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

27:40And 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, 5 ,200 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 maceye 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 days 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.

28:35And that's the key thing. They are well off enough in our westernized sense that they consider 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 tigers were chasing us instead of psychosocial stuff that we invent and that we can wallow in for hours every day and that's exactly what baboons do through great models for Westernized stress. Do we have evidence 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.

29:30That's my guess. So 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, a 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. is one of the things that I focused on. You know, I spent my first 10 years deciding rank and status, social status, 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 glucoticoid levels, you're resting blood pressures lower, all sorts of stuff works better.

30:16But 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 is there, 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 world where to use for another species these days. In one troop being low ranking can be a whole lot crappier than in another true, in terms of how often somebody in a bad mood displays as aggression on you, in terms of how often somebody actually grooms you, and often, in terms of how often you get to finish a meal before somebody steals it from you, kind of thing.

31:09So 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, 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.

31:46Absolutely. And one of the most interesting things about us, us humans, when we can talk about across all sorts of primates being low ranking in general is bad for your health or 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 hierarchies at once and we can have very different ranks in them. So for example, family work sports team hobby. It's probably you've got some guy who's the mail room 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.

32:31And you better bet when you ask him what's important in his life, nine to five 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.

33:12You 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 hypercordosolemia 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 a scientific word as this culture.

33:53If you're a high ranking baboon and you're worst rival sneezing a hundred yards away has seen as a major provocation, you're going to have much higher cordicoid levels than And if you're a highest ranking baboon for whom that's no big deal. And in fact, often you may have higher glucoticoid cortisol levels than if you're number 10 or number 20 on 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.

34:33there 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. These adjutate and these vigilantes got to look at the guy and lunge towards him a couple of times. If we're 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?

35:22So I understand the book ends, 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.

36:05Does 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 and 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.

36:46I 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. Limpic 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.

37:39But limbic system underneath, they're all the subterranean emotion stuff. And a migdala 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 didn't use to scare you. And you're a migdala does the exact same sort of cellular basis of learning that goes on another part 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.

38:22There are some say, 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 can think of the human brain as having very grossly three parts. This brain stem, this mid brain, 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. The brain stem basically handles everything we don't have to think about ever, breathing and all of those autonomic and sympathetic parasympathetic functions.

39:03and 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 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. And 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 that on top is that cerebral thinking, cognitive cortex thing.

39:45It's very easy to come up with a 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 or an earth can do. You're sitting there and you're some will to beast and some other scary will to be 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.

40:26Aha, your emotional brain can alter sort of the basic regulatory stuff down on the basement. Now you go one step higher and you lay where 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 some day. And you start breathing faster. And your brains, then 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 warthog can do, which is think, think about something that's scary or arousing or remember the time that you would.

41:09And 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 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, this This is like this classic, great study and 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.

41:56And 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, what do you think of this bridge or how is it walking across this or whatever. The other half of the time you would not encounter this person until you were safely out of the other end. Then they would ask you to evaluate the attractiveness of the person. Same person. That's seeing her in the middle of the bridge or at the far end.

42:36Exactly. Say, hey, remember all you were doing that you there was this you know do you want to rate her attractiveness was she friendly did she seem smart with it 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 it's 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 accelerate and they don't rate the person as attractive.

43:15Is it the same with the beta blocker? You would treat you. 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. While boring reptilian regulatory stuff down there is helping influence what you think your emotions are at that point. That reminds me of the 1995 -ish movie Speed with Kiano Reeves and Blankenar name. Bullock. That's right, center Bullock. We're at the end of that movie. There's some cheesy line about how relationships that start under this much distress, you know, it's dangerous.

43:53But of course, the other read on that now is, yeah, if you're on a bus that's about to blow up, like I think you're going to think that chair is attractive, right? Potentially. Wow, I haven't thought of that movie in years, thanks. I'm sorry. That was so. You can go home and I'm sure Netflix will stream that for a while. So I've 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.

44:28And 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 microsubsides 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 it the number of our neurons? Like what is it that enables us to have all of this additional torture?

45:05Yeah, it's incredibly interesting because I mean there's 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 -shroom neuron and a human neuron and could recognize it and their sleep. But yeah, for the most part, we are not humans because we've 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. Here's a couple of types of neurons that people use to think we're specific to humans and turns out to find them in elephants and whales, also, and that's plenty interesting.

