Peter Attia Drive - #301 - AMA #59： Inflammation： its impact on aging and disease risk, and how to identify, prevent, and reduce it

00:00:00.000 Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.

00:00:15.820 I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can access

00:00:20.280 the AMA episodes in full, along with a ton of other membership benefits we've created,

00:00:24.900 or you can learn more now by going to peteratiyahmd.com forward slash subscribe.

00:00:30.600 So without further delay, here's today's sneak peek of the ask me anything episode.

00:00:38.900 Welcome to ask me anything episode 59. I'm once again joined by my cohost, Nick Stenson.

00:00:44.900 In today's episode, we cover a topic that we get asked about a lot, but have not really covered

00:00:48.980 in much detail before. And that's the broad topic of inflammation. Inflammation is a word

00:00:54.720 maybe a buzzword and a topic that got thrown around so much. And there appears to be so much

00:00:59.740 confusion about it that we thought it would make sense to gather every and all question you have

00:01:05.280 posed on this topic and try to put together an episode that is all encompassing. So in this

00:01:11.500 discussion, we of course define what inflammation is, the differences between acute and chronic

00:01:16.400 inflammation and how chronic inflammation is indeed connected to aging and age-related diseases.

00:01:21.380 We speak about how inflammation is related specifically to obesity and metabolic health.

00:01:26.100 And from there, we look at ways that folks can know if indeed they are suffering from chronic

00:01:31.200 inflammation. But we focus the majority of the conversation around what to do if you are

00:01:36.640 experiencing chronic inflammation as determined by certain measures. We get into all facets of this,

00:01:43.160 looking at food, inflammatory tests, elimination, diets, the role of exercise, sleep, and stress on

00:01:48.600 inflammation. And even ask the question, are there any drugs or supplements that play a role here?

00:01:54.400 If you're a subscriber and you want to watch the full video of this podcast, you can find it

00:01:58.580 on the show notes page. And if you're not a subscriber, you can watch a sneak peek of the

00:02:02.700 video on our YouTube page. So without further delay, I hope you enjoy AMA number 59.

00:02:07.420 Peter, welcome to another AMA. How are you doing?

00:02:15.800 I'm doing especially good today, actually.

00:02:18.560 Yeah. What's different about today than usual?

00:02:21.400 Just reflecting on 20 years almost since Napoleon Dynamite came out and just reflecting on what an

00:02:28.980 important contribution that was to mankind.

00:02:31.560 If you look back at what you learned in medical school compared to what Napoleon Dynamite taught

00:02:37.940 you, which do you use more on a day-to-day basis?

00:02:41.840 It depends on the context, but in terms of referencing, probably Napoleon Dynamite.

00:02:48.420 I wouldn't believe that.

00:02:49.840 Yeah.

00:02:50.280 Now, for today's AMA, we're talking about inflammation. And I'm trying to think it's been

00:02:54.880 a bit since I watched Napoleon Dynamite. Does that get covered in Napoleon Dynamite?

00:02:58.520 I mean, I think Tina, the llama that he's got, is on a low FODMAP diet, if I recall,

00:03:06.700 when he's slapping the food at her. Also, I think the talons on those chickens were large,

00:03:15.040 probably due to some of the inflammatory changes in the talons. I think indirectly,

00:03:19.540 there is a thread of inflammation and other very important ideas in Napoleon Dynamite.

00:03:24.340 And the Venn diagram of Napoleon Dynamite inflammation and what we're talking about today

00:03:28.740 is quite big.

00:03:30.220 And I think you know this story. I've told it before, but Bob Montgomery, who is one of

00:03:35.000 the legends in the field of transplant surgery, was the head of transplant surgery at Hopkins

00:03:39.180 when I was there. And he was also a huge Napoleon Dynamite fan. So back in 2005, so this is like

00:03:44.960 about a year after the movie came out, we still just couldn't get enough of it. This is back when

00:03:49.520 you listened to CDs. So there was a Napoleon Dynamite CD soundtrack, and it was great because

00:03:53.600 it had like 45 tracks on it. So all the songs from the movies, but just as importantly, millions

00:04:00.380 of little clips of funny actual sections of the movie. And surgeons often are listening to music

00:04:06.020 in the OR, but we only listened to that CD. So for an entire month, that CD never left the operating

00:04:16.520 room. And it was just on repeat. And God bless the nurses who didn't find it as funny as we did. 1.00

00:04:23.940 That was like just probably a completely annoying thing. But we never stopped laughing at this thing.

