RHR: The Keys to Longevity with Peter Attia

http://chriskresser.com/

Longevity is something Peter has some unique insight into, given his range of experience all the way back in medical school, his position at NIH and his work with patients over the years, and his own personal exploration and biohacking. Peter has an approach to longevity that he has thought a lot about and presents to any patient that is considering working with you, so maybe we can just kind of go through that and then take some interesting detours along the way.In this episode, we cover:

2:45  Peter’s approach to longevity
22:55  Commonalities of degenerative diseases
45:00  Social support and sense of purpose

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Chris Kresser: Hey, everybody, it’s Chris Kresser. Welcome to another episode of Revolution Health Radio.

Today I’m really excited to welcome Dr. Pete Attia to the podcast. Peter is the founder of Attia Medical, PC, a medical practice with offices in San Diego and New York City, focusing on the applied science of longevity and optimal performance. The practice applies nutrition science, lipidology, four-system endocrinology, sleep physiology, stress management, and exercise physiology to minimize the risk of chronic disease onset while simultaneously improving healthspan—something I want to talk to Pete about today.

Peter trained for five years at the Johns Hopkins Hospital in General Surgery, where he was the recipient of several prestigious awards, including resident of the year, and the author of a comprehensive review of general surgery. He also spent two years at NIH as a surgical oncology fellow at the National Cancer Institute, where his research focused on immune-based therapies for melanoma. He has since been mentored by some of the most experienced and innovative lipidologists, endocrinologists, gynecologists, sleep physiologists, and longevity scientists in the US and Canada.

Peter was the founder and president of a medical research organization that funded human clinical trials in nutrition and metabolic disease. During his four years as president, they raised and deployed over $40 million.

Peter earned his MD from Stanford and holds a bachelor’s in science in mechanical engineering and applied mathematics, and he’s licensed in California and New York.

I met Pete several years ago. I’m actually having trouble remembering exactly where we met. We travel in the same circles, of course, and our paths crossed a number of different times, but we hit it off and became fast friends. Pete is one of the smartest people I know, without a doubt. Every time we talk, I always learn something new and we have a fascinating conversation. He’s someone I always look forward to speaking with, and I’m frankly surprised that I haven’t had him on the podcast yet. That was mostly due to the fact that he’s also one of the busiest people I know! We finally made our schedules match up, and I’m really looking forward to diving in and speaking with him.

As I was thinking about the interview, there were any number of things that we could talk about. Pete is one of the most knowledgeable people when it comes to lipids and diagnosis and management of cardiovascular disease, so that was an obvious topic, but in the end, I thought it would be more interesting to talk about longevity because that’s something that we haven’t discussed in an encapsulated way on the podcast yet, and it’s something that Pete thinks a lot about and has a lot of insight into, so that’s what we’re going to do. Let’s jump in.

Pete, I’m so glad we could finally make this work. Actually as I was recording the intro, I was saying I couldn’t believe that it has taken me this long to get you on the show. I mean, you had been on the top of my list as a potential guest, but I think I’ve had the show for four or five years now and here we are!

Peter Attia, MD: It’s great to finally be on.

Chris Kresser: Yeah, it was a little bit of a scheduling dance. You are a busy guy and I’m a busy guy, but I’m happy we could make it work.

I was also thinking a lot about what we could talk about, which would be any number of fascinating topics, but the one that really stuck out when we were shooting ideas back and forth was longevity because that’s something that you have thought a lot about and, I think, you have some unique insight into, given your range of experience all the way back in medical school and then your position at NIH and your work with patients over the years and just your own personal exploration and kind of biohacking. You have an approach to longevity that you have clearly thought a lot about and have laid out and even present to any patient that is considering working with you, so maybe we can just kind of go through that and then take some interesting detours along the way.

Peter Attia, MD: Yeah, that sounds great. One caveat before we begin, Chris, I’m actually in San Diego today, which is not that common, but one of the beautiful things about San Diego is the F/A-18s that fly over us constantly.

Chris Kresser: Right!

Peter Attia, MD: So there’s a small chance we’ll get through this call without me being completely droned out, just so in advance you know that. We refer to that as the beauty of freedom. We’re pretty happy to have those F/A-18s over here.

Chris Kresser: That’s OK, Pete, because my listeners have been putting up with me living in a construction zone. We bought a new house, and I’ve been in this transition phase, so at any point you could hear a power tool outside of my window or below me in the crawl space where people are working.

Peter Attia, MD: Very well.

Chris Kresser: We’ll just have to put up with it.

Peter Attia, MD: So my approach to longevity is the product of probably about six years of thinking about this problem and not necessarily thinking about it correctly, but at the very least, it’s an evolution. I think there are a handful of moments when I think I had an aha thought. One of them was, are we thinking about this problem correctly? Obviously this is a problem people much smarter than I have thought about, and people have been thinking about it for a very long time. As you know, it’s a space that’s largely sort of full of nothing. I mean, every year there’s sort of a new secret to longevity that doesn’t pan out. Obviously the most famous example of that is resveratrol, which turned into probably a 700 to 900-million-dollar debacle.

So my first aha moment was, if we ask the question differently, does it become more answerable? If the question is, how do I live longer? that turns into, at least to me, a hard question to answer. If the question is, to start with, when and how will I die? all of a sudden, that seems more manageable. We actually have pretty good data on that. Then you can start to reverse engineer the problem. If you know how and when, roughly, you’re going to die—and when I say that, just for the listener who maybe isn’t used to sort of thinking probabilistically, that’s not to suggest for a moment you can look at an individual and say, “That person will die of a heart attack at the age of 78.” What it means is you can put together a probability distribution of how a person is likely to die and in what window of time they’re likely to die. Again, probability distributions are just that. It doesn’t mean that it’s a guaranteed thing, of course. You could get hit by a bus tomorrow, or you could be afflicted by cancer tomorrow.