45:44But 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 binobo. So you say, we're going to 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 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 Program cell death you can do that.

46:26So what's the big difference for every neuron that a fruit fly has we have a hundred 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 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 on, I 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 and the colony plus or minus two degrees and they have specialization of labor.

47:15And no ant has any more rules than he had when he was watering around on the 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.

47:59If 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, maybe it 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 epigenetics, but that was the only assumption I could make was that this must be modulated through that mechanism.

48:36Do you see evidence of this in animals? I mean, it's absolutely. And it's one of the trendiest topics around, I mean, like hooray science finally, record places childhood matters. What your child is like has a lot to do with what sort of adult you're going a wine to being what do you know and like lots of childhood 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?

49:19is 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 whole trendy field of epigenetics, which is early experience doesn't change your genes. It doesn't change your DNA sequence with some like, you know, circus trick exceptions. You've pretty much got your DNA sequence forever. However, 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.

50:03And 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've picked the wrong room 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 and to 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?

50:46It size in 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.

51:33Okay, so you were fetus and got exposed to lots of mom's glucocorticoid levels. And as a result, as an adult, you've gotten a large domigdala and you see threat all over the place that other rats don't. And among other things, you secrete elevated levels of glucocorticoids the corticoids, 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.

52:25Exactly. Something term non -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 their half a dozen generations later. And the exact equivalent of some of these have and found in humans. In other words, individual differences are rising not only from experience, but from the multigenerational transmission 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.

53:08I'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? We can quantify this stuff in terms of what hormones are happening in the body and how the hormones are moving the body.

53:42It'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 hypercordicellemia and or its accompanying features will impact the brain, especially, well, through any timeline you want. 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.

54:24You 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 glucoticoids, translated more reductively. It's got extremely high levels of receptors for glucoticoids by the standard to 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. thing, you don't remember where you were on 910 as opposed to 911 kind of thing.

55:05Your memory processes has to come with a filter saying, is this one important? So you're saying the cortisol amplifies memory consolidation and that you use this to consolidate stressful memories as a way of learning. Exactly. Along with epinephrine and neuroepinephrine and directly 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 them as readily. But some of it is also Norepi being released within the brain during stress.

55:38So 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. You're, if you're like three coordinate, your glucoricoid 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.

56:19So 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 stressed 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.

57:03They 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 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 glucotoxoid 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 know use the example of a 10 -year -old.

57:54Well 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 that's 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 if stated the other way.

58:23I have a friend who's a cardiologist who splits his time between a hospital in Oakland and a private practice in San Francisco. Some of the time what he's doing is dealing with eight -year -old who are considering getting a pacemaker because the ski season is coming and they are wondering if they're going to be in shape in time for that and maybe a... and then back in Oakland, he's dealing with 50 -year -old elderly men who are having heart disease. Yeah, socioeconomic disparities are... I won't get on my soapbox now. When you look at the source of variability and health among humans on this planet, socioeconomic differences, differences in absolute levels, differences in degrees of inequality within cultures and within communities and so on.

59:12There's 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 socio -economic 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 Nuban Mountains in the south of Sudan. So he's the only physician to take care of one million people who, as you know, are being killed by their own government.

59:55But sheer 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 is 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 in the center and the trauma, like, you know, the shrapnel blowing people apart. Not surprisingly, they're just not getting the same chronic diseases, you know, 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.

1:00:34But what really surprised me is there was no suicide. And I found that as the single most interesting thing I, yes, I learned from Tom, which was we would look at their life and 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.

1:01:20Like 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.

1:01:59But 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 that you as 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 the worlds of social capital and social support. And when you look at the whole literature and you look basically at every westernized country under the Earth and it's now seen as they become westernized and what you see is the health socioeconomic gradient.

1:02:50The 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 in any country on earth. And 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.

1:03:39Okay, 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 wrong of the way, the poorer you are.

1:04:23The poorer you are with respect to health. I'm sorry. The poorer your health. Yes, thanks. So now you unpack that and what's the most obvious explanation and this is what people call a neomaterialist explanation, which is obvious the poor you are, you don't have healthcare access, you don't have health insurance, you can't go to the doctor is readily your car 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.

