The impact of stress on our physical and emotional health | Robert Sapolsky, Ph.D. (#51 rebroadcast)

Hey everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode, I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay, here's today's episode. Welcome to another special episode of the Drive. For this week's episode, we're going to rebroadcast my conversation with Robert Sapolsky, going to we're, which was originally released back in April of 2019 about four years ago. Many of you may recognize that name because Robert has written some incredible books, including the very popular why Zebras Don't Get A Guide to Stress, Stress Related Disease, and Coping. I had first seen Robert speak about a year and a half prior to my interview with him, and I remember thinking during his talk, this is the first time I'm really being convinced of the true pathology of stress. You know, I think prior to that I'd always heard the old adage that stress could kill you, but I kind of dismissed it as yeah, yeah, yeah. And we used to think that stress caused ulcers, but then we found out it was H. Pylori, et cetera, et cetera. But the way Robert spoke about it, I really began to pay more attention to it, which of course led to me reading up on this more. And at that point I just decided I needed to meet Robert. Robert's work in particular, his presentation that day, got me to think about the molecular and physiologic harm of hypercorticolemia. In particular, in my conversation with Robert, we spoke a great deal about that, but we also talked about things outside of that. We talked about the role of depression, what the impact is of stress on the developing brain, and also on the brain later in life, and even on areas where the relationship between stress and disease is not that well understood yet. That clearly came across in our discussion of cancer. Robert is a professor of biology, of neurobiology, and of neurosurgery at Stanford. He's also a MacArthur Fellow. In 1987 he was awarded the fellowship which some of you may recognize by its other name, the genius grant, something I consider very appropriate for a man of Robert's talents. Overall, I found this discussion riveting, and I hope to speak with Robert again. But for now, I hope you'll enjoy revisiting this discussion as much as I did. So without further delay, please enjoy or re. Enjoy my conversation with the wonderful Robert Sapolsky. Robert, thank you so much for making the time to meet with me today on a lovely rainy San Francisco afternoon.

Sure. Glad to be indoors here.

As I was saying earlier, we had met once before, really briefly. So briefly that you would not remember it. And, of course, only I would. Summer of 17, I believe you were giving a talk in Sun Valley, and I was there, and you gave a talk on stress. Now, it was to a lay audience, so you didn't really get to go into the depth. And I remember sitting in the audience thinking, oh, you know, a lot of what he's saying is really starting to make sense to me. And I can't wait to get a little deeper into this stuff because truthfully, and I'm just going to open with sort of my mea culpa. You've always heard people say stress kills. And I got to be honest with you, I always thought that was sort of nonsense. I was like, come on, what do you mean stress kills? Stress is good. It builds resilience. Blah, blah, blah, blah. What is the mechanism by which stress, quote, unquote, kills? But of course, once you start to understand the endocrine system and of course, training as a surgeon and not an endocrinologist, I sort of missed out on that. You start to see it. And in that talk, you admittedly, at a sort of high level for the audience, really walked through the danger of hypercorticolemia. And so in many ways, I guess, you know, a year and a half ago is really when I became a fan of your work and then kind of said, you know what? There is something to this. So anyway, with that, I appreciate you taking this time. Sure.

And just to sort of back off a bit from that, I actually don't think stress kills you outright very often. Often. But it sure makes other things that kill you more effective at doing it.

Maybe it's semantic, but you're right. Stress can amplify and accelerate the diseases of aging. You grew up in New York, right? If I recall, you grew up in Brooklyn or in Brooklyn. I remember reading that after college, you actually went straight off to Kenya first. Is that right?

Yep.

What prompted that?

Well, I was one of those, I've sort of spent my career oscillating between being a lab neuroscientist, studying the effects of cortisol on the brain. Punchline to decades of work is you don't want to have a whole lot of it marinating inside your head. But also for more than 30 years, I've alternated spending my summers studying a population of wild baboons in a national park in East Africa. And it's the same animals I go back to each year. These are animals I can dart, anesthetize, get blood, do whole workups on them, and essentially asking among them, what, what does your social rank have to do with patterns of stress related disease? What does your personality, what does your patterns of social affiliation? So it's been sort of a counterbalance to the lab where, you know, we've been sticking artificial genes into neurons and fairly reductive stuff like that. So I was actually about 8 years old when I decided I wanted to be a primatologist. So I was kind of planning on that for a long time. And lucked out, I spent all of college brown nosing the right person who shipped me off to a field site right after graduation. And I wound up sort of inheriting that site. And those have been my, my baboons ever since.

Did you spend the whole time in Kenya? I remember reading that you also were in Uganda. And obviously they're, I think if my geography is correct, they're neighbors, so that's a pretty easy switch. Where do the actual baboons, like, what is their scope of their residence, how broadly?

Oh, they're spread actually all over Africa. They're one of the most ubiquit primates for a lot of the same reasons that we are, which is they'll eat anything. They're carnivores, but they're also herbivores, they're omnivores, they scavenge dead stuff, they eat insects, they'll eat most anything. So they can fill a lot of niches. So they're scattered everywhere. But my main work over the years has been this one troop in the Serengeti and southwest Kenya. You know, for about 25 years I camped under the same tree. So it's really has been continuity with the same population of animals.

What is their natural predator besides man, Leopards, lions, hyenas.

Nonetheless, if you're a male baboon, the most likely thing to kill you violently is another male.

Another male?

Yeah, exactly.

Sort of like humans.

Yes, indeed.

Did you say it's every summer or every Other summer?

Well, it was initially for about 25 straight summers and then parenthood and all those complications came in, so wound up being every other summer. And then our kids were old enough to go with us one summer. But unfortunately the field work ended about eight years ago.

So why is that?

My Kenyan field Assistant of 30 years, we started together when we were 20. He died of AIDS. Political issues there, some game park issues that made it harder and harder to sort of get research done and kind of that middle aged realization that I could find some new game park or new country or something and start all over, but it was kind of time to pack it in instead.

So after you did your PhD, which you did it in New York, right?

Yeah, Rockefeller University.

Did you come straight out to Stanford for a postdoc or.

Postdoc to the Salk Institute down in San Diego, Spent a couple of years there. If people are sort of familiar with the hypothalamic hormone that runs the stress response or hormone crh. Crf, Corticotropin releasing hormone. I went and postdoc with this guy Wiley Vale, who had discovered it like two years before. So that was a pretty exciting time to be there. So spent a couple of years there. Stanford hired me and I've been there for 31 years since.

That's kind of amazing. I keep coming back to people at Stanford that, you know, would have been there when I was there in medical school, but if it wasn't in the medical school, like you just weren't paying as close attention. And I honestly don't recall if you ever gave us a lecture in med school. Do you remember giving lectures in Med School 20 plus years ago?

I did. Almost certainly the students were paying as little attention as I was, so.

Because I was about to say it certainly seems like something we should have been learning in medical school and yet I feel ashamed to say I don't know if I recall it.

It was not much of an emphasis and was sort of snuck in embarrassedly.

Like a lunchtime seminar or something.

Yeah, exactly.

Thrived them with free food.

Yes. And even still only about five people would stay past the cookies.

That's a much bigger issue we can come to. So you wrote a book, Gosh, how many years ago was why Zebras Don't get ulcers? Is that 20 years ago?

Let's see, first edition was 94. It's gone through three editions now. Most recent one was 2004. So at some point I got to do another one.

As we talk about that and you've written A book more recently that I want to talk about as well. Let's back up and explain something you touched on a second ago, which is sort of the physiology of a stress response. So walk us through the relationship between the hypothalamus, the pituitary and the adrenal glands.

So when we're under stress, levels of eleventy different hormones changing our body, most of them are relatively minor players. The two workhorses overwhelmingly. First one famously adrenaline. British term epinephrine, sort of North American term, output from the sympathetic nervous system. It's on the scene in your bloodstream within 12 seconds or so after all hell breaks loose.

And I just want to explain what sympathetic means to the listener. We've had this discussion before. It's not to say it's a nervous system that is kind, it just means it's one of the two branches of these so called autonomic or immediate, not under your conscious control. Right, so the fight or flight.

Exactly. And the other half being parasympathetic, sympathetic, fight or flight, all hell breaking loose, alarms going off, parasympathetic calm vegetative function. So not only do you turn on the sympathetic during stress, you very emphatically turn off the parasympathetic second main workhorse, which has already been alluded to. The steroid hormone class of hormones called glucocorticoids. Human versus version cortisol, also known as hydrocortisone, rat version corticosterone, synthetic versions, prednisone, dexamethasone and such. These come out of the adrenal glands. Your brain notes something stressful is happening. Within two seconds your hypothalamus is secreting that CRH, which within about 10 seconds is getting your pituitary to release a hormone called Acthe, which within about 30 seconds has gotten to your adrenals. And you are slowly starting the glucocorticoid component of your stress response. And in lots of ways the adrenaline, the sympathetic response, glucorticoid response, they work on hand in hand, they synergize. You want a metaphor? Adrenaline in two seconds is handing guns out of the gun locker to whatever's going happen to defend you. Glucocorticoids are building the aircraft carriers that a year from now are going to be essential. It does some of the slower components of the stress response stretching out over minutes to hours.

Because I was just about to ask you and I think your question basically answers it was why would we have evolved these two separate systems? One can only speculate on Such things. But it's basically that certainly norepinephrine, epinephrine, they stick around for such a short period of time. I mean, we don't even measure these things clinically. I can't poke your arm and measure your norepinephrine or epinephrine level. The best I can do is collect its metabolites in your urine for evidence that it's been around. So I guess we have this hormone or pair of hormones that are on the scene in seconds, gone in seconds, and really deal with the. I guess from an evolutionary perspective, when the tiger is there, this is what gets you to jump into the tree. Is it doing much beyond that? And is there some evidence of chronic low levels of those hormones which come out of a totally different part of the adrenal gland? I mean, that's the other thing that's sort of interesting is you have two separate pieces, the cortex, the medulla, that secrete these hormones separately and embryologically, they're.

Two very different tissues. They start off separately. It could have just as randomly wound up that your adrenaline comes from your big toe and glucorticoids from your thumbs. Why they wound up being in the same organ is, in fact, somewhat just.

I think, serendipitous, probably because you're more likely to have your toes and fingers lopped off, and we wouldn't want to have incidental adrenalectomies happening.

You're right. That's certainly why they didn't wind up out there in the extreme.

What about in lower species? Is one of these considered more primitive? Is the epinephrine arm, something that began earlier, and the cortisol arm more recent?

Yep. Nonetheless, the cortical arm is just ancient. When you get stressed and you're secreting glucorticoids, it's basically the exact same class of molecules as if you were a fish or bird or reptile. Nonetheless, it's very ancient wiring, and that's part of what winds up getting us in trouble. It's a system that's been serving vertebrates, doing a lot of help for them for an awful long time. And it's been a very recent modification to instead secrete them in response to thinking about taxes. This basic dichotomy between the very human domains where we activate the stress response and the more typical domains of animals.

So if you and I were sitting here 10,000 years ago, I can think of lots of things that we would want an adrenaline response for. You know, the tiger jumps out of the thing, whatever what are some of the things that would result in that cortisol response? Because, you know, you described it as building the aircraft carrier. Well, you know, gosh, if the tiger's there, either I'm dead or I'm not. But I don't need a stress response a day from now or the next day. So what is it that Cortisol was doing 10,000 years ago that was serving our interests? I want to certainly talk about what it's not doing today.

When you look at what it does, it actually makes perfect sense. As long as you're being stressed like a normal mammal running for your life, running after a meal where if you don't catch something, you're going to be dead by tomorrow. A short term physical crisis. The first five seconds of doing that, which epinephrine is critical for. That's great. If we're heading into a couple of minutes of evading a predator, being vigilant, thinking there might be. If you're getting into the realm of a couple of minutes worth of a stress response, cortisol related glucorticoid hormones are absolutely essential.

So the glucose that's coming rushing out of your liver, pretty important in that situation.