Chris Kresser: Horseshoes and hand grenades!

Peter Attia, MD: Yeah!

Chris Kresser: Just trying to get close.

Peter Attia, MD: Right. When you have that understanding, you then ask the question, OK, what can we do about it? That was sort of aha moment number one.

Aha moment number two was sort of digging into the literature on centenarians. When you look at these people who live to be a hundred or more, there’s what I call the depressing hypothesis, which is the only way they die is in car accidents and—I don’t know—suicides or something like that, which would give you the impression that whatever genetic gifts the centenarians have—and in a moment we can talk about what some of those genetic gifts are because many of them have been well elucidated—absent those genetic gifts, we’re all doomed. But in fact, we don’t see that, right? We see the opposite. We see that they die of largely the same types of diseases in largely the same distribution that people who aren’t centenarians die of.

So the aha moment number two there is something about those genes that they have delays the onset of chronic disease.

Chris Kresser: Right.

Peter Attia, MD: Because that’s basically what they’re still dying of. What are those genes? Well, that’s certainly the most exciting thing for many people to think about, and I think it’s interesting from a mechanistic standpoint. We certainly see known defects in growth hormone receptor IGF-1, APOC3, and so what’s interesting about those things is those things probably tend to more result in their benefit by reducing the probabilities of these chronic diseases, whether APOC3 on the lipid side or GHR or IGF probably on the cancer promotion side. It’s all still sort of moving in the same direction. That’s sort of pillar number one of insight.

Pillar number two of insight—again, I say this like I’m the only guy that has had these insights, but I wouldn’t say that at all. I’m just suggesting. This is my framework and how I’m applying it.

Chris Kresser: Yeah, this is how you’re looking at it.

Peter Attia, MD: It’s basically looking at the commonality between caloric restriction and drugs that inhibit nutrient-sensing pathways. Now for me personally, nothing is more interesting than rapamycin. Whether rapamycin itself will go on to become a drug that we all one day take in small intermittent doses, I think, remains to be seen, but what seems likely to me is that rapalogs—analogs of rapamycin—will eventually become a very important part of how we think about modulating the activity of its target affectionately known as mTOR, the mammalian or mechanistic target of rapamycin. Why that’s interesting is rapamycin is the only drug that has ever enhanced the lifespan in all four model species—yeast, worms, flies, and mammals.

Chris Kresser: Right, and this is something that was identified from Streptomyces. Is that right?

Peter Attia, MD: That’s correct.

Chris Kresser: Back in the ‘70s. It was originally found on Easter Island, I think.

Peter Attia, MD: Yeah, in 1964 an expedition from McGill University went down to Easter Island, looking for novel species of bacteria, that identified a Streptomyces there. It was brought back to Montreal. It eventually found its way into a division of a company that was also in Montreal. It’s actually a really amazing story. I am guessing that the listenership might not have the appetite for the full story, but I certainly find it interesting. A guy by the name of Suren Sehgal was working at this company called Ayerst Laboratories, and he purified this stuff in the mid ‘70s. I think a vial first made it into his hand in, like, 1972 or something, but by 1975 he had purified it. I actually have the first paper that was ever published for which he was the first author, in a very obscure chemistry journal. It was named rapamycin because the natives refer to Easter Island as Rapa Nui.

Chris Kresser: Right.

Peter Attia, MD: Of course, you put the rapa with the mycin, and you get rapamycin. What’s really interesting to me is—and by the way, if his son is listening to this, I want to reach him. Suren has long since passed away, and I’ve been trying to actually get a hold of his son because a few of us are actually planning a trip to Easter Island this fall as sort of a pilgrimage to this.

Chris Kresser: Nice.

Peter Attia, MD: But anyway, according to what I’ve read, Suren believed that he had basically found the best treatment ever for athlete’s foot because—let’s call a spade a spade—this is a pretty amazing antifungal agent, right? What could be better than getting rid of one of the greatest problems afflicting our society.

The company basically decided to shut down its Montreal lab, and virtually everybody was fired, and nonviable compounds were ordered to be destroyed, including rapa, but Suren had a hunch that this was really special, so he froze a bunch down and literally transferred it with himself all the way over to New Jersey and kept it in his home’s freezer until 1987 when Wyeth ended up buying that company and he was able to convince the new bosses at Wyeth to let him explore uses of rapamycin.

Chris Kresser: Wow.

Peter Attia, MD: Now, again, this gets even more interesting, and I’m sorry to deviate on this, but I never get to tell this story and I love it. In about the same period of time, a cousin of rapamycin, a drug called FK506, was discovered in Japan. It’s also a Streptomyces, and this goes by the name tacrolimus, which most people may have heard of if they are familiar with transplant patients.

Now, this is interesting because tacrolimus was very similar to rapamycin except that it also inhibited calcineurin, and this generated a great deal of interest for people at that time, in the early ‘90s, who were looking to ameliorate the damage of reperfusion in stroke. This is where the story gets sort of personal because I’ve become very close friends with a guy by the name of David Sabatini. David Sabatini, who was an MD PhD student at Hopkins in the early ‘90s, decided in ‘92 to do his PhD in the lab of a guy named Sol Snyder who was working on FK506 in rats in this stroke model. They used this obscure drug called rapamycin as the control because it did not inhibit calcineurin.