1:05:04So 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 life spans 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.

1:05:55Turns 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? but where would you place yourself on this 10th 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.

1:06:38In other words, if you took someone's income, which is quite objective, it would offer no more prediction than asking that person in the new but 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.

1:07:23And you would 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 for this guy, Richard Wilkinson in the UK, who shows what's the best, most like 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. This is where social media, it's the amplifier to all amplifiers of this, right? 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?

1:08:09Lifestyle of the rich and famous or You could be driving down a freeway and somebody passes you in I don't know what counts as a high status car these days The cost of fortune but they come speeding past you and 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 a primate 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 Renabor has more camels than you, that's a very tangible, real thing in terms of likelihood of surviving the extra income inequality explains the mediating effect between objective socioeconomic status, subjective socioeconomic status, and health outcome.

1:09:06What 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 is allowed is to do. It makes the local counts as low. That's right. That's exactly right. It's expanded. What local means? You can sit there and watch, I don't know, lifestyles are the rich and famous. Back when you would never have gotten into like the petty or fiftims, 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.

1:09:45This 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 and that have 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?

1:10:24And 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 We'll 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 suggests that we are at a critical juncture?

1:11:09Because now 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?

1:11:29Is this truly people have been worrying about for centuries. Oh my, 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.

1:12:08Maybe 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, pariahd -alessent kid who's vulnerable in all sorts of ways, no matter what, decade or century it was you're the last one picked for the game, you're the one released 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 24 -7 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 And it amplifies further.

1:12:58And the technology does absolutely that. What I think it does is it makes the 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 take a 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 Think about this personally, the one I most worry about is the last one.

1:13:55I think I've got a pretty good hand -lawn 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. Like, and again, I'm not saying this for anybody else, but this is just my personal thing. And even with sleep, like 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 matters. And to forgo this thing, bad idea.

1:14:29It'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 post -prandial 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. It's kind of a weird guy. For almost four years I've been wearing a glucose monitor all the time. So it measures my glucose 24 -7 at one 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.

1:15:10And without a question, when you look at a 24 -hour period, if you stripped away the x -axis of time, I could easily identify mourning 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.

1:15:35I normally 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 day, so 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 110 milligrams per deciliter 24 hours after my last meal, which by the way was bacon and eggs.

1:16:15It'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. And 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.

1:17:00And fits perfectly with morning awakening is when you get your highest glute corticoid levels, which is probably one of the main driving forces on the increased blood glucose low. And 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, which is, why is it that someone who already has glucose dysregulation would have an even higher cortisol response in the morning, and you'll see enormous fluctuations in glucose?

1:17:44I 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 pill. 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 hypercordisolemia. It's one of the most complicated endocrine situations, and yet as you've described eloquently, it's also so innately wired into us.

1:18:22And 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. Which is someone else be thinking? Right off the bat, I'm delighted to see that I have a persona of us and I'm actually like one of the most type -based rest 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.

1:19:12I'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 low subjective sense of health, you should have objective measures as well, with all sorts of interventions. What 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.

1:19:53It needs to be your 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. The benefits of aerobic exercise, I don't know what the magic number is. these days about 20 or 30 minute blocks is 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.

1:20:28And 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.

1:21:00And what you're basically saying is, if you want to combat this hypercord of salibia, 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 know to and you're just going 24 -7. And if you've gotten to the point of saying, this is crazy, this is not a quality life. I want to live a healthy quality old age. Well, I got to get this stuff under control. I'm going to start doing something stress management.

1:21:40And 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 know to them enough that none the less 20 minutes every single day you were doing this, it almost doesn't matter what intervention you're doing, you're 80 % of the way they're 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're finally saying, I matter enough to do something about this or I'm activated enough or I'm optimistic enough to actually go your halfway there at that point merely by doing something on a near daily basis.

1:22:33So 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 a daily seven times a week, you were 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 stress or 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.

1:23:26And 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 nader 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 level 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.

1:24:02It had gone up like six beats per minute. And if anything, I was in better shape, exercising more regular. 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 a 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.

1:24:48It 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, if I spend an hour on Twitter, my blood pressure could be through the roof.