00:04:31.880 And I will say this, because people often ask if I tell this story, did it compromise the outcomes?

00:04:36.880 And I will say that there was a period of three days when we did 13 kidney transplants.

00:04:44.820 Every one of those patients had a remarkable achievement outcome. And look, 13, you know,

00:04:51.520 it's not uncommon for one of those to have a graph that goes down or something. But

00:04:54.940 we thought that there really should be a clinical trial done where you randomize patients to undergo a

00:05:00.760 kidney transplant with Napoleon Dynamite soundtrack playing versus some other soundtrack. And I wouldn't be

00:05:06.240 surprised if that was done. And it did produce superior outcomes.

00:05:10.320 To be honest, based on some of the studies we see, it would not be the most ridiculous study 0.86

00:05:14.520 that has been done. Bob Montgomery, he was the person who did the first 0.59

00:05:20.100 transplant of a kidney. Yeah. Bob's up at NYU now. Amazing guy. I'd love to get Bob on the podcast

00:05:27.000 at some point. Awesome. Well, with that divergence, we are now going to move into what we're talking

00:05:33.160 about, which is inflammation. And it's a topic that seems to be talked about so much online,

00:05:39.240 so much in different podcasts, different things of that nature. And it is talked about in a variety

00:05:44.540 of ways. It's also when we get asked about a lot and we haven't covered it in detail before. So what

00:05:49.380 we did is we pulled all the questions that we saw and what we're going to hope to cover today is

00:05:54.140 not only what is inflammation, but how do you measure it? How do you know if you have it?

00:05:58.220 And most importantly, and what I think people care about the most is what you can do about it.

00:06:03.980 And so I think it'd be insanely helpful just to start off with a definition of what is

00:06:09.920 inflammation? How do you define it? Because again, it seems it's defined and talked about in so many

00:06:14.620 different ways that I think we almost need to set the stage early on and just be talking about how

00:06:19.860 are we going to define it for the conversation today? As you know, and just for the listeners,

00:06:24.740 I was almost hesitant to do this AMA because I just hate buzzwords and inflammation is just such

00:06:31.400 a buzzword that gets thrown around so much with no meaning. So on the one hand, I felt the tug of

00:06:37.100 doing this as sort of a public service announcement. And on the other hand, I was like, oh my God,

00:06:41.400 it's just, we're actually going to have to do a lot of heavy lifting to get people to really

00:06:45.420 understand what we're talking about. And ultimately we've decided to do that because I do think it is

00:06:49.640 important and I want to make sure people have a very clear understanding of what they're talking about.

00:06:54.140 And what is often misconstrued in popular circles. So let's define inflammation. So inflammation

00:07:00.100 is a biological response of the immune system to defend against some sort of stimulus, usually

00:07:10.160 harmful, but not always, and to eliminate the cause of injury. Now look, as is often stated,

00:07:16.600 of course, inflammation is not always bad. So oftentimes inflammation is essential. It is the

00:07:22.080 fundamental issue for tissue repair for the clearance of infectious pathogens. And obviously the immune

00:07:28.400 response plays a very important role in that. You know, in medical school, I think the first thing

00:07:32.980 you learn about on this front is the acute inflammatory response. There's a mnemonic for

00:07:37.660 what happens when you are experiencing acute inflammation and it deals, I can't remember the

00:07:42.840 mnemonic, but of course it talks about how things get red, things get swollen, things get sore,

00:07:47.200 all of those things. And that of course results from both the infection and also the response of

00:07:52.780 the body. And then of course there's something that is more chronic in its nature. And truthfully,

00:07:58.200 that's really where we're going to spend our time today because I don't really think there's much to

00:08:04.460 talk about as far as acute inflammation that goes well. So if acute inflammation goes unresolved and