Exactly. So it takes you about one second to decide you're going to use your thigh muscles and run like mad. You need energy for them. And the main thing glucorticoids are doing in the metabolic realm is glucocorticoids. They're increasing glucose levels in your bloodstream. They're going to storage sites throughout your body, your liver, your muscle, and breaking stuff down. What they do is they go to the bank, they empty out your savings accounts and turn it into cash. Glucose in the bloodstream to hand to whichever muscles are going to save your neck. What they also do makes perfect sense whether you were running for your life or running for a meal, which is they increase cardiovascular tone and epinephrine is doing the first five seconds of it. By 30 seconds in glucocorticoids, you're bolstering it as well. And it's that same logic. You're running like crazy. You want to deliver that glucose to your thigh muscles as quickly as possible. You increase your heart rate, you increase your breathing rate, your blood pressure, you alter your vasculature. So you're preferentially shunting to the exercising muscle. So that makes perfect sense. Also turns out some of the most interesting stuff glucocorticoids do in those circumstances is basically run a triage program. They shut down everything that's not Essential, not essential to surviving the next five minutes of this massive physical challenge.

So digestion would be important.

Digestion, exactly. You got better things to do than digest breakfast when you're trying to avoid being somebody's lunch. And you're sure not going to get any metabolic benefits of digestion during those five minutes. It's slow, expensive. The energy you're getting, you're getting from your liver, you're getting from your fat cells. It shuts down growth. Obvious logic there. You know, grow antlers tomorrow, if you're still around, don't bother right now. Shuts off reproduction. Same logic there. It shuts off all the long term building projects and just focuses your energies on what's immediately there. And this makes perfect sense if you are running for your life, running after a meal. And all you need to do is look at a couple of diseases where people don't turn on the endocrine stress response. Addison's disease, shy Draker syndrome, whatever. These were not diseases where somebody who now is more at risk for adult onset diabetes eight months from now. These are diseases where somebody goes running after their commuter bus and they drop dead from hypoglycemic shock.

JFK had this. Didn't JFK have Addison's?

He had Addison's. And that greatly constrained the famed pictures of all those kinds of Kennedys playing touch football out in, you know, Martha's Vineyard or stuff were mostly for the benefit of the photographers.

How did he survive World War II? Because he had done some pretty heroic things in that war.

Although I've seen it's hard to tell if it's snarky revisionism as to how much that was public relations stuff afterward sort of orchestrated.

But just to get through basic training even strikes me as an accomplishment because most people, I guess, who don't have a medical background wouldn't appreciate this. But the tan that seemed to be eternally on JFK is the result of the Addison's disease because the hormone you alluded to earlier that is released by the pituitary ACTH in someone who's not making cortisol is gonna be very, very high. And ACTH stimulates the pigment producing cells in the skin. And that's what would give someone with Addison's disease darker skin.

The fascinating thing with Kennedy is if it were this situation now, presumably his doctors would be on the air somewhere 24 7. There's remarkably little known about when his onset was, what the course of it was, how severe it was. So it's not quite clear. But what little is Known is it had a hell of an impact on his functioning. You really do need a hormone if you like glucorticoids, if you were going to be physically activated in a moment of crisis.

This is sort of the amazing thing with hormones like insulin and cortisol. I'm always impressed by how tight the U shape is on those curves. Thyroid hormone would be another example, certainly less so with something like testosterone, you have just a much wider range that you can function in. And the benefit is largely monotonically increasing. Sometimes, if my patients will tolerate me going on and on about this, I love to draw the pictures of which of these hormones can you, you know, but to me, cortisol, probably, if you thought of it as a drug, it has the narrowest therapeutic index. To your point, too much of it will kill you eventually and make you miserable as hell on the way, and too little of it will kill you quite quickly.

And what's most interesting about it is, okay, so there's an optimal level, among other ways of translating that. That means we don't hate stress, we hate the wrong amount of stress. When it's the right amount, we love it. We pay money to be stressed, to get on a roller coaster, to go to a scary movie. When it's the right amount, when it's the optimal amount, we call it stimulation. Okay, so exactly as you say, it's a narrow range. So that's a tough biological problem. Understanding a hormonal system, that's pretty damn essential. And where an awful lot of the time you're walking on a knife edge where either side is bad news, too much or too little. But when it comes to glucorticoids and what counts as good stress and stimulation, there's the added factor that there's incredible individual variation as to what counts as the optimal level in between. And one person's like hair raising, Audubon Society walk one Saturday morning looking for birds while the other person goes and signs up to be a mercenary in Yemen because that's when they feel alive and awake and all of that. Not only that it's a narrow range, but we differ so much as to what each person's optimum is.

Now, I want to make sure I understand that point, Robert, and this is probably overly simplistic, so feel free to correct this. One of it would be the external scenario that is being perceived. And I can see definitely how two people can have vastly different views on that. I mean, it's the reason someone can voluntarily go and be a Navy SEAL and someone can say I feel much better not doing that. Right. There's clearly a different appetite and. Or capacity for distress. Is that what you're referring to? Or are you also referring to you and I could be sitting here and have different levels of physiologic benefit and harm at the same level of cortisol.

Both.

I see.

Absolutely.

So, I mean, the former, I think most people would acknowledge the latter is pretty new, right? I mean, I shouldn't say pretty new. That's not intuitive to me because there's.

Centuries of endocrinology saying what's the most important thing about hormones, how much of the stuff there is in your bloodstream, what the levels are. And if you and I are sitting here with the same circulating levels of whatever centuries of dogma was, that will translate into the same biological effects. And then, I don't know, sort of endocrine revolution of 70s, 80s or so turns out how loud someone is yelling at you counts what the hormone levels are, how sensitively you can hear them. The levels of your receptors in target cells turn out to be essential as well. And there's all sorts of endocrine domains where in fact, screwy receptor levels are much more consequential and impactful than our screwy levels of the hormone itself. And individual differences in levels of receptors, what version you have, how well it works, how avidly it holds onto the hormone, what it is then coupled with afterward downstream inside the cell, that whole world turns out to be as central to understanding individual differences as are the levels of hormones themselves, and as sensitive to all those things ranging from genes to prenatal environment to early development to psychological factors and so on. So, yeah, that's a huge, A huge piece of the story.

Now, when I hear you say it like that, Robert, it seems pretty obvious because we would talk about insulin in exactly that way. You could have two people with the exact same level of insulin, completely different physiologic response because of insulin sensitivity. When insulin hits its receptor, it leads to the phosphorylation of Akt. Akt. And that's what leads to the GLUT4 transporter coming up to the surface. And different people with the same insulin can do that totally differently. And different people will have a different insulin response to the same food to the same meal. That's the reason we do glucose tolerance tests. So you could basically say someone is cortisol sensitive and cortisol resistant to make the analogy to insulin at the end product end.

Absolutely. If you're an obsessive with cortisol stuff in the 80s, there was briefly this deep puzzle in that it turned out New World monkeys, monkeys in South America, marmosets, tamarins or whatever, when you compare them to traditional Old World monkeys, the Asian and the African ones, turns out they have like an order of magnitude higher glucocorticoid levels. Oh my God, that's crazy. What's that about? All sorts of theorizing about how for some reason it's more stressful to be a New World primate than an Old world, which didn't make a whole lot of sense. And then there was this issue of these animals should have been falling out of trees from their Cushing's Disease. And. And finally somebody found an explanation. Oh, somewhere back when there was a mutation in the gene for the glucocorticoid receptor in New World primates, and it has roughly 110 the sensitivity. So the system just equilibrated out at a different set point. But that's such a great example of just natural variation not only in how loudly you speak hormone, but how effectively your cells listen to hormone.

Do you have a sense in the human population today? I mean, a log fold difference like you just described sounds extreme, but do you have a sense of what the variability is in humans today? Is it a twofold, threefold delta on the receptor side?

Gut feeling. And reflecting the fact that my world, the brain, you don't get to measure receptor levels anywhere near as easily as in a white blood cell well under an order of magnitude.

We just acknowledged, or you just pointed out that when a zebra sees a lion, everything that happens, as far as the fast and what I would call the acute and the subacute stress response is perfectly evolutionarily sound and completely in the best interest of that zebra. We could also come up with countless examples of 10,000 years ago or even today, when the same thing is true in humans. When did that transition occur in our species to where you started to see either something in the civilization or society that was unhealthy. So today I could point to a thousand examples. Social media, you name it. I mean, it's an infinite number. When did that start to crop up? What does your research suggest is the arrival of that?

I think it predated us being humans and instead is a feature of smart social mammals because you see indices of stress, related stuff. Baboons, that's what I've spent my whole career on. And other non human primates, cetaceans, elephants and such. Okay, so why study baboons if you're trying to understand Human stress. And it turns out they perfectly illustrate the point you just brought up. If you're a baboon living in the Serengeti in East Africa, your life is pretty good. It's a fantastic ecosystem. Baboons, they live in these big troops, 50 to 100 animals or so, so they really don't have to worry about lions very often. The infant mortality rate is lower than among the neighboring Maasai tribes, people. And probably most importantly, unless it's a once a generation drought, if you're just a baboon going about your everyday business, it takes you about three hours a day to get your day's calories. And that has a critical implication, which is if you only need to spend three hours of sunlight each day getting enough food to get by, you've got nine hours of free time every day to devote to being miserable to some other baboon. And that's the key thing. They are well off enough in our westernized sense that they can sit around and generate psychological stress for each other. Overwhelmingly. If you're a baboon in the Serengeti and you're miserable, it's because another baboon has worked very hard to bring that state about. They're wonderful models for westernized disease in that very few of us get hypertensive because, you know, tigers are chasing us instead. It's psychosocial stuff that we invent and that we can wallow in for hours every day. And that's exactly what baboons do. They're great models for westernized stress.

Do we have evidence? I mean, I'm sure it exists, but in the humans, I would just be willing to bet that if you and I were subjected to the same external stressor, I would probably internalize it more than you. That's my guess. So you. If we were both baboons and there was a third baboon tormenting us, is it safe to say that you could be the baboon that would roll with it more than me?

Individual differences like that? Absolutely. My guess is both of us would respond to it by saying, I'm just going to get a longer and longer CV and then he's going to regret it someday, pushing me around. They'll be sorry when they see how many degrees I have. But yeah, individual differences. One of the things that I focused on, you know, I spent my first 10 years deciding rank and status. Social status is everything. If you're a baboon and you got a choice in the matter, you want to be high ranking. Because on the Average, you have lower glucorticoid levels, your resting blood pressure is lower. All sorts of stuff works better. But what took me some growing up out there to do was to realize that, yeah, social rank is important. Far more important is the contextual meaning of your rank.

Is that the same as your perception of your rank or there's more to it, right?

Well, it's what the rank means in your particular troop. You can be a low ranking guy in one of two different troops and one troop simply because of its culture. And that's a perfectly scientific word to use for another species these days. In one troop, being low ranking could be a whole lot crappier than in another troop in terms of how often somebody in a bad mood displays his aggression on you, in terms of how often somebody actually grooms you, and off in terms of how often you get to finish a meal before somebody steals it from you kind of thing. So the same exact rank means different things in different sort of baboon cultures.

So I'll take an extreme example. In a prison, there's a clear hierarchy, starting with the warden, the guards, the inmates, and of course, within the inmates there's a hierarchy. Presumably I'm making this up, but certainly the pedophiles would be at the bottom of that list and a violent criminal would probably be at the top of that list. So within that hierarchy there's probably a manner in which you would be perceived as a function of that unique environment, which is so artificial in its own way. But that wouldn't necessarily be the same outside.

Absolutely. And one of the most interesting things about us, us humans, when we talk about across all sorts of primates, being low ranking in general is bad for your health. Well, what about humans? We don't have ranking in the same system that sort of other primates do in a strict linear kind of way. But the other thing about us is we belong to multiple, multiple hierarchies at once. And we can have very different ranks in them.