1:25:22So it's like, everyone's got to kind of pick their thing. you said your type A, which obviously you are. I mean, you know what I didn't say at the outset when it starts being, 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.

1:25:52What 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 hang out with people who are field biologists of any sort and again I've only been a part time. Anyone who are over the decades but nonetheless still think of myself as a field biologist. We're kind of a solitary tribe. During my peak periods of doing field work, I'm 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.

1:26:35Temperamentally, 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 bathrooms because I'm a primate social behavior. I'm interested in primates, social behavior. And there's big sort of piphony I had in my work that, okay, you're a 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 do 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.

1:27:12So there was something ironic that I was like studying the health benefits of sociality, living alone in a tent 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 as a refusional 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 that point I could not 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, like being in love with them and stuff.

1:28:20That 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?

1:28:54I mean, you couldn't get up there and 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? for it was 33 or something early 90s. I mean, you live in San Francisco, so you're not making that commute every day, I hope.

1:29:35Nope. But I did for about a quarter century. Yeah, that'll hurt the court of Saul levels, won't it? I use the commuter train, countering here. So you could read and... I loved it. This was much of it was before Saul phone. So you'd take it up at fourth in King and you'd 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 Fourth and King and you could go anywhere in the city. Yeah, 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 are the conductors on Cal trains, or as you're watching them grow up on you and things like that.

1:30:16But 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 that are 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 in 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.

1:31:13And 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 are where weather 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. generally totally boring biology is to like how your brain makes you do something like pull a trigger. Which muscle groups have been told? 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.

1:31:59And 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.

1:32:40If you've concluded, aha, we now know this is the part of the brain that explains everything. Or this is the neuro transmitter or the hormone or the gene or the child. Instead to make sense of human behavior, You got a factor in what your neurons did one second ago, but you got a factor in the environmental triggers of that 30 seconds ago and you've got a 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 rear 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 all the thing of that.

1:33:32What 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 evolution. Like if you got to understand the stuff it's everything from one second before to a hundred million years before, and all these levels interact, and it's complicated to sell. 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.

1:34:10The 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 sick and that we were capable of doing it. And most of us are capable of in some circumstance of doing something that is so damn heroic. And most of us spending most of our time doing things that are instead of 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.

1:34:51So 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 loodial 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 a 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.

1:35:32And on the first day of their mencees, 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.

1:36:07So, your 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 they have the same exact progesterone levels and as soon as they start menstruating progesterone drops in the exact same way. And one of them is a totally irritable, awful, like a jerk to all the other females around or 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. It's probably not going to be progesterone receptor levels.

1:36:44It's a... 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, post or child of individualist thinking, collectivist, 99 % of the research has been done on East Asian cultures, and how you somatisize your mood shifts and your physical shifts during your period differs in collectivist versus individualist cultures.

1:37:31How irritable you become. Not because there's a difference in how much of negative 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 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.

1:38:13And of course, as you describe, 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 habit is, or even depression is quite heritable, versus the ecosystem you're in purely environmental? Well, the answer is you really can't choose one of 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.

1:39:05And, 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 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 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 serotonin transporter and serotonin, SSRIs, prozac, although the serotonin is just like we're right in the middle of what we understand about the neurochemistry of depression.

1:40:00And 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, etc. 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 Shulam Kaspe, 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, quote, bad version of this gene by age 25 or you more likely to have a history of clinical depression.

1:40:43And what's the prevalence of the gene approximately depends on the population in his population. His was a mixed one, but Westernized Western New York 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.

1:41:23So just to be clear, on aggregate, there was no difference. The hazard ratio was 1 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 scaryant vulnerability, variant, and look at the same severity of childhood stressors and loss, and you got to 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 ass is growing up.

1:42:12And 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 for the people who are interested in the genetics of aggression, this gene model would mean oxidase, and it comes in variants. And there's a class of drugs that targets these perceptors. 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 more be more predisposed towards violence. And in fact, the same group working with the same population, massive data set, winds of showing just having that variant doesn't get you a higher risk of antisocular violent behavior, yh 25, if and only if it was coupled with abuse, childhood abuse growing up.

1:43:02Oh, 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 of the serotonin transporter gene, huge boost in their, over and over the genes that are interesting when it comes to this 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 geneotype, 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.

