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

Foreign.

Hey everyone welcome to a sneak.

Peek ask me anything or ama episode of the drive podcast i'm your host.

Peter attia at the end of this.

Short episode i'll explain how you can.

Access the ama episodes in full along.

With a ton of other membership benefits we've created or you can learn more now by going to peteratti md dot.

Com forward slash subscribe so without further delay here's today's sneak peek of the.

Ask me anything episode welcome to ask me anything episode fifty nine i'm once again joined by my co host nick stenson in today's episode we cover a topic that we get asked about a lot but have not really covered in much detail before and that's the broad topic of inflammation inflammation is a word maybe a buzzword and a topic that get thrown around so much and there appears to be so much confusion about that we thought it would make sense to gather every and all question you have posed on this topic and try to put together an episode that is all encompassing so in this discussion we of course define what inflammation is the differences between acute and chronic inflammation and how chronic inflammation is indeed connected to aging and age related diseases we speak about how inflammation is related specifically to obesity and metabolic health and from there we look at ways that folks can know if indeed they are suffering from chronic inflammation but we focus the majority of the conversation around what to do if you are experiencing chronic inflammation as determined by certain measures we get into all facets of this looking at food inflammatory tests elimination diets the role of exercise sleep and stress on inflammation and even ask the question are there any drugs or supplements that play a role here if you're a subscriber and you want to watch the full video of this podcast you can find it on the show notes page and if you're not a subscriber you can watch a sneak peek of the video on our youtube page so without further delay i hope you enjoy ama number fifty nine.

Peter welcome to another ama how you.

Doing i'm doing especially good today actually.

Yeah what's different about today than usual.

Just reflecting on twenty years almost since napoleon dynamite came out and just reflecting on what an important contribution that was to mankind 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 it depends on the context but in terms of referencing probably napoleon dynamite i would believe that yeah.

Now for today's ama we're talking about inflammation and i'm trying to think it's been a bit since i watched napoleon dynamite does that get covered in napoleon.

Dynamite 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 also i think the talons on those chickens were large probably due to some of the inflammatory changes in the talons i think indirectly there is a threat of inflammation and other very important ideas in.

Napoleon dynamite the venn diagram of napoleon dynamite inflammation of what we're talking about today is quite big and i think.

You know this story i've told it before but bob montgomery who is one of the legends in the field at 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 two thousand five so this is like about a year after the movie came out we still just couldn't get enough of it this is back when you listened to cd so there was a napoleon dynamite cd soundtrack and it was great because it had like forty five tracks on it so all the songs from the movies but just as importantly millions of little clips of funny actual sections of the movie and surgeons often are listening to music in the or but we only listen 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 we never stopped laughing at this thing and i will say this because people often ask if i tell this story did it compromise the outcomes and i will say that there was a period of three days when we did thirteen kidney transplants every one of those patients had a remarkable achievement outcome and look thirteen you know it's not uncommon for one of those to have a graph that goes down or something but 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 to.

Be honest based on some of the studies we see it would not be the most ridiculous study that has been done bob montgomery he was the person.

Who did the first xeno transplant of a kidney yeah bob's up at nyu now amazing guy i'd love to get bob on the podcast at some point.

Awesome well with that divergence we are now going to 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 going to 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 going to define it for the conversation today.

As you know and just for the listeners 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 so on the one hand i felt the tug of doing this as sort of a public service announcement and on the other hand i was like oh my it's just we're actually going to 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 want to make sure people have a very clear understanding of what they're talking about and what is often misconstrued in popular circles so let's define inflammation so inflammation is a biological response of the immune system to defend against some sort of stimulus usually harmful but not always and to eliminate the cause cause of injury now look as is often stated of course inflammation is not always bad so oftentimes inflammation is essential it is the fundamental issue for tissue repair for the clearance of infectious pathogens and obviously the immune response plays a very important role in that 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 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 and that of course results from both the infection and also the response of the body and then of course there's something that is more chronic in its nature and truthfully that's really where we're going to spend our time today 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 but again what we're here to really talk about today is the maladaptive side of.