00:08:10.520 becomes chronic, then we should talk about that. But again, what we're here to really talk about

00:08:14.580 today is the maladaptive side of inflammation. I think just early on it'd be also really important

00:08:20.860 just to maybe double click on the difference between acute and chronic inflammation. Again,

00:08:25.740 you spoke about a little bit there, but you maybe just kind of want to walk people through that again

00:08:29.740 with the idea that we're going to focus mainly on the chronic aspect today. Anybody who's had a

00:08:35.120 mosquito bite or who's cut themselves knows what acute inflammation is. So again, if think about a

00:08:41.700 mosquito bite, it's going to be warm, it's going to be painful, it's going to be swollen, you might

00:08:47.040 even have loss of function. This is actually for the most part a very important aspect of healing the

00:08:54.520 insult or inflammation. What we're here to talk about is chronic inflammation, which again can be

00:09:00.860 something that lasts from months into years. And here you don't have, this is a very important point,

00:09:06.260 you don't tend to have the same physical signs or symptoms, the redness, the swelling, the pain,

00:09:13.840 the obvious things. And so oftentimes we think of this as low grade inflammation. It's often

00:09:20.880 asymptomatic, although we'll get into some examples of maybe where it's not, for example, when it's diet

00:09:25.960 induced. But why we talk about this, of course, is the role that this plays in disease and ultimately

00:09:33.540 in life. What do we know about why acute inflammation can be good, but then it becomes

00:09:41.740 bad in the sense of chronic inflammation once that acute trigger is gone? Acute inflammation is essential

00:09:47.800 to heal the body. So we have an innate immune system that is able to react immediately with soluble

00:09:54.580 antibodies to harmful infectious pathogens. As one example, if you have injury, tissue is damaged. So

00:10:02.660 damaged tissue needs to be cleared. All of these things have to happen really, really quickly

00:10:06.900 and very efficiently. And anything that inhibits that process, by the way, is often quite deleterious,

00:10:13.560 right? So people who have shortcomings in their immune system, especially for that type of acute stuff

00:10:19.660 are going to have significant problems. And there are, of course, certain disease states that do that.

00:10:23.940 It's when inflammation becomes more chronic, even after the acute problem has resolved, or sometimes when it

00:10:30.920 lingers, that it becomes maladaptive and the balance tips against the organism or the host, which is us.

00:10:37.660 So a prolonged immune activation can lead to a persistent release of inflammatory cytokines or

00:10:44.040 mediators. We're going to talk about a bunch of those here. And that can also damage healthy tissue.

00:10:48.840 We're going to talk about something that I think people loosely understand, which is the relationship

00:10:52.920 between chronic inflammation and poor metabolic health. So inflammation really becomes chronic once it's

00:10:58.660 persisted for several months, but it can persist for much longer than that. And we definitely see

00:11:03.600 patients who show up and you can tell based on even their biomarkers, which we'll also discuss the

00:11:10.240 utility of biomarkers and the futility of biomarkers in times that, hey, they've been in a state of low

00:11:15.560 grade inflammation for a decade. There's simply no scenario by which I can imagine that being a good

00:11:20.960 thing.

00:11:21.260 You mentioned it there, but I think it'd also be worth touching on again, which is what is the

00:11:26.500 connection between chronic inflammation, aging, age-related disease that makes that ongoing

00:11:33.640 inflammation so dangerous to people and something that they should really try and be aware of if it's

00:11:39.820 affecting them?

00:11:41.140 We've certainly talked a lot on the podcast about these hallmarks of aging, these cellular hallmarks of

00:11:46.540 aging. And we talk about them both as things that occur as we age. We also talk about them,

00:11:51.580 by the way, as targets for geroprotection. So we talk about geroprotective drugs are drugs that

00:11:56.840 don't target specific diseases, but instead target these cellular mechanisms. So when you think about

00:12:02.720 these, again, decreased nutrient sensing, cellular senescence, genomic instability, epigenetic

00:12:09.540 remodeling or epigenetic change, we know that inflammation or low-grade inflammation is actually

00:12:15.300 one of those things. So out of the gate, we just recognize this as something that happens more