1:43:52It'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 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.

1:44:34But 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. In any time 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 and then you give an individual and you have like 4 % predictability of their height. You know, Christ, if you're talking about genes for propensity towards feeling poignancy or genes for anything that's interesting. It's just not a chance.

1:45:18Even if you just limit yourself to diseases, you know, of the 20 ,000 genes in our body, you can really only point to about a hundred 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 APA we for 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, you know, through stating the obvious, you said something a while ago that I made a note of because I wanted to come back to it.

1:45:57You talked about the effective 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, 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. But 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.

1:46:35I 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, not with any of the fact that higher cortisol will then prevent this. I think that's probably the best sort of piece of teleology for that. But if you're like a basic mammal, which means either you are emphatically diurnal or emphatically nocturnal, and if instead you're wide awake eight hours into what should be the 12th, this does not happen by chance. The odds are you have something stressful going on. I think that's the logic of it.

1:47:10Turns 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 glucoticoids 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 glucoticoid 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 the address in an hour before people wake spontaneously.

1:47:57Glue corticoid 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 gonna wake you up at four in the morning. And what you see is around three o 'clock, group corticoid 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 sleep. And the person is about 90 minutes into their sleep stage and all of that and cortisol rises and stays high for the rest of the night.

1:48:37You 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 every night of call you have this And you're in this call room and you just want so desperately to sleep for an hour or 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.

1:49:21And I'm not making this up. I've never told this story before. It's so ridiculous. I used to use this really heavy paper tape and tape the page to my forehead at full volume because you would get both the sound to your ear and then you'd get the transmission 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 gonna wake up. Yeah, I'm guessing that wasn't great sleep. Oh, that's like wildly destructive.

1:50:00And what do you know? It turns out if you have elevated glucoticoid 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 medallated through the immune system? I mean cortisol can be quite damaging. Yeah, all right. Huge, hugely controversial subject.

1:50:40There is a common perception that stress can play a very substantial role in the onset of cancer in coming out of remission and rates of tumor growth and such. So, 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 in variable 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.

1:51:21When 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 backwinded 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 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 it sleeps.

1:52:01So 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 glute -4 glucose transporter. And that's the one that's further upregulated by glucoticoids and target cells. So you're just shoveling energy over those cells.

1:52:38Yeah, but these are - Which preferentially consumed glucose anyway, just given the number of them that fall by the warberg 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 in very artificial systems that turn out not to be terribly applicable to human cancers. And what you wind up seeing then, okay, yes, glucocorticoids can be potently immunosuppressive.

1:53:20Usually by the time you have a tumor growing, that's a 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, yes, sure, you can acutely disrupt the immune system and maybe get sick, right? That, you know, I could explain why you might get a cold under a period of great stress, but not necessarily cancer.

1:54:00And what I want to meaning is that should be a massive, massive take -home message for anyone who is predisposed towards thinking, ooh, stress caused my cancer. Too bad I didn't have better priorities in life. Now I know who's faulted is. That sort of thing. And it certainly makes you damn cautious if there's some highly credentialed quack out there who is selling a stress management. We'll stop your tumor. We'll make a disappear entirely. me 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 Speagle, who showed that things like supportive group therapy among cancer patients enhance a survival.

1:54:49So 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 mean, I don't remember when it was published, but I remember learning about it in medical school. Massive finding. And one is immediately tempted to release 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 glucoticoids. And therefore you're not having loose adverse effects of it. When your immune systems, you're better able to fight the tumor.

1:55:21You live longer, trull -off. 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 path. It 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 biotype 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 either.

1:56:06And 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, winter. 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 outer hell.

1:56:48When 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 hypercordisolemia and the accelerated stress response are probably most demonstrated in cardiovascular disease and atherosclerosis roses, vis -a -vis several mechanisms, not the least of which is hypertension, both macro and microvascular, but also through endothelial disruption.

1:57:27Adhesion 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 an 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 hypercortisolemia is going to, and we actually measure this, right?

1:58:07We can measure overnight urinary cortisol and overnight urinary melatonin. You can see this association quite strongly. Well, melatonin, it's a pro -nerogenic 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 of research, first evidence for stress damaging the hippocampus and hippocampal dependent memory type stuff, late 70s.