So for example, family, work, sports team, hobby.

You've got some guy who's the mailroom clerk in this giant corporation, and you could not possibly be lower status, but he's the captain of the company softball team this year. And you better bet when you ask him what's important in his life, 9 to 5, Monday to Friday is just a stupid way to pay the rent. And what really matters is when the weekend comes around, you have somebody with a horrible low status job who's the deacon of their church. We belong to multiple hierarchies. And we are very good psychologically at deciding that whichever hierarchy we're highest in, that's the one we define ourselves by.

Let's take another extreme example, which is you take people who are very successful in what they do, you know, whatever, they're the most famous hedge fund manager or an entrepreneur that started some great company, you would argue, well, they seem to be pretty good on the food chain, but yet many of them would say, or you could measure objectively, their hypercortisolemia is problematic. So it seems like there's even more than just that ranking, right? Isn't there something else? Because they're at the top. If they were baboons, they're the alpha, but they're still grossly stressed out.

In other words, thank God we're more subtle than baboons. But it turns out baboons are even more subtle than just rank. They have personality. And you can be a high ranking baboon and personality differences. And again, this is as scientific a word as is culture. If you're a high ranking baboon and your worst rival sneezing 100 yards away is seen as a major provocation, you are going to have much higher glucorticoid levels than if you're a highest ranking baboon for whom that's no big deal. And in fact, often you may have higher glucorticoid cortisol levels than if you're number 10 or number 20 in the hierarchy. There's lots of psychological filter stuff and I spent a ton of time studying that. Baboons differ as to how readily they see things as being provocative or not, threatening or not. You're sitting there and again, your worst rival shows up and takes a nap 100 yards away. There can be two baboons of the same rank and one of them keeps doing exactly what he's doing and the other one is interrupted from whatever nice social thing is happening. He's agitated and he's vigilant. He's got to look at the guy and lunge towards him a couple of times before going back. If your worst rival taking a nap is as disruptive as the guy threatening you in your face, you average about twice the cortisol levels in your bloodstream after controlling for rank. As a guy who can tell the difference between the big thing and the.

Little thing, maybe this is too deep a question and the answer isn't known. But what is it that actually transmits that information through the filter of your personality into the physiology? That's very well understood. So I Understand the bookends. Right. I understand how the visual cortex takes the guy who's your enemy sleeping over there and transmits that to your cortex. And then I understand how the sympathetic chain kicks off the response. Is there a link in between those? The processing link?

Here's one of those filters. You take people and you're flashing up faces at them, stick them in a brain scanner, and you're looking at how jumpy their amygdala is. Their amygdala central to fear, anxiety, aggression and such. And what you see is tremendous individual differences in. You show somebody a face with kind of a neutral expression. Does this person look happy, sad, angry, threatening, whatever, and lots of variability. And you look at the people who tend to view neutral expressions as threatening. In other words, they see threats that most other people don't. What does that correlate with?

A bigger amygdala, Physically larger amygdala.

A physically larger amygdala. Amygdala with a higher metabolic rate, an amygdala that is more electrophysiologically reactive than stuff.

Let's back up for a moment. I mean, tell people, in case they don't know where the amygdala sits, what part of the brain it evolved from, and why it's sort of referred to as this reptilian brain. I think everybody's heard of the amygdala, but I think you could explain this in a more interesting and accurate way.

Okay. Amygdala is like one of the anchors of what's called the limbic system in the brain. Limbic system, it's the part of the brain that's all about emotion. Not surprisingly, mammals have a whole lot more limbic development than fish do. Fish are not famous for their emotional lives. Limbic system is arousal, fear, anger, lust, love, maternal pair bonding, mother, infant bonding, all of that. And it's a whole series of structures, not surprisingly ancient in mammals, not surprisingly highly complex, interconnected, not surprisingly sitting underneath the cortex, the cortex that more recently evolved, part of the brain that does your taxes, all of that limbic system underneath there, all this subterranean emotion stuff. And amygdala is one of the key limbic structures, and it's involved in fear, it's involved in anxiety, it's involved in aggression. You learn to be afraid of something or somebody that does. It didn't used to scare you. And your amygdala does the exact same sort of cellular basis of learning that goes on in other parts of your brain. When you learn somebody's middle name and actually remember it your amygdala learns to be afraid of new things. And when you manage to stop being afraid of something, when you stop being afraid of thems, because it turns out, oh, they're actually more similar to use than you thought or something, it's your amygdala that becomes less reactive to stimuli like that. So your amygdala is absolutely central to some of our worst human moments.

It's so interesting because it's sandwiched between, you know, you can think of the human brain as having sort of very grossly three parts, right? This brainstem, this midbrain, which the amygdala you could argue is the mayor, and then the cortex that you describe. It's not an oversimplification, I think, to say that as the complexity of the organism evolved, so too did that hierarchy, right? I mean, the brainstem basically handles everything. We don't have to think about ever breathing and all of those autonomic and sympathetic parasympathetic functions. And then you layer on this midbrain that does everything that you said, which is still kind of happening beneath consciousness. And then, of course, there's where most of us live in our cortex, where we're. Or where we think we live, which is we're thinking these thoughts. But it seems we're maybe not as aware of how influenced the cortex is by what lies beneath it.

Exactly. Which is incredibly important. If you think of this kind of ancient, reptilian brainstem part of the brain, what does it do? It keeps track. It makes you breathe every now and then without having to think about a boring sort of stuff. Then on top is the emotional limbic system. The then on top is that cerebral thinking, cognitive cortex thing. It's very easy to come up with the conceptualization that what's fancy about humans is, for example, you're a lizard. And the only thing that's going to change the functioning of that ancient brainstem stuff is if you're bleeding, if you're too hot, if you're too cold. Just like boring physiological states. Once you layer a mammalian emotional limbic system on top, suddenly you can do something no lizard on Earth can do. You're sitting there and you're some wildebeest, and some other scary wildebeest shows up and is peeing on some tree in your territory. And nothing regulatory has changed in your body, but your heart starts beating faster. Aha. Your emotional brain can alter sort of the basic regulatory stuff down in the basement. Now you go one step higher and you layer a cortex on top of it. And now you could do amazing stuff. You sit there and you think about the fact that your heart's going to stop beating someday and you start breathing faster and your brainstem, the more ancient stuff, has altered as a result. And you've just done something not only that no reptile can do, you've just done something that no one warthog can do, which is think, think about something that's scary or arousing or remember the time that you would. And suddenly something changes down below there. So there's this easy picture of sort of top down complexity once you get to us. And where the cortex can regulate your emotional brain and that regulatory brain, brain at the bottom, your emotional limbic brain can regulate. What's far more interesting or underappreciated is exactly what you bring up, which is those lower levels can influence what's going on up above. One example of this is like this classic great study in sort of physiological psychology, social psych. You take people, and I think in this study they would take male volunteers, heterosexual male volunteers, and of course they were no doubt college freshmen taking psych 101. And they had these guys walk across this really scary suspended bridge. And the deal was that either halfway across the bridge you were met by from the other side, a researcher who happened to be an attractive female. And she would ask the volunteer some questions about what do you think of this bridge? Or how is it of walking across this? Or whatever. The other half of the time you would not encounter this person until you were safely out at the other end. Then they would ask you to evaluate the attractiveness of the person.

Same person, that same person compared to seeing her in the middle of the bridge or at the far end?

Exactly. Say, hey, remember while you were doing that there was this, you know, do you want to rate her attractiveness? Was she friendly? Did she seem smart with her? And what you would see is guys in the middle of the bridge with their hearts racing because they're terrified would do some misinterpretation. Why is my heart beating so much faster than if I was standing safely?

So they would rate her more attractively in the middle of the bridge.

Exactly. And then as the ceiling of detail is now you do the same experiment and you give the person a beta blocker so that they don't have the accelerated and they don't rate the person as attractive.

Is it the same with the beta blocker you would treat.

Yeah, you do nothing to their ratings of them as how smart they seem, how kind they seem. Whatever. It's just this. Okay. If my heart's racing, it must be because. So that's a great example. Boring reptilian regulatory stuff down there is helping influence what you think your emotions are at that point.

That reminds me of that 1995ish movie, Speed, with Keanu Reeves. And I'm blanking our name.

Bullock.

That's right, Senator Bullock. Where at the end of that movie there's some cheesy line about how relationships that start under this much distress, it's dangerous. But of course, the other read on that now is, yeah, if you're on a bus that's about to blow up, I think you're going to think the chair is attractive. Right? Potentially. Right.

Yes. Wow. I haven't thought of that movie in years. Thanks.

I'm sorry.

You can go home.

And I'm sure Netflix will stream that for you.

Right.

So I read something you wrote. I can't remember where it might have been in another interview that. And I didn't know this, and this is a great example of why I just love doing this podcast because there's never an exception to how much I'm learning. It's like drinking from a fire hose. And you'd think I would have remembered this from medical school. The neuron of a human and the neuron of some other organism, when you look at it at the single cell level, can't really differentiate it. If I showed you two Microsoft slides and here's a human and here's a fish. So what is it about? And this is maybe getting us a little off topic, but I also think it feeds into this broader issue of, like, the stew and the alchemy of how this stuff is put together. But if we all have the same neurons, what is. Is it the number of our neurons, like, what is it that enables us to have all of this additional torture?

Yeah, it's incredibly interesting because, I mean, there's three and a half people on Earth who have spent their entire careers being able to tell the difference between, like, a tree shrew neuron and a human neuron and could recognize it in their sleep. But yeah, for the most part, we are not humans because we have invented brain areas that you don't find in other mammals, or because we've invented neurotransmitters that you don't find in other vertebrates or types of neurons. There's a couple of types of neurons that people used to think were specific to humans, and turns out you find them in elephants and whales also. And that's Plenty interesting. But it's the same enzymes, it's the same gene regulation, it's the same, you know, we're sharing 98% of our DNA with a chimp or a bonobo. So you say, where do humanists come from? And I think it's exactly the issue you talk about. We have the same signal transduction pathways and neurons as you see in a fruit fly. And what's the key difference?

Isn't that a bit humbling?

Yes.

When we just think we're that special and it's the.

Where you can take one of their genes or one of our genes and stick it in the other one and it functions just fine. Or you could take it from a single cell organism, some genes related to programmed cell death, you could do that. So what's the big difference? For every neuron that a fruit fly has, we have 100 million. And sort of the sound bite that I think summarizes all of that is with enough quantity, you invent quality. And this is this whole world of emergent properties of, of complex systems. You take one ant and you put it on a table and nothing that it does makes a huge amount of sense. And you put 10 ants there and pretty much the same thing, and you put, I don't know, a thousand. And maybe they start making a trail or something and you put 10,000. And they build a colony and they farm mushrooms and they take aphids as slaves and they could keep the temperature in the colony plus or minus 2 degrees. And they have specialization of labor. And no ant has any more rules than he had when he was wandering around on a table by himself. And you put enough of them together and complex adaptive stuff emerges out of the very simple rules that each of those components has for dealing with another component.

It almost defies entropy, doesn't it? Like, why does that happen?

It's amazing that it does that. And that's what our brains are. We've got more ants that are coming together in our heads than does a fruit fly. And you get more complex emergent stuff happening.

It blows my mind. So let's go back to some of this stuff. Maybe about a year ago, I read something that really frightened me because the implications were so significant. If a mother is under great stress, there was this critical window in which her child could see something in her eyes that would communicate that stress to her. Or maybe it wasn't in her eyes. It might have been just through her entire face, but it would imprint epigenetically into the child and alter many features about Them as they would age, for example, their propensity to be depressed. I mean, I remember reading this in sort of a lay press thing. So I don't even think it got into the description of epigenetic genetics. But that was the only assumption I could make, was that this must be modulated through that mechanism. Do you see evidence of this in animals? I mean, absolutely.

