The Peter Attia Drive - The impact of stress on our physical and emotional health

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.760 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.780 here's today's episode. Welcome to another special episode of the drive for this week's episode.

00:00:55.220 We're going to rebroadcast my conversation with Robert Sapolsky, which was originally released

00:01:01.320 back in April of 2019, about four years ago. Many of you may recognize that name because Robert has

00:01:06.840 written some incredible books, including the very popular Why Zebras Don't Get Ulcers,

00:01:12.840 A Guide to Stress, Stress-Related Disease, and Coping. I had first seen Robert speak about a year and a

00:01:19.200 half prior to my interview with him. And I remember thinking during his talk, this is the first time

00:01:24.200 I'm really being convinced of the true pathology of stress. You know, I think prior to that,

00:01:29.600 I'd always heard the old adage that stress could kill you, but I kind of dismissed it as yeah, yeah,

00:01:34.140 yeah. And we used to think that stress caused ulcers, but then we found out it was H. pylori,

00:01:38.720 et cetera, et cetera. But the way Robert spoke about it, I really began to pay more attention to it,

00:01:43.540 which of course led to me reading up on this more. And at that point, I just decided I needed to meet

00:01:48.720 Robert. Robert's work in particular, his presentation that day got me to think about

00:01:53.060 the molecular and physiologic harm of hypercortisolemia in particular. In my

00:01:57.500 conversation with Robert, we spoke a great deal about that, but we also talked about things

00:02:01.920 outside of that. We talked about the role of depression, what the impact is of stress on

00:02:05.820 the developing brain and also on the brain later in life. And even on areas where the relationship

00:02:10.500 between stress and disease is not that well understood yet. That clearly came across in our

00:02:15.080 discussion of cancer. Robert is a professor of biology, of neurobiology and of neurosurgery

00:02:20.180 at Stanford. He's also a MacArthur fellow in 1987. He was awarded the fellowship, which some of you may

00:02:26.040 recognize by its other name, the genius grant, something I consider very appropriate for a man

00:02:30.900 of Robert's talents. Overall, I found this discussion riveting and I hope to speak with Robert again,

00:02:34.900 but for now, I hope you'll enjoy revisiting this discussion as much as I did. So without further delay,

00:02:40.440 please enjoy or re-enjoy my conversation with the wonderful Robert Sapolsky.

00:02:50.980 Robert, thank you so much for making the time to meet with me today on a lovely rainy San Francisco

00:02:57.340 afternoon. Sure. Glad to be indoors here. As I was saying earlier, we had met once before really

00:03:02.680 briefly, so briefly that you would not remember it. And of course, only I would. Summer of 17,

00:03:07.920 I believe you were giving a talk in Sun Valley and I was there and you gave a talk on stress. Now it

00:03:13.560 was to a lay audience. So you didn't really get to go into the depth. And I remember sitting in the

00:03:19.360 audience thinking, Oh, you know, a lot of what he's saying is really starting to make sense to me.

00:03:25.500 And I can't wait to get a little deeper into this stuff because truthfully, and I'm just going to open

00:03:30.720 with sort of my mea culpa. You've always heard people say stress kills. And I got to be honest with

00:03:36.420 you. I always thought that was sort of nonsense. I was like, come on. What do you mean stress kills?

00:03:42.380 Stress is good. It builds resilience, blah, blah, blah, blah. What is the mechanism by which stress

00:03:47.300 quote unquote kills? But of course, once you start to understand the endocrine system, and of course,

00:03:51.740 training as a surgeon and not an endocrinologist, I sort of missed out on that. You start to see it.

00:03:56.220 And in that talk, you admittedly at a sort of high level for the audience really walked through

00:04:01.580 the danger of hypercortisolemia. And so in many ways, I guess, you know, a year and a half ago

00:04:06.260 was really when I became a fan of your work and then kind of said, you know what, there is something

00:04:10.260 to this. So anyway, with that, I appreciate you taking this time. Sure. And just to sort of back

00:04:16.180 off a bit from that, I actually don't think stress kills you outright very often, but it sure makes

00:04:22.820 other things that kill you more effective at doing it. Maybe it's semantic, but you're right.

00:04:28.180 Stress can amplify and accelerate the diseases of aging.

00:04:30.960 You grew up in New York, right? If I recall, you grew up in Brooklyn or in Brooklyn.

00:04:35.240 I remember reading that after college, you actually went straight off to Kenya first. Is that right?

00:04:41.380 Yep.

00:04:41.780 What prompted that?

00:04:43.640 Well, I was one of those. I've sort of spent my career oscillating between being a lab neuroscientist,

00:04:50.700 studying the effects of cortisol on the brain, punchline to decades of work is you don't want

00:04:56.700 to have a whole lot of it marinating inside your head. But also for more than 30 years,

00:05:01.800 I've alternated spending my summers studying a population of wild baboons in a national park in

00:05:08.380 East Africa. And it's the same animals I go back to each year. These are animals I can dart,

00:05:13.480 anesthetize, get blood, do whole workups on them. And essentially asking among them,

00:05:19.860 what does your social rank have to do with patterns of stress-related disease? What does

00:05:26.180 your personality, what does your patterns of social affiliation? So it's been sort of a counterbalance

00:05:32.220 to the lab where, you know, we've been sticking artificial genes into neurons and fairly reductive

00:05:38.900 stuff like that. So I was actually about eight years old when I decided I wanted to be a primatologist.

00:05:45.020 So I was kind of planning on that for a long time and lucked out. I spent all of college brown-nosing

00:05:52.660 the right person who shipped me off to a field site right after graduation. And I wound up sort

00:05:58.400 of inheriting that site. And those have been my baboons ever since.

00:06:03.640 Did you spend the whole time in Kenya? I remember reading that you also were in Uganda and obviously

00:06:08.560 they're, I think if my geography is correct, they're neighbors. So that's a pretty easy switch.

00:06:13.420 Where do the actual baboons, like what is their scope of their residence? How broadly?

00:06:17.300 Oh, they're spread actually all over Africa. They're one of the most ubiquitous primates

00:06:22.500 for a lot of the same reasons that we are, which is they'll eat anything. They're carnivores,

00:06:28.620 but they're also herbivores. They're omnivores. They scavenge dead stuff. They eat insects. They'll

00:06:34.700 eat most anything so they can fill a lot of niches. So they're scattered everywhere. But my main work

00:06:41.080 over the years has been this one troop in the Serengeti in Southwest Kenya, you know,

00:06:46.960 for about 25 years, I camped under the same tree. So it's really, it's been a continuity with the

00:06:53.480 same population of animals. What is their natural predator besides man?

00:06:58.420 Leopards, lions, hyenas. Nonetheless, if you're a male baboon, the most likely thing to kill you

00:07:04.200 violently is another male. Another male.

00:07:05.720 Wow. Yeah, exactly.

00:07:07.460 Sort of like humans.

00:07:08.740 Yes, indeed.

00:07:09.440 Did you say it's every summer or every other summer?

00:07:12.940 Well, it was initially for about 25 straight summers and then parenthood and all those complications

00:07:19.760 came in. So wound up being every other summer. And then our kids were old enough to go with us one

00:07:26.860 summer. But unfortunately the field work ended about eight years ago. So.

00:07:31.480 Why is that?

00:07:31.940 My Kenyan field assistant of 30 years, we started together when we were 20. He died of AIDS,

00:07:41.320 political issues there, some game park issues that made it harder and harder to sort of get

00:07:46.480 research done. And kind of that middle-aged realization that I could find some new game park

00:07:52.640 or new country or something and start it all over. But it was kind of time to pack it in instead.

00:07:57.360 So after you did your PhD, which you did it in North New York, right?

00:08:01.380 Yeah. Rockefeller University.

00:08:03.540 Did you come straight out to Stanford for a postdoc or?

00:08:06.240 Postdoc to the Salk Institute down in San Diego, spent a couple of years there.

00:08:11.580 If people are sort of familiar with the hypothalamic hormone that runs the stress response, a hormone

00:08:18.860 CRH, CRF, corticotropin releasing hormone. I went and postdoc with this guy, Wiley Vale,

00:08:25.420 who had discovered it in like two years before. So that was a pretty exciting time to be there.

00:08:31.380 So spent a couple of years there. Stanford hired me and I've been there for 31 years since.

00:08:39.520 That's kind of amazing. I keep coming back to people at Stanford that, you know, would have been

00:08:45.500 there when I was there in medical school. But if it wasn't in the medical school, like you just

00:08:49.260 weren't paying as close attention. And I honestly don't recall if you ever gave us a lecture in med

00:08:53.920 school. Do you remember giving lectures in med school 20 plus years ago?

00:08:56.920 I did. Almost certainly the students were paying as little attention as I was. So

00:09:01.180 I was about to say, it certainly seems like something we should have been,

00:09:05.440 you know, learning in medical school. And yet I feel ashamed to say, I don't know if I recall it.

00:09:09.920 It was not much of an emphasis and was sort of snuck in embarrassedly.

00:09:14.080 Like a lunchtime seminar or something.

00:09:16.040 Yeah, exactly.

00:09:16.880 So that-

00:09:17.320 Thrive them with free food.

00:09:18.800 Yes. And even still, only about five people would stay past the cookies.

00:09:23.560 That's a much bigger issue we can come to. So you wrote a book, gosh, how many years ago was

00:09:28.880 Why Zebras Don't Get Ulcers? Is that 20 years ago?

00:09:30.980 Let's see. First edition was 94. It's gone through three editions now. Most recent one was 2004. So

00:09:38.760 at some point I got to do another one.

00:09:41.080 Yeah. As we talk about that, and you've written a book more recently that I want to talk about as

00:09:45.820 well, let's back up and explain something you touched on a second ago, which is sort of the

00:09:51.660 physiology of a stress response. So walk us through the relationship between the hypothalamus,

00:09:56.600 the pituitary, and the adrenal glands.

00:09:58.840 So when we're under stress, levels of 11D different hormones change in our body. Most of them are

00:10:06.020 relatively minor players. The two workhorses overwhelmingly, first one, famously adrenaline,

00:10:13.740 British term, epinephrine, sort of North American term, output from the sympathetic nervous system.

00:10:20.620 It's on the scene in your bloodstream within one, two seconds or so after all hell breaks loose.

00:10:26.320 And I just want to explain what sympathetic means to the listener. We've had this discussion before.

00:10:30.360 Or it's not to say it's a nervous system that is kind. It just means it's one of the two branches

00:10:35.820 of these so-called autonomic or immediate, not under your conscious control, right? So the fight or

00:10:41.780 flight.

00:10:42.300 Exactly. And the other half being parasympathetic, sympathetic fight or flight, all hell breaking

00:10:47.620 loose alarms going off, parasympathetic calm vegetative function. So not only do you turn

00:10:54.820 on the sympathetic during stress, you very emphatically turn off the parasympathetic.

00:11:00.620 Second main workhorse, which has already been alluded to, the steroid hormone class of hormones

00:11:06.480 called glucocorticoids, human version, cortisol, also known as hydrocortisone, rat version,

00:11:13.820 corticosterone, synthetic versions, prednisone, dexamethasone, and such. These come out of the

00:11:19.460 adrenal glands, your brain notes something stressful is happening within two seconds. Your hypothalamus

00:11:25.980 is secreting that CRH, which within about 10 seconds is getting your pituitary to release a

00:11:32.320 hormone called ACTH, which within about 30 seconds has gotten to your adrenals and you are slowly

00:11:39.040 starting the glucocorticoid component of your stress response. And in lots of ways, the adrenaline,

00:11:46.380 the sympathetic response, the glucocorticoid response, they work on hand in hand, they synergize.

00:11:53.160 You want a metaphor, adrenaline in two seconds is handing guns out of the gun locker to whatever

00:11:59.920 is going to defend you. Glucocorticoids are building the aircraft carriers that a year from

00:12:05.800 now are going to be essential. It does some of the slower components of the stress response,

00:12:10.340 stretching out over minutes to hours.

00:12:13.200 Because I was just about to ask you, and I think your question basically answers it was,

00:12:17.340 why would we have evolved these two separate systems? One can only speculate on such things,

00:12:22.360 but it's basically that certainly norepinephrine, epinephrine, they stick around for such a short

00:12:27.100 period of time. I mean, we don't even measure these things clinically. I can't poke your arm and

00:12:30.980 measure your norepinephrine or epinephrine level. The best I can do is collect its metabolites in your

00:12:36.620 urine for evidence that it's been around. So I guess we have this hormone or pair of hormones that,

00:12:43.000 are on the scene in seconds, gone in seconds, and really deal with the, I guess, from an

00:12:49.320 evolutionary perspective, when the tiger is there, this is what gets you to jump into the tree.

00:12:54.000 Is it doing much beyond that? And is there some evidence of chronic low levels of those hormones,

00:13:00.720 which come out of a totally different part of the adrenal gland? I mean, that's the other thing

00:13:03.840 that's sort of interesting is you have two separate pieces, the cortex, the medulla,

00:13:07.900 that secrete these hormones separately. And embryologically, they're two very different

00:13:13.820 tissues. They start off separately. It could have just as randomly wound up that your adrenaline

00:13:19.760 comes from your big toe and glucocorticoids from your thumbs. Why they wound up being in the same

00:13:25.080 organ is in fact, somewhat just, I think, serendipitous. Probably because you're more

00:13:29.600 likely to have your toes and fingers lopped off and we wouldn't want to have an incidental

00:13:33.380 adrenalectomy is happening. You're right. That's certainly why they didn't wind up out there in

00:13:37.960 the extremities. What about in lower species? Is one of these considered more primitive? Is the

00:13:42.060 epinephrine arm something that began earlier and the cortisol arm more recent? Yep. Nonetheless,

00:13:48.860 the cortisol arm is just ancient. When you get stressed and you're secreting glucocorticoids,

00:13:54.800 it's basically the exact same class of molecules as if you were a fish or bird or a reptile.

00:14:01.760 Well, nonetheless, it's a very ancient wiring and that's part of what winds up getting us in

00:14:06.360 trouble. It's a system that's been serving vertebrates, doing a lot of help for them for

00:14:12.700 an awful long time. And it's been a very recent modification to instead secrete them in response

00:14:18.120 to thinking about taxes. This basic dichotomy between the very human domains where we activate

00:14:25.520 the stress response and the more typical domains of animals.

00:14:30.260 So if you and I were sitting here 10,000 years ago, I can think of lots of things that we would

00:14:36.400 want an adrenaline response for, you know, the tiger jumps out of the thing, whatever.

00:14:41.060 What are some of the things that would result in that cortisol response? Because, you know,

00:14:45.600 you described it as building the aircraft carrier. Well, you know, gosh, if the tiger's there,

00:14:49.720 either I'm dead or I'm not, but I don't need a stress response a day from now or the next day.

00:14:54.040 So what is it that cortisol was doing 10,000 years ago that was serving our interests? I want

00:14:59.940 to certainly talk about what it's not doing today. When you look at what it does, it actually makes

00:15:04.400 perfect sense. As long as you're being stressed like a normal mammal running for your life, running

00:15:10.700 after a meal where if you don't catch something, you're going to be dead by tomorrow, a short-term

00:15:16.240 physical crisis. The first five seconds of doing that, which epinephrine is critical for,

00:15:22.700 that's great. If we're heading into a couple of minutes of evading a predator, being vigilant,

00:15:30.260 thinking there might be, if you're getting into the realm of a couple of minutes worth of a stress

00:15:34.900 response, cortisol related glucocorticoid hormones are absolutely essential.

00:15:40.760 So the glucose that's coming rushing out of your liver, pretty important in that situation.