1:58:52I mean, that was really the first domain. And superb studies from a number of groups. And I had my two cents, and that would return also, showing you could accelerate aspects of hippocampal aging with lots of stress, lots of glucoticoids, extensive neuron loss, a sense of memory problem, extent of reactive galeosis, 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 as PTSD.

1:59:33you see expansion of the amygdala and you see atrophy of the hippocampus and glooc corticoids probably play the driving role in both. So in the amygdala, like the hippocampal story, is stressing gloocorticoids screw it up. Neurons don't work as well, networks don't work as well. The overall size decreases, you had 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, hip campuses, and working as well as usual.

2:00:12The problem with chronic stress and 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 and 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.

2:00:51But then a whole literature showing what distress and glucose do there, they mess with the dopamine system. It's less clean of a story than a mignolary hippocampus, but in ways that predisposed 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 of 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.

2:01:37What 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's dressing the glucoticoids to to the frontal cortex. judgments, impulse control, executive function, long -term planning, strategizing, and it turns out virtually every bad thing cellularly that's dressing glucoticoids doing the hippocampus, they're turning out to do in the frontal cortex as well. And what does that begin to explain in this entire world of why it is during moments of extreme emotional arouse, so especially aversive ones, why we make terrible, terrible decisions that seem brilliant at the time.

2:02:30And you spend the rest of your life regretting it, because impulse control, you're a miktola 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 judgments 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 worked with this guy at McGill named Jeffrey Mogel, we're by 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.

2:03:32Glucocorticoids, the stressfulness of dealing with scary novel humans or scary novel mice, case, if you're a rodent, glucocorticoids narrow your window as to who counts as an us and who's pain registers and things of that sort. So for me, it's incredibly interesting if you're stressed and suddenly your SAT scores plummet, the fact that stress makes people crappier 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.

2:04:15I've done a podcast on this topic where it was very fortunate to go into a maximum security prison with a program that is really there to do 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. 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 his life in solitary confinement, his total life.

2:04:54So 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, you know, 60 % step to the line of the inmates, five step to the line, right? Step to the line if you're gripping 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. I mean, and it's a very emotional thing to go through because as this game is unfolding, you're just, you're feeling more and more fortunate on the one hand because you realize if not for the grace of this luck.

2:05:30And 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 guy. So it's one volunteer, one inmate. And you are each telling the other person the greatest regret of your life, the biggest mistake you've made.

2:06:07And 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 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 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.

2:06:48I 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.

2:07:27But 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 is Corey McCarthy. And it really strikes me as the exception and not the rule that people are able to emerge from that 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.

2:08:10And 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 spent a lot of time thinking about now. Well, 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 as the wrong word.

2:08:51I don't want to. 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.

2:09:24I've got every child trauma. I've got tucked away. I've titrated in just the right way that I've turned it into more productivity and incredibly lucky in that regard. My capacity to sublimate a motion into intellectual pursuit and to really, really, really wanting to understand something and to 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. At least now coming later in life, an increasing capacity to more carefully try to analyze what cost each type of ambition comes with.

2:10:20Say more about that. I don't know. This had much to do with my closing my lab four years ago, the big booming lab with lots of people and all sorts of labs around the world. We were going to kick the asses of by getting the answer to this or that. 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 disease as you're going to vanquish in the 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?

2:11:02Was it that much of a cerebral realization or was it combined with other factors? You've described obviously having this network of people around you who matter the most. And I mean, it was part of it just thinking, haven't spent enough time with them at the expense of this or was it the, this problem is enormous. and when, you know, a thousand years from now, whether I worked this much harder or this much less, it won't have altered the trajectory of X, Y, I mean, how much of it is all of these? Only both. Family growing 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 is just sit for really long stretches, can in 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.

2:12:04What advice would you give the 25 -year -old Robert as he was just finishing that PhD at Rockefeller? BLS 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. 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.

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2:15:18I'm gonna have to go back to the hotel. I'm gonna have to go back to the hotel. I'm gonna have to go back to the hotel. I'm gonna have to go back to the hotel. I'm gonna have to go back to the hotel. I'm gonna have to go back to the hotel. I'm gonna have to go back to the hotel.