So when Sabatini shows up, he’s asked the question, what do you want to work on for your PhD thesis? He’s thinking to himself, I don’t even really like neuroscience that much; I have to think of something to do in this neuroscience lab. He decided he was going to go after figuring out how this drug rapamycin worked, and you sort of can see how the story ends, right? Two years later he’s publishing this paper that’s saying, hey, it inhibits this thing called TOR, the target of rapamycin, something that we now really know of as perhaps the single most important sensing protein complex in the body when it comes to regulating autophagy and growth.

Long digression, I apologize, but between Easter Island and TOR and mTOR and rapa, there’s something really exciting and interesting there. Now the question then becomes, how do we manipulate that system, using things other than the direct drug that we know inhibits it but comes with too many side effects?

Chris Kresser: Right. But let’s take a step back. What we see, from my understanding—I haven’t looked into this in nearly the detail that you have—is an extension of lifespan by 10 to 15 percent, or thereabouts, in mice?

Peter Attia, MD: Yeah, it depends on the gender. What’s really interesting with rapa, what I think really blew everybody’s socks off, was that even beyond what CR could do… see CR would only work in this animal model if you started calorically restricting from birth, but with rapa, you could take mice that were the equivalent of 60 years old and begin dosing with rapamycin and you could still add 10 to 15 percent life extension from that time forward, relative to their peers, which really is a 25 to 30 percent aggregate life extension.

Chris Kresser: Right.

Peter Attia, MD: I, by the way, have those numbers reversed. It’s 10 to 15 percent in aggregate, 25 to 30 percent from that moment forward.

Chris Kresser: Relative.

Peter Attia, MD: Yeah. That’s the big first. Nothing else does that. The second thing is, and we saw this last year, in December of 2014, a paper was published that showed intermittent dosing of rapamycin actually enhanced immunity in humans age 60 to 70. Again, very counterintuitive, given that the clinical application for rapamycin is immune suppression. But of course, that’s constitutive dosing, meaning it’s consistently dosed.

Chris Kresser: Yeah.

Peter Attia, MD: What we think is going on is that we now know, of course, that there are two complexes of mTOR complex 1, which is called mTORC1, and mTOR complex 2, or mTORC2, and of course, these protein complexes exist in multiple different tissues. They exist within the muscle, they exist within the liver, they exist within the fat cells, and you’re going to get a very different response depending on which ones you’re activating and deactivating. For example, we don’t want to turn off mTORC1 in the muscle. That would lead to muscle wasting. In fact, we want that one turned up as much as possible. But we do want fat and liver to have mTORC1 turned down but not so much mTORC2. What looks like happens when you give somebody rapamycin, it looks like initially you just inhibit globally mTORC1 and then ultimately mTORC2, and that’s where you actually get a lot of the unwanted side effects like insulin resistance and things like that.

Chris Kresser: Yeah. Well, let’s get back to your framework because there are a couple of things that really struck me about it. So far we’ve talked about changing the question from how can you live longer to basically how do you die later.

Peter Attia, MD: Exactly.

Chris Kresser: And more specifically, how do you delay the death from chronic disease, because that’s what we’re dying of. Maybe 30,000 years ago we were dying from trauma, warfare, exposure to the elements, more acute disease, but now that’s not typically what we’re dying from in the First World. We’re dying from chronic diseases, and these are, almost without exception, preventable—or delayable, at the very least, I should say—diseases. So let’s talk a little bit more about your framework. How do we delay these diseases? We can’t change our genes. Maybe these genes will become targets for drug therapies in the future, but for now, what is the option for people who don’t have access to rapamycin, which is pretty much everyone, right?

Peter Attia, MD: Right.

Chris Kresser: So what can we do?

Peter Attia, MD: I like the way you said that. I think you summarized that very cleanly. Let’s take a look at the numbers again. You have to draw a line in the sand somewhere when you look at actuarial tables, like what age group you are interested in and how you want to simplify your dataset, because that’s sort of what data management is all about. So here are the simplifications I’ll take. I’m going to limit this to people over about 40, because if you really want to talk about longevity in infants, it’s actually a different story. We have work to do there, but that’s not the problem I’m going to try to solve.

Chris Kresser: Yeah.

Peter Attia, MD: If we talk about people being over 40, I’m going to make two other stipulations. One is you’re a nonsmoker. I guess I wouldn’t be allowed to have my medical license if I didn’t put in at least one plug for that. If you’re listening to this and you’re still smoking, that might be the single most impactful thing—

Chris Kresser: Turn off the show and spend that time figuring out how to quit smoking, right?!

Peter Attia, MD: I know it’s hard to do, but it moves the needle. But let’s just assume that we’re dealing with a population that’s over 40 that does not smoke, and the third stipulation I’m going to make is not going to commit suicide. Again, all of those are difficult assumptions. Suicide is actually a leading cause of death. It’s a top-10 cause of death in, I believe, every age bracket of teenager and above.

Chris Kresser: Yeah.

Peter Attia, MD: OK, so if you do that simplification to the dataset, you realize that 70 to 80 percent of all deaths will be due to four diseases or what I really think of as three disease processes. It’s a better way to think about it. The first is atherogenic diseases, which obviously includes heart disease and cerebrovascular disease. The second is neoplasm, cancer, and the third is neurodegenerative disease of which two particular diseases make it into the top 10—Alzheimer’s disease and Parkinson’s disease.

Chris Kresser: Yeah, all of which are on the rise, huh?

Peter Attia, MD: That’s correct, and probably none more on the rise than Alzheimer’s disease. Heart disease is actually on the decline. Cancer, more or less, for the purpose of argument, has pretty much flatlined, and neurodegenerative, especially Alzheimer’s, is on the uptick. Again, we could probably spend an entire podcast debating the nuances of how much of that is diagnostic bias and things like that. I’m sure there is some diagnostic bias, but I would always share with people who push back on that that it’s all diagnostic bias. The annual rate of increase in lifespan in the United States for the past 50 years is 0.6 percent per year, and during that same period of time, the annual average increase in the incidence of Alzheimer’s disease is 2.6 percent per year.