00:15:45.520 Exactly. So it takes you about one second to decide you're going to use your thigh muscles and run

00:15:50.900 like mad. You need energy for them. And the main thing glucocorticoids are doing in the metabolic

00:15:56.820 realm is glucocorticoids. They're increasing glucose levels in your bloodstream. They're going

00:16:04.440 to storage sites throughout your body, your liver, your muscle and breaking stuff down. What they do is

00:16:10.340 they go to the bank, they empty out your savings accounts and turn it into cash, glucose in the

00:16:15.500 bloodstream to hand to whichever muscles are going to save your neck. What they also do makes better

00:16:21.640 perfect sense, whether you were running for your life or running for a meal, which is they increase

00:16:26.880 cardiovascular tone. And epinephrine is doing the first five seconds of it by 30 seconds in glucocorticoids,

00:16:35.240 you're bolstering it as well. And it's that same logic. You're running like crazy. You want to deliver

00:16:40.240 that glucose to your thigh muscles as quickly as possible. You increase your heart rate, you increase

00:16:45.900 your breathing rate, your blood pressure, you alter your vasculature. So you're preferentially shunting

00:16:52.000 to the exercising muscle. So that makes perfect sense also. Turns out some of the most interesting

00:16:58.160 stuff glucocorticoids do in those circumstances is basically run a triage program. They shut down

00:17:05.400 everything that's not essential, not essential to surviving the next five minutes of this massive

00:17:11.520 physical challenge. So digestion would be impaired? Digestion, exactly. You got better things to do

00:17:16.760 than digest breakfast when you're trying to avoid being somebody's lunch. And you're sure not going to

00:17:21.620 get any metabolic benefits of digestion during this five minutes. It's slow, expensive, the energy you're

00:17:28.120 getting, you're getting from your liver, you're getting from your fat cells. It shuts down growth.

00:17:33.020 Obvious logic there, you know, grow antlers tomorrow. If you're still around, don't bother right now.

00:17:40.100 Shuts off reproduction. Same logic there. It shuts off all the long-term building projects

00:17:46.200 and just focuses your energies on what's immediately there. And this makes perfect sense. If you are

00:17:53.020 running for your life, running after a meal, and all you need to do is look at a couple of diseases

00:17:57.940 where people don't turn on the endocrine stress response. Addison's disease, Chey-Drager syndrome,

00:18:04.400 whatever. These are not diseases where somebody who now is more at risks for adult diabetes eight

00:18:11.720 months from now. These are diseases where somebody goes running after their commuter bus and they drop

00:18:17.080 dead from hyperglycemic shock.

00:18:19.100 JFK had this. Didn't JFK have Addison's?

00:18:21.460 He had Addison's. And that greatly constrained the famed pictures of all those Kennedys playing

00:18:28.140 touch football out in, you know, Martha's Vineyard or stuff were mostly for the benefit of the

00:18:34.260 photographers.

00:18:35.220 How did he survive World War II? Because he had done some pretty heroic things in that war.

00:18:41.160 Although I've seen, it's hard to tell if it's snarky revisionism as to how much that was public

00:18:46.700 relations stuff afterward sort of orchestrated. But just to get through basic training even

00:18:51.920 strikes me as an accomplishment because most people, I guess, who don't have a medical background

00:18:56.120 wouldn't appreciate this, but the tan that seemed to be eternally on JFK is the result of the Addison's

00:19:04.780 disease because the hormone you alluded to earlier that is released by the pituitary ACTH in someone

00:19:11.380 who's not making cortisol is going to be very, very high. And ACTH stimulates the pigment producing

00:19:17.480 cells in the skin. And that's what would give someone with Addison's DeGee's darker skin.

00:19:21.600 The fascinating thing with Kennedy is if it were this situation now, presumably his doctors would

00:19:27.860 be on the air somewhere 24 seven. There's remarkably little known about when his onset was, what the

00:19:34.860 course of it was, how severe it was. So it's not quite clear, but what little is known is it had a

00:19:40.800 hell of an impact on his functioning. You really do need a hormone if you like glucorticoids, if you

00:19:47.120 were going to be physically activated in a moment of crisis. This is sort of the amazing thing with

00:19:53.740 hormones like insulin and cortisol. I'm always impressed by how tight the U-shape is on those

00:20:00.940 curves. Thyroid hormone would be another example, certainly less so with something like testosterone.

00:20:06.600 You have just a much wider range that you can function in. And the benefit is largely monotonically

00:20:13.420 increasing. Sometimes if my patients will tolerate me going on and on about this, I love to draw the

00:20:19.280 pictures of which of these hormones can you, you know, but to me, cortisol probably, if you thought

00:20:26.220 of it as a drug, it has the narrowest therapeutic index. To your point, too much of it will kill you

00:20:32.580 eventually and make you miserable as hell on the way. And too little of it will kill you quite quickly.

00:20:38.360 And what's most interesting about it is, okay, so there's an optimal level among other ways of

00:20:43.820 translating that. That means we don't hate stress. We hate the wrong amount of stress. When it's the

00:20:50.180 right amount, we love it. We pay money to be stressed, to get on a roller coaster, to go to a scary movie.

00:20:56.860 When it's the right amount, when it's the optimal amount, we call it stimulation. Okay, so exactly as

00:21:03.560 you say, it's a narrow range. So that's a tough biological problem. Understanding a hormonal system

00:21:11.180 that's pretty damn essential and where an awful lot of the time you're walking on a knife edge where

00:21:15.600 either side is bad news, too much or too little. But when it comes to glucocorticoids and what counts

00:21:21.720 is good stress and stimulation, there's the added factor that there's incredible individual variation

00:21:28.840 as to what counts as the optimal level in between. And one person's like hair-raising Audubon Society

00:21:37.300 walk one Saturday morning looking for birds while the other person goes and signs up to be a mercenary

00:21:43.080 in Yemen because that's when they feel alive and awake and all of that. Not only that it's a narrow

00:21:48.720 range, but we differ so much as to what each person's optimum is. Now I want to make sure I understand

00:21:54.000 that point, Robert. And this is probably overly simplistic, so feel free to correct this. One of it

00:22:01.200 would be the external scenario that is being perceived. And I can see definitely how two people can have

00:22:10.220 vastly different views on that. I mean, it's the reason someone can voluntarily go and be a Navy SEAL

00:22:16.060 and someone can say, I'd feel much better not doing that, right? There's clearly a different

00:22:21.460 appetite and or capacity for distress. Is that what you're referring to? Or are you also referring to

00:22:29.400 you and I could be sitting here and have different levels of physiologic benefit and harm at the same

00:22:36.340 level of cortisol? Both. Absolutely. I mean, the former, I think most people would acknowledge the

00:22:42.720 latter is pretty new, right? I mean, I shouldn't say pretty new. That's not intuitive to me.

00:22:46.720 Because there's centuries of endocrinology saying, what's the most important thing about hormones?

00:22:53.240 How much of the stuff there is in your bloodstream? What the levels are? And if you and I are sitting

00:22:58.280 here with the same circulating levels of whatever centuries of dogma was, that will translate into the

00:23:04.280 same biological effects. And then, I don't know, sort of endocrine revolution of seventies,

00:23:10.280 eighties or so, turns out how loud someone is yelling at you counts, what the hormone levels are,

00:23:16.740 how sensitively you can hear them. The levels of your receptors and target cells turn out to be

00:23:23.300 essential as well. And there's all sorts of endocrine domains where in fact, screwy receptor levels are

00:23:30.920 much more consequential and impactful than our screwy levels of the hormone itself. And individual

00:23:38.060 differences in levels of receptors, what version you have, how well it works, how avidly it holds

00:23:45.500 on to the hormone, what it is then coupled with afterward downstream inside the cell, that whole

00:23:52.380 world turns out to be as central to understanding individual differences as are the levels of hormones

00:23:59.580 themselves. And as sensitive to all those things ranging from genes to prenatal environment, to early

00:24:08.680 development, to psychological factors and so on. So yeah, that's a huge piece of the story now.

00:24:14.940 When I hear you say it like that, Robert, it seems pretty obvious because we would talk about insulin

00:24:21.060 in exactly that way. You could have two people with the exact same level of insulin, completely different

00:24:25.840 physiologic response because of insulin sensitivity. When insulin hits its receptor, it leads to the

00:24:31.460 phosphorylation of AKT, and that's what leads to the GLUT4 transporter coming up to the surface. And

00:24:37.240 different people with the same insulin can do that totally differently. And different people will have a

00:24:42.000 different insulin response to the same food, to the same meal. That's the reason we do glucose tolerance

00:24:46.240 tests. So you could basically say someone is cortisol sensitive and cortisol resistant to make the analogy to

00:24:51.780 insulin. At the end product end, absolutely. If you're an obsessive with cortisol stuff, in the 80s, there was

00:24:58.840 briefly this deep puzzle in that it turns out new world monkeys, monkeys in South America, marmosets, tamarins,

00:25:06.160 or whatever, when you compare them to traditional old world monkeys, the Asian and the African ones, turns out they

00:25:12.140 have like an order of magnitude higher glucocorticoid levels. Oh my god, that's crazy. What's that about? All sorts of

00:25:19.880 theorizing about how for some reason it's more stressful to be a new world primate than an old

00:25:24.900 world, which didn't make a whole lot of sense. And then there was this issue of these animals should

00:25:30.020 have been falling out of trees from their Cushing's disease. And finally, somebody found an explanation.

00:25:36.260 Oh, somewhere back when there was a mutation in the gene for the glucocorticoid receptor in new world

00:25:42.460 primates, and it has roughly one-tenth the sensitivity. So the system just equilibrated out at a different

00:25:48.740 set point. But that's such a great example of just natural variation, not only in how loudly you speak

00:25:57.900 hormone, but how effectively your cells listen to hormone. Do you have a sense in the human

00:26:04.880 population today, I mean, a log-fold difference like you just described sounds extreme, but do you

00:26:10.760 have a sense of what the variability is in humans today? Is it a two-fold, three-fold delta on the receptor

00:26:16.480 side? Gut feeling and reflecting the fact that my world, the brain, you don't get to measure receptor

00:26:23.600 levels anywhere near as easily as in a white blood cell, well under an order of magnitude.

00:26:29.220 We just acknowledged, or you just pointed out that when a zebra sees a lion, everything that happens as

00:26:36.000 far as the fast and what I would call the acute and the subacute stress response is perfectly

00:26:42.240 evolutionarily sound and completely in the best interest of that zebra. We could also come up

00:26:48.220 with a countless examples of 10,000 years ago, or even today, when the same thing is true in humans.

00:26:53.920 When did that transition occur in our species to where you started to see either something in the

00:27:02.180 civilization or society that was unhealthy? So today I could point to a thousand examples,

00:27:06.800 social media, you name it. I mean, it's an infinite number. When did that start to crop up? What does

00:27:12.400 your research suggest is the arrival of that? I think it predated us being humans and instead as a

00:27:20.640 feature of smart social mammals, because you see indices of stress-related stuff, baboons, that's what

00:27:29.280 I've spent my whole career on, and other non-human primates, cetaceans, elephants, and such. Okay,

00:27:37.200 so why study baboons if you're trying to understand human stress? And it turns out they perfectly

00:27:42.060 illustrate the point you just brought up. If you're a baboon living in the Serengeti in East Africa,

00:27:48.540 your life is pretty good. It's a fantastic ecosystem. Baboons, they live in these big troops,

00:27:55.180 50 to 100 animals or so, so they really don't have to worry about lions very often. The infant mortality

00:28:02.060 rate is lower than among the neighboring Maasai tribes people. And probably most importantly,

00:28:09.000 unless it's a once-a-generation drought, if you're just a baboon going about your everyday business,

00:28:14.800 it takes you about three hours a day to get your day's calories. And that has a critical implication,

00:28:20.940 which is if you only need to spend three hours of sunlight each day getting enough food to get by,

00:28:26.560 you've got nine hours of free time every day to devote to being miserable to some other baboon.

00:28:34.280 And that's the key thing. They are well off enough in our westernized sense that they can sit

00:28:43.880 around and generate psychological stress for each other. Overwhelmingly, if you're a baboon in the

00:28:49.740 Serengeti and you're miserable, it's because another baboon has worked very hard to bring that

00:28:54.700 state about. They're wonderful models for westernized disease in that very few of us get hypertensive

00:29:01.700 because tigers are chasing us. Instead, it's psychosocial stuff that we invent and that we can

00:29:09.080 wallow in for hours every day. And that's exactly what baboons do. They're great models for westernized

00:29:15.460 stress. Do we have evidence? I mean, I'm sure it exists, but in the humans, I would just be willing

00:29:22.060 to bet that if you and I were subjected to the same external stressor, I would probably internalize

00:29:29.140 it more than you. That's my guess. So if we were both baboons and there was a third baboon tormenting

00:29:35.520 us, is it safe to say that you could be the baboon that would roll with it more than me?

00:29:40.820 Individual differences like that, absolutely. My guess is both of us would respond to it by saying,

00:29:46.380 I'm just going to get a longer and longer CV and then he's going to regret it someday pushing me

00:29:50.680 around. They'll be sorry when they see how many degrees I have. But yeah, individual differences.

00:29:56.740 One of the things that I focused on, you know, I spent my first 10 years deciding rank and status,

00:30:03.680 social statuses, everything. If you're a baboon and you got a choice in the matter, you want to be

00:30:08.380 high ranking because on the average, you have lower glucocorticoid levels, you're resting blood

00:30:13.420 pressure is lower, all sorts of stuff works better. But what took me some growing up out there to do

00:30:21.060 was to realize that, yeah, social rank is important. Far more important is the contextual meaning of your

00:30:30.000 rank. Is that the same as your perception of your rank or is there, there's more to it, right?

00:30:34.460 Well, it's what the rank means in your particular troop. You can be a low ranking guy in one of two

00:30:41.480 different troops and one troop simply because of its culture. And that's a perfectly scientific

00:30:47.000 word to use for another species these days. In one troop, being low ranking can be a whole lot

00:30:53.500 crappier than in another troop in terms of how often somebody in a bad mood displays aggression on you,

00:31:00.380 in terms of how often somebody actually grooms you, in terms of how often you get to finish a meal

00:31:06.900 before somebody steals it from you kind of thing. So the same exact rank means different things in

00:31:12.980 different sort of baboon cultures. So I'll take an extreme example. In a prison, there's a clear

00:31:18.580 hierarchy starting with the warden, the guards, the inmates. And of course, within the inmates,

00:31:24.300 there's a hierarchy. Presumably, I'm making this up, but certainly the pedophiles would be at the

00:31:28.880 bottom of that list. And a violent criminal would probably be at the top of that list.