And it's one of the trendiest topics around. Hooray. Science finally recognizes childhood matters. What your childhood is like has a lot to do with what sort of adult you're going to wind up being. What do you know and like, lots of childhood advice, adversity versus childhood security, and, you know, very different trajectories. And what's been the huge mechanistic challenge for the field is understanding. So what is it about being in a scary neighborhood or an unstable home or having a parent read to you, or what is it about this whole world of developmental individual differences? What are the nuts and bolts changes that occurs in a kid so that as an adult, they are now 30 fold more likely than the next person for this or that to happen to them. And this, this whole trendy field of epigenetics, which is early experience, doesn't change your genes, doesn't change your DNA sequence. With some like, you know, circus trick exceptions, you've pretty much got your DNA sequence forever. What epigenetics is, is early experience changing the regulation of your genes, how easily you turn certain genes on, how easily you turn others off in different parts of your body, different parts of your brain and so on. And that's exactly the sort of domain where you see the sort of stuff that you outlined. So that, for example, if you're a fetal rat and you, that rat have made a terrible decision, you, you've picked the wrong womb to be developing in, and you happen to be inside a mother who's highly stressed. She's secreting a lot of rat glucocorticoids, which get into the circulation, through the placenta, into the fetal circulation, into the kid's brain. And one of the things that it does is it causes an epigenetic change in the amygdala.

So is that rat going to be born with a larger amygdala, or is the phenotype more complicated than just size?

It's size and a bunch of other things. As an adult, it's going to have a bigger amygdala and it's going to be more excitable and it's going to be more prone towards interpreting a neutral situation as a threatening one. That's virtually the definition of rat anxiety disorder. Seeing menace that other people don't. And you see much the same evidence in humans by now. Early experience. Forget early experience. What kind of kindergarten teacher you had? This is fetal early experience. And this is exactly a domain where you get potentially a lifelong epigenetic effect. Okay, so that turns out to have a hell of an implication. That's just the most exciting subfield around there by now. Okay, so you were fetus and got exposed to lots of mom's glucocorticoid levels. And as a result, as an adult, you've got an enlarged amygdala and you see threat all over the place that other rats don't. And among other things, you secrete elevated levels of glucocorticoids because the world is full of menace that only you are seeing. So you get pregnant, and during your pregnancy, as a result, your fetus is exposed to elevated glucocorticoid levels.

And to be clear, it's not because you have altered the germline genome, it's that you have changed the expression of the gene which has altered the phenotype. And now that phenotype is being passed generation to generation through parallel expression.

Exactly. Something termed non genetic genetic transmission of traits. Non mendelian. And people have now shown some of those traits. You see that ripple, it gets smaller each generation, but it's there half a dozen generations later. And the exact equivalent of some of these have been found in humans. In other words, individual differences are arising not only from experience, but from the multi generational transmission of. Of some of the consequences of experience. Which is just mind boggling that that can work that way.

Let's go back a little bit to why this is problematic. So at the outset we alluded to this idea that it's a misnomer to say stress kills. I'd love to hear if you have a particular definition of stress. I probably butcher this stuff, but I sort of think of stress as the external thing. And I think about it as it's anything that is sort of emotionally or physically, either chronically or acutely distressing. I mean, that's sort of a dumb definition because it contains the word stress, but I think people understand distress a little more than they understand stress. But of course, it's your response to that physiologic response. Right, Which. So we can quantify this stuff in terms of what hormones are happening in the body and how the hormones are moving in the body. It's your response to that that probably has a greater impact on your health. So let's go through three things. Help me understand how hypercortisolemia and or its accompanying features will impact the brain especially well through any timeline you want. I'm, I'm obviously interested in the aging brain, but I can't imagine this also doesn't impact the developing brain.

This is basically what I've spent my whole professional career thinking about. And historically, the first place where people sort of realized something scary was happening was a brain region called the hippocampus. Hippocampus is all about learning and memory. You want to have a hippocampus. It's the main brain region that's damaged in Alzheimer's disease and it's vulnerable in lots of other ways. Turns out it's extremely sensitive to glucorticoids. Translated more reductively, it's got extremely high levels of receptors for glucorticoids by the standards of the rest of the brain.

And what's the evolutionary basis for that? Is that to have a feedback loop?

There's two reasons. One is to have a feedback loop, but the other is, okay, so the hippocampus remembers stuff for you. You don't remember everything. You don't remember where you were on 910 as opposed to 911 kind of thing. Your memory processes has to come with a filter, saying, is this one important?

So you're saying that cortisol amplifies memory consolidation and that you use this to consolidate stressful memories as a way of learning.

Exactly. Along with epinephrine and norepinephrine indirectly, they have some of the same effects.

So cortisol crosses the blood brain barrier with no difficulty.

Exactly.

I assume EPI and norepi do the same.

They have to work more indirectly, heavily through the vagal nerve because they don't get in as readily. But some of it is also neuroepi being released within the brain during stress, so it has some of its own memory enhancing effects.

Again, a great example of evolution's got this awesome system set up and it only gets out of whack when the stimulus becomes too much. You do want that imprint, but you don't want that happening full time.

Or stated another way, this is the reason why you don't get much out of a class. If you're semi comatose and you had two hours of sleep last night. If you're like three quarter, your glucorticoid levels are low, you're not consolidating stuff. If you are out of your mind Terrified because there's a lion sitting next to you, you're not going to absorb much either. Inverse you optimal range, all of that. So it turns out the optimal amount of glucocorticoids, something that is moderately stressful, in other words, something stimulating, does great stuff to your hippocampus. It increases blood delivery there, glucose, oxygen, it makes the synapses, the connections between neurons more excitable in the hippocampus. Does great stuff. A little bit of arousal, alertness is a good thing for learning and memory. Now instead, transition to your stress 24, 7 ever since you were like 10 years old kind of thing. And you're in the range where glucorticoids do exactly the opposite. They decrease oxygen and glucose delivery to the hippocampus, they make neurons less excitable, they disconnect synapses, they cause the processes in neurons to shrivel, they block the birth of new neurons there. They make other insults more damaging to neurotypes. Neurons in the hippocampus. What do you have there? That's the world in which if you were stressed out of your mind, memory doesn't work so hot. And what we're increasingly realizing is if you're exposed to excessive glucorticoid levels, like on the scale of years to decades, you're going to make this part of the brain get older faster.

Which speaks to something that I know you're quite passionate about, which is the differences in how socioeconomic status can sort of affect generational changes in this manner. Because you use the example of a 10 year old. Well, I did my residency in Baltimore, Let me tell you, a 10 year old in inner city Baltimore who's in the wrong house versus a 10 year old in Palo Alto who's in, quote unquote, the right house. And look, that's not to say that you could have a 10 year old in Baltimore that's got a great environment and 10 year old in Palo Alto to that's going dealing with a whole bunch of other different issues which you know, especially in the era of social media. But all things considered probabilistically, that 10 year old in Baltimore is going to have a much harder time given what you just said or, I don't know.

Stated the other way. I have a friend who's a cardiologist who splits his time between a hospital in Oakland and private practice in San Francisco. Some of the time what he's doing is dealing with 80 year olds who are considering getting a pacemaker because the ski season is coming and they are wondering if they're going to be in shape and time for that and maybe. And then back in Oakland, he's dealing with 50 year old elderly men who are having heart disease. Yeah, Socioeconomic disparities are. I will get on my soapbox now. When you look at the source of variability in health among humans, humans on this planet, socioeconomic differences, differences in absolute levels, differences in degrees of inequality within cultures and within communities and so on, is an enormous predictor of health. You want to look at the most medically impacted low ranking primates you could find on Earth, look at poor humans. Because when humans invented socioeconomic status and the capacity to be poor, they invented a way to subordinate the have nots like no chimp on Earth could ever dream of doing.

As you've alluded to, there's something else to it. You know, recently I interviewed an amazing physician named Tom Catena who practices in the Nuba Mountains in the south of Sudan. So he's the only physician to take care of 1 million people who, as you know, are being killed by their own government. Bashir is sort of indiscriminately killing these people. So my discussion with Tom was one of the most riveting discussions I've ever had with a human being. It just happened to be in front of a microphone. But one of the things that just as an afterthought we were discussing that surprised me as we were going through all of the different things that people die of there. You know, they don't have vaccines, you've got measles outbreaks that are killing people left, right and center. And the trauma, like, you know, the shrapnel blowing people apart, not surprisingly, they're just not getting the same chronic diseases. And the cancers they get are not the cancers we get. And they're not getting heart disease and they're almost unheard of to get type 2 diabetes. But what really surprised me is there was no suicide. And I found that as the single most interesting thing I guess I learned from Tom, which was we would look at their life and think, think that is an abysmal existence that I couldn't tolerate for one second. And yet I would have to guess that their level of cortisol might be lower than ours, even though they're in a much worse environment. So whether it's that sense of community that they have or the shared purpose, there's something about it. So in other words, my point is, even in the presence of such great poverty, it seems that there's ways that this can be overcome. Whether it's through, there's no comparison to anybody else. Because another point he made was most of the folks there don't even know they're in Africa. Like, they don't necessarily know that Africa is the continent in which their country resides. So is the bigger issue there, you think that there's no disparity? So even though that's complete poverty, there's no real perceived disparity? Or do you think it's the sense of community? Like, what would you hypothesize explains that health, that mental health, all the above.

There's a whole world of people who study happiness along with more traditional public health, people who study things like longevity. You look at the quarter poorest places on Earth, and indeed people there don't live very long and are miserable. But once you get past sort of the subsistence level, there's not a great relationship between the wealth of a country, GDP per capita, anything, and levels of happiness or life expectancy. And you look at the fact the US has a shorter life expectancy than Cuba and Lebanon and Costa Rica, and it's like the shame of this country kind of thing. Once you get past mere subsistence level, income is not a great predictor of any of this stuff. And that's instead where you get into worlds of social capital and social support. And when you look at the whole literature and you look basically at every westernized country on earth, and it's now seen as they become westernized, and what you see is the health socioeconomic gradient, the poorer you are, the worse your health on the average, the more of a whole array of diseases you get, not all of them, but a huge number, the more impactful they are. And when you look in the west, the United States is the poster child for that. We've got the steepest curve of any country on earth. In the westernized world, the least steep ones are, you bet, of course, the Scandinavian countries, ever reliable sort of utopias. And then you begin to unpack why this relationship occurs. And like some incredibly smart people have spent their careers looking at it, the most obvious one is if you're not healthy, it's very hard to pull off being the CEO of a company. Poor health precedes and gives rise to poor socioeconomic status. Okay, that's plausible. That turns out to explain a tiny percentage of the variability. And you could look at the status, socioeconomic status of the home in which a child is raised, and that's a predictor of their likelihood of diabetes half a century later. So absolutely, the socioeconomic status comes first in explaining the vast percentage of the variability. Okay, so next thing, maybe it's just that, well, everybody's kind of equally healthy. It's just that the really poor people are very unhealthy. We have a step function. No, you start with Jeff Bezos and Bill Gates and every step down there and statistically the lower you go down every rung of the way, the poorer you are.

The poorer you are with respect to health.

The poorer your health. Yes, yes, thanks. So now you unpack that. And what's the most obvious explanation? And this is what people call a neo materialist explanation, which is obvious, the poorer you are. You don't have health care access, you don't have health insurance, you can't go to the doctor as readily, your care is more lousy. That's obviously that explains everything. That explains virtually none of the variability in the data. Because you see the gradient. Nonetheless, in countries with socialized medicine, universal healthcare, you see it for diseases where it doesn't matter how often you get healthcare access, juvenile diabetes. So it shows an SES gradient kind of thing. So it's not healthcare access. You then look cross culturally and you see wildly different income levels and wildly different levels of healthcare access. And you see very similar lifespans across these countries and very similar gradients. So what people spent like the last 30 years doing is having this huge shift towards. It's got so little to do with the material aspects of wealth or poverty. It's got to do with the psychological aspects, it's got to do with the stress. First key finding somebody at UCSF named Nancy Adler who's done wonderful research showing, okay, your socioeconomic status, your wealth, your objective measure of wealth is indeed a predictor of your health. Turns out at least as good of a predictor is your subjective socioeconomic status. On the level, when you look at people around you, how are you doing compared to other people? Where would you place yourself on this 10 step ladder in terms of what's your absolute SES, what's your subjective one? And by asking it that way, you're asking the person to consider the community that's most pertinent to them. Who's the comparison group? My next door neighbors? Warren Buffett, in between, Whatever. When you think of other people, how are you doing compared to them? And it turns out your subjective SES is at least as good of a predictor of your health as is your objective.