Chris Kresser: Right.

Peter Attia, MD: It’s very hard for me to explain a delta that wide purely as a diagnostic one.

Chris Kresser: Well, there’s another thing, too, and this is purely subjective, but I think Alzheimer’s, as a way of dying, is more terrifying than just about any other way of dying, both for the person who gets it and their family members. I mean, none of these are any picnic, but there’s something uniquely scary about Alzheimer’s, I think, at least when I talk to patients. When I see what people are concerned about, that’s pretty high on the list.

Peter Attia, MD: Oh, I would echo that completely.

Chris Kresser: It’s a devastating condition in so many different ways. Yeah, anything that we can do that’s going to halt the rise and prevalence of that—and, of course, all of these other conditions—is absolutely crucial.

So here we are. We have these four major causes or triad of disease processes that 70 to 80 percent of people over 40 who don’t smoke and are not going to commit suicide die of.

Peter Attia, MD: So if you want to live longer, you have to figure out a way to delay the onset of those things.

Chris Kresser: Yeah.

Peter Attia, MD: And as far as the other 20 percent goes, there’s obviously a hodgepodge of diseases in there, but far and away the largest is what’s referred to by the CDC as accidental death.

Chris Kresser: Yeah. Texting while driving.

Peter Attia, MD: Well, there you go. Again, we’re going to do a breakdown on accidental death. Accidental death overall is the fifth leading cause of death, and 80 percent of all accidental deaths—and that’s an enormously long list—but 80 percent of them are just three types, which are motor vehicle accident, accidental poisoning, and fall.

Chris Kresser: Right.

Peter Attia, MD: Then we double click on all of those things. Within automotive, half of those, or actually 55 percent, are on freeways, and of the 45 percent that are not, three-quarters of them are at intersections. So then we double click on what are the steps you want to take to mitigate death at an intersection, and then on the freeway, what do you want to do. It’s very simple stuff. We don’t text while we drive. We don’t drive with any alcohol in our system, not just below the legal limit. We assume that everybody on the road is trying to kill us. It sounds sort of crazy, but the reality of it is, especially in Southern California, this is literally the worst collection of drivers ever.

Chris Kresser: The Bay Area is a pretty close second.

Peter Attia, MD: And then what are the steps you can take? I mean, it depends on how much you want to geek out on this stuff, but you can double click and triple click on each of these things, and you can start to deconstruct what this looks like.

Again, I really feel like it’s important when I talk about this to make sure everybody understands what I’m saying, which is not that there’s some magic way to prevent death. There isn’t. It’s just a probabilistic game. It’s the difference between playing Russian roulette with one bullet in the chamber of a six-chamber versus five.

Chris Kresser: Yeah.

Peter Attia, MD: Those are very different games.

Chris Kresser: I know when I talked to you about this before a little bit you had said something about if you’re going to work with a patient and he or she is still texting while they’re driving, that’s like… I mean, what percentage are we talking about here? If 20 percent are accidents…

Peter Attia, MD: Yeah, it’s a good question. I don’t think we know the answer because we can’t get an honest assessment of how many people are texting and driving, although I’ve read estimates that are based on survey data that suggest 80 percent of people admit to at least occasionally checking or sending a text message while driving.

Chris Kresser: It’s like self-reported food intake, diet and nutrition studies.

Peter Attia, MD: Yeah.

Chris Kresser: But anyway, it’s significant.

Peter Attia, MD: Yes.

Chris Kresser: So if you want to make one change that could significantly reduce your risk of death without touching diet or anything else, it’s not texting while driving.

Peter Attia, MD: Yeah, if you don’t talk about any of the lifestyle factors, I would say complete attentiveness to driving—if you live in a driving-centered place.

Chris Kresser: Right.

Peter Attia, MD: My practice is in New York and San Diego. In New York, it’s actually very different instruction because most people in New York don’t ever drive.

Chris Kresser: Exactly.

Peter Attia, MD: In New York, it’s actually much more attentive—

Chris Kresser: It’s watching out for other drivers, right?

Peter Attia, MD: Actually it’s your behavior at intersections.

Chris Kresser: Yeah.

Peter Attia, MD: It’s do you have headphones on when you’re walking through the streets? Are you jaywalking? Are you standing on the side of the curb, looking the wrong way when a car is passing you, and the mirror clips you? It’s that sort of stuff.

Chris Kresser: Yeah.

Peter Attia, MD: So back to the chronic diseases, is there a commonality? Is there anything common to neurodegenerative disease, neoplasm, and atherosclerosis? And the answer is, sort of. They’re obviously quite different diseases, but they’re all diseases of civilization, which is not to say that even our ancestors wouldn’t have gotten these diseases if they weren’t dying in war or of infections, but there’s something about the flavor of them that we’re getting that appears a little bit more related to our civilization than maybe it would have our ancestors.

Again, everything I’ve said today is largely just factual, and now we’re sort of getting into what’s the leap, what’s the speculation. My speculation is twofold. One is there are sort of overarching themes that matter, and then there are nuances that we can plug in. The overarching theme is this. We go back to what we know about rapamycin and caloric restriction, and we ask, what is it doing? Now, caloric restriction, most people today in this space, the super-in-the-weeds people on this topic that I’ve spoke with at length, do not believe caloric restriction actually enhances survival in the wild.

Chris Kresser: Mm-hmm.