00:31:33.560 So within that hierarchy, there's probably a manner in which you would be perceived as a function of

00:31:39.780 that unique environment, which is so artificial in its own way, but that wouldn't necessarily be the

00:31:45.880 same outside. Absolutely. And one of the most interesting things about us, us humans, when we

00:31:53.060 talk about across all sorts of primates, being low ranking in general is bad for your health. Well,

00:32:00.260 what about humans? We don't have ranking in the same system that sort of other primates do in a strict

00:32:06.000 linear kind of way. But the other thing about us is we belong to multiple hierarchies at once,

00:32:11.780 and we can have very different ranks in them. So for example, family, work, sports team,

00:32:18.680 hobby. Exactly. You've got some guy who's the mailroom clerk in this giant corporation,

00:32:24.560 and you could not possibly be lower status, but he's the captain of the company softball team this

00:32:30.400 year. And you better bet when you ask him what's important in his life, nine to five, Monday to Friday

00:32:37.600 is just a stupid way to pay the rent. And what really matters is when the weekend comes around,

00:32:43.080 you have somebody with a horrible, low status job who's the deacon of their church. We belong to

00:32:50.800 multiple hierarchies, and we are very good psychologically at deciding that whichever

00:32:56.020 hierarchy we're highest in, that's the one we define ourselves by. Let's take another extreme example,

00:33:02.640 which is you take people who are very successful in what they do, you know, whatever, they're the

00:33:08.060 most famous hedge fund manager or an entrepreneur that started some great company, you would argue,

00:33:13.160 well, they seem to be pretty good on the food chain, but yet many of them would say, or you could

00:33:19.220 measure objectively, their hypercortisolemia is problematic. So it seems like there's even more

00:33:27.180 than just that ranking, right? Isn't there something else? Because they're at the top,

00:33:30.280 if they were baboons, they're the alpha, but they're still grossly stressed out.

00:33:35.720 In other words, thank God we're more subtle than baboons, but it turns out baboons are even more

00:33:40.320 subtle than just rank. They have personality and you can be a high ranking baboon and personality

00:33:48.640 differences. And again, this is a scientific word as his culture. If you're a high ranking baboon

00:33:55.020 and your worst rival sneezing a hundred yards away is seen as a major provocation,

00:34:01.740 you're going to have much higher glucocorticoid levels than if you're a highest ranking baboon

00:34:06.460 for whom that's no big deal. And in fact, often you may have higher glucocorticoid cortisol levels

00:34:12.740 than if you're number 10 or number 20 in the hierarchy. There's lots of psychological filter

00:34:17.940 stuff. And I spent a ton of time studying that. Baboons differ as to how readily they see things

00:34:25.020 as being provocative or not, threatening or not. You're sitting there. And again, your worst rival

00:34:31.440 shows up and takes a nap a hundred yards away. There can be two baboons of the same rank. And one

00:34:37.800 of them keeps doing exactly what he's doing. And the other one is interrupted from whatever nice social

00:34:44.580 thing is happening. He's agitated and he's vigilant and he's got to look at the guy and lunge towards

00:34:49.140 him a couple of times before going back. If your worst rival taking a nap is as disruptive as the

00:34:55.080 guy threatening you in your face, you average about twice the cortisol levels in your bloodstream

00:35:00.140 after controlling for rank as a guy who can tell the difference between the big thing and the little

00:35:05.500 thing. Maybe this is too deep a question and the answer isn't known, but what is it that actually

00:35:13.440 transmits that information through the filter of your personality into the physiology that's very

00:35:21.760 well understood? So I understand the bookends, right? I understand how the visual cortex takes the guy

00:35:28.500 who's your enemy sleeping over there and transmits that to your cortex. And then I understand how the

00:35:35.280 sympathetic chain kicks off the response. Is there a link in between those, the processing link?

00:35:41.200 Here's one of those filters. You take people and you're flashing up faces at them, stick them in a brain

00:35:47.700 scanner, and you're looking at how jumpy their amygdala is. Their amygdala central to fear, anxiety,

00:35:55.820 aggression, and such. And what you see is tremendous individual differences in you show somebody a face

00:36:03.260 with kind of a neutral expression. Does this person look happy, sad, angry, threatening, whatever, and lots of

00:36:10.140 variability? And you look at the people who tend to view neutral expressions as threatening. In other

00:36:16.900 words, they see threats that most other people don't. What does that correlate with? A bigger amygdala.

00:36:24.140 Physically larger amygdala.

00:36:25.820 A physically larger amygdala, amygdala with a higher metabolic rate, an amygdala that is more

00:36:32.320 electrophysiologically reactive than stuff.

00:36:35.140 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

00:36:41.100 brain it evolved from, and why it's sort of referred to as this reptilian brain. Like, I think everybody's heard of

00:36:47.100 the amygdala, but I think you could explain this in a more interesting and accurate way.

00:36:50.820 Okay. Amygdala is like one of the anchors of what's called the limbic system in the brain.

00:36:57.940 Limbic system, it's the part of the brain that's all about emotion. Not surprisingly, mammals have a

00:37:05.340 whole lot more limbic development than fish do. Fish are not famous for their emotional lives.

00:37:11.980 Limbic system is arousal, fear, anger, lust, love, maternal, pair bonding, mother-infant bonding,

00:37:21.160 all of that. And it's a whole series of structures. Not surprisingly, ancient in mammals. Not surprisingly,

00:37:28.700 highly complex, interconnected. Not surprisingly, sitting underneath the cortex. The cortex that

00:37:35.580 more recently evolved part of the brain that does your taxes, all of that. Limbic system underneath

00:37:41.280 there, all the subterranean emotion stuff. And amygdala is one of the key limbic structures, and

00:37:46.840 it's involved in fear. It's involved in anxiety. It's involved in aggression. You learn to be afraid

00:37:53.920 of something or somebody that didn't used to scare you. And your amygdala does the exact same sort of

00:38:01.160 cellular basis of learning that goes on in other parts of your brain when you learn somebody's middle

00:38:06.500 name and actually remember it. Your amygdala learns to be afraid of new things. And when you manage to

00:38:13.300 stop being afraid of something, when you stop being afraid of thems, because it turns out, oh, they're

00:38:20.360 actually more similar to you than you thought or something, it's your amygdala that becomes less

00:38:26.220 reactive to stimuli like that. So your amygdala is absolutely central to some of our worst human moments.

00:38:33.860 It's so interesting because it's sandwiched between, you know, you can think of the human brain as having

00:38:37.980 sort of a very grossly three parts, right? This brainstem, this midbrain, which the amygdala,

00:38:44.260 you could argue is the mare, and then the cortex that you describe. It's not an oversimplification,

00:38:49.640 I think, to say that as the complexity of the organism evolved, so too did that hierarchy, right?

00:38:55.740 I mean, the brainstem basically handles everything we don't have to think about ever,

00:38:59.540 breathing and all of those autonomic and sympathetic parasympathetic functions. And then you layer on this

00:39:05.520 midbrain that does everything that you said, which is still kind of happening beneath consciousness.

00:39:10.440 And then, of course, there's where most of us live in our cortex, where we're, or where we think we live,

00:39:15.340 which is where we're thinking these thoughts, but it seems we're maybe not as aware of how influenced

00:39:21.300 the cortex is by what lies beneath it.

00:39:23.740 Exactly, which is incredibly important. If you think of this kind of ancient reptilian brainstem part

00:39:31.900 of the brain, what does it do? It keeps track. It makes you breathe every now and then without

00:39:36.280 having to think about a boring sort of stuff. Then on top is the emotional limbic system. Then on top

00:39:41.220 is that cerebral thinking cognitive cortex thing. It's very easy to come up with a conceptualization

00:39:47.840 that what's fancy about humans is, for example, you're a lizard. And the only thing that's going to

00:39:54.600 change the functioning of that ancient brainstem stuff is if you're bleeding, if you're too hot,

00:40:00.280 if you're too cold, just like boring physiological states. Once you layer a mammalian emotional limbic

00:40:06.960 system on top, suddenly you can do something no lizard on earth can do. You're sitting there and

00:40:12.760 you're some wildebeest and some other scary wildebeest shows up and is peeing on some tree in your

00:40:20.040 territory and nothing regulatory has changed in your body, but your heart starts beating faster. Aha,

00:40:26.880 your emotional brain can alter sort of the basic regulatory stuff down in the basement.

00:40:34.780 Now you go one step higher and you layer a cortex on top of it. And now you could do amazing stuff.

00:40:41.260 You sit there and you think about the fact that your heart's going to stop beating someday.

00:40:47.060 And you start breathing faster and your brainstem, the more ancient stuff has altered as a result.

00:40:53.900 And you've just done something not only that no reptile can do, you've just done something that

00:40:58.940 no warthog can do, which is think, think about something that's scary or arousing or remember

00:41:07.300 the time that you would, and suddenly something changes down below there. So there's this easy

00:41:14.680 picture of sort of top-down complexity once you get to us and where the cortex can regulate your

00:41:23.700 emotional brain and that regulatory brain at the bottom, your emotional limbic brain can regulate

00:41:28.540 what's far more interesting or underappreciated. This is exactly what you bring up, which is those

00:41:34.960 lower levels can influence what's going on up above. One example of this, this is like this classic

00:41:41.720 great study in sort of physiological psychology, social psych, you take people. And I think in

00:41:48.180 this study, they would take male volunteers, heterosexual male volunteers. And of course they

00:41:53.700 were no doubt college freshmen taking psych 101. And they had these guys walk across this really scary

00:42:01.000 suspended bridge. And the deal was that either halfway across the bridge, you were met by, from the other

00:42:10.340 side, a researcher who happened to be an attractive female. And she would ask the volunteer some

00:42:17.280 questions, what do you think of this bridge? Or how is it walking across this? Or whatever. The other half

00:42:22.820 of the time, you would not encounter this person until you were safely out at the other end.

00:42:27.520 Then they would ask you to evaluate the attractiveness of the person.

00:42:33.460 Same person.

00:42:34.060 That same person.

00:42:34.880 You're either seeing her in the middle of the bridge or at the far end.

00:42:36.940 Exactly. Saying, hey, remember while you were doing that, you, there was this, you know,

00:42:41.840 do you want to rate her attractiveness? Was she friendly? Did she seem smart? And what you would

00:42:46.680 see is guys in the middle of the bridge with their hearts racing because they're terrified would do

00:42:53.360 some misinterpretation. Why is my heart beating so much faster than if I was standing safely?

00:42:58.520 So they would rate her more attractively in the middle of the bridge.

00:43:02.040 Exactly. And then it's the ceiling of detail is now you do the same experiment and you give the

00:43:07.620 person a beta blocker so that they don't have the accelerate and they don't rate the person as

00:43:14.240 attractive.

00:43:15.100 Is it the same with the beta blocker?

00:43:16.900 You would treat, yeah.

00:43:17.500 You do nothing to their ratings of them as how smart they seem, how kind they seem, whatever. It's

00:43:21.980 just this, okay, if my heart's racing, it must be because, so that's a great example. Boring

00:43:29.040 reptilian regulatory stuff down there is helping influence what you think your emotions are at

00:43:37.080 that point.

00:43:37.440 That reminds me of that 1995-ish movie Speed with Keanu Reeves and I'm blanking our name.

00:43:44.160 Bullock.

00:43:44.480 That's right. Sandra Bullock. Where at the end of that movie, there's some cheesy line about how

00:43:49.440 relationships that start under this much distress, it's dangerous. But of course, the other read on

00:43:55.600 that now is, yeah, if you're on a bus that's about to blow up, I think you're going to think the chair

00:44:00.260 is attractive, right? Potentially.

00:44:02.260 Right. Yes.

00:44:04.120 Wow. I haven't thought of that movie in years. Thanks.

00:44:07.900 I'm sorry.

00:44:08.740 You can go home and I'm sure Netflix will stream that for you.

00:44:12.640 Right.

00:44:13.400 So I read something you wrote, I can't remember where, it might've been in another interview

00:44:17.700 that, and I didn't know this, and this is a great example of why I just love doing this podcast,

00:44:23.960 because there's never an exception to how much I'm learning. It's like drinking from a fire hose.

00:44:28.240 And you'd think I would have remembered this from medical school. The neuron of a human and the

00:44:33.800 neuron of some other organism, when you look at it at the single cell level, can't really

00:44:39.300 differentiate it. If I showed you two microscope slides and here's a human and here's a fish.

00:44:45.340 So what is it about, and this is maybe getting us a little off topic, but I also think it feeds

00:44:49.920 into this broader issue of like the stew and the alchemy of how this stuff is put together. But

00:44:55.800 if we all have the same neurons, what is, is it the number of our neurons? Like what is it that

00:45:01.540 enables us to have all of this additional torture?

00:45:05.120 Yeah. It's, it's incredibly interesting because I mean, there's, there's three and a half people

00:45:11.800 on earth who have spent their entire careers being able to tell the difference between

00:45:16.060 like a tree shrew neuron and a human neuron and could recognize it in their sleep. But yeah,

00:45:21.560 for the most part, we are not humans because we have invented brain areas that you don't find in

00:45:28.040 other mammals or because we've invented neurotransmitters that you don't find in other

00:45:32.680 vertebrates or types of neurons. Here's a couple of types of neurons that people used to think were

00:45:38.300 specific to humans. And it turns out you find them in elephants and whales also. And that's plenty

00:45:43.400 interesting, but it's the same enzymes. It's the same gene regulation. It's the same, you know,

00:45:50.460 we're sharing 98% of our DNA with a chimp or a bonobo. So you say, where did a human has come from?

00:45:57.100 And I think it's exactly the issue you talk about. We have the same signal transduction pathways and

00:46:03.600 neurons as you see in a fruit fly. And what's the key difference?

00:46:07.280 Isn't that, isn't that a bit humbling?

00:46:08.700 Yes, it is.

00:46:09.480 When we, when we just think we're that special.

00:46:11.460 And it's the, where you can take one of their genes or one of our genes and stick it in the other

00:46:17.060 one. And it functions just fine. Or you could take it from a single cell organism, some genes related

00:46:24.000 to program cell death. You can do that. So what's the big difference for every neuron that a fruit

00:46:29.500 fly has, we have a hundred million. And sort of the sound bite that I think summarizes all of that

00:46:36.840 is with enough quantity, you invent quality. And this is this whole world of emergent properties

00:46:45.780 of complex systems. You take one ant and you put it on a table and nothing that it does makes a huge

00:46:52.420 amount of sense. And you put 10 ants there and pretty much the same thing. And you put on a thousand

00:46:58.460 and maybe they start making a trail or something. And you put 10,000 and they build a colony and they

00:47:04.900 farm mushrooms and they take aphids as slaves. And they could keep the temperature in the colony plus or

00:47:11.100 minus two degrees. And they have specialization of labor and no ant has any more rules than he had

00:47:18.960 when he was wandering around on the table by himself. And you put enough of them together and

00:47:24.480 complex adaptive stuff emerges out of the very simple rules that each of those components has for

00:47:31.700 dealing with another component. It almost defies entropy, doesn't it? Like why does that happen?

00:47:37.320 It's amazing that it does that. And that's what our brains are. We've got more ants that are coming

00:47:43.560 together in our heads than does a fruit fly. And you get more complex emergent stuff happening.

00:47:49.500 It blows my mind. So let's go back to some of this stuff. Maybe about a year ago, I read something

00:47:55.600 that really frightened me because the implications were so significant. If a mother is under great stress,

00:48:02.000 there was this critical window in which her child could see something in her eyes that would

00:48:11.000 communicate that stress to her, or maybe it wasn't in her eyes. It might've been just through her

00:48:14.180 entire face, but it would imprint epigenetically into the child and alter many features about them

00:48:22.860 as they would age. For example, their propensity to be depressed. I mean, I remember reading this in

00:48:28.080 sort of a lay press thing. So I don't even think it got into the description of epigenetics,

00:48:31.360 but that was the only assumption I could make was that this must be modulated through that

00:48:34.920 mechanism. Do you see evidence of this in animals? I mean, is this-

00:48:39.040 Absolutely. And it's one of the trendiest topics around. I mean, like hooray, science finally

00:48:45.840 recognizes childhood matters. Like what your childhood is like has a lot to do with what sort

00:48:52.340 of adult you're going to wind up being. What do you know? And like lots of childhood adversity

00:48:57.520 versus childhood security and, you know, very different trajectories. And what's been the huge

00:49:03.180 mechanistic challenge for the field is understanding. So what is it about being in a scary neighborhood

00:49:10.520 or an unstable home or having a parent read to you? Or what is it about this whole world of

00:49:17.580 developmental individual differences? What are the nuts and bolts changes that occurs in a kid?