In other words, if you took someone's income, which is quite objective, it would offer no more prediction than asking that person in The Nuba Mountains. Where do you rack up in this tribe? And it's sort of like, you know, sort of top two thirds.

Yeah, exactly. Or another way of stating that is you look in some bloated corporation and there's some guy who's the assistant manager of the mail room and that's an incredibly status filled position for that guy. And there's some other guy who's number two in the company who was just passed over to be number one. And the only pertinent thing in his mind is not the 99,000 employees that he's higher ranking in that there's still somebody ahead of me. And you can see the same thing in baboons. In other words, it's not being poor, it's feeling poor. The next critical piece in the story is work from this guy, Richard Wilkinson in the uk, who shows what's the best, most effective way to make somebody feel poor, independent of their absolute levels of income. Surround them by inequality, surround them by reminders of all the people who are doing better than them.

I mean this is where social media, it's the amplifier to all amplifiers of this, right? It's you can't go 10 minutes if you're on it without looking at somebody who's obviously better looking, obviously smarter, obviously richer, obviously having more fun. I think this has been pretty well documented, right?

Lifestyle of the rich and famous. Or you could be driving down a freeway and somebody passes you and I don't know what counts as a high status car these days that cost a fortune, but they come speeding past you and you can feel crappy and diminished and like a less successful human and you never even saw that person's face. This is unheard of in the history of humans or primates of being able to feel socially subordinated and you don't even interact with the person. Oh, there's people out there with, you know, at least if the next door neighbor has more camels than you, that's a very like tangible, real thing in terms of like likelihood of surviving the next drought. Income inequality explains the mediating effect between objective socioeconomic status, status, subjective socioeconomic status and health outcome.

What I'm hearing you also say, though, that's a more subtle spin on this is it's not necessarily global income inequality, it's local income inequality that is much bigger.

But what technology has allowed us to.

Do, it makes the local counts as. That's right. That's exactly right. It's expanded what local means.

You can sit there and watch, I don't know Lifestyles of the Rich and famous and back when you would never have gotten into like the head of your fiefdom's castle or whatever. And now you can see all the crap they have that you're never going to get and feel less loved as a result.

It's so interesting to hear you talk about this. This is a topic that I think anybody listening to this is well aware of, especially if you're a parent, because you also have to think about this through a developmental lens, which is at least when you and I grew up, I didn't grow up with a lot. But you really had no idea what was different, right? Like you simply, everybody was the same. I mean, everybody's parents bought used cars instead of new cars and everybody had more or less the same sort of clothing that wasn't exactly the best and whatever. So at least you could argue, well, were we at least spared some of this difficulty during a critical window of development? And what happens now to a 10 year old that's got a smartphone and is subjected to this? Because I remember that funny show, Lifestyles of the Rich and Famous. I can still sort of hear the goofy, cheesy theme song. I think I even probably watched it once or twice as a kid. But it's a lot easier when that's the one exposure you have to extreme wealth or disparity. And either you can watch it for one hour or not, but it's quite a different thing. If not to pick on the Kardashians, I'm just. But if you're inundated with, oh my God, look at how awesome the Kardashians are and what they're doing and how great their life is, and multiply that by three log orders. Do we have any data that suggest that we are at a critical juncture? Because I was having this discussion with a friend yesterday which is, is there evidence of any greater transition in technology in both a positive and negative way than this generation to the last? Is this truly the greatest step forward?

I would assume so. But the things we worry about, people have been worrying about for centuries. Kids, they don't go outside, they don't play, they don't have like meaningful relationships because they spend all their time talking on the telephone. They spend all their time listening to their transistor radio.

So maybe we're blowing this up. Maybe this is just this generation's version. I mean, I guess the one difference is when you're talking on the telephone, when you're listening to the transistor radio, I don't Know if it creates that global to local phenomenon quite as easily or as quickly or with less resistance as we see. But maybe you're right. Maybe this has always been one generation's struggle with the last.

But what you get is an amplifier now. Because if you're an insecure, socially isolated, peri. Adolescent kid who's vulnerable in all sorts of ways, and you know, no matter what decade or century it was, you're the last one picked for the game, you're the one who's least popular or whatever. And that has all its corrosive effects. Now, if you really set your mind to it and you're that kid, you could spend 247 just wallowing toxically in evidence of a gazillion other people who are better looking than you and more popular and invited to parties you'll never be in. It amplifies further. And the technology does absolutely that. What I think it does is it makes the volume vulnerable, more damaged than in the past.

I think it's safe to say these amplifiers aren't going anywhere. So rather than wallow in their harm, I guess the more relevant question is, what do we do? If you're a parent today, or not a parent today, and you're thinking about this through the lens of yourself versus your kids, whatever, what are the steps that one can take to become less susceptible to these forces that seem to drive this? Because I want to step back for a moment when I think about these areas that we've talked about before, about the impact of nutrition and sleep and exercise and stress or distress, to make it more the term I use when I think about this personally, the one I most worry about is the last one. I think I've got a pretty good handle on nutrition and it's in many ways easier to control. I feel like I'm more in control of what I eat. And when I make bad choices, I'm usually doing them consciously. Like, I've decided, I'm going to eat this pizza versus I can't help myself, I'm going to eat this pizza. Similarly with exercise. And again, I'm not saying this for anybody else, but this is just my personal thing. And even with sleep, once you commit to it, which is not something I did until probably seven or eight years ago, that I sort of committed to, wow, this really, really matters. And to forego this thing, bad idea. It's this last one that really drives me crazy, which of course doesn't help matters because the fact that it drives you crazy makes it worse. But I'll Give you an example. As a general rule, outside of the immediate postprandial period of a high glucose meal, far and away my highest blood glucose is always in the morning. Now I wear a 24 hour glucose meter. So I'm kind of a weird guy. For almost four years I've been wearing a glucose monitor all the time. So it measures my glucose 247 at 1 minute increments and out of say 365 days in a year, I'm easily wearing it 330 days of the year. So I've got a lot of data. And without a question, when you look at a 24 hour period, if you stripped away the x axis of time, I could could easily identify morning for you without exception. I'll give you an example. This is not something I'd plan to do. I had breakfast yesterday, yesterday being Sunday really early because I woke up with my kids, made breakfast. I normally don't eat breakfast, but I did. So I had a breakfast 7:30 in the morning, did a workout, had to catch a flight, didn't have time to eat after, had a very, very busy day, didn't eat a single thing, got to the hotel around 10:30 or 11, didn't want to eat. So didn't, you know, got up this morning, it's been almost 24 hours since a meal. And I looked at my glucose meter and it was like said, you know, 110, 110 milligrams per deciliter. I was like there's no way that's right. Calibrated it, sure enough it was 110. Now there is no earthly reason I should have had a glucose of 110mg per deciliter 24 hours after my last meal, which by the way was bacon and eggs. It's not like I was eating pancakes, right? Well I promise you, if I could spot check my cortisol, it was high. And here's the thing, before I went to bed, my glucose was quite low. You know, my glucose was probably 80 when I went to bed and it slowly rose. And sure enough, as my day wore on today the glucose went lower, lower, lower, lower, lower. It was about 78 before you walked in here. I'm not alone by the way. So I've seen this a lot clinically with patients. Once you start putting these 24 hour glucose sensors on people, which a lot of my patients are now doing, you get this insight into this horrible thing that's happening when we think we're sleeping and nothing else is going on. But we're ruminating or God knows what else.

And fits perfectly with morning wakening is when you get your highest glucorticoid levels, which is probably one of the main driving forces on the increased blood glucose level. When you think about it from a circadian standpoint, what's the most challenging thing you have to do each day in the absence of any major tumult? Get up, start functioning, all of that.

It just seems like it's disproportionate. Certainly the dawn effect has been well described. It's more amplified in people with type 2 diabetes, which is another interesting point, right? Which is why is it that someone who already has glucose dysregulation would have an even higher cortisol response in the morning, and yet you'll see enormous fluctuations in glucose? I guess my point here is this seems like a harder problem to fix and certainly meditation is by far the best tool I have ever found to even approximate getting this under control. But it's still hard because it's not like you have a pillow. If your blood pressure is high, well, I think it's probably best to fix it in any way possible. But we also have really great drugs that fix high blood pressure that can at least mask these things. We don't have a pill to fix hypercorticolemia. It's one of the most complicated endocrine situations. And yet, as you've described eloquently, it's also so innately wired into us and we have this miserable midbrain that's just killing us. First of all, I'd love to hear your thoughts on meditation, but then also other things that given how much time you've spent thinking about this problem, I'd love to know how you would suggest someone who doesn't have quite the Zen mindset that I can tell you do. What should someone else be thinking right off the bat?

I'm delighted to see that I have a Persona of a Zen. I'm actually like one of the most type A stressed people you're ever going to run across. I've spent 40 years professionally studying how bad the outcome is going to be of all of these, like, bad lifestyle aspects without having anything insightful to say about how to actually fix it or prevent it. And I certainly have learned personally absolutely nothing from my lifetime of work. I'm like, incredibly stressed. I'm mostly good at telling you what's going to happen if you don't get stuff under control rather than how to get things under control. When I look at the stress management Literature, I don't do it very often because I tend to get sort of agitated at that point. But broadly it works. It works as in, you can lower blood pressure, you can lower cholesterol levels, you can lower subjective sense of health. Use objective measures as well with all sorts of interventions. What do you see when you look at the literature closely? First off is you can't do your stress management on the weekends kind of thing. It needs to be a regular sort of thing. You can't do it while you're on hold on the phone for 30 seconds. You need to set time out for it. You know the benefits of aerobic exercise, I don't know what the magic number is these days, but 20 or 30 minute blocks as a minimum to start getting the cardiovascular benefits. So it's got to be something like you stop things to do.

So that's important. Let's double click on that. What you're basically saying is because I think you're understating how much you know about this topic. Obviously it's something you know a lot about as seriously as we would take nutrition. And if you think about how many hours a week do you put into eating, I mean, even if you're shoveling food down your throat, it still takes quite a bit of time if you're going to exercise to the levels that have demonstrated benefit. We're talking about hours a week, not minutes a week. If you're going to make the difference between getting by on sleep versus getting restorative sleep, I'm not talking about the absolute amount of sleep. I'm just talking about the delta between those two. Think about how many hours that is. In fact, for the average American, that would work out to be about an extra seven to eight hours a week of sleep. And what you're basically saying is if you want to combat this hypercorticolemia, dude, guess what? It ain't a 20 minute a week thing.

And in some ways that taps into one of the 80, 20 rules of sort of mental health professionals. Okay, so you have this crazy stressful lifestyle and there's just a bazillion things you can't say no to and you're just going 24, 7. And if you've gotten to the point point of saying this is crazy, this is not a quality life. I want to live a healthy, quality old age. I got to get this stuff under control. I'm going to start doing something stress management. And if you've gotten to the point where in this lifestyle where there's a billion things you can't say no to each day, you're saying no to them enough that nonetheless, 20 minutes every single day you are doing this. It almost doesn't matter what intervention you're doing. You're 80% of the way there already if you're managing to do that. And that's very similar to this sort of amazing classic finding. You get people who are clinically depressed and finally, finally, finally they're going to do something about it. And merely making a first appointment even before you've seen the person, people feel significantly better because you are finally saying, I matter enough to do something about this, or I'm activated enough, or I'm optimistic enough to actually go. You're halfway there at that point merely by doing something on a near daily basis.