00:12:20.860 with aging. We also understand that the association between chronic inflammation and the four horsemen,

00:12:27.000 so the atherosclerotic diseases, cancer, neurodegenerative diseases, and metabolic diseases

00:12:31.080 is incredibly high. Now, I can just cite a couple of examples. I don't think we will go into all the

00:12:38.320 detail here because it's one of those things that is so reproducible that I think quoting even one

00:12:44.220 study might be sufficient. So here I'll quote from one observational study that looked at 160,000

00:12:50.280 participants, and it asked the question, if they had a high degree of inflammation as measured by just

00:12:58.400 two biomarkers, C-reactive protein and serum albumin, so high C-reactive protein, low serum albumin,

00:13:05.600 it asked the question, what was their relationship to all-cause mortality or disease-specific mortality?

00:13:12.560 Now, people have heard me talk about all-cause mortality before. Something that increases all-cause

00:13:17.480 mortality by 20% is a pretty big deal. And yet, if you look at people with very high C-reactive

00:13:24.360 protein, and again, it had to be darn high, right? Above 10 milligrams per liter. Their hazard ratio for

00:13:29.840 all-cause mortality is 2.71, meaning they have 171% increase in the risk of all-cause mortality,

00:13:36.220 meaning for any, at any given year, they have a 171% increase in the risk of death from any cause

00:13:42.640 relative to someone with a low CRP. When it comes to cancer mortality, that hazard ratio is 3.16,

00:13:49.380 cardiovascular mortality, 2.33, and cerebrovascular mortality, 2.17. So in other words, for every one

00:13:57.100 of these things, there's more than a doubling in the risk of all-cause mortality. Now, does that mean

00:14:02.500 that inflammation is causing that? No. But again, when you look at epidemiology, and it's so consistently

00:14:10.540 finding these things, and the magnitude of these findings is so significant, it becomes very

00:14:16.900 difficult to dismiss them. And therefore, I think it is generally regarded, and I tend to regard this

00:14:22.960 as also true, that there is a causal relationship between inflammation and disease. And again, why do I

00:14:29.380 harp on this? Because when things are causal, they are targets of therapy. When things are associative

00:14:36.140 but not causal, well, it's great to know that, but it doesn't mean it's a target for therapy. But if you

00:14:41.740 believe, as I do, that high inflammation plays a causal role in these diseases, then reducing inflammation

00:14:50.240 should therefore reduce the risk of those things. And again, I think that's true not just of those

00:14:56.760 diseases, but I think it's true in diseases that extend to them, you know, or diseases that extend

00:15:02.000 from them, such as NAFLD, which we're starting to talk about more and more. Now, of course, one other

00:15:07.600 way that one could go about trying to understand the role of causality here would be to try to

00:15:15.520 effectively treat inflammation and see if by proxy you reduced the incidence of any of these conditions.

00:15:23.820 And there's not a huge amount of literature here. There's a little bit. And I'll point to one trial

00:15:30.340 called the Cantos trial that tested a monoclonal antibody against interleukin-1-beta. So the

00:15:39.240 monoclonal antibody, the name of which is irrelevant, but it's canakinumab, was used to do what's called a

00:15:46.220 secondary prevention trial in patients with significant ASCVD. So it took 10,000 patients who had

00:15:52.060 previously suffered heart attacks. So we're talking about people who are very, very high risk for a

00:15:57.780 subsequent event and who had a CRP, and this is an HSCRP, we'll kind of use those terms interchangeably,

00:16:04.480 but HSCRP, highly sensitive C-reactive protein is what we typically use. They had HSCRP above two

00:16:10.220 milligrams per liter. Normal is kind of below one, just for reference. And they were randomized to either

00:16:17.720 a placebo or a dose escalation of this antibody, and they were treated, I believe, every three months

00:16:24.600 for a period of about four years. Okay, so what did they find when they did this study? They actually

00:16:30.520 found that at a median follow-up of just under four years, the incidence of MACE, major adverse cardiac

00:16:36.620 events, so remember non-fatal MI, stroke, or death from either of those things, was lower in the treatment

00:16:43.380 group than in the placebo group. And it actually didn't really seem to be that dose dependent.