00:49:22.720 So that as an adult, they are now 30-fold more likely than the next person for this or that to

00:49:29.620 happen to them. And this whole trendy field of epigenetics, which is early experience doesn't

00:49:37.220 change your genes, doesn't change your DNA sequence. With some like, you know, circus trick

00:49:43.780 exceptions, you've pretty much got your DNA sequence forever. What epigenetics is, is early experience

00:49:50.380 changing the regulation of your genes, how easily you turn certain genes on, how easily you turn

00:49:57.840 others off in different parts of your body, different parts of your brain, and so on. And that's exactly

00:50:04.260 the sort of domain where you see the sort of stuff that you outlined. So that, for example, if you're a

00:50:12.540 fetal rat and you, that rat, have made a terrible decision, you've picked the wrong womb to be

00:50:19.380 developing in. And you happen to be inside a mother who's highly stressed. She's secreting a lot of

00:50:26.400 rat glucocorticoids, which get into the circulation through the placenta and to the fetal circulation

00:50:32.660 into the kid's brain. And one of the things that it does is it causes an epigenetic change in the

00:50:39.640 amygdala. So is that rat going to be born with a larger amygdala or is the phenotype more complicated

00:50:45.500 than just size? It's size and a bunch of other things. As an adult, it's going to have a bigger

00:50:49.960 amygdala and it's going to be more excitable. And it's going to be more prone towards interpreting

00:50:55.960 a neutral situation as a threatening one. That's virtually the definition of rat anxiety disorder,

00:51:02.560 seeing menace that other people don't. And you see much the same evidence in humans by now.

00:51:08.780 Early experience. Forget early experience. What kind of kindergarten teacher you had? This is fetal

00:51:15.580 early experience. And this is exactly a domain where you get potentially a lifelong epigenetic effect.

00:51:23.480 Okay. So that turns out to have a hell of an implication. That's just the most exciting subfield

00:51:31.420 around there by now. Okay. So you were a fetus and got exposed to lots of mom's glucocorticoid levels.

00:51:39.840 And as a result, as an adult, you've got an enlarged amygdala and you see threat all over the

00:51:46.180 place that other rats don't. And among other things, you secrete elevated levels of glucocorticoids

00:51:53.940 because the world is full of menace that only you are seeing. So you get pregnant and during your

00:52:02.220 pregnancy, as a result, your fetus is exposed to elevated glucocorticoid levels.

00:52:08.660 And to be clear, it's not because you have altered the germline genome. It's that you have changed the

00:52:15.400 expression of the gene, which has altered the phenotype. And now that phenotype is being passed

00:52:21.760 generation to generation through parallel expression. Exactly. Something termed non-genetic

00:52:27.340 transmission of traits, non-Mendelian. And people have now shown some of those traits. You see that

00:52:33.640 ripple, it gets smaller each generation, but it's there half a dozen generations later. And the exact

00:52:40.320 equivalent of some of these have been found in humans. In other words, individual differences are

00:52:47.580 arising not only from experience, but from the multi-generational transmission of some of the

00:52:53.000 consequences of experience, which is just mind boggling that that can work that way.

00:53:00.160 Let's go back a little bit to why this is problematic. So at the outset, we alluded to this

00:53:04.920 idea that it's a misnomer to say stress kills. I'd love to hear if you have a particular definition

00:53:10.100 of stress. I probably butcher this stuff, but I sort of think of stress as the external thing.

00:53:14.500 And I think about it as it's anything that is sort of emotionally or physically,

00:53:20.040 either chronically or acutely distressing. I mean, that's sort of a dumb definition because

00:53:24.860 it contains the word stress, but I think people understand distress a little more than they

00:53:30.180 understand stress. But of course, it's your response to that physiologic response, right?

00:53:36.600 So we can quantify this stuff in terms of what hormones are happening in the body and how the

00:53:41.800 hormones are moving the body. It's your response to that that probably has a greater impact on your

00:53:46.620 health. So let's go through three things. Help me understand how hypercortisolemia and or its

00:53:54.840 accompanying features will impact the brain, especially, well, through any timeline you want.

00:54:02.000 I'm obviously interested in the aging brain, but I can't imagine this also doesn't impact the

00:54:06.600 developing brain. This is basically what I've spent my whole professional career thinking about.

00:54:13.240 And historically, the first place where people sort of realized something scary was happening

00:54:18.380 was a brain region called the hippocampus. Hippocampus is all about learning and memory.

00:54:24.680 You want to have a hippocampus. It's the main brain region that's damaged in Alzheimer's disease,

00:54:30.340 and it's vulnerable in lots of other ways. Turns out it's extremely sensitive to glucocorticoids

00:54:37.040 translated more reductively. It's got extremely high levels of receptors for glucocorticoids by the

00:54:43.560 standards of the rest of the brain. And what's the evolutionary basis for that? Is that to have a

00:54:48.000 feedback loop? There's two reasons. One is to have a feedback loop, but the other is, okay,

00:54:54.420 so the hippocampus remembers stuff for you. You don't remember everything. You don't remember

00:55:00.880 where you were on 9-10 as opposed to 9-11 kind of thing. Your memory processes has to come with a

00:55:08.700 filter saying, is this one important? So you're saying that cortisol amplifies

00:55:13.840 memory consolidation and that you use this to consolidate stressful memories as a way of learning?

00:55:18.940 Exactly. Along with epinephrine and norepinephrine indirectly, they have some of the same effects.

00:55:23.240 So cortisol crosses the blood-brain barrier with no difficulty?

00:55:26.380 Exactly.

00:55:27.120 I assume epi and norepi do the same?

00:55:29.360 They have to work more indirectly heavily through the vagal nerve because they don't get them as

00:55:33.860 readily. But some of it is also norepi being released within the brain during stress. So it

00:55:38.880 has some of its own memory enhancing effects. Again, a great example of evolution's got this awesome

00:55:45.180 system set up and it only gets out of whack when the stimulus becomes too much. You do want that

00:55:52.860 imprint, but you don't want that happening full-time.

00:55:54.900 Or stated another way, this is the reason why you don't get much out of a class if you're semi-comatose

00:56:01.600 and you got two hours of sleep last night. If you're like three-quarter, your glucocorticoid

00:56:07.560 levels are low, you're not consolidating stuff. If you are out of your mind terrified because there's

00:56:12.900 a lion sitting next to you, you're not going to absorb much either. Inverse U, optimal range,

00:56:17.860 all of that. So it turns out the optimal amount of glucocorticoids, something that is moderately

00:56:24.460 stressful, in other words, something stimulating, does great stuff to your hippocampus. It increases

00:56:31.580 blood delivery there, glucose, oxygen. It makes the synapses, the connections between neurons more

00:56:39.520 excitable in the hippocampus. It does great stuff. A little bit of arousal, alertness is a good thing for

00:56:45.500 learning and memory. Now instead, transition to you are stressed 24-7 ever since you were like 10

00:56:53.960 years old kind of thing, and you're in the range where glucocorticoids do exactly the opposite.

00:56:58.940 They decrease oxygen and glucose delivery to the hippocampus. They make neurons less excitable.

00:57:06.020 They disconnect synapses. They cause the processes in neurons to shrivel. They block the birth of new

00:57:12.840 neurons there. They make other insults more damaging to neurons in the hippocampus. What do you

00:57:18.360 have there? That's the world in which if you were stressed out of your mind, memory doesn't work so

00:57:24.140 hot. And what we're increasingly realizing is if you're exposed to excessive glucocorticoid levels, like

00:57:31.540 on the scale of years to decades, you're going to make this part of the brain get older faster.

00:57:37.000 Which speaks to something that I know you're quite passionate about, which is the differences in how

00:57:44.600 socioeconomic status can sort of affect generational changes in this manner. Because, you know, use the

00:57:53.000 example of a 10-year-old. Well, I did my residency in Baltimore. Let me tell you, a 10-year-old in

00:57:58.000 inner-city Baltimore who's in the wrong house versus a 10-year-old in Palo Alto who's in quote-unquote

00:58:03.040 at the right house. And look, that's not to say that you could have a 10-year-old in Baltimore that's

00:58:06.620 got a great environment and a 10-year-old in Palo Alto that's dealing with a whole bunch of other

00:58:09.820 different issues, which, you know, especially in the era of social media. But all things considered,

00:58:14.380 probabilistically, that 10-year-old in Baltimore is going to have a much harder time given what you

00:58:20.320 just said. Or, I don't know, stated the other way, I have a friend who's a cardiologist who splits his

00:58:26.620 time between a hospital in Oakland and a private practice in San Francisco. Some of the time what

00:58:33.960 he's doing is dealing with 80-year-olds who are considering getting a pacemaker because the ski

00:58:38.980 season is coming and they're wondering if they're going to be in shape and time for that and maybe

00:58:43.580 that. And then back in Oakland, he's dealing with 50-year-old elderly men who are having heart

00:58:51.100 disease. Yeah. Socioeconomic disparities are, I won't get on my soapbox now. When you look at the

00:58:58.800 source of variability in health among humans on this planet, socioeconomic differences, differences

00:59:05.300 in absolute levels, differences in degrees of inequality within cultures and within communities

00:59:12.060 and so on, there's an enormous predictor of health. You want to look at the most medically impacted

00:59:20.980 low-ranking primates you could find on Earth. Look at poor humans. Because when humans invented

00:59:27.840 socioeconomic status and the capacity to be poor, they invented a way to subordinate the have-nots

00:59:35.140 like no chimp on Earth could ever dream of doing. As you've alluded to, there's something else to it.

00:59:39.920 You know, recently I interviewed an amazing physician named Tom Katana who practices in the Nuba

00:59:44.600 Mountains in the south of Sudan. So he's the only physician to take care of one million people who,

00:59:51.500 as you know, are being killed by their own government. Bashir is sort of indiscriminately

00:59:57.160 killing these people. So my discussion with Tom was one of the most riveting discussions I've ever

01:00:03.000 had with a human being. It just happened to be in front of a microphone. But one of the things that

01:00:07.220 just as an afterthought we were discussing that surprised me is we were going through all of the

01:00:12.740 different things that people die of there. You know, they don't have vaccines. You've got measles

01:00:16.620 outbreaks that are killing people left, right, and center. And the trauma, like, you know, the

01:00:20.780 shrapnel blowing people apart. Not surprisingly, they're just not getting the same chronic diseases,

01:00:26.720 you know, and the cancers they get are not the cancers we get. And they're not getting heart

01:00:30.340 disease. And they're, you know, almost unheard of to get type 2 diabetes. But what really surprised me

01:00:36.020 is there was no suicide. And I found that as the single most interesting thing I guess I learned

01:00:42.840 from Tom, which was we would look at their life and think that is an abysmal existence that I

01:00:50.000 couldn't tolerate for one second. And yet I would have to guess that their level of cortisol might be

01:00:57.820 lower than ours, even though they're in a much worse environment. So whether it's that sense of

01:01:02.440 the community that they have or the shared purpose, there's something about it. So in other words,

01:01:07.620 my point is even in the presence of such great poverty, it seems that there's ways that this can

01:01:12.840 be overcome, whether it's through there's no comparison to anybody else. Because another point

01:01:17.420 he made was most of the folks there don't even know they're in Africa. Like they don't necessarily

01:01:21.920 know that Africa is the continent in which their country resides. So is the bigger issue there,

01:01:26.600 you think that there's no disparity? So even though that's complete poverty, there's no real

01:01:31.440 perceived disparity. Or do you think it's the sense of community? Like what would you hypothesize

01:01:36.740 explains that health, that mental health? All the above. There's a whole world of people who study

01:01:43.940 happiness along with more traditional public health people who study things like longevity.

01:01:49.060 You look at the quarter poorest places on earth and indeed people there don't live very long and

01:01:57.500 are miserable. But once you get past sort of the subsistence level, there's not a great relationship

01:02:04.480 between the wealth of a country, GDP per capita, anything, and levels of happiness or life expectancy.

01:02:13.920 And you look at the fact that the US has a shorter life expectancy than Cuba and Lebanon and Costa Rica,

01:02:20.460 and it's like the shame of this country kind of thing. Once you get past mere subsistence level,

01:02:27.240 income is not a great predictor of any of this stuff. And that's instead where you get into

01:02:33.460 worlds of social capital and social support. And when you look at the whole literature,

01:02:40.800 and you look basically at every westernized country on earth, and it's now seen as they become

01:02:45.620 westernized. And what you see is the health socioeconomic gradient. The poorer you are,

01:02:51.720 the worse your health on the average. The more of a whole array of diseases you get, not all of them,

01:02:58.020 but a huge number, the more impactful they are. And when you look in the West, the United States is the

01:03:05.120 poster child for that. We've got the steepest curve of any country on earth. In the westernized world,

01:03:10.700 the least steep ones are, you bet, of course, the Scandinavian countries, ever reliable sort of

01:03:16.720 utopias. And then you begin to unpack why this relationship occurs. And like some incredibly

01:03:23.740 smart people have spent their careers looking at it. The most obvious one is, if you're not healthy,

01:03:30.900 it's very hard to pull off being the CEO of a company. Poor health precedes and gives rise to

01:03:37.360 poor socioeconomic status. Okay, that's plausible. That turns out to explain a tiny percentage of the

01:03:43.120 variability. And you could look at the status, socioeconomic status of the home in which a child

01:03:50.320 is raised. And that's a predictor of their likelihood of diabetes half a century later.

01:03:55.600 So absolutely, the socioeconomic status comes first in explaining the vast percentage of the

01:04:01.540 variability. Okay, so next thing, maybe it's just that, well, everybody's kind of equally

01:04:07.200 healthy. It's just that the really poor people are very unhealthy. We have a step function.

01:04:12.660 No, you start with Jeff Bezos and Bill Gates and every step down there. And statistically,

01:04:19.620 the lower you go down every rung of the way, the poorer you are.

01:04:24.040 The poorer you are with respect to health, I mean?

01:04:25.380 I'm sorry, the poorer your health. Yes, yes, thanks. So now you unpack that. And what's the most obvious

01:04:30.660 explanation? And this is what people call a neo-materialist explanation, which is obvious.

01:04:35.480 The poorer you are, you don't have health care access. You don't have health insurance. You can't

01:04:40.820 go to the doctor as readily. Your care is more lousy. That's obviously, that explains everything.

01:04:46.180 That explains virtually none of the variability in the data. Because you see the gradient nonetheless

01:04:51.260 in countries with socialized medicine, universal health care. You see it for diseases where it doesn't

01:04:58.760 matter how often you get health care access. Juvenile diabetes. So it shows an SES gradient kind of

01:05:07.100 thing. So it's not health care access. You then look cross-culturally and you see wildly different

01:05:14.840 income levels and wildly different levels of health care access. And you see very similar lifespans

01:05:20.780 across these countries and very similar gradients. So what people spent like the last 30 years doing

01:05:27.220 is having this huge shift towards, it's got so little to do with the material aspects of wealth

01:05:34.120 or poverty. It's got to do with the psychological aspects. It's got to do with the stress.