Peter Attia, MD: Nobody disputes that for most species it enhances survival in the laboratory, but once you get into the wild, you’re basically trading one type of mortality for another, so for the sake of argument, let’s just assume that that’s true. What can we learn about it in the laboratory, and what can we learn from the rapa experiments in the laboratory? What it appears to tell us is that a signalling environment that does the following is good: one in which insulin is very low, one in which IGF is low, one in which mTORC1 is low, one in which AMP kinase is high, and one in which Ras is low, if you really wanted to be specific. If we were at the candy store and we could have anything, that’s kind of the environment you’re favoring for someone over 40—not the environment I want for my 18-month-old little guy. He’s in growth mode. But for an old geezer like me, that’s a pretty good environment, especially if I can target that to a certain set of cells because I don’t actually want that in my muscles, but I would like that in my liver and I would like that in my adipose tissue.

So how do I control that? Well, I can control that by eating a certain way. I can control that by exercising a certain way, sleeping a certain way, managing stress a certain way, using a bunch of hormones or not using them, and using a bunch of drugs. That’s your toolkit, basically.

Chris Kresser: Yeah.

Peter Attia, MD: On the nutrition front—and I don’t like talking about nutrition much, which is ironic, given my former job, because I’m not a big fan of religion and I’m not a big fan of politics, and nutrition is kind of like that. I don’t really care about diet. None of that stuff interests me. I don’t care if you’re paleo, I don’t care if you’re vegan, I don’t care if you like South Beach or Atkins or Ornish. None of that stuff interests me. I’m really just interested in the biochemistry of these molecules, and given that different people can tolerate these molecules in different fractions, the name of the game is glucose disposal. Can you maintain a low average level of glucose and a low variance of glucose and a low area under the curve of insulin? Those are really the things I care about. Now the challenge is it’s not easy to measure those things. For me, it’s very easy because I wear a continuous glucose monitor.

Chris Kresser: I didn’t know you were doing that.

Peter Attia, MD: Yes, I’ve been wearing a continuous glucose monitor for several months now, actually. These are devices that are typically worn by patients with type 1 diabetes, but I think for my interest it’s a totally reasonable thing to do. Every day I just have it spit out my 24-hour average of glucose plus a standard deviation, and I now know sort of what’s my sweet spot. I like to have a 24-hour average of between 91 and 93 mg/dL with a standard deviation less than 10. We can’t measure insulin in real time. To me, the holy grail would be to have an AUC, area under the curve, of insulin, but this becomes a pretty good proxy. It also gives me tremendous insight into non-dietary impacts on that.

Chris Kresser: Sure.

Peter Attia, MD: Primarily stress, sleep, and exercise.

Chris Kresser: I was just going to ask you what you’ve learned that would be, not unexpected, but not sort of the most expected finding.

Peter Attia, MD: There are two things, actually, that stand out. The first is the impact of stress on glucose.

Chris Kresser: Yeah.

Peter Attia, MD: A couple of months ago, I was going through something pretty stressful, and my evening—meaning from the time I went to bed until the time I woke up, obviously not eating—my glucose readings were at their absolutely highest.

Chris Kresser: Yeah, cortisol isn’t called a glucocorticoid for nothing.

Peter Attia, MD: That’s right! What was interesting to me is it was very easy for me to predict, before looking at the glucose meter in the morning, how high my glucose was that night, based on not just the quality or lack thereof of my sleep, but also just the amount of sort of ruminating that I was doing during my sleep. Of course, I found that it was actually pretty easy to temper that by using phosphatidylserine before bed to suppress adrenal output and therefore bring glucose down.

Chris Kresser: Right.

Peter Attia, MD: That was one super-interesting finding. Then, of course, it made me think about all of my patients who are, by definition, all going through their own really stressful things and how much stress can undo all the great things we do during the daytime.

Chris Kresser: I’m so glad we’re talking about this because I’ve been kind of on a tear for the last month or so, talking about this, because I just moved my house and office. I discovered a mold problem. It’s been an incredibly stressful time, and I’ve just watched my health unravel in front of my eyes. And I didn’t make any changes in anything else. It was a really as kind of controlled experiment as I could do in a sort of wild-type environment. Then I started to dive into the research literature and look at all of the mechanisms by which the sympathetic nervous system and the HPA axis regulate things like glucose disposal and insulin sensitivity and metabolic function in a number of different ways. I really do think it’s the elephant in the room that’s just often either not talked about at all or just given lip service. I find it really hard to get anyone to pay any attention to it.

Peter Attia, MD: I agree with that completely, by the way, and, yes, you’re absolutely correct. When you start to look at the HPA component of it, which is going to be the glucocorticoid pathway, and then the sympathetic component through the epi/norepi pathway, they’re both basically doing the same thing. One is more chronic, one is more acute, and they serve a remarkable purpose when that’s what we need, but—this is my personal belief—we just didn’t evolve in an environment where this level of chronic stimulation was what to be expected, and I just think we’re in a failure state.

Chris Kresser: Yeah.

Peter Attia, MD: For me, when I think about the sort of eight levers that I put in terms of longevity, the six I mentioned a moment ago—nutrition, sleep, etc.—and then two others, one that we’ve talked about and one that we haven’t, the one where I most consistently feel challenged is on managing my own stress.

Chris Kresser: Yeah. I’m right there. I love this concept of allostatic load. Bruce McEwen developed this years back, and it’s the metabolic cost of maintaining homeostasis. What is the price we pay for the body having to work to respond to these repeated stressors? I would say the number-one price is this decline in metabolic function or inability to continue to be able to process glucose effectively.