Inflammation 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 a little bit there but do you maybe just kind of want to walk people through that again with the idea that we're going to focus mainly on the chronic aspect today anybody who's had.

A mosquito bite or who's cut themselves knows what acute inflammation is so again think about a mosquito bite right it's going to be warm it's going to be painful it's going to be swollen you might even have loss of function this is actually for the most part a very important aspect of healing the insulter inflammation what we're here to talk about is chronic inflammation which again can be something that lasts from months into years 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 it's often asymptomatic although we'll get into some examples of maybe where it's not for example when it's diet induced but why we talk about this of course is the role that this plays in disease and ultimately in life 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 acute inflammation.

Is essential to heal the body so we have an innate immune system that is able to react immediately with soluble antibodies to harmful infectious pathogens as one example if you have injury tissue is damaged so damaged tissue needs to be cleared all of these things have to happen really really quickly and very efficiently and anything that inhibits that process by the way is often quite deleterious right so people who have shortcomings in their immune system especially for that type of acute stuff are going to have significant problems and there are of course certain disease states that do that it's when inflammation becomes more chronic 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 a prolonged immune activation can lead to a persistent release of inflammatory cytokines or mediators we're going to talk about a bunch of those here and that can also damage healthy tissue we're going to talk about something that i think people loosely understand which is the relationship between chronic inflammation and poor metabolic health so inflammation really becomes chronic once it's persisted for several months 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 there's simply no scenario by which i can imagine that being a good.

Thing 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 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 zero protection so we talk about jira protective drugs are drugs that don't target specific diseases but instead target these cellular mechanisms so when you think about these again decreased nutrient sensing cellular senescence genomic instability epigenetic remodeling or epigenetic change we know that inflammation or low grade inflammation is actually one of those things so 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 so the atherosclerotic diseases cancer neurodegenerative diseases and metabolic diseases is incredibly high now i can just cite a couple of examples i don't think we will go into all the detail here because it's one of those things that is so reproducible that i think quoting even one study might be sufficient so here i'll quote from one observational study that looked at one hundred sixty thousand participants 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 people have heard me talk about all cause mortality before something that increases all cause mortality by twenty percent 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 ten milligrams per liter their hazard ratio for all cause mortality is two point seven one meaning they have one hundred seventy one percent increase in the risk of all cause mortality meaning for any at any given year they have one hundred and seventy one percent 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 three point one six cardiovascular mortality two point three three and cerebrovascular mortality two point one seven 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 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 nafld which we'll be 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 one 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 ten thousand patients who had previously suffered heart attacks so we're talking about people who are very very high risk for a subsequent event and who had a crp and this is an hs crp we'll kind of use those terms interchangeably but hscrp highly sensitive c reactive protein is what we typically use they had a 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 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 event 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 actually didn't really seem to be that dose dependent and there's a little bit of an improvement by dose and this was not true in the fifty 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 it was a reasonable reduction i believe it was about a fifteen percent 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 fifteen percent 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 one 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 truthfully i think that's a cautionary tale 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 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 one it's like big deal you've still got il six illinois eleven you've still got all these other cytokines so in that sense i'm actually kind of surprised it worked but notwithstanding that that to me at least does bolster the claim that there's causality on this side last.

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 well there's a very clear relationship between inflammation and excess adiposity that lives outside of the sub q space so when you look at even small amounts of 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 exists under the skin and obviously has whatever aesthetic components it has but 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 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 other stores of fat so 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 topic and visceral stories and conversely you have 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 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 in the acute sense but again on the chronic sense 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 ama's sans the spiel you're listening to now and in your regular podcast feed fifth the qualys 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 dot 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 dot com about where i keep an up to date and active list of all disclosures.

Sam.