So just on that logic, even though I don't know that this has been done, you would argue that 10 minutes of deliberate, mindful practice of meditation daily would probably be better than one hour once a week.

Absolutely. In part because if nothing else, if you do it daily seven times a week, you are sitting in the aftermath of having done that versus only one time a week. And an awful lot of what's most interesting about physiology and its impact on sort of mental health, things like that, is what's happening in the recovery period after something like that. In the same way, one awful hour long stressor a week versus punctuated episodes of it throughout the week. Without question, the latter is worse because you've now got umpteen different times that you have to recover from having turned on the stress response. And that's where a lot of the damage occurs.

You know, I learned something about myself that's going to sound so stupid because it's so obvious. Although I don't think it's true for everybody. Email is a huge stress to me. To be blunt, I hate it. That would be the kindest thing I could say about email. I really, a few months ago hit a true nadir in my response. And I'm like looking at these glucose levels going up and I'm looking at these morning glucose levels. So even though my overall glucose levels still look great, I mean, this trend was upsetting to me. I'm watching my resting heart rate in the morning go up. Over the course of four months, it had gone up like six beats per minute. And if anything I was in better shape exercising more regularly. I made this observation one day, which is how many times in a day do I stop to look at email? Even if it's just to check one or two and the answer was like 50. And every time I do it, to your point, even if it's very brief, the after effect is not that brief. So I could look at an email and see two stressful things, but it might sit with me for 20 minutes. So I tried this experiment which is I'm going to just check email twice a day, two 30 minute blocks of email. And I would say within two weeks, I just really felt better. It seems to me like we just have to figure out ways to figure out what those triggers are for us individually. There's probably some people for whom email doesn't trigger them at all. Right. There's probably, you know, for me, Twitter doesn't trigger anything because a, I have a very narrow window that I pay attention to and it doesn't involve things that are aggravating like politics or religion or whatever. It just sort of. I'm only really following science. So anytime I look at Twitter, I'm actually learning something kind of new and there. But I'm sure there are many people listening to this who would say, oh my God, like if I spend an hour on Twitter, my blood pressure could be through the roof. So it's like everyone's got to kind of pick their thing. Thing. You said you're type A, which obviously you are. I mean, you know what I didn't say at the outset when we started speaking, but you've won one of the most prestigious awards imaginable, which is the MacArthur Award. And you won that about 30 years ago. Right. That's impressive. They don't give that award out lightly. So that's the one that's referred to as the genius award. And I know you're probably like your skin is crawling when I say that. My point being is you're an incredibly accomplished, successful guy. It's not surprising you would describe yourself as a type A. What have you learned about yourself over the past 30 years or even longer, going back to your first days in Kenya, about what those triggers are for you and what you can do to lower your cortisol levels.

Not surprisingly, if you, you hang out with people who are field biologists of any sort. And again, I've only been a part time annual one over the decades, but nonetheless still think of myself as a field biologist. We're kind of a solitary tribe. I mean, during my peak periods of doing fieldwork, I was spending three, four months a year alone living in a tent where 12 hours a day, I wouldn't say a word to another person. Temperamentally, this is kind of who I'VE been for a long time. And there was always this ironic thing because I was sitting there studying these baboons because primate social behavior, and I'm interested in primate social behavior and this big sort of epiphany I had in my work that, okay, yeah, your social rank as a baboon has something to do with your health, but much more importantly is your patterns of socialization and social networks. And how often do you groom, and how often does somebody groom you and how often do you sit in contact with another baboon or playing with an infant and then I, you know, finish the day's work and go back to my tent. So there was something ironic that I was like, studying the health benefits of sociality, living alone in a tent a large part of the year.

Your wife is a scientist too, isn't she?

She was. She kind of decided she was sick of it. And she now directs a musical theater program, which is much more fulfilling for her. But at one point my wife came along.

Yeah, yeah, that's what I was going to ask.

And eventually family and, you know, kind of realizing, oh, I've missed out on an awful lot of what are really like the wonderful worth living for moments in life out of the sociality stuff. And that is a refuge and a sanctuary from the world's madness. And I could not have predicted as a 20 year old who had been planning to be a field biologist for a dozen years at the. At that point, I could not have predicted sort of how much of my equilibrium at this point turns out to be due to interacting with the right two or three other primates and like, being in love with them and stuff. That one was kind of a revelation for me. I am not the social being that I would have guessed I would have been back when.

Which is interesting because having this discussion with you today, I can sense much more of your introversion than the first time we met when you were giving an unbelievably charismatic, animated talk. And I don't know how many of us were there, maybe a hundred people, which is so interesting, right, because you would, I think anybody sitting in the audience would look at this and say, oh, that's the life of the party. But it's interesting that we can compartmentalize and separate those things, right? I mean, you couldn't get up there and you, you can do what you need to do. And you're at your happiest, I'm guessing, in the way you described it versus in the aftermath of that talk, when a hundred people run up to you to ask you four questions each.

Not to get too self reflective or something, but I'm a fairly introverted person who does better with scripts and giving a lecture is a pretty structured script. And having sort of an academic Persona or whatever is another version of it as well.

What year did you become a full professor at Stanford?

I was 33 or something. Early 90s.

I mean, you live in San Francisco, so you're not making that commute every day, I hope.

Nope. But I did for about a quarter century.

Yeah, that'll. That'll hurt the cortisol levels, won't it?

I use the commuter train caltrain here.

So you could read.

And I loved it. I love. This was much of it was before cell phones.

So you'd take it up at 4th and King and you just go, yeah, I used to make that ride all the. I used to have a girlfriend that lived in San Francisco and I loved that train ride. And then you get off on your bike at 4th and King and you could go anywhere in the city.

Exactly. I wrote. Half my book writing was on the train there. It's pretty weird when you realize that like one of your valid social communities or the conductors on caltrain, sort of as you're watching them grow up on you and things like that. But yeah, no, that was. I was a big fan of train commuting.

So speaking about books, let's talk about your more recent book. It's about human behavior, which, you know, I mean, I can see based on this discussion now how your interest would shift to that. What was the impetus for that research?

Well, title is Behave the Biology of Humans at Our Best and Worst. And sort of as we were talking about before I closed my lab four years ago and stopped active research to sit for four years and write this book. And it's basically trying to make sense of the biology of what is for me the most puzzling thing about us as a behaving species, which is we are simultaneously the most miserably violent species on earth and the most altruistic and cooperative and empathic. And any given human is capable, depending on the setting of incredible gyrations as to whether they are being wonderful or awful or in between, where behaviors where. Whether that counts as good or bad is incredibly dependent on what culture they happen to be doing it in. Just trying to make sense of the biology. I mean, it's totally boring biology as to like how your brain makes you do something like pull a trigger, like which muscle groups have been told, like that's. That's like studying cockroach neurobiology. What's totally interesting is the fact that we're a species where sometimes pulling a trigger can be one of the most awful things a human can do, and sometimes it could be one of the most wondrous ones. If you're suicidally drawing fire from innocent people and you're sacrificing yourself, or in one setting, you put your hand on somebody else's, and that could be a moment of incredible compassion, or in another moment, you do the exact same thing with your primate muscles. And that's the first step of betraying a loved one, of just making sense of this contextual stuff about human behavior, which is hugely complicated. And the song and dance that I go through in nearly 800 agonizing pages in the book is, you're going to understand nothing about that if you've concluded, aha, we now know this is the part of the brain that explains everything, or this is the neurotransmitter or the hormone, or the gene or the child. Instead, to make sense of human, human behavior, you got to factor in what your neurons did one second ago, but you got to factor in the environmental triggers of that 30 seconds ago. And you've got to factor in what your hormone levels were like this morning and what neuroplasticity you've done over the last two seasons, and what your adolescence was like in your childhood and your fetal life and your genes, and amazingly, what sort of culture were your ancestors inventing centuries ago because that influenced the way you were raised within minutes of birth? And what things you value and what things your amygdala does or doesn't respond to, and a whole thing of that. What sort of ecosystems produce different types of cultures? And then finally, evolution. And why we're, in some ways like chimps and in some ways like bonobos, but we're not chimps, we're not bonobos. We've solved our own special evolutionary. Like, you gotta understand this stuff. It's everything from one second before to 100 million years before, and all these levels interact, and it's complicated as hell.

When people ask the question, which I'm sure you've heard this a hundred times, and you hear people asking all the time, are we innately good or bad? That question doesn't really permit the level of nuance you're describing, the answer is yes.

Yes, exactly. And what's most startling about us is most of us have the capacity to do something that we would be stunned and sickened that we were capable of doing it and most of us are capable in some circumstances of doing something that is so damn heroic. And most of us spending most of our time doing things that instead are ambiguous and multi layered and full of ulterior motives and what's really going on there. And you look at the worst of us and the best of us and there's not a whole lot of really reliable predictors beforehand.

And how much of this, like, you know, you wrote a little bit about pms. So when I think about pms, I think about it purely through the lens of the endocrine system. Right. I think of it purely through the lens of when a woman is in her luteal phase, that progesterone level has to rise for the placenta. And then of course, virtually every time it's a false alarm, you don't need it, you shed that lining and that progesterone level comes crashing down. And it's this crashing down of progesterone that has always interested me. Why two women could experience the same. We can measure progesterone levels throughout the cycle and we could know that at day 22, two women could have the exact same progesterone and on the first day of their menses they could have the same progesterone. So you know, they had the same peak to valley. And yet two women can experience that in two totally different ways. Now I've thought about that through the lens of progesterone receptors and you know, the way we sort of talked about the cortisol stuff. Is there something else to that that you layer on top of that that is even more subtle about those differences?

Yeah, tons of this sort of additional insights. Here's one example that comes completely out of left field. And this was actually my wife's thesis research on baboons. So you're a female baboon and you're coming up on your period and we could frame it as you just did. Here's two females who are both about to have their period and have the same exact progesterone levels. And as soon as they start mentally menstruating, progesterone drops in the exact same way. And one of them is a totally irritable, awful like jerk to all the other females around her for three days afterward. And the other one is not. The other one withdraws and becomes socially isolated. Okay, what's the difference? It sure can't be progesterone levels and it's probably not going to be progesterone receptor levels. One of them's high Ranking she could afford to be a jerk to everybody else and get away with it. The other one's low ranking. Oh, it's not just your hormone levels, it's what sort of position in your society you have, even if you're a baboon or now you look at humans and depending on what sort of culture you're in, are you in an individualist culture or a collectivist? One individualist. The United States, poster child of individualist thinking, collectivist. 99% of the research has been done on East Asian cultures. And how you somaticize your mood shifts and your physical shifts during your period differs in collectivist versus individualist cultures. How irritable you become, not because there's a difference in how much of negative affect affect your feeling during the time. Are you in a culture where it's culturally acceptable to bitch and moan to all your best friends when you're not feeling well? Or are you in a culture where when you're feeling lousy, what you're supposed to do is reach out affiliatively and reify your like social values?

And how much of that do you think is also genetic? So for example, I mean even though I'm not a gynecologist and therefore don't see a lot of of this, I see enough to realize that women will often say my sister and my mother either go through or went through the same feelings. And of course as you described, there are so many different variants. The stereotypical one is the, you know, the sort of the nasty phenotype, but actually the one that I think might be more prevalent is the sadder phenotype. The more emotionally distraught, just emotionally labile, but in a non aggressive way. That's probably the phenotype I see more easier to cry or something like that. So how much of that do you think is heritable in the way that eye color or some other aspect of body habitus or even depression is quite heritable versus the ecosystem you're in. Purely environmental.