Peter Attia, MD: Yeah, and actually I want to just jump on that before I come back to this other topic about the research on stress. To that point, I would even go one step further than the allostatic load, and I typically use this analogy with my patients, who all know that I’m obsessed with race cars, and of course, they always throw back at me, well, how can that be good for your longevity?

Chris Kresser: Right!

Peter Attia, MD: What they don’t understand is I’m at greater risk driving to the racetrack than I am being in the race car on the racetrack, but that’s another story.

I just had this discussion with a patient last Friday, actually. We’re sitting in his office and looking out over Park Avenue—this was in New York, obviously—and I said, “Look out the window. You see all those cars there? You have that Ford Taurus there, you have that Honda Accord, you have that 3 Series BMW. Do you think that for any of those cars right now the PSI in each tire is exactly to spec, 32.5 PSI or whatever the number is? No, of course not. What’s the chance that some of the cars out there are 400 or 500 miles past due on their oil change? Half of them, right? But yet they’re all fine. They’re all getting away with it. Why? Then contrast that with, let’s go to watch a Formula One Grand Prix. Do you think one of those cars out there is literally half a PSI out of whack on their tire?”

Chris Kresser: Nope.

Peter Attia, MD: Nothing. So what’s the difference? The difference is tolerance and what capacity the vehicle is within its technical limit. When you’re out there driving, commuting, doing whatever the heck you’re doing, you’re nowhere near the technical specification of the car, and as such, the car is incredibly forgiving.

Chris Kresser: Right.

Peter Attia, MD: But when you push that vehicle to its technical limit, the forgiveness goes away in a second. In many parts, I think that’s why I love racing. I love knowing what it’s like to be in a car at its limit and then see if I can put me at my limit and then see how long those two things can stay on that edge. But the lesson for us, and I don’t say this to sort of diminish the work that has gone into understanding Blue Zones and things like that, but it’s very important to understand that, at least for my patients, none of them live in Blue Zones. So while I think that there’s a lot of interesting stuff that can be learned from how we could live longer if we had the fortune of being around our elders 24/7 and we could sleep nine hours a night and we could hunt our own food and do all these things, whatever the situation is, what if you don’t have the luxury? What if you work two jobs? What if you’re running a hedge fund that’s collapsing? What if two of your kids are having this problem and the stress of that is killing you? Right? You can only be as happy as your least happy child, as the saying goes.

Chris Kresser: Yeah.

Peter Attia, MD: And so, to me, the analogy is you’re now on a racetrack. You gave up the luxury of not worrying about when your oil gets changed and not worrying about the PSI in your tires. This is like allostatic load and then some.

Chris Kresser: Yeah.

Peter Attia, MD: It’s not just the price, the wear and tear on the body. It’s now the alpha that’s necessary, the performance alpha that’s necessary to survive under a brutal amount of stress.

Speaking of stress, coming back to this, the area, Chris, where there is more research on this than I could have ever imagined if I hadn’t looked into a year ago, is in the area of transcendental meditation.

Chris Kresser: Yeah. Tons. Tons of research.

Peter Attia, MD: Unbelievable.

Chris Kresser: Yeah, all the way back to the ‘70s.

Peter Attia, MD: Yeah. My only guess is that Maharishi… some people assume it’s sort of like a cult-like thing and are very dismissive, but if you actually go back and look at the clinical trials, which I’ve done in pretty close detail, and I’m talking better trials than nutrition, Chris. Literally, better trials than we see in human nutrition. I realize that’s a low bar, but nevertheless. You can never eliminate performance bias. That’s the biggest challenge. And obviously trials aren’t blinded, but they’ve done pretty good things to actually identify the effect of TM versus even just sort of quiet resting. The effects on blood pressure, on cortisol, on glucose, on metabolic factors—I think it’s real.

Chris Kresser: It’s remarkable. Yeah, I’ve seen all that research myself, and I’ve just experienced it myself as well, numerous times. I’ve talked about this before, but my dad actually introduced me to meditation, to TM, when I was 16. It’s probably one of the most amazing gifts I’ve received, of many gifts from my father. I haven’t been doing TM for 25 years, because I’ve moved on to a different technique, but one of the things that happened in my move was—and this is rare in 25 years—I stopped sitting consistently. After two or three weeks of not doing that, I really felt it in an acute way. It has almost been such a part of my routine that it took me a moment to even realize what was going on. I was, oh, yeah, that’s right. I’m not sitting regularly. And I started again, and I watched just everything change again.

Peter Attia, MD: Interesting.

Chris Kresser: My sleep, my attitude, my mood, my exercise recovery, my mental and cognitive performance, my digestion. There’s no single intervention that I’m aware of that can have an effect over so many different parameters in my life, and I’ve learned that time and time again, so the research doesn’t surprise me at all.

Peter Attia, MD: Yeah. One of the things I do want all of my patients doing—and some of them are resistant to it, and I think they have to come to it in their own time—but I do “prescribe,” for lack of a better word, transcendental meditation to all my patients, especially the phenotype that’s sort of like me that probably needs it the most.

Chris Kresser: Right. Yeah. OK, so we went off on a stress management tangent, which is a very good tangent to go off on. I’m beating this drum a lot, but I think it’s a drum that needs to be beaten—perhaps to death!—but let’s talk about some of these other levers that you have identified.

Peter Attia, MD: Right, so rounding out the nutrition one, you want to consume basically as much glucose as you can tolerate before you start to get out of that homeostasis that I’ve talked about. Again, I’m not really going to get into more details because it takes too long, but for me there’s a different number than there is for you, than there is for the next person, and you have to find what the level is.

Then on the protein side, I think the IGF protein data are interesting. I still don’t know that they’re entirely conclusive, but I would say this. You’re probably better off with excess fat in your diet than excess protein in your diet.