01:05:39.580 First key finding, somebody at UCSF named Nancy Adler, who's done wonderful research showing,

01:05:47.040 okay, your socioeconomic status, your wealth, your objective measure of wealth,

01:05:52.340 is indeed a predictor of your health. Turns out at least as good of a predictor is your subjective

01:06:01.180 socioeconomic status. On the level when you look at people around you, how do you, how are you doing

01:06:07.420 compared to other people? Where would you place yourself on this 10-step ladder in terms of what's

01:06:13.140 your absolute SES? What's your subjective one? And by asking it that way, you're asking the person

01:06:18.480 to consider the community that's most pertinent to them. Who's the comparison group? My next door

01:06:23.460 neighbors, Warren Buffett, in between, whatever. When you think of other people, how are you doing

01:06:29.900 compared to them? And it turns out your subjective SES is at least as good of a predictor of your health

01:06:36.440 as is your objective. In other words, if you took someone's income, which is quite objective,

01:06:42.020 it would offer no more prediction than asking that person in the Nuba mountains, where do you rack up

01:06:49.660 in this tribe? And it's sort of like, huh, you know, sort of the top two thirds.

01:06:54.540 Yeah, exactly. Or another way of stating that is you look in some bloated corporation and there's some

01:07:02.280 guy who's the assistant manager of the mailroom, and that's an incredibly status-filled position for

01:07:08.080 that guy. And there's some other guy who's number two in the company who was just passed over to be

01:07:13.860 number one. And the only pertinent thing in his mind is not the 99,000 employees that he's higher

01:07:19.440 ranking in, that there's still somebody ahead of me. And you could see the same thing in baboons.

01:07:24.900 In other words, it's not being poor, it's feeling poor. The next critical piece in the story is work

01:07:32.620 from this guy, Richard Wilkinson in the UK, who shows what's the best, most effective way to make

01:07:39.640 somebody feel poor, independent of their absolute levels of income, surround them by inequality,

01:07:47.300 surround them by reminders of all the people who are doing better than them.

01:07:51.540 I mean, this is where social media, it's the amplifier to all amplifiers of this, right?

01:07:56.660 You can't go 10 minutes if you're on it without looking at somebody who's obviously better

01:08:02.840 looking, obviously smarter, obviously richer, obviously having more fun. I think this has

01:08:08.260 been pretty well documented, right? I mean, lifestyle of the rich and famous, or you could

01:08:12.980 be driving down a freeway and somebody passes you, and I don't know what counts as a high status car

01:08:18.960 these days, the cost of fortune, but they come speeding past you, and you can feel crappy and

01:08:26.640 diminished and like a less successful human, and you never even saw that person's face.

01:08:33.260 This is unheard of in the history of humans or primates of being able to feel socially subordinated,

01:08:39.960 and you don't even interact with the person. Oh, there's people out there with, you know,

01:08:45.780 at least if the next door neighbor has more camels than you, that's a very like tangible,

01:08:50.660 real thing in terms of like likelihood of surviving the next door. Income inequality explains the

01:08:58.760 mediating effect between objective socioeconomic status, subjective socioeconomic status, and health

01:09:06.080 outcome. What I'm hearing you also say, though, that's a more subtle spin on this, is it's not

01:09:12.080 necessarily global income inequality, it's local income inequality that is much bigger.

01:09:17.960 But what technology has allowed us to do is explain what counts as low.

01:09:21.580 That's right. That's exactly right. It's expanded what local means.

01:09:24.040 You can sit there and watch, I don't know, Lifestyles of the Rich and Famous. And back when,

01:09:29.520 you would never have gotten into like the head of your fiefdom's castle or whatever. And now you can see

01:09:36.020 all the crap they have that you're never going to get and feel less loved as a result.

01:09:43.560 It's so interesting to hear you talk about this. This is a topic that I think anybody listening to

01:09:47.360 this is well aware of, especially if you're a parent, because you also have to think about this

01:09:53.520 through a developmental lens, which is at least when you and I grew up, I didn't grow up with a lot,

01:09:59.860 but you really had no idea what was different, right? Like you simply, everybody was the same.

01:10:04.420 I mean, everybody's parents bought used cars and that have new cars and everybody had more or less

01:10:10.860 the same sort of, you know, clothing that wasn't exactly the best and whatever. So at least you

01:10:17.160 could argue, well, were we at least spared some of this difficulty during a critical window of

01:10:23.060 development? And what happens now to a 10 year old that's got a smartphone and is subjected to this?

01:10:31.420 Because I remember that funny show Lifestyles of the Rich and Famous. I can still sort of hear the

01:10:35.940 goofy, cheesy theme song. I think I even probably watched it once or twice as a kid, but it's a lot

01:10:42.180 easier when that's the one exposure you have to extreme wealth or disparity. And either you can

01:10:47.400 watch it for one hour or not, but it's quite a different thing if not to pick on the Kardashians.

01:10:52.940 I'm just, but if you're inundated with, oh my God, look, look at how awesome the Kardashians are

01:10:57.560 and what they're doing and how great their life is and multiply that by three log orders. Do we have

01:11:04.560 any data that suggest that we are at a critical juncture? Because I was having this discussion

01:11:10.500 with a friend yesterday, which is, is there evidence of any greater transition in technology

01:11:18.760 in both a positive and negative way than this generation to the last? Is this truly the greatest

01:11:25.940 step forward? I would assume so. But the things we worry about, people have been worrying about for

01:11:34.840 centuries. Kids, they don't go outside. They don't play. They don't have like meaningful relationships

01:11:42.660 because they spend all their time talking on the telephone. They spend all their time listening to

01:11:47.740 their transistor radio. So maybe we're blowing this up. Maybe this is just this generation's version.

01:11:52.620 I mean, I guess the one difference is when you're talking on the telephone, when you're listening

01:11:58.340 to the transistor radio, I don't know if it creates that global to local phenomenon quite as easily or

01:12:06.020 as quickly or with, with less resistance as we see, but maybe you're right. Maybe this has always been

01:12:11.020 one generation's struggle with the last. But what you get is an amplifier now, because if you're an

01:12:19.280 insecure, socially isolated, peri-adolescent kid who's vulnerable in all sorts of ways,

01:12:27.660 and you know, no matter what decade or century it was, you're the last one picked for the game,

01:12:33.960 you're the one who's least popular or whatever, and that has all its corrosive effects. Now, if you

01:12:39.880 really set your mind to it and you're that kid, you could spend 24-7 just wallowing toxically

01:12:47.000 in evidence of a gazillion other people who are better looking than you and more popular and

01:12:53.620 invited to parties you'll never be in. It amplifies further. And the technology does absolutely that.

01:13:01.320 What I think it does is it makes the vulnerable more damaged than in the past.

01:13:06.020 I think it's safe to say these amplifiers aren't going anywhere. So rather than wallow in their

01:13:15.100 harm, I guess the more relevant question is, what do we do? If you're a parent today or not a parent

01:13:22.900 today, and you're thinking about this through the lens of yourself versus your kids, whatever,

01:13:26.700 what are the steps that one can take to become less susceptible to these forces that seem to drive

01:13:36.600 this? Because I want to step back for a moment. When I think about these areas that we've talked

01:13:42.420 about before, about the impact of nutrition and sleep and exercise and stress or distress to make

01:13:49.080 it more the term I use. When I think about this personally, the one I most worry about is the last

01:13:54.980 one. I think I've got a pretty good handle on nutrition and it's in many ways easier to control.

01:14:00.580 I feel like I'm more in control of what I eat. And when I make bad choices, I'm usually doing them

01:14:05.600 consciously. Like I've decided I'm going to eat this pizza versus I can't help myself. I'm going to eat

01:14:10.820 this pizza. Similarly with exercise, like, and again, I'm not saying this for anybody else, but this is

01:14:15.220 just my personal thing. And even with sleep, like once you commit to it, which is not something I did

01:14:21.200 until probably seven or eight years ago that I sort of committed to, wow, this really matters.

01:14:25.620 And to forego this thing, bad idea. It's this last one that really drives me crazy, which of course

01:14:33.320 doesn't help matters because the fact that it drives you crazy makes it worse. But I'll give you an

01:14:36.920 example. As a general rule, outside of the immediate postprandial period of a high glucose meal,

01:14:45.420 far and away, my highest blood glucose is always in the morning. Now I wear a 24-hour glucose meter.

01:14:52.540 So I'm kind of a weird guy. For almost four years, I've been wearing a glucose monitor all the time.

01:14:58.440 So it measures my glucose 24-7 at one minute increments. And out of say 365 days in a year,

01:15:05.360 I'm easily wearing it 330 days of the year. So I've got a lot of data. And without a question,

01:15:11.920 when you look at a 24-hour period, if you stripped away the x-axis of time, I could easily identify

01:15:19.660 morning for you without exception. I'll give you an example. This is not something I'd planned to do.

01:15:26.820 I had breakfast yesterday, yesterday being Sunday, really early because I woke up with my kids,

01:15:32.340 made breakfast. I normally don't eat breakfast, but I did. So I had a breakfast, 7.30 in the morning,

01:15:36.940 did a workout, had to catch a flight, didn't have time to eat after, had a very, very busy day,

01:15:44.760 didn't eat a single thing, got to the hotel around 10.30 or 11, didn't want to eat, so didn't.

01:15:52.500 You know, got up this morning. It's been almost 24 hours since a meal. And I looked at my glucose

01:15:58.180 meter and it was like, said, you know, 110, 110 milligrams per day. I was like, there's no way

01:16:02.320 that's right. Calibrated it. Sure enough, it was 110. Now there is no earthly reason I should have

01:16:08.400 had a glucose of 110 milligrams per deciliter 24 hours after my last meal, which by the way,

01:16:14.760 was bacon and eggs. It's not like I was eating pancakes, right? Well, I promise you if I could

01:16:20.560 spot check my cortisol, it was high. And here's the thing. Before I went to bed, my glucose was quite

01:16:27.280 low. You know, my glucose was probably 80 when I went to bed and it slowly rose. And sure enough,

01:16:32.980 as my day wore on today, the glucose went lower, lower, lower, lower, lower. It was about 78 before

01:16:39.120 you walked in here. I'm not alone, by the way. So I've seen this a lot clinically with patients.

01:16:44.280 Once you start putting these 24-hour glucose sensors on people, which a lot of my patients are

01:16:48.780 now doing, you get this insight into this horrible thing that's happening when we think we're sleeping

01:16:55.180 and nothing else is going on, but we're ruminating or God knows what else.

01:17:00.200 And fits perfectly with morning wakening is when you get your highest glucocorticoid levels,

01:17:06.460 which is probably one of the main driving forces on the increased blood glucose. When you think about

01:17:12.820 it from a circadian standpoint, what's the most challenging thing you have to do each day in

01:17:17.800 the absence of any major tumult? Get up, start functioning, all of that.

01:17:23.360 It just seems like it's disproportionate.

01:17:25.180 Certainly the Dawn effect has been well described. It's more amplified in people with type 2 diabetes,

01:17:30.680 which is another interesting point, right? Which is why is it that someone who already has

01:17:35.220 glucose dysregulation would have an even higher cortisol response in the morning? And yet you'll

01:17:40.500 see enormous fluctuations in glucose. I guess my point here is this seems like a harder problem to

01:17:47.680 fix. And certainly meditation is by far the best tool I have ever found to even approximate

01:17:54.000 getting this under control. But it's still hard because it's not like you have a pill. If your blood

01:17:59.840 pressure is high, well, I think it's probably best to fix it in any way possible. But we also have really

01:18:05.840 great drugs that fix high blood pressure that can at least mask these things. We don't have a pill to fix

01:18:11.380 hypercortisolemia. It's one of the most complicated endocrine situations. And yet, as you've described eloquently,

01:18:18.160 it's also so innately wired into us. And we have this miserable midbrain that's just killing us.

01:18:27.160 First of all, I'd love to hear your thoughts on meditation, but then also other things that given

01:18:31.500 how much time you've spent thinking about this problem, I'd love to know how you would suggest

01:18:36.180 someone who doesn't have quite the Zen mindset that I can tell you do. What should someone else be

01:18:41.140 thinking? Right off the bat, I'm delighted to see that I have a persona of a Zen. I'm actually like

01:18:47.500 one of the most type A stressed people you're ever going to run across. I've spent 40 years

01:18:53.080 professionally studying how bad the outcome is going to be of all of these bad lifestyle aspects

01:19:02.120 without having anything insightful to say about how to actually fix it or prevent it. And I certainly

01:19:08.500 have learned personally absolutely nothing from my lifetime of work. I'm incredibly stressed. I'm

01:19:14.240 mostly good at telling you what's going to happen if you don't get stuff under control rather than how

01:19:18.420 to get things under control. When I look at the stress management literature, I don't do it very

01:19:25.440 often because I tend to get sort of agitated at that point. But broadly, it works. It works as in

01:19:34.380 you can lower blood pressure, you can lower cholesterol levels, you can lower subjective sense of health,

01:19:39.620 these objective measures as well with all sorts of interventions. What do you see when you look at

01:19:46.100 the literature closely? First off is you can't do your stress management on the weekends kind of

01:19:53.340 thing. It needs to be a regular sort of thing. You can't do it while you're on hold on the phone for 30

01:19:58.560 seconds. You need to set time out for it. You know, the benefits of aerobic exercise, I don't know what

01:20:05.100 the magic number is these days, but 20 or 30 minute blocks is a minimum to start getting the

01:20:09.880 cardiovascular benefits. So it's got to be something like you stop things to do.

01:20:16.240 So that's important. Let's double click on that. What you're basically saying is,

01:20:19.580 because I think you're understating how much you know about this topic. Obviously it's something you

01:20:23.480 know a lot about. As seriously as we would take nutrition, and if you think about how many hours a

01:20:29.280 week do you put into eating? I mean, even if you're shoveling food down your throat, it still takes

01:20:33.180 quite a bit of time. If you're going to exercise to the levels that have demonstrated benefit,

01:20:38.120 we're talking about hours a week, not minutes a week. If you're going to make the difference between

01:20:44.720 getting by on sleep versus getting restorative sleep, I'm not talking about the absolute amount

01:20:50.020 of sleep. I'm just talking about the delta between those two. Think about how many hours that is. In fact,

01:20:54.960 for the average American, that would work out to be about an extra seven to eight hours a week of sleep.

01:21:00.280 And what you're basically saying is, if you want to combat this hypercortisolemia dude,

01:21:05.800 guess what? It ain't a 20 minute a week thing. And in some ways that taps into one of the

01:21:11.760 80-20 rules of sort of mental health professionals. Okay. So you have this crazy stressful lifestyle

01:21:19.300 and there's just a bazillion things you can't say no to, and you're just going 24 seven.

01:21:25.040 And if you've gotten to the point of saying, this is crazy, this is not a quality life. I want to live

01:21:31.960 a healthy quality old age. Well, I got to get this stuff under control. I'm going to start doing

01:21:37.460 something stress management-y. And if you've gotten to the point where in this lifestyle,

01:21:43.940 where there's a billion things you can't say no to each day, you're saying no to them enough that

01:21:49.260 nonetheless, 20 minutes every single day you are doing this, it almost doesn't matter what

01:21:54.720 intervention you're doing. You're 80% of the way there already if you're managing to do that.