Well, the answer is you really can't choose one or the other, blah, blah. But if you could only manipulate one, which would be the first one. And I'm definitely of the school of genes get overrated in terms of their impact and you know, a gene affecting your eye color, it's okay to use words like determine and it's probably not even 100% accurate. But when you get to genetic influences on all the interesting stuff and behavior and our internal lives and all of that, yeah, genes are important, but overweight, overwhelmingly these are Genes that modify vulnerability, vulnerability to certain types of environments. Okay, so for example, you bring up depression and catastrophic pandemic of that. And you know, there's a whole shopping list by now of genes that have been implicated. And probably the single most important one, it's called the gene for the, the serotonin Transporter and Serotonin, SSRIs, Prozac, all of those. Serotonin is just like right in the middle of what we understand about the neurochemistry of depression. And it turns out the serotonin transporter gene comes in a few different flavors, a few different genetic variants, and a ton of basic research, rats, monkeys, et cetera, suggested that if you had one particular variant, you were more at risk for major depression. Okay, so this classic work, this guy at Duke of Sholom Caspi, who's sort of a God in the field, goes out and he follows like 17,000 people from birth up to age 25 or so. He's got genetic information on them and he's able to ask this critical question, okay, if you have the bad version of this Gene by age 25, are you more likely to have a history of clinical depression?

And what's the prevalence of the gene? Gene approximately depends on the population. In his population, his was a mixed.

One, but westernized western uterine populations, I think it's got about a 20% incidence.

So the question then is of those 20%, how many go on to get depressed? Of the 80%, how many go on to get depressed? The answer is very likely going to be it's not a one to one mapping. It might be an increase in risk by some factor.

And what they saw was overall there was no increase in risk having the bad variant. However, if it was coupled with a lot of childhood stress, you had about a 20 fold increase in the risk.

So just to be clear, on aggregate there was no difference. The hazard ratio is one for with gene versus without because of a ton of variability. But if you wanted to amplify it, take that gene and expose it to childhood stress or trauma and you almost.

Assure depression, you get a massive boost in predictability. Look at people without the scary and vulnerability variant and look at the same severity of childhood stressors and loss and you got a moderate increase in incidence of depression. These folks massive order of magnitude multiples of that more increase there. What that tells you is this is a gene whose variants alter how readily you deal with experiential kicks in the asses growing up. And it turns out these different variants are regulated in different ways. By glucocorticoids. Aha. So there's a stress angle, all of that. The same way there's another gene to the people who are interested in the genetics of aggression. This gene, monoamine oxidase, and it comes in variants and it.

And there's a class of drugs that targets these receptors. Yeah.

Again, a ton of basic research had suggested, ooh, there's a scary variant of it which if you have it, you are going to be more predisposed towards violence. And in fact the same group working with the same population, massive data set, winds up showing just having that variant doesn't get you a higher risk of antisocial violence, violent behavior by age 25, if and only if it was coupled with abuse, childhood abuse, growing up. Oh, if you didn't have the scary variant, childhood abuse, a little bit of increased risk, have this variant with the abuse and it was virtually the same figure as with the serotonin transporter gene. Huge boost over and over. The genes that are interesting when it comes to the stage stuff, these are all genes about vulnerability and potentialities and tendencies that are emerging only in certain environments and not in others. The factors are inseparable.

It makes me think of the APOE genotype, which is linked to Alzheimer's disease, and there we see that there is a difference. About 25% of the population carries at least one copy of that gene and they represent about two thirds of the cases of Alzheimer's disease. It's not a deterministic gene, but it does increase risk. Now, of course you could argue that maybe in a decade or more we will be able to say something very similar about apoe, which is it's not remotely deterministic. It only gets turned on when X, Y and Z happen before this period of time or in absolute. And of course we don't know what those things are right now. At least in the examples you gave you could say, well, trauma or childhood, you know, some event in childhood was, was the trigger. And if you're seeing a 20 fold difference, it's pretty clear that you found the trigger.

Nonetheless, there's still variability to explain after that. But yeah, it's pathetically that counts as virtually state of the art for understanding the modifying factors. And it's going to be that way. I mean, anytime you do these like gwas massive fishing expeditions and you come out with 300 genes are implicated in a trait that's as boring as height. 300 genes, which you put together all of your knowledge of the variation in them in any given individual and you have like 4% predictability of their height. Christ. If you're talking about genes for propensity towards feeling poignancy, or genes for like, anything that's interesting, it's just not a chance.

Even if you just limit yourself to diseases, you know, of the 20,000 genes in our body, you can really only point to about 100 that are directly this mutation means this disease. And they're all pretty esoteric, right? It's all like inborn errors of metabolism and certain things like that. But when you start to talk about the complex diseases like Alzheimer's disease, even as Predictive as the Apoe 4 is, it's not even close to being enough to understand it. And I think, yeah, it's funny, when you talk about it through that lens, you realize the importance of environment, which is the risk of stating the obvious. You said something a while ago that I made a note of because I wanted to come back to it. You talked about the effect of glucocorticoids on the hippocampus, and not only how harmful it was for memory consolidation, but overall cognitive impairment. And listening to you talk about that was exactly the way Matthew Walker at Berkeley speaks about sleep deprivation and its impact on the hippocampus, which then makes me wonder, I assume it's been well studied that when people are sleep deprived, we see greater elevations of cortisol. Do you have a sense of what the evolutionary basis of that is? Because it seems counterintuitive. You would think even evolution would want that to be in the opposite direction. I mean, the only explanation I can come up with is if you're sleep deprived, you're assuming that there's a reason for it that's good, and therefore you want that. Of course, notwithstanding the fact that higher cortisol will then prevent sleep, I think.

That'S probably the best sort of piece of teleology for that. Yeah. If you're like a basic mammal, which means either you are emphatically diurnal or emphatically nocturnal, and if instead you are wide awake eight hours into what should be the 12, this does not happen by chance. The odds are you have something stressful going on. I think that's the logic of it turns out the stress, sleep, sleep quality, cortisol cluster of interactions, even more subtle, incredibly cool study. This was a science paper some years back that. Okay, so as we talked about the circadian peak of glucorticoids, or around the time you wake up, what's interesting is about an hour before you wake up, levels begin to rise, telling you something, a subtle point, which is a lot of glucorticoidal actions are not for dealing with a stressor that has already commenced, but can be preparatory. So the preparatory stressor is having to actually get up and get out of bed and start functioning, get dressed in an hour before people wake spontaneously, glucorticoid levels are elevating. Now, in the study, what you do is you take a whole bunch of volunteers who are sleeping and you see the preparatory rise, all of that, and you tell them, tonight we're doing something different. I'm going to wake you up at 4 in the morning and what you see is around 3 o', clock, glucorticoid levels start rising. Okay? Now you do something even more interesting. You say, okay, tonight, I'm not going to tell you when, but I'm going to wake you up at some point during the night and that's the end of your night's sleep. And the person's about 90 minutes into their sleep stage and all of that and cortisol rises and stays high for the rest of the night.

You get one sleep cycle and then the adrenal gland says, that's it, I'm on ready alert.

Yeah, exactly. So not only is it bad not to get enough sleep, not only is it bad if the insufficient sleep is fragmented, but the worst is if it's fragmented unpredictably. And that's like every medical resident in history.

It's the first thought I had, actually, when you said that, which was, was every night of call, you have this pager and you're in this call room and you just want so desperately to sleep for an hour, two hours, three hours. I remember as my residency went on, the degree of sleep deprivation got greater and greater that the steps I had to take to ensure I wouldn't sleep through a page got greater and greater. And I'm not making this up. I don't think I've ever told this story before. It's so ridiculous. I used to use this really heavy paper tape and tape the pager to my forehead at full volume. Because you would get both the sound to your ear and then you'd get the transmission, you know, through the bone. But imagine laying in bed with tape wrapped around your head, holding a pager on your forehead in anticipation of what's coming, not knowing when it's coming. It could be in five minutes or it could be in two hours. You know you're going to wake up. Yeah, I'm guessing that wasn't great sleep.

No, it's like wildly destructive. And what do you know? It turns out if you have elevated glucorticoid levels while you're asleep, you have less delta sleep time, which is the restorative stuff. You make less adenosine stores in your brain during. So even if you manage to go to sleep, if it's under the. I could be asleep for two hours now or 30 seconds, the sleep quality is going to be horrible.

This interplay becomes more pronounced. What about cancer? What role do you think stress plays in cancer? And do you think it's mostly mediated through the immune system? I mean, cortisol can be quite damaging.

Yeah, hugely, hugely controversial subject. There is a common perception that stress can play a very substantial role in the onset of cancer, in coming out of the remission and rates of tumor growth and such, sufficiently so that there's been all sorts of studies where you ask cancer patients, what do you think is the cause of your cancer? And stress is invariably way up there. The actual evidence for a role of stress in causing cancer, bringing it out of remission, accelerating tumor growth, is very, very minimal. There's been a remarkably small number of good prospective studies of humans that have really, truly ruled out all the confounding factors. When you look at the animal studies, what they typically involve is you experimentally induce a tumor, you inject transformed cells, you give a carcinogen, some such thing. My lab back when did some of that work. Under those circumstances, you can accelerate the growth of a tumor, but those are circumstances of cancer acquisition that are virtually irrelevant than to human cancer.

And the other question is, can you do it without perturbing other things? So, for example, if you go ahead and stick the tumor into the mouse and apply a stress to it, it seems that that by definition will alter some other parameter. What it eats, how much it sleeps, the quality of its sleep. So it becomes difficult to disentangle cortisol. I mean, I guess the only thing I can think of is what does the experiment look like where you take the mouse that experimentally has the tumor and you just start injecting more glucocorticoid. So, in other words, you don't actually increase the stress level, you just increase the readout state of stress.

You accelerate the tumor growth. We did one study showing that as soon as cells become transformed, they upregulate the GLUT4 glucose transporter, and that's the one that's further upregulated by gluticoids and target cells. So you're just shoveling energy over to those cells. Yeah.

But preferentially consume glucose anyway, just given the number of them that followed by the Warburg effect. So to me, even though that's very mechanistic and artificial, that strikes me as pretty reasonable evidence that cortisol can play a role in cancer. I mean, I guess it's going to be much more difficult to disentangle that in the real world.

Yep. And again, these are types of cancers where this was virally induced transformation of cells that are then transplanted very artificial systems that turn out not to be terribly applicable to puma cancers. And what you wind up seeing then. Okay, yes, glucocorticoids can be potently immunosuppressive. Usually by the time you have a tumor growing that's long past the point where it's an immunological problem. It's. Now, can you keep the tumor from growing a whole bunch of capillaries that will feed it? Can you keep it from stealing all sorts of energy? Can you keep it from turning off cell death programs? It's no longer in the immune realm.

So it seems that there'd be hard to make the case that acute bouts of stress can really have any impact because, you know, yeah, sure, you can acutely disrupt the immune system and maybe get sick. Right. That could explain why you might get a cold under a period of great stress, but not necessarily cancer.

And what that wants meaning is that should be a massive, massive take home message for anyone who's predisposed towards thinking, ooh, stress caused my cancer. Too bad I didn't have better priorities in life. Now I know whose fault it is, that sort of thing. And it should certainly make you damn cautious if there's some highly credentialed quack out there who is selling a stress management will stop your tumor, will make it disappear entirely, and we watch your wallet at that point. All that being said, there's been some wonderful work and a lot of this was pioneered by a Stanford colleague of mine, David Spiegel, who showed that things like supportive group therapy among cancer patients enhances survival.

So what do you think is the mechanism of that?

Okay, this was when he first published this in the late 80s. This was front page news.

I remember this. I don't remember it when it was published, but I remember learning about it in medical school.

Massive finding. And one is immediately tempted to, at least as a biology type like me, to come up with a biological explanation along the lines of what you proposed. Okay. Supportive group therapy. You're less stressed, so you don't secrete as many glucorticoids and therefore you're not having those adverse effects of it on your immune system. So you're better able to fight the tumor. You live longer trala and lower glucose.

Levels and lower glucose and lower insulin and lower ig. If you could, you could come up with a complete biological.