Chris Kresser: Especially lean protein, right? Where you’re eating really methionine-rich food?

Peter Attia, MD: Right. That’s right. It’s interesting you bring up methionine because when you start to think about which amino acids are probably driving up IGF the most, it’s actually probably methionine.

Chris Kresser: Yeah, which is why we’re always telling people to eat nose to tail.

Peter Attia, MD: That’s right.

Chris Kresser: If you’re going to eat animal foods, you eat all the odd bits, not just the boneless, skinless chicken breasts and the egg whites.

Peter Attia, MD: Well, not only that, but I think there’s pretty reasonable evidence when you look at the carnivorous societies that they actually preferenced that meat.

Chris Kresser: Absolutely.

Peter Attia, MD: They were actually feeding the muscle to their animals.

Chris Kresser: The dogs.

Peter Attia, MD: That’s right. They were themselves consuming the organ meats.

Chris Kresser: Yeah.

Peter Attia, MD: So basically what I’m telling my patients is really you only need as much protein as is necessary to preserve muscle mass. That’s sort of the goal. The goal is muscle mass. That’s the name of the game. So when we’re seeing nitrogen balance as positive, we’re overdoing it. You can see now you have a sliding scale, which is carbohydrate goes up until you hit your glucose and insulin ceiling, protein comes down until you’re about to erode into muscle mass and slip into positive nitrogen balance, and then fat becomes the delta. So in somebody like me, that’s probably about a 20 percent carb, 20 percent protein, 60 percent fat diet. We’ve talked about this before. Obviously I’ve done everything from vegan to full ketogenic. I mean, I’ve sort of experimented with the entire spectrum of religions, but nevertheless, that’s the framework.

On exercise, the framework is one around glucose disposal and maintaining muscle mass. Today I was at the gym with a good friend of mine, and he was telling me about this new bike he just got. He just got this brand-new road bike this week, and he was telling me about it, but it was in the middle of a set, so I said, “Hey, man, do you mind if I just do this set, and we’ll finish the story afterwards?” He goes, “No problem.” So I go back over to my hex bar where I have more than 350 pounds on it, and I do my deadlifts with it. And it looks painful. Let me just call a spade a spade. There’s nothing sort of smokin’ and jokin’ about doing heavy deadlifts.

Chris Kresser: Yeah.

Peter Attia, MD: And he looks at me after, and he goes, “Why the hell are you doing that?!” He’s like, “Is that really necessary?! You bike, you swim, you run. I mean, what is that possibly doing for you that those other things don’t do?” And I said, “Well, actually it is doing something for me that those other things don’t do. Those other things don’t activate my IIB muscle fibers, and that’s something I’m placing a high premium on.” It’s very hard to activate the type IIB fiber, and yet if I can get all of those fibers working—type I, IIA, IIAB, and IIB—I’m going to have a much more glucose-hungry muscle, I’m going to have much more mitochondrial activity, and frankly I think squats and deadlifts are the two most important exercises.

Going back to your point about sitting, we are all born knowing how to squat perfectly.

Chris Kresser: Right.

Peter Attia, MD: When I look at my son, who is a year and a half, he squats like it’s his job. It’s incredible to watch him pick things up with perfect biometrics.

Chris Kresser: Yeah.

Peter Attia, MD: Then I look at my daughter. She’s seven and a half. She used to be able to do that, and now even though she’s flexible—she does gymnastics and all these other things—she’s actually lost the perfection in her squatting mechanism. I’m actually convinced it’s the moment we start sitting that we lose this hip flexibility necessary to perfectly squat.

Chris Kresser: Yeah.

Peter Attia, MD: The good news is you can get it back. With a lot of conscious effort, you can actually learn those movements again, but I do think that those hip hinge movements are so important, one, for biomechanics and sort of back health and longevity, and also because there are no two exercises that I think really allow us to stress the body as maximally as that, as safely as that, if they’re done correctly, so that we can sort of maintain this idea of these very hungry muscles.

Chris Kresser: Yeah. That makes sense. All right, so that’s the diet and exercise framework.

Peter Attia, MD: We’ve talked about stress already.

Chris Kresser: Yeah.

Peter Attia, MD: Then we have sleep.

Chris Kresser: Yeah.

Peter Attia, MD: I could probably spend all day talking about sleep. I don’t know if you’ve had Kirk Parsley on your show.

Chris Kresser: Not yet. He’s on the list!

Peter Attia, MD: Well, I don’t need to steal Kirk’s thunder. Kirk will tell you everything you need to know about sleep, but maybe the really quick version is that if you want to take an animal, including a human, and make it insulin resistant, all you have to do is sleep deprive it. All things equal, just sleep deprive it.

Chris Kresser: Yeah.

Peter Attia, MD: And it doesn’t have to be exceptional. There was a study done at the University of Chicago that took a group of subjects and for 14 days restricted them down to four hours a night. They used euglycemic insulin clamps, so this is the gold standard for measuring insulin resistance, and in that 14-day period, they’re insulin sensitivity deteriorated by 50 percent.

Chris Kresser: Right.

Peter Attia, MD: In 14 days at four hours a night. When I think about my residency, for five years I slept four hours a night on average. I probably averaged 26 to 28 hours of sleep a week for five years, so maybe it’s not so surprising how insulin resistant i was at the end of that period in my life.