01:22:01.140 And that's very similar to this sort of amazing classic finding. You get people who are clinically

01:22:05.040 depressed and finally, finally, finally, they're going to do something about it and merely making

01:22:10.700 a first appointment. Even before you've seen the person, people feel significantly better

01:22:16.540 because you are finally saying, I matter enough to do something about this, or I'm activated enough,

01:22:24.760 or I'm optimistic enough to actually go. You're halfway there at that point, merely by

01:22:30.360 doing something on a near daily basis. So just on that logic, even though I don't

01:22:34.940 know that this has been done, you would argue that 10 minutes of deliberate, mindful practice of

01:22:40.640 meditation daily would probably be better than one hour once a week. Absolutely. In part because

01:22:46.520 if nothing else, if you do a daily seven times a week, you were sitting in the aftermath of having

01:22:54.480 done that versus only one time a week. And an awful lot of what's most interesting about physiology and

01:23:01.360 its impact on sort of mental health, things like that, is what's happening in the recovery period

01:23:06.920 after something like that. In the same way, one awful hour long stressor a week versus

01:23:14.220 punctuated episodes of it throughout the week without question, the latter is worse because

01:23:19.680 you've now got umpteen different times that you have to recover from having turned on the stress

01:23:25.500 response. And that's where a lot of the damage occurs. You know, I learned something about myself

01:23:30.040 that's going to sound so stupid because it's so obvious. Although I don't think it's true for

01:23:34.080 everybody. Email is a huge stress to me. To be blunt, I hate it. That would be the kindest thing

01:23:40.520 I could say about email. I really, a few months ago, hit a true nadir in my response. And I'm like

01:23:48.020 looking at these glucose levels going up and I'm looking at these morning glucose levels. So even

01:23:53.400 though my overall glucose levels still look great, I mean, this trend was upsetting to me. I'm watching

01:23:58.000 my resting heart rate in the morning go up over the course of four months. It had gone up like

01:24:03.500 six beats per minute. And if anything, I was in better shape exercising more regularly. I made this

01:24:10.380 observation one day, which is how many times in a day do I stop to look at email, even if it's just

01:24:16.100 to check one or two? And the answer was like 50. And every time I do it to your point, even if it's very

01:24:22.620 brief, the after effect is not that brief. So I could, I could look at an email and see two stressful

01:24:28.880 things, but it might sit with me for 20 minutes. So I tried this experiment, which is I'm going to

01:24:35.380 just check email twice a day, two 30 minute blocks of email. And I would say within two weeks, I just

01:24:45.180 really felt better. It seems to me like we just have to figure out ways to figure out what those

01:24:53.180 triggers are for us individually. There's probably some people for whom email doesn't trigger them at

01:24:57.200 all, right? There's probably, you know, for me, Twitter doesn't trigger anything because a, I have

01:25:03.300 a very narrow window that I pay attention to and it doesn't involve things that are aggravating like

01:25:08.660 politics or religion or whatever. It just sort of, I'm only really following science. So anytime I look

01:25:14.340 at Twitter, I'm actually learning something kind of new and they're, but I'm sure there are many

01:25:17.660 people listening to this who would say, oh my God, like if I spend an hour on Twitter, my blood

01:25:21.480 pressure could be through the roof. So it's like, everyone's got to kind of pick their thing. You

01:25:25.760 said you're type A, which obviously you are. I mean, you know what I didn't say at the outset when

01:25:29.220 we started speaking, but you've won one of the most prestigious awards imaginable, which is the

01:25:33.200 MacArthur award. And you won that about 30 years ago, right? That's impressive. They don't give that

01:25:38.680 award out lightly. So that's the one that's referred to as the genius award. And I know you're

01:25:42.700 probably like your skin is crawling. When I say that my point being is you're an incredibly

01:25:48.220 accomplished, successful guy. It's not surprising. You would describe yourself as a type A. What have

01:25:53.920 you learned about yourself over the past 30 years or even longer going back to your first days in

01:25:58.820 Kenya about what those triggers are for you and what you can do to lower your cortisol levels?

01:26:04.560 Not surprisingly, if you, you hang out with people who are field biologists of any sort. And

01:26:10.800 again, I've, I've only been a part-time annual one over the decades, but nonetheless still think of

01:26:16.920 myself as a field biologist. We're kind of a solitary tribe. I mean, during my peak periods of

01:26:25.500 doing field work, I was spending three, four months a year alone living in a tent where 12 hours a day,

01:26:32.600 I wouldn't say a word to another person. Temperamentally, this is kind of who I've been for a long

01:26:38.600 time. And there was always this ironic thing because I was sitting there studying these baboons

01:26:43.460 because primate social behavior and I'm interested in primate social behavior. And this big sort of

01:26:50.420 epiphany I had in my work that, okay, your, your social rank as a baboon has something to do with

01:26:55.420 your health, but much more importantly is your patterns of socialization and social networks.

01:27:00.600 And how often do you groom? And how often does somebody groom you? And how often do you sit in contact

01:27:06.560 with another baboon or playing with an infant? And then I, you know, finish the day's work and go

01:27:10.960 back to my tent. So there was something ironic that I was like studying the health benefits of

01:27:16.920 sociality, living alone in a tent, a large part of the year.

01:27:21.160 Your wife is a scientist too, isn't she?

01:27:22.760 She was, she kind of decided she was sick of it. And she now directs a musical theater program,

01:27:27.720 which is much more fulfilling for her. But at one point my wife came along.

01:27:34.940 Yeah. Yeah. That's what I was going to ask.

01:27:36.020 And eventually family and, you know, kind of realizing, oh, I've missed out on an awful lot

01:27:43.480 of what are really like the wonderful worth living for moments in life out of the sociality stuff.

01:27:51.360 And that is a refuge and a sanctuary from the world's madness. And I could not have predicted

01:27:59.280 as a 20 year old who had been planning to be a field biologist for a dozen years at that point,

01:28:04.500 and I could not have predicted sort of how much of my equilibrium at this point turns out to be due to

01:28:12.580 interacting with the right two or three other primates and like being in love with them and

01:28:19.660 stuff. That one was kind of a revelation for me. I am not the social being that I would have guessed

01:28:25.820 I would have been back when.

01:28:27.120 Which is interesting because having this discussion with you today, I can sense much more of your

01:28:33.760 introversion than the first time we met when you were giving an unbelievably charismatic animated

01:28:41.060 talk. And I don't know how many of us were there, maybe a hundred people. And which is so interesting,

01:28:46.640 right? Because you would, I think anybody sitting in the audience would look at this and say,

01:28:49.480 oh, that's a, that's the life of the party. But it's interesting that we can compartmentalize and

01:28:53.520 separate those things, right? I mean, you can get up there and you can do what you need to do and

01:28:56.780 you're at your happiest, I'm guessing, in the way you described it versus in the aftermath of that

01:29:01.400 talk when a hundred people run up to you to ask you four questions each.

01:29:05.100 Not to get too self-reflective or something, but I'm a fairly introverted person who does better with

01:29:11.360 scripts and giving a lecture is a pretty structured script. And having sort of an academic

01:29:19.360 persona or whatever is a, another version of it as well.

01:29:23.980 What year did you become a full professor at Stanford?

01:29:26.280 It was 33 or something, early nineties.

01:29:31.300 I mean, you live in San Francisco, so you're not making that commute every day, I hope.

01:29:35.180 Nope. But I did for about a quarter century.

01:29:39.200 Yeah. That'll, that'll hurt the cortisol levels, won't it?

01:29:41.320 I used the commuter train, Cal train here.

01:29:44.360 So you could read and...

01:29:45.600 Oh, I loved it. I loved, this was much of it was before cell phones.

01:29:49.360 So you'd pick it up at 4th and King and you'd just go, yeah, I used to make that ride all

01:29:53.320 the time. I used to have a girlfriend that lived in San Francisco and I loved that train

01:29:57.720 ride. And then you'd get off on your bike at 4th and King and you could go anywhere in

01:30:01.320 the city.

01:30:01.800 Yeah, exactly. I wrote half my book writing was on the train there. It's pretty weird when

01:30:07.620 you realize that like one of your valid social communities or the conductors on Cal

01:30:12.380 train sort of as you're watching them grow up on you and things like that. But yeah, no,

01:30:17.940 that was, I was a big fan of train commuting.

01:30:22.280 So speaking about books, let's talk about your more recent book. It's about human behavior,

01:30:28.540 which, you know, I mean, I can see based on this discussion now, how your interest would

01:30:34.760 shift to that. What was the impetus for that research?

01:30:37.540 Well, title is Behave the Biology of Humans at Her Best and Worst. And sort of as we were

01:30:44.080 talking about before, I closed my lab four years ago and stopped active research to sit

01:30:49.720 for four years and write this book. And it's basically trying to make sense of the biology

01:30:57.240 of what is for me the most puzzling thing about us as a behaving species, which is we are simultaneously

01:31:05.900 the most miserably violent species on earth and the most altruistic and cooperative and

01:31:12.340 empathic. And any given human is capable, depending on the setting of incredible gyrations as to

01:31:23.640 whether they are being wonderful or awful or in between, or behaviors where whether that counts

01:31:28.920 as good or bad is incredibly dependent on what culture they happen to be doing it in.

01:31:34.500 Just trying to make sense of the biology. I mean, it's totally boring biology as to

01:31:39.720 like how your brain makes you do something like pull a trigger, like which muscle groups have been

01:31:46.260 told. That's like studying cockroach neurobiology. What's totally interesting is the fact that we're a

01:31:53.520 species where sometimes pulling a trigger can be one of the most awful things a human can do.

01:31:59.200 And sometimes it could be one of the most wondrous ones. If you're suicidally drawing fire from

01:32:05.820 innocent people and you're sacrificing yourself, or in one setting, you put your hand on somebody else's

01:32:12.540 and that could be a moment of incredible compassion. Or in another moment, you do the exact same thing

01:32:18.280 with your primate muscles. And that's the first step of betraying a loved one, of just making sense of

01:32:25.340 this contextual stuff about human behavior, which is hugely complicated. And the song and dance that

01:32:32.120 I go through in nearly 800 agonizing pages in the book is you're going to understand nothing about that

01:32:39.840 if you've concluded, aha, we now know this is the part of the brain that explains everything,

01:32:45.940 or this is the neurotransmitter or the hormone or the gene or the childhood. Instead, to make sense of

01:32:53.660 human behavior, you got to factor in what your neurons did one second ago, but you got to factor

01:32:59.480 in the environmental triggers of that 30 seconds ago. And you've got to factor in what your hormone

01:33:05.280 levels were like this morning, and what neuroplasticity you've done over the last two

01:33:09.920 seasons, and what your adolescence was like, and your childhood, and your fetal life, and your genes.

01:33:15.740 And amazingly, what sort of culture were your ancestors inventing centuries ago, because that

01:33:22.280 influenced the way you were raised within minutes of birth, and what things you value, and what things

01:33:28.720 your amygdala does or doesn't respond to, and a whole thing of that. What sort of ecosystems produce

01:33:34.880 different types of cultures, and then finally evolution, and why we're in some ways like chimps,

01:33:42.720 and in some ways like bonobos, but we're not chimps, we're not bonobos, we've solved our own

01:33:47.300 special evolutionary. You've got to understand this stuff, it's everything from one second before to

01:33:52.640 a hundred million years before, and all these levels interact, and it's complicated as hell.

01:33:57.960 When people ask the question, which I'm sure you've heard this a hundred times, and you hear people

01:34:02.600 asking all the time, are we innately good or bad? That question doesn't really permit the level of

01:34:08.740 nuance you're describing. The answer is yes.

01:34:11.400 Yes, exactly. And what's most startling about us is most of us have the capacity to do something that

01:34:19.780 we would be stunned and sickened that we were capable of doing it, and most of us are capable,

01:34:25.440 in some circumstance, of doing something that is so damn heroic, and most of us spending most of

01:34:31.060 our time doing things that instead are ambiguous and multi-layered and full of ulterior motives and

01:34:37.900 what's really going on there. And you look at the worst of us and the best of us, and there's not a

01:34:43.620 whole lot of really reliable predictors beforehand. And how much of this, like, you know, you wrote a

01:34:49.660 little bit about PMS. So when I think about PMS, I think about it purely through the lens of the

01:34:56.080 endocrine system, right? I think of it purely through the lens of when a woman is in her

01:35:02.540 luteal phase, that progesterone level has to rise for the placenta. And then, of course,

01:35:08.800 virtually every time it's a false alarm, you don't need it, you shed that lining, and that progesterone

01:35:14.340 level comes crashing down. And it's this crashing down of progesterone that has always interested me

01:35:20.740 why two women could experience the same. We can measure progesterone levels throughout the cycle,

01:35:26.540 and we could know that at day 22, two women could have the exact same progesterone. And on the first

01:35:32.960 day of their menses, they could have the same progesterone. So you know they had the same peak

01:35:36.840 to valley, and yet two women can experience that in two totally different ways. Now, I've thought about

01:35:43.620 that through the lens of progesterone receptors and, you know, the way we sort of talked about the

01:35:47.520 cortisol stuff. Is there something else to that that you layer on top of that that is even more

01:35:53.380 subtle about those differences? Yeah, tons of this sort of additional insights. Here's one example that

01:36:00.380 comes completely out of left field, and this was actually my wife's thesis research on baboons. So

01:36:07.600 you're a female baboon, and you're coming up on your period, and we could frame it as you just did.

01:36:13.460 Here's two females who are both about to have their period, and they have the same exact progesterone

01:36:19.240 levels, and as soon as they start menstruating, progesterone drops in the exact same way. And one

01:36:24.520 of them is a totally irritable, awful, like, jerk to all the other females around her for three days

01:36:31.560 afterward. And the other one is not. The other one withdraws and becomes socially isolated. Okay,

01:36:39.240 what's the difference? It sure can't be progesterone levels, and it's probably not going to be

01:36:43.120 progesterone receptor levels. It's one of them's high ranking. She could afford to be a jerk to

01:36:49.120 everybody else and get away with it. The other one's low ranking. Oh, it's not just your hormone

01:36:55.120 levels. It's what sort of position in your society you have, even if you're a baboon. Or now you look

01:37:01.900 at humans, and depending on what sort of culture you're in, are you in an individualist culture or a

01:37:09.180 collectivist one? Individualist, the United States poster child of individualist thinking,

01:37:14.860 collectivist, 99% of the research has been done on East Asian cultures. And how you somaticize

01:37:22.760 your mood shifts and your physical shifts during your period differs in collectivist versus

01:37:30.260 individualist cultures. How irritable you become, not because there's a difference in how much of

01:37:36.900 negative affect you're feeling during the time. Are you in a culture where it's culturally acceptable

01:37:42.980 to bitch and moan to all your best friends when you're not feeling well? Or are you in a culture

01:37:47.700 where when you're feeling lousy, what you're supposed to do is reach out affiliatively and

01:37:52.320 reify your like social values? And how much of that do you think is also genetic? So for example,

01:38:00.160 I mean, even though I'm not a gynecologist and therefore don't see a lot of this,

01:38:04.820 I see enough to realize that women will often say my sister and my mother either go through or went

01:38:12.220 through the same feelings. And of course, as you described, there are so many different variants.

01:38:17.360 The stereotypical one is the, you know, the sort of the nasty phenotype, but actually the one that I

01:38:22.660 think might be more prevalent is the sadder phenotype, the more emotionally distraught,

01:38:29.420 just emotionally labile, but in a non-aggressive way. That's probably the phenotype I see more,

01:38:34.440 easier to cry or something like that. So how much of that do you think is heritable in the way that

01:38:41.260 eye color or some other aspect of body habit is, or even depression is quite heritable versus

01:38:46.620 the ecosystem you're in purely environmental? Well, the answer is you really can't choose one

01:38:53.300 of the other blah, blah, blah. But if you could only manipulate one, which would be the first one.