And in general those studies have shown that pathway does not occur. Spiegel and I did some of those studies things. So what's actually going on? Something which if you're a nuts and bolts reductive bio type person, is terribly disappointing, but is so interesting and important. People, when they have supportive cancer therapy with other people going through the same hell, they become more compliant. When they're medical regimes, they're more likely to go the extra round of chemo because everybody else is cheering them on saying I didn't want to do it all either. And they're more likely to take the meds that make them nauseous as hell. Have you eaten today? Me neither. We're going to eat right after we're done with the group. Have you taken your meds? You're going to take them right now. People become more compliant. And that was very hard to demonstrate because what cancer patient ever wants to admit to a researcher? Actually I skip about a third of my meds because they make me feel so damn sick. They're saving your life, Witter. It's in some ways a dark, dirty secret in cancer therapeutics how much people diverge from their optimal treatment regime. Because the treatment regimes are sheer utter hell. When you're surrounded by people who are going through the same thing and understand you're more likely to be compliant, I think that winds up explaining an awful lot of that effect.

So when you look at cancer, atherosclerosis and neurodegenerative disease, it seems to me that the direct lines of evidence for the damage of hypercorticolemia and the accelerated stress response are probably most demonstrated in cardiovascular disease and atherosclerosis vis a vis several mechanisms, not the least of which is hypertension, both macro and microvasculature, but also through endothelial disruption, adhesion of cells and sludging.

And yeah, it's the best understood realm. Cancer is probably the weakest realm.

I would expect that it's playing a role in dementia. But again, this probably gets to the layer of susceptibility right there's probably in isolation, maybe this wouldn't play a role. But in combination with other factors it would. And it seems that, for example, we know that cortisol inhibits melatonin secretion. So even if you take two people who have the same amount of blue light reduction, which should therefore stimulate melatonin, the one with hypercorticolemia is going to. And we actually measure this, right? We can measure overnight urinary cortisol and overnight urinary melatonin. You can see this association quite strongly. Well, melatonin, it's a pro neurogenic molecule. So having less of that is less restorative to the brain, even beyond its important role, which is sort of removing the brakes on being awake. So what other lines of evidence do you see beyond what you've already described at the developmental stage, now, later in life?

Basically everything we talked about with the hippocampus applies in the adult brain as well.

And it's the first place we tend to see changes.

And it was the first area researched, first evidence for stress damaging the hippocampus and hippocampal dependent memory type stuff. Late 70s, I mean, that was really the first domain and superb studies from a number of groups. And I had my 2 cents in that literature also showing you could accelerate aspects of hippocampal aging with lots of stress, lots of glucorticoids, extent of neuron loss, extensive memory problem, extent of reactive gliosis, et cetera, et cetera. Next big outpost that people began to appreciate in adult brains was derivative of what we talked about before, which was the amygdala.

I was just about to say, is there a direct correlation, I guess, between amygdala size and dementia?

What you see instead is the syndrome where it's most demonstrated is ptsd. You see expansion of the amygdala and you see atrophy of the hippocampus.

And.

And glucocorticoids probably play the driving role in both. So in the amygdala, like the hippocampal story is stress and glucorticoids screw it up. Neurons don't work as well, networks don't work as well, the overall size decreases, you get atrophy in the amygdala. It's the exact opposite story. Neurons work better than they should. Neurons become more excitable, form denser networks, the amygdala gets bigger. What's that about? The problem with chronic stress is your memory goes down the tubes. Hippocampus isn't working as well as usual. The problem with chronic stress in the amygdala is it works better than it's supposed to. And this is the link between stress and anxiety disorders, stress and fear Stress and all of that. Next sort of outpost that people started looking at was the dopamine system in the brain. And dopamine neurotransmitter most famously associated with reward pleasure. Cocaine works on the dopamine system. A much more accurate, subtle picture of it is dopamine is actually more about the anticipation of pleasure than it is about pleasure itself and about goal directed behavior you're willing to do in anticipation of reward. But then a whole literature showing what does stress and glue corticoids do there, they mess with the dopamine system. It's less clean of a story than amygdala or hippocampus, but in ways that predispose towards the two big psychiatric diseases of screwed up dopamine systems. Number one, addiction. More vulnerability to addiction, harder to get off of addictive substances. Number two, depression. Depression is a disease on a certain level. Dopamine depletion, it's a disease of inability to feel pleasure and hedonia. And that's the neurochemistry of the link between chronic stress and why that increases the likelihood of the first three, four episodes of major depression. What for me is the most exciting area is one where if I was starting over, you know, forget the hippocampus, who cares about like how many digits you could remember backwards or whatever. The most interesting domain is turning out to be what stress and glucorticoids do to the frontal cortex. Judgment, impulse control, executive function, long term planning, strategizing, and it turns out virtually every bad thing cellularly that stress and glucorticoids do in the hippocampus, they're turning out to do in the frontal cortex as well. And what does that mean? Begin to explain this entire world of why it is during moments of extreme emotional arousal, especially aversive ones, why we make terrible, terrible decisions that seem brilliant at the time. And you spend the rest of your life regretting it. Because impulse control, your amygdala overpowers your frontal cortex at those times. Your amygdala has a lot more talking to your motor systems than your frontal cortex does. It's the reason why judgment and impulse control become terrible when we're frazzled. It's also looking like as a side story with that. It's one of the reasons why when we're very stressed, it's hard for the frontal cortex to do one of its harder jobs, which is to take the view of the world from somebody else's perspective.

Empathy.

Empathy, exactly. Some research on animal models of empathy, and this was work with this guy at McGill named Jeffrey Mogul, where I collaborated with him, showing in both rats and humans, you're less empathic towards strangers when they're in pain. And if you block glucocorticoid release, you don't get that effect anymore. Glucocorticoids, the stressfulness of dealing with scary novel humans or scary novel mice. If you're a rodent, Glucocorticoids narrow your window as to who counts as an us and whose pain registers and things of that sort. So for me, you know, it's incredibly interesting if you're stressed and suddenly your SAT scores plummet. The fact that stress makes people crappy to each other and less empathic and more parochial and more xenophobic and more impulsive with the worst of our impulses. That's the stuff that really interests me these days.

Everything you just said, Robert, is almost a call to action in criminal justice reform. And I've done a podcast on this topic where, you know, I was very fortunate to go into a maximum security prison with a program that is really there to do incredible, incredible rehabilitative work led by this woman named Catherine Hoke. It's a humbling experience. There's a game that we played about halfway through the day called Step to the Line. This is a game that's used to basically identify the vast difference between those of us who are volunteers. Like, in other words, the role of luck in our lives versus the gentleman who two thirds of these men are never going to get out of prison. One man had even spent more than half, half his life in solitary confinement, his total life. So it starts with these questions of Step to the line. If you grew up in a home that had two parents and you know, of the volunteers, 60% step to the line of the inmates. 5. Step to the line. Right. Step to the line. If you grew up in a home where there were more than four books, you can imagine the disparity. Step to the line. If you saw someone die with your own eyes before this age. Step. I mean, and it's a very emotional thing to go through because as this game is unfolding, you're feeling more and more fortunate, on the one hand, because you realize, if not for the grace of this luck and at the same time, the empathy you have for these men who have done the most heinous things grows and you start to realize, boy, there's a fine line between those of us on the inside, those of us on the outside. Because everything you said really resonated when I was thinking about Some of the stories the men told us about the decisions that they made. And there's this one part of the exercise that's incredibly emotional where you're partnered with one, one guy. So it's one volunteer, one inmate, and you were each telling the other person the greatest regret of your life, the biggest mistake you've made. And hearing some of these stories, it's not to justify anything that's been done, and it's not to say that there shouldn't be consequences for it. But a lot of these things that people have wound up in prison for are really impulsive, horrible decisions as opposed to decades of sinister planning. It's one thing to look at what, you know, like Hitler did. It's hard to argue that anything that he did that was bad was impulsive. It's quite another thing when you look at someone in a gang related incident where you know, this guy gets shot and you're going to shoot this guy back, or this guy's about to shoot you and you shoot him. I mean, and yet that type of drug related violence is disproportionately represented in, certainly in the US penal system. And then to build on what you said, it's not clear that the environment in there is reducing cortisol levels to the level that would enable rehabilitation, which is really the thesis of. And a lot of people I'm sure listening to this are thinking, why would you feel empathy for these folks that are in there and why should society care about them? But the reality of it is if they're going to get out, you should care. That says nothing of maybe the higher level that you should care, which is the injustice of it. But even if you took a purely selfish view, a non trivial number of these men and women are going to get out. So wouldn't you rather they get out and function better? And yet it's really tragic to see this. And I know two people actually very well who spent a great deal of time in prison, one of whom I interviewed on this podcast, his name's Cory McCarthy. And it really strikes me as the exception and not the rule that people are able to emerge from that in a environment and go on to be successful outside.

It's a system that is so, so broken. Any study, the last century and a half's worth of neurobiology and genetics and child development and all of that, and the notion that we are free agents of our action is so destructively misplaced.

I'm sure you're familiar with the work of Sam Harris. Sam has been one of the most interesting forces in my life at getting me to really even question this notion of free will. And once you realize that free will may not even be yours, it takes luck to a new level.

It's something I spend a lot of time thinking about.

Now, what advice would you offer somebody who is interested in the neurobiology of stress or behavior and who wants to be able to look back when they're your age and be as, you know, maybe accomplished is the wrong word. I don't want. I know you sort of bristle at that, but to have made as many contributions as you've made, I mean, what in retrospect, was sort of the secret to being able to pursue your bliss and be as successful as you've been and look, frankly, to be where you are and to still have the passion that you have for what you're doing, which to me is really the marker of success, it's that you're sitting here saying, there's this other problem. And I, you know, like, I could spend, you know, the next 20 years just thinking about that. How do you think about how you've done that?

Just damn luck. Every bit of neurosis, every bit of affective instability I've got, every childhood trauma I've got tucked away, I've titrated in just the right way that I've turned it into more productivity. Been incredibly lucky in that regard. My capacity to sublimate emotion into intellectual pursuit, into really, really, really wanting to understand something into. I've just been very lucky in that regard. I've gotten just the right levels of all sorts of, like, tumult that have synergized most productively. In other words, just huge amounts of luck. Huge amounts of luck. And at least now, coming later in life, an increasing capacity to more carefully try to analyze what cost each type of ambition comes with.

Say more about that.

Oh, I don't know. This had much to do with my closing my lab four years ago as a big, booming lab with lots of people in all sorts of labs around the world, we were going to kick the asses of by getting the answer to this or that. And, you know, if you're raised in the right sort of rarefied, ambitious world of biomedical research at age 25, you've got a list down to the floor of the diseases you're going to vanquish and the problems you're going to solve and all of that, and, you know, getting to that point in life where you're realizing it's not going to happen.

Is that what actually happened four years ago? Was it that much of a cerebral realization or was it combined with other factors? You know, you've described obviously having this network of people around you who matter the most and I mean, was part of it just thinking I haven't spent enough time with them at the expense of this? Or was it the this problem is enormous and when a thousand years from now, whether I worked this much harder or this much less, it won't have altered the trajectory of xyz? I mean, how much of it is all of these, all the above.

Family growing up real fast as they tend to do, realizing your best work was decades behind you, realizing there's this book you want to write where the only way you can do it is to just sit for really long stretches, Kenyan field work having collapsed a few years before, body feeling older limits to how many 80 hours of work a week you can do all of them converging.

What I mean, it's such a cliche question. What advice would you give the 25 year old Robert as he was just finishing that PhD at Rockefeller?

Be less ambitious?

Well, I think on that note, which by the way, I think is some of the greatest advice one could ever get and receive and those of us who are still on the climbing ambition curve should do everything to listen to it. I want to thank you so much for taking the time to sit down with me and more importantly, I think for just all of the work you've done and you're continuing to do. Thank you so much.

No, thanks for having me on. This has been fun is the wrong word, but stimulating and good. Glad we did this.

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