Part of it is quality, part of it is quantity, so we work on basically a handful of sleep hygiene things. Keeping the room completely dark, keeping the room really cold, not looking at blue light after a certain period of time. If we do need to look at light, using apps that basically can pull the blue light out. And then, of course, the entire spectrum of agents that you can take to aid in sleep. We measure melatonin levels in the urine overnight and deem whether melatonin makes sense. Direct activation of GABA, and then I talked a little bit earlier about phosphatidylserine. Whenever we sort of see a certain cortisol pattern, we obviously want to inhibit that level of cortisol in the evening. Vitamin D probably makes sense in the evenings along with magnesium, provided you have a magnesium transporter like L-threonate to get into the CNS.

It turns out sleep is pretty easy to fix once the patient buys into why they need to fix it, and actually I find, frankly, that’s probably the biggest challenge.

Chris Kresser: Absolutely. The same with stress management, right?

Peter Attia, MD: Yeah.

Chris Kresser: We have a few more minutes. What we haven’t talked about yet are hormone optimization, pharmacotherapy, although we did talk a little bit about that in some context, avoiding harmful behaviors, all of which we could probably spend an entire podcast on, but here’s another kind of less tangible one that tends to get short shrift, which is a sense of purpose and social support. I have chapters on those in my book, actually, because I think they’re so important. There’s this fascinating study—you’ve probably seen it—that showed that social support is a better predictor of lifespan than body mass index, air pollution, and even smoking 15 cigarettes a day.

Peter Attia, MD: Yeah.

Chris Kresser: I’ll send it to you if you haven’t seen it, but it’s just amazing. This idea that we work until we’re 65 and then we sit on a lawnchair, what’s wrong with that?

Peter Attia, MD: It’s funny. I had lunch with one of my best friends today, and we were just talking about something completely unrelated, but I hadn’t seen him in a couple of months, and I asked him how his dad was doing. His dad is pretty young. He’s 73. And he said, “Yeah, he’s just not doing well. I’m kind of worried about him, his balance.” And I was like, geez, for 73, that’s a lot of stuff going wrong. His dad used to be just the most successful lawyer ever, a really big-deal guy. And I said, “When did your dad retire?” And he was like, “You know, 10 years ago.” And I said, “But what does he do now?”

Chris Kresser: Yeah.

Peter Attia, MD: He said, “Nothing. He sometimes plays golf.” We sort of looked at each other, and I didn’t need to say any more. It was pretty obvious what the problem is.

Yeah, there’s something to be said, I think, for not retiring from life. You can retire from career X or job X and even be completely financially free of the need for money, but I think the epidemiologic evidence is stronger in favor of this than it is on anything that we talk about epidemiology for. I acknowledge that we will not be able to do a prospective experiment on those who retire versus those who don’t and draw a meaningful causal conclusion, but we are really happy to talk about hazard ratios of 1.15 when it comes to goofy things like red meat, and yet when you look at the hazard ratios associated with retiring and not retiring, they’re more. So if I’m going to put my faith in epidemiology, it’s actually going to be more around this sense of purpose and social support.

Chris Kresser: Yeah. I’m a big believer in that. I mean, look. If you talk about sleep, stress management, and social support, making changes in those areas requires a shift in how we relate to ourselves, how we relate to the world around us, and how we act and behave. You can take different pills without changing any of that, and even though when you make dietary changes you do sometimes have to make some changes in how you live that are not insignificant, you still aren’t fundamentally changing the way you relate to the world around you, necessarily. But when you start talking about changing your sleep, changing how you manage stress, and then social support and sense of purpose and meaning, those are, frankly, harder changes to make, and that’s even if people buy into the necessity of making them, which is the first hurdle to get over.

Peter Attia, MD: Yeah, what I typically explain to patients is with each of those eight levers, I divide each one into efficacy and effectiveness. Efficacy is, what’s the right intervention? Then effectiveness is, how do you make it stick? And I walk through each one with each patient and say, “Here’s, on average, what the experience looks like, and then for you we’re going to handicap it.”

For example, when it comes to nutrition, they’re both hard. Maybe it’s just that I’m stupid and I don’t know how to do it yet, but I find I can’t, out of the gate, just look at a person and figure out what they should be eating. It actually requires an iteration or two or three. So I say the efficacy is quite challenging. It just takes a while to get it totally dialed in. Now, sometimes it doesn’t. It depends on the person coming in, and maybe for another time we can talk about the nuances there, but I say it’s the effectiveness that tends to be harder. How do you put it into place, day in and day out, by changing your food environment? That becomes harder.

And then, of course, I noticed that there are some individuals I meet for whom effectiveness becomes trivial there. They’re completely unemotional about their food, and they just need to know what to eat.

Chris Kresser: Yeah.

Peter Attia, MD: Then exercise is the same sort of thing, but once you get into sleep and stress management, the efficacy is actually very easy. Knowing what to do is quite trivial. Doing it is hard.

Chris Kresser: Yeah. And sticking with it.

Peter Attia, MD: That’s right. On the hormone and the drug side, it’s the opposite. The efficacy is very hard. It’s really hard, if you’re going to be nuanced about this, to get the perfectly right answer and to get the perfectly right optimization. But once you have it figured out, it’s actually trivial for the patient.

Chris Kresser: Yeah. I would agree with that.

Peter Attia, MD: Anyway, I think, through that lens, the patient realizes they’re sort of on a journey with you and that you each have your own challenges, but being able to confront them and acknowledge them makes them a lot easier than just sort of acting like, “Oh, you should be able to do all of this, no problem.”

Chris Kresser: Mm-hmm. That makes sense. Pete, it’s such a pleasure to have you on the show. I feel like we could just go on and on. I always enjoy our conversations, and I hope we can cross paths sometime in the near future.

Peter Attia, MD: Sounds great, Chris. This was a lot of fun.

Chris Kresser: All right. Take care.

Peter Attia, MD: Bye.

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