01:38:57.660 And I'm definitely of the school of genes get overrated in terms of their impact. And, you know,

01:39:06.040 a gene affecting your eye color, it's okay to use words like determine, and it's probably not even

01:39:12.120 100% accurate. But when you get to genetic influences on all the interesting stuff and behavior and our

01:39:19.180 internal lives and all of that, yeah, genes are important, but overwhelmingly, these are genes

01:39:26.300 that modify vulnerability. Vulnerability to certain types of environments. Okay. So for example,

01:39:35.560 you bring up depression and catastrophic pandemic of that. And, you know, there's a whole shopping list

01:39:43.980 by now of genes that have been implicated. And probably the single most important one, it's called

01:39:48.940 the gene for the serotonin transporter, serotonin, SSRIs, Prozac, all of those serotonin is just like

01:39:56.680 right in the middle of what we understand about the neurochemistry of depression. And it turns out

01:40:01.440 the serotonin transporter gene comes in a few different flavors, a few different genetic variants,

01:40:07.280 and a ton of basic research, rats, monkeys, et cetera, suggested that if you had one particular

01:40:15.440 variant, you were more at risk for major depression. Okay. So this classic work, this guy at Duke,

01:40:23.140 Afshalom Kaspi, who's sort of a god in the field, goes out and he follows like 17,000 people from birth

01:40:29.840 up to age 25 or so. He's got genetic information on them. And he's able to ask this critical question,

01:40:35.360 okay, if you have the quote bad version of this gene, by age 25, are you more likely to have a

01:40:42.000 history of clinical depression? And what's the prevalence of the gene approximately?

01:40:45.800 Depends on the population. In his population?

01:40:48.740 His was a mixed one, but westernized, western urine populations, I think it's got about a 20%

01:40:54.340 incidence. So the question then is of those 20%, how many go on to get depressed? Of the 80%,

01:41:00.420 how many go on to get depressed? The answer is very likely going to be, it's not a one-to-one mapping.

01:41:05.360 It might be an increase in risk by some factor. And what they saw was, overall, there was no

01:41:12.660 increase in risk having the bad variant. However, if it was coupled with a lot of childhood stress,

01:41:20.780 you had about a 20-fold increase in the risk. So just to be clear, on aggregate,

01:41:26.380 there was no difference. The hazard ratio is one for with gene versus without.

01:41:30.540 Because of a ton of variability.

01:41:32.800 But if you wanted to amplify it, take that gene and expose it to childhood stress or trauma,

01:41:38.420 and you almost assure depression.

01:41:40.700 You get a massive boost in predictability. Look at people without the scary and vulnerability variant,

01:41:46.980 and look at the same severity of childhood stressors and loss, and you got a moderate increase in

01:41:52.540 incidence of depression. These folks, massive order of magnitude, multiples of that, more increase there.

01:42:00.180 What that tells you is, this is a gene whose variants alter how readily you deal with experiential

01:42:09.400 kicks in the asses growing up. And it turns out, these different variants are regulated in different

01:42:15.540 ways by glucocorticoids. Aha, so there's a stress angle, all of that. The same way there's another gene,

01:42:21.300 which of the people who are interested in the genetics of aggression, this gene monoamine oxidase,

01:42:26.400 and it comes in variants, and it's- And there's a class of drugs that targets these

01:42:31.960 receptors, yeah. Again, a ton of basic research had suggested,

01:42:36.200 ooh, there's a scary variant of it, which if you have it, you are going to be more predisposed towards

01:42:42.360 violence. And in fact, the same group working with the same population, massive data set,

01:42:47.920 winds up showing just having that variant doesn't get you a higher risk of antisocial violent behavior

01:42:55.420 by age 25, if and only if it was coupled with abuse, childhood abuse growing up.

01:43:03.080 Oh, if you didn't have the scary variant, childhood abuse, a little bit of an increased risk,

01:43:08.580 have this variant with the abuse, and it was virtually the same figure as with the serotonin

01:43:13.740 transporter gene. Huge boost in very- Over and over the genes that are interesting when it comes to

01:43:20.240 this stuff. These are all genes about vulnerability and potentialities and tendencies that are emerging

01:43:29.060 only in certain environments and not in others. The factors are inseparable.

01:43:33.380 It makes me think of the ApoE genotype, which is linked to Alzheimer's disease. And

01:43:38.520 there we see that there is a difference. About 25% of the population carries at least one copy of that

01:43:46.560 gene, and they represent about two-thirds of the cases of Alzheimer's disease. It's not a

01:43:52.820 deterministic gene, but it does increase risk. Now, of course, you could argue that maybe in

01:43:59.440 a decade or more, we will be able to say something very similar about ApoE, which is it's not remotely

01:44:06.780 deterministic. It only gets turned on when X, Y, and Z happen before this period of time or in

01:44:14.440 absolute. And of course, we don't know what those things are right now. At least in the examples you

01:44:19.660 gave, you could say, well, trauma or childhood, some event in childhood was the trigger. And if you're

01:44:27.360 seeing a 20-fold difference, it's pretty clear that you found the trigger.

01:44:30.920 Nonetheless, there's still variability to explain after that. But yeah, it's pathetically,

01:44:36.520 that counts as virtually state of the art for understanding the modifying factors. And it's

01:44:42.660 going to be that way. I mean, anytime you do these like GWAS massive fishing expeditions,

01:44:49.000 and you come out with 300 genes are implicated in a trait that's as boring as height, 300 genes,

01:44:58.000 which you put together all of your knowledge of the variation of them in any given individual,

01:45:02.340 and you have like 4% predictability of their height. You know, Christ, if you're talking about

01:45:08.560 genes for propensity towards feeling poignancy or genes for like anything that's interesting.

01:45:16.340 Yeah, it's just not a chance. Even if you just limit yourself to diseases, you know, of the 20,000

01:45:22.300 genes in our body, you can really only point to about 100 that are directly, this mutation means this

01:45:30.260 disease. And they're all pretty esoteric, right? It's all like inborn errors of metabolism and certain

01:45:36.860 things like that. But when you start to talk about the complex diseases like Alzheimer's disease,

01:45:41.800 even as predictive as the APOE4 is, it's not even close to being enough to understand it. And I think,

01:45:48.720 yeah, it's funny when you talk about it through that lens, you realize the importance of environment,

01:45:53.020 which is, you know, the risk of stating the obvious. You said something a while ago that I

01:45:56.020 made a note of because I wanted to come back to it. You talked about the effect of glucocorticoids

01:46:00.760 on the hippocampus, and not only how harmful it was for memory consolidation, but overall

01:46:06.680 cognitive impairment. And listening to you talk about that was exactly the way Matthew Walker

01:46:12.920 at Berkeley speaks about sleep deprivation and its impact on the hippocampus, which then makes me

01:46:19.680 wonder, I assume it's been well studied that, you know, when people are sleep deprived, we see greater

01:46:25.760 elevations of cortisol. Do you have a sense of what the evolutionary basis of that is? Because it seems

01:46:30.040 counterintuitive. You would think even evolution would want that to be in the opposite direction.

01:46:35.020 I mean, the only explanation I can come up with is if you're sleep deprived,

01:46:38.000 you're assuming that there's a reason for it that's good. And therefore you want that,

01:46:42.700 of course, not with any of the fact that higher cortisol will then prevent sleep.

01:46:45.740 I think that's probably the best sort of piece of teleology for that. Yeah. If you're like a basic

01:46:52.880 mammal, which means either you are emphatically diurnal or emphatically nocturnal. And if instead

01:46:58.880 you're wide awake eight hours into what should be the 12th, this does not happen by

01:47:04.940 chance. The odds are you have something stressful going on. I think that's the logic of it.

01:47:09.880 Turns out the stress, sleep, sleep quality, cortisol cluster of interactions, even more subtle,

01:47:20.320 incredibly cool study. This was a science paper some years back that, okay, so as we talked about

01:47:28.180 the circadian peak of glucocorticoids are around the time you wake up. What's interesting is about an

01:47:33.720 hour before you wake up, levels begin to rise, telling you something, a subtle point, which is

01:47:40.480 a lot of glucocorticoid actions are not for dealing with a stressor that has already commenced, but can

01:47:47.700 be preparatory. So the preparatory stressor is having to actually get up and get out of bed and start

01:47:53.760 functioning and get dressed in an hour before people wake spontaneously. Glucocorticoid levels are

01:47:58.940 elevating. Now in the study, what you do is you take a whole bunch of volunteers who are sleeping and

01:48:04.560 you see the preparatory rise, all of that, and you tell them, tonight we're doing something different.

01:48:09.960 I'm going to wake you up at four in the morning. And what you see is around three o'clock,

01:48:15.600 glucocorticoid levels start rising. Okay, now you do something even more interesting. You say,

01:48:22.140 okay, tonight I'm not going to tell you when, but I'm going to wake you up at some point during the

01:48:26.720 night and that's the end of your night's sleep. And the person's about 90 minutes into their

01:48:31.520 sleep stage and all of that. And cortisol rises and stays high for the rest of the night.

01:48:37.760 You get one sleep cycle and then the adrenal gland says, that's it. I'm on ready alert.

01:48:42.460 Yeah, exactly. So not only is it bad not to get enough sleep, not only is it bad if the

01:48:49.140 insufficient sleep is fragmented, but the worst is if it's fragmented unpredictably.

01:48:54.140 And that's like every medical resident in history.

01:49:00.540 It's the first thought I had actually, when you said that, which was every night of call,

01:49:05.060 you have this pager and you're in this call room and you just want so desperately to sleep for an

01:49:09.820 hour, two hours, three hours. I remember as my residency went on, the degree of sleep deprivation

01:49:15.600 got greater and greater that the steps I had to take to ensure I wouldn't sleep through a page got

01:49:21.020 greater and greater. And I'm not making this up. I don't think I've ever told this story before.

01:49:24.340 It's so ridiculous. I used to use this really heavy paper tape and tape the pager to my head,

01:49:30.700 my forehead at full volume, because you would get both the sound to your ear and then you'd get the

01:49:37.720 transmission, you know, through the bone. But imagine laying in bed with tape wrapped around your

01:49:43.900 head, holding a pager on your forehead in anticipation of what's coming, not knowing when

01:49:49.900 it's coming. It could be in five minutes or it could be in two hours. You know, you're going to wake

01:49:54.840 up. Yeah. I'm guessing that wasn't great sleep.

01:49:58.300 No, it's like wildly destructive. And what do you know? It turns out if you have elevated

01:50:04.600 glucocorticoid levels while you're asleep, you have less Delta sleep time, which is the restorative

01:50:10.980 stuff. You make less adenosine stores in your brain during. So even if you manage to go to sleep,

01:50:17.360 if it's under the, I could be asleep for two hours now or 30 seconds, the sleep quality is going to be

01:50:22.900 horrible. This interplay becomes more pronounced. What about cancer? What role do you think stress

01:50:28.720 plays in cancer? And do you think it's mostly mediated through the immune system? I mean,

01:50:33.560 cortisol can be quite damaging. Yeah. Hugely, hugely controversial subject. There is a common

01:50:41.880 perception that stress can play a very substantial role in the onset of cancer, in coming out of

01:50:49.200 remission and rates of tumor growth and such, sufficiently so that there's been all sorts of

01:50:54.400 studies where you ask cancer patients, what do you think is the cause of your cancer? And stress is

01:50:58.600 invariably way up there. The actual evidence for a role of stress in causing cancer, bringing it out

01:51:07.940 of remission, accelerating tumor growth is very, very minimal. There's been a remarkably small number

01:51:14.640 of good prospective studies of humans that have really, truly ruled out all the confounding factors.

01:51:21.700 When you look at the animal studies, what they typically involve is you experimentally induce a tumor,

01:51:27.880 you inject transformed cells, you give a carcinogen, some such thing. My lab back when did some of that

01:51:34.720 work. Under those circumstances, you can accelerate the growth of a tumor, but those are circumstances

01:51:41.060 of cancer acquisition that are virtually irrelevant to human cancer. And the other question is, can you do

01:51:46.580 it without perturbing other things? So for example, if you go ahead and stick the tumor into the mouse

01:51:51.980 and apply a stress to it, it seems that that by definition will alter some other parameter,

01:51:58.360 what it eats, how much it sleeps, the quality of its sleep. So it becomes difficult to disentangle

01:52:03.500 cortisol. I mean, I guess the only thing I can think of is what does the experiment look like where you

01:52:07.860 take the mouse that experimentally has the tumor and you just start injecting more glucocorticoid?

01:52:13.300 So in other words, you don't actually increase the stress level. You just increase the readout state

01:52:18.340 of stress. You accelerate the tumor growth. We did one study showing that as soon as cells become

01:52:24.140 transformed, they upregulate the GLUT4 glucose transporter. And that's the one that's further

01:52:30.960 upregulated by glucocorticoids and target cells. So you're just shoveling energy over to those cells.

01:52:37.960 Yeah. Which preferentially consume glucose anyway, just given the number of them that fall by the

01:52:43.160 Warburg effect. So to me, even though that's very mechanistic and artificial, that strikes me as

01:52:48.020 pretty reasonable evidence that cortisol can play a role in cancer. I mean, I guess it's going to be

01:52:54.720 much more difficult to disentangle that in the real world. Yep. And again, these are types of cancers

01:53:00.640 where this was virally induced transformation of cells that are then transplanted in very artificial

01:53:07.720 systems that turn out not to be terribly applicable to human cancers. And what you wind up seeing then,

01:53:16.720 okay, yes, glucocorticoids can be potently immunosuppressive. Usually by the time you have

01:53:22.280 a tumor growing, that's long past the point where it's an immunological problem. It's now,

01:53:29.320 can you keep the tumor from growing a whole bunch of capillaries that will feed it? Can you keep it

01:53:34.720 from stealing all sorts of energy? Can you keep it from turning off cell death programs? It's no longer

01:53:41.920 in the immune realm. So it seems that there'd be hard to make the case that acute bouts of stress

01:53:48.100 can really have any impact because, you know, yeah, sure. You can acutely disrupt the immune system and

01:53:53.960 maybe get sick, right? That, you know, I could explain why you might get a cold under a period of great

01:53:58.860 stress, but not necessarily cancer. And what that wants meaning is that should be a massive,

01:54:04.260 massive take-home message for anyone who is predisposed towards thinking, ooh, stress caused

01:54:10.980 my cancer. Too bad I didn't have better priorities in life. Now I know whose fault it is, that sort of

01:54:18.160 thing. And it should certainly make you damn cautious if there's some highly credentialed quack

01:54:23.460 out there who is selling a stress management will stop your tumor, will make it disappear entirely.

01:54:29.760 Watch your wallet at that point. All that being said, there's been some wonderful work. And a lot

01:54:37.160 of this was pioneered by a Stanford colleague of mine, David Spiegel, who showed that things like

01:54:43.860 supportive group therapy among cancer patients enhances survival.

01:54:48.820 So what do you think is the mechanism of that?

01:54:51.040 Okay. This was when he first published this in the late eighties, this was front page news.

01:54:55.420 I remember this. I mean, I don't remember it when it was published, but I remember learning about it

01:54:58.820 in medical school. Massive finding. And one is immediately tempted to, at least as a biology

01:55:04.980 type like me, to come up with a biological explanation along the lines of what you proposed.

01:55:10.220 Okay. Supportive group therapy, you're less stressed. So you don't secrete as many glucocorticoids.

01:55:16.360 And therefore you're not having those adverse effects of it on your immune systems. You're

01:55:20.820 better able to fight the tumor. You live longer. Trelaw. That's wonderful.

01:55:23.440 And lower glucose levels and lower glucose and lower insulin and lower IgF. You could come up

01:55:28.000 with a complete biological. And in general, those studies have shown that pathway does not occur.