00:16:48.380 There's a little bit of an improvement by dose. And this was not true in the 50 milligram. I think

00:16:53.040 it was only true in the two higher doses, and there was really no difference between them. The point is

00:16:56.520 when they reduced CRP in response to this drug, they reduced events. Now, I will say this. The reduction

00:17:04.660 was not enormous. It was a reasonable reduction. I believe it was about a 15% relative reduction

00:17:15.860 in the two higher dose groups. The lower dose did not reach statistical significance. And I think you could

00:17:23.580 argue, look, given the size of the problem, a 15% relative reduction was reasonable. However, the drug was

00:17:32.080 never approved because those patients went on to experience a higher incidence of infections and even

00:17:39.260 very serious infections called sepsis. So this is a bit of an interesting study in that it's a cool proof

00:17:46.520 of principle that says if you target inflammation, at least this one very, very narrow component of

00:17:53.960 inflammation, which is interleukin-1 beta, you could reduce MACE in a very susceptible population.

00:18:00.000 The drawback was, oh, and by the way, you made them less robust against an infection.

00:18:05.960 And truthfully, I think that's a cautionary tale. I think what that says to me is, well,

00:18:11.100 several things, but perhaps most important is be very careful of how you target inflammation and

00:18:16.380 holistic, as much as I hate that word, holistic ways to target inflammation, which is really what

00:18:20.580 we're going to talk about in this podcast, are probably the better way to go as opposed to

00:18:25.120 pharmacologic hammers that really get at, in this case, one kind of isolated pathway.

00:18:30.620 I have to be honest with you as well. I'm a little surprised this trial showed any benefit at all.

00:18:35.080 I didn't expect it to because of the redundancy within the human immune system. In other words,

00:18:42.300 if you target IL-1, it's like big deal. You've still got IL-6, IL-11, you've still got all these

00:18:46.940 other cytokines. So in that sense, I'm actually kind of surprised it worked. But notwithstanding that,

00:18:51.800 that to me at least does bolster the claim that there's causality on this side.

00:18:56.960 Last question on background is, when we hear inflammation talked about, we often hear it

00:19:02.020 talked about in the context of obesity, fat mass, metabolic health. What do we know about the

00:19:08.040 relationship between metabolic health and inflammation? Well, there's a very clear relationship

00:19:14.340 between inflammation and excess adiposity that lives outside of the sub-Q space.

00:19:21.800 So when you look at even small amounts of ectopic and visceral fat, that appears to promote far

00:19:28.640 more inflammation than sub-Q fat. So sub-Q fat is the fat none of us like because we see it in the

00:19:35.100 mirror. It's the fat that exists under the skin and obviously has whatever aesthetic components it has.

00:19:40.800 But it's the visceral fat, it's the organ fat that we don't see that's really driving the

00:19:46.380 inflammatory response we want to avoid. And that's why there's such an association,

00:19:51.380 a strong association between obesity and chronic disease. It's really less about the sub-Q fat. 0.58

00:19:56.760 It's just that the more sub-Q fat you have, the more likely you are to have these other stores of fat.

00:20:02.980 So that relationship's not one-to-one. So that's why we have sometimes the obesity paradox where we have

00:20:08.960 people who are obese, but their risk of disease seems to be normal. Those tend to be people that

00:20:13.380 don't have these topic and visceral stores. And conversely, you have lean people who at least

00:20:19.620 on the outside look lean, but on the inside, they're quite fat. And lo and behold, their risk

00:20:23.500 of disease is much higher as is their inflammation. Moving now from kind of that background section to

00:20:29.620 what people are probably curious on now is, do I have inflammation? Am I at risk for inflammation?

00:20:36.280 So what do we know about someone's ability to understand if they have inflammation that they

00:20:42.780 are dealing with? Not in the acute sense, but again, on the chronic sense.

00:20:46.960 Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested

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00:24:16.020 Thank you.

The Peter Attia Drive - May 13, 2024

#301 - AMA #59： Inflammation： its impact on aging and disease risk, and how to identify, prevent, and reduce it

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