01:55:33.760 Spiegel and I did some of those studies things. So what's actually going on? Something which,

01:55:38.940 if you're a nuts and bolts reductive bio type person is terribly disappointing, but is so

01:55:46.300 interesting and important. People, when they have supportive cancer therapy with other people going

01:55:54.340 through the same hell, they become more compliant with their medical regimes. They're more likely to

01:56:01.060 go the extra round of chemo because everybody else is cheering them on saying, I didn't want to do it

01:56:06.280 either. And they're more likely to take the meds that make them nauseous as hell. Have you eaten today?

01:56:13.320 Me neither. We're going to eat right after we're done with the group. Have you taken your meds?

01:56:18.160 You're going to take them right now. People become more compliant. And that was very hard to demonstrate

01:56:23.960 because what cancer patient ever wants to admit to a researcher, actually, I skip about a third of

01:56:31.080 my meds because they make me feel so damn sick. They're saving your life, Twitter. It's in some

01:56:37.020 ways a dark, dirty secret in cancer therapeutics how much people diverge from their optimal treatment

01:56:45.600 regime because the treatment regimes are sheer utter hell. When you're surrounded by people who are going

01:56:51.220 through the same thing and understand, you're more likely to be compliant. I think that winds up

01:56:56.840 explaining an awful lot of that effect. So when you look at cancer, atherosclerosis, and

01:57:03.100 neurodegenerative disease, it seems to me that the direct lines of evidence for the damage of

01:57:10.660 hypercortisolemia and the accelerated stress response are probably most demonstrated in

01:57:17.040 cardiovascular disease and atherosclerosis vis-a-vis several mechanisms, not the least of which is

01:57:22.160 hypertension, both macro and microvasculature, but also through endothelial disruption.

01:57:27.520 Adhesion of cells and sludging. And yeah, it's the best understood realm. Cancer is probably the

01:57:33.600 weakest realm. I would expect that it's playing a role in dementia, but again, this probably gets to

01:57:40.580 the layer of susceptibility, right? There's probably in isolation, maybe this wouldn't play a role, but

01:57:47.040 in combination with other factors, it would. And it seems that, for example, we know that

01:57:53.280 cortisol inhibits melatonin secretion. So even if you take two people who have the same amount of

01:57:59.460 blue light reduction, which should therefore stimulate melatonin, the one with hypercortisolemia

01:58:04.500 is going to, and we actually measure this, right? We can measure overnight urinary cortisol and

01:58:09.440 overnight urinary melatonin. You can see this association quite strongly. Well, melatonin,

01:58:14.740 it's a pro-neurogenic molecule. So having less of that is less restorative to the brain,

01:58:21.600 even beyond its important role, which is sort of removing the brakes on being awake.

01:58:26.440 So what other lines of evidence do you see beyond what you've already described at the developmental

01:58:31.960 stage now, later in life? Basically everything we talked about with the hippocampus applies in the

01:58:38.260 adult brain as well. And it's the first place we tend to see changes. And it was the first area

01:58:43.860 researched first evidence for stress damaging the hippocampus and hippocampal dependent memory type

01:58:49.700 stuff, late 70s. I mean, that was really the first domain. And superb studies from a number of groups,

01:58:58.160 and I had my two cents in that literature also, showing you could accelerate aspects of hippocampal

01:59:04.220 aging with lots of stress, lots of glucocorticoids, extent of neuron loss, extent of memory problem,

01:59:10.340 extent of reactive gliosis, et cetera, et cetera. Next big outpost that people began to appreciate

01:59:17.100 in adult brains was derivative of what we talked about before, which was the amygdala.

01:59:23.020 I was just about to say, is there a direct correlation, I guess, between amygdala size and

01:59:26.780 dementia? What you see instead is that the syndrome where it's most demonstrated is PTSD.

01:59:33.460 You see expansion of the amygdala and you see atrophy of the hippocampus. And glucocorticoids

01:59:40.300 probably play the driving role in both. So in the amygdala, like the hippocampal story is

01:59:45.640 stress and glucocorticoids screw it up. Neurons don't work as well. Networks don't work as well.

01:59:50.580 The overall size decreases. You get atrophy. In the amygdala, it's the exact opposite story.

01:59:56.560 Neurons work better than they should. Neurons become more excitable, form denser networks,

02:00:03.440 the amygdala gets bigger. What's that about? The problem with chronic stress is your memory goes

02:00:09.160 down the tubes, hippocampus isn't working as well as usual. The problem with chronic stress in the

02:00:13.500 amygdala is it works better than it's supposed to. And this is the link between stress and anxiety

02:00:19.700 disorders, stress and fear, stress and all of that. Next sort of outpost that people started looking at

02:00:26.860 was the dopamine system in the brain. And dopamine neurotransmitter, most famously associated

02:00:33.200 with reward, pleasure, cocaine works on the dopamine system. A much more accurate, subtle

02:00:38.980 picture of it is dopamine is actually more about the anticipation of pleasure than it is about

02:00:45.020 pleasure itself and about goal-directed behavior you're willing to do in anticipation of reward.

02:00:51.880 But then a whole literature showing what distress and glucocorticoids do there, they mess with the

02:00:57.800 dopamine system. It's less clean of a story than amygdala or hippocampus,

02:01:01.240 but in ways that predispose towards the two big psychiatric diseases of screwed up dopamine

02:01:08.600 systems. Number one, addiction. More vulnerability to addiction, harder to get off of addictive

02:01:15.700 substances. Number two, depression. Depression is a disease of on a certain level dopamine depletion.

02:01:22.220 It's a disease of inability to feel pleasure and hedonia. And that's the neurochemistry of the link

02:01:29.040 between chronic stress and why that increases the likelihood of the first three, four episodes of

02:01:36.100 major depression. What for me is the most exciting area is one where if I was starting over, you know,

02:01:43.540 forget the hippocampus, who cares about like how many digits you could remember backwards or whatever,

02:01:49.400 the most interesting domain is turning out to be what stress and glucocorticoids do to the frontal

02:01:54.000 cortex. Judgment, impulse control, executive function, long-term planning, strategizing.

02:02:04.660 And it turns out virtually every bad thing cellularly that stress and glucocorticoids do in the hippocampus,

02:02:11.860 they're turning out to do in the frontal cortex as well. And what does that begin to explain?

02:02:16.740 This entire world of why it is during moments of extreme emotional arousal, especially aversive

02:02:23.840 ones, why we make terrible, terrible decisions that seem brilliant at the time. And you spend the

02:02:31.880 rest of your life regretting it because impulse control, your amygdala overpowers your frontal

02:02:37.020 cortex at those times. Your amygdala has a lot more talking to your motor systems than your frontal

02:02:43.060 cortex does. It's the reason why judgments and impulse control become terrible when we're frazzled.

02:02:51.420 It's also looking like as a side story with that, it's one of the reasons why when we're very stressed,

02:02:57.640 it's hard for the frontal cortex to do one of its harder jobs, which is to take the view of the world

02:03:05.880 from somebody else's perspective. Empathy.

02:03:08.640 Empathy. Exactly. Some research on animal models of empathy. And this was work with this guy at

02:03:16.160 McGill named Jeffrey Mogul, where I collaborated with him, showing in both rats and humans,

02:03:22.900 you're less empathic towards strangers when they're in pain. And if you block glucocorticoid release,

02:03:28.860 you don't get that effect anymore. Glucocorticoids, the stressfulness of dealing with scary novel

02:03:36.860 humans or scary novel mice, if you're a rodent, glucocorticoids narrow your window as to who

02:03:45.560 counts as an us and whose pain registers and things of that sort. So for me, you know, it's incredibly

02:03:51.700 interesting if you're stressed and suddenly your SAT scores plummet. The fact that stress makes people

02:03:58.060 crappier to each other and less empathic and more parochial and more xenophobic and more impulsive

02:04:05.420 with the worst of our impulses, that's the stuff that really interests me these days.

02:04:10.200 Everything you just said, Robert, is almost a call to action in criminal justice reform.

02:04:15.780 And I've done a podcast on this topic where, you know, I was very fortunate to go into a maximum

02:04:20.920 security prison with a program that is really there to do incredible rehabilitative work led by this

02:04:26.600 woman named Catherine Hoke. It's a humbling experience. There's a game that we played

02:04:31.820 about halfway through the day called step to the line. This is a game that's used to basically

02:04:36.560 identify the vast difference between those of us who are volunteers. Like in other words,

02:04:40.840 the role of luck in our lives versus the gentleman who two thirds of these men are never going to get

02:04:47.040 out of prison. One man had even spent more than half his life in solitary confinement, his total life.

02:04:53.080 So it starts with these questions of step to the line. If you grew up in a home that had two parents

02:04:58.260 and, you know, of the volunteers, you know, 60% step to the line of the inmates, five step to the line,

02:05:04.660 right? Step to the line. If you grew up in a home where there were more than four books,

02:05:07.820 you can imagine the disparity step to the line. If you saw someone die with your own eyes before

02:05:14.140 this age step, I mean, and it's, it's a very emotional thing to go through because as this game is

02:05:20.520 unfolding, you're just, you're feeling more and more fortunate on the one hand, because you realize

02:05:26.740 if not for the grace of this luck. And at the same time, the empathy you have for these men who have

02:05:33.680 done the most heinous things grows. And you start to realize, boy, there's a fine line between those

02:05:42.300 of us on the inside, those of us on the outside. Cause everything you said really resonated when I was

02:05:48.020 thinking about some of the stories the men told us about the decisions that they made.

02:05:53.160 And there's this one part of the exercise that's incredibly emotional where you're partnered with

02:05:56.920 one, one guy. So it's, it's one volunteer, one inmate, and you were each telling the other person

02:06:03.080 the greatest regret of your life, the biggest mistake you've made. And hearing some of these stories,

02:06:09.880 it's not to justify anything that's been done. And it's not to say that there shouldn't be

02:06:15.200 consequences for it. But a lot of these things that people have wound up in prison for are really

02:06:22.720 impulsive, horrible decisions, as opposed to decades of sinister planning. It's one thing to

02:06:32.240 look at what, you know, like Hitler did. It's hard to argue that anything that he did that was bad was

02:06:36.820 impulsive. It's quite another thing when you look at someone in a gang related incident where,

02:06:43.400 you know, this guy gets shot and you're going to shoot this guy back, or this guy's about to shoot

02:06:47.420 you and you shoot him. I mean, and yet that type of drug related violence is disproportionately

02:06:54.060 represented in certainly in the U S penal system. And then to build on what you said, it's not clear

02:07:01.720 that the environment in there is reducing cortisol levels to the level that would enable rehabilitation,

02:07:07.980 which is really the thesis of, and a lot of people I'm sure listening to this are thinking,

02:07:12.860 why would you feel empathy for these folks that are in there and why should society care about them?

02:07:18.220 But the reality of it is if they're going to get out, you should care. That says nothing of maybe the

02:07:24.660 higher level that you should care, which is the injustice of it. But even if you took a purely

02:07:28.980 selfish view, a non-trivial number of these men and women are going to get out.

02:07:33.440 So wouldn't you rather they get out and function better? And yet it's really tragic to see this.

02:07:39.400 And I know two people actually very well who spent a great deal of time in prison. One of whom I

02:07:44.220 interviewed on this podcast, his name is Corey McCarthy. And it really strikes me as the exception

02:07:48.800 and not the rule that people are able to emerge from that environment and go on to be successful

02:07:53.580 outside. It's a system that is so, so broken. Any study the last century and a half's worth

02:08:03.360 of neurobiology and genetics and child development and all of that. And the notion that we are free

02:08:12.460 agents of our action is so destructively misplaced. I'm sure you're familiar with the work of Sam

02:08:19.020 Harris. Sam has been one of the most interesting forces in my life at getting me to really even

02:08:24.720 question this notion of free will. And once you realize that free will may not even be yours,

02:08:30.960 it takes luck to a new level. It's something I spent a lot of time thinking about now.

02:08:36.460 What advice would you offer somebody who is interested in the neurobiology of stress or

02:08:43.140 behavior and who wants to be able to look back when they're your age and be as, you know, maybe

02:08:50.280 accomplished is the wrong word. I don't want, I know you sort of bristle at that, but to have made

02:08:54.480 as many contributions as you've made. I mean, what in retrospect was sort of the secret to being able

02:08:58.980 to pursue your bliss and be as successful as you've been. And look, frankly, to be where you

02:09:03.300 are and to still have the passion that you have for what you're doing, which to me is really the

02:09:06.960 marker of success. It's that you're sitting here saying there's this other problem. And I, you know,

02:09:11.820 like I could spend, you know, the next 20 years just thinking about that. How do you think about

02:09:16.380 how you've done that? Just damn luck, every bit of neurosis, every bit of affective instability I've

02:09:24.880 got, every childhood trauma I've got tucked away. I've titrated in just the right way that I've turned

02:09:31.520 it into more productivity and incredibly lucky in that regard. My capacity to sublimate emotion into

02:09:41.160 intellectual pursuit into really, really, really wanting to understand something into, I've just

02:09:49.720 been very lucky in that regard. I've gotten just the right levels of all sorts of like tumult

02:09:56.620 that have synergized most productively. In other words, just huge amounts of luck, huge amounts of luck.

02:10:05.420 And at least now coming later in life, an increasing capacity to more carefully try to

02:10:16.740 analyze what cost each type of ambition comes with. Say more about that.

02:10:22.920 Oh, I don't know. This had much to do with my closing my lab four years ago. It was a big booming

02:10:29.460 lab with lots of people in all sorts of labs around the world. We were going to kick the asses of,

02:10:35.300 by getting the answer to this or that. If you're raised in the right sort of rarefied, ambitious

02:10:44.460 world of biomedical research at age 25, you've got a list down to the floor of the diseases you're

02:10:52.560 going to vanquish and the problems you're going to solve and all of that. And getting to that point

02:10:58.240 in life where you're realizing it's not going to happen. Is that what actually happened four years

02:11:02.560 ago? Was it that much of a cerebral realization or was it combined with other factors? You've described

02:11:11.060 obviously having this network of people around you who matter the most. And I mean, was part of it just

02:11:15.420 thinking, I haven't spent enough time with them at the expense of this, or was it the, this problem

02:11:20.960 is enormous. And when, you know, a thousand years from now, whether I worked this much harder or this

02:11:27.020 much less, it won't have altered the trajectory of X, Y, Z, like, I mean, how much of it is all of

02:11:32.040 these? Only of both. Yeah. Family growing up real fast as they tend to do, realizing your best work

02:11:41.020 was decades behind you, realizing there's this book you want to write where the only way you can do it

02:11:47.220 is to just sit for really long stretches. Kenyan field work having collapsed a few years before

02:11:53.960 body feeling older, limits to how many 80 hours of work a week you can do all of them converging.

02:12:02.320 What advice, I mean, it's such a cliche question. What advice would you give the,

02:12:05.840 the 25 year old Robert as he was just finishing that PhD at Rockefeller?

02:12:11.320 Be less ambitious.

02:12:15.640 Well, I think on that note, which by the way, I think is some of the greatest advice one could

02:12:20.180 ever get and receive. And those of us who are still on the climbing ambition curve should do

02:12:25.540 everything to listen to it. I want to, I want to thank you so much for taking the time to sit down

02:12:30.200 with me. And more importantly, I think for just all of the work you've done and you're continuing to

02:12:33.920 do. Thank you so much. Well, thanks for having me on. This has been fun is the wrong word,

02:12:40.680 but stimulating good. Glad we did this. Thank you for listening to this week's episode of

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The Peter Attia Drive - April 24, 2023

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

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Length

Words per Minute

Word Count

Sentence Count

Misogynist Sentences

Hate Speech Sentences

Summary

Transcript