The Peter Attia Drive - #51 - Robert Sapolsky, Ph.D.： The pervasive effect of stress

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00:04:10.560 for a monthly subscription. My guest today is professor Robert Sapolsky. And many of you may

00:04:15.340 recognize that name because Robert has written some incredible books. Probably the one that you

00:04:20.060 would recognize the most is why zebras don't get ulcers, a guide to stress, stress-related diseases,

00:04:25.240 and coping. But he's also the author of a primate's memoir, which grew out of work that he spent

00:04:30.380 in his early years in Africa. And he spent nearly 30 years in Africa, four months at a time,

00:04:35.860 the trouble with testosterone and other essays on the biology of the human predicament.

00:04:40.400 And his most recent book, behave the biology of humans at our best and worst. This is a book that

00:04:46.540 Robert spent nearly four years researching and writing. And the book is almost 800 pages long.

00:04:51.680 This is a treatise on the topic of human biology and behavior. Robert is a professor of biological

00:04:57.780 sciences at Stanford, where he's been, I believe, since he completed his PhD and his postdoc,

00:05:02.340 which he did back on the East coast. He spent a lot of time in Kenya right after college. He went

00:05:07.680 to Kenya, then Uganda, where he studied for the next 30 years, the behavior of baboons and other

00:05:14.100 primates. He is a MacArthur fellow in 1987. He was awarded the fellowship, which many of you may

00:05:19.500 recognize by its other name, the genius grant. He is very modest and soft-spoken about this and

00:05:24.600 really doesn't like to be reminded of that. But Robert is a really impressive guy.

00:05:29.180 Today is actually the first time we really met in person. I had seen him speak about a year and a

00:05:33.860 half ago. And after the talk, you know, introduced myself and we spoke very briefly. But I remember

00:05:38.240 during his talk thinking to myself, this is the first time I'm really being convinced

00:05:43.400 at the true pathology of stress. I think I had certainly appreciated the benefits of meditation before

00:05:50.500 when it came to being less miserable. But I think it was really Robert's work. And in particular,

00:05:56.660 that presentation on that day that got me to really start to think about the molecular and

00:06:01.660 physiologic harm of hypercortisolemia. So we talk a great deal about that in this discussion,

00:06:08.600 but we also talk about things that go far outside of that. We talk about the role of depression.

00:06:12.980 We talk about the impact of stress on the developing brain and also in the brain later in life.

00:06:19.540 And even some of the areas where the relationship between stress and disease is not as well

00:06:23.840 understood. And that clearly came across in our discussion of cancer. Overall, I found this

00:06:29.240 discussion riveting and I could have continued this discussion for many hours longer. On a personal

00:06:33.960 level, I was also, you know, really kind of touched by the way he spoke about this sort of change in

00:06:39.680 heart he had around the relentless ambition and pursuit and how over the past few years, he's really

00:06:45.400 re-evaluated that. And that comes across at the end when we sort of get into more of a philosophical

00:06:50.520 discussion about what one would do different given what he knows today. It was an honor to spend so

00:06:55.520 much time with Robert today discussing this. And I appreciated the confidence he had in basically

00:07:00.120 sight unseen sitting down with a stranger to have this discussion. So I hope you'll enjoy this

00:07:05.540 discussion with Robert half as much as I do. Robert, thank you so much for making the time to

00:07:13.600 meet with me today on a lovely rainy San Francisco afternoon. Sure. Glad to be indoors here.

00:07:19.420 As I was saying earlier, we had met once before really briefly, so briefly that you would not

00:07:23.840 remember it. And of course, only I would. Summer of 17, I believe you were giving a talk in Sun

00:07:29.280 Valley and I was there and you gave a talk on stress. Now it was to a lay audience. So you

00:07:35.360 didn't really get to go into the depth. And I remember sitting in the audience thinking,

00:07:39.700 oh, you know, a lot of what he's saying is really starting to make sense to me. And I can't wait to

00:07:45.840 get a little deeper into this stuff because truthfully, and I'm just going to open with sort

00:07:50.440 of my mea culpa. You've always heard people say stress kills. And I got to be honest with you.

00:07:55.820 I always thought that was sort of nonsense. I was like, come on, what do you mean stress kills?

00:08:01.640 Stress is good. It builds resilience, blah, blah, blah, blah. What is the mechanism by which

00:08:06.120 stress quote unquote kills? But of course, once you start to understand the endocrine system,

00:08:10.300 and of course, training as a surgeon and not an endocrinologist, I sort of missed out on that.

00:08:14.720 You start to see it. And in that talk, you admittedly at a sort of high level for the audience

00:08:19.560 really walked through the danger of hypercortisolemia. And so in many ways, I guess, you know,

00:08:24.720 a year and a half ago was really when I became a fan of your work and then kind of said, you know

00:08:28.940 what, there is something to this. So anyway, with that, I appreciate you taking this time.

00:08:33.640 Sure. And just to sort of back off a bit from that, I actually don't think stress kills you

00:08:39.080 outright very often, but it sure makes other things that kill you more effective at doing it.

00:08:45.860 Maybe it's semantic, but you're right. Stress can amplify and accelerate the diseases of aging.

00:08:50.260 You grew up in New York, right? If I recall, you grew up in Brooklyn or in

00:08:53.860 Brooklyn. I remember reading that after college, you actually went straight off to Kenya first. Is

00:08:59.980 that right? Yep. What prompted that? Well, I was one of those. I've sort of spent my career

00:09:06.600 oscillating between being a lab neuroscientist, studying the effects of cortisol on the brain,

00:09:13.000 punchline to decades of work is you don't want to have a whole lot of it marinating inside your head,

00:09:18.480 but also for more than 30 years, I've alternated spending my summers studying a population of wild

00:09:25.440 baboons in a national park in East Africa. And it's the same animals I go back to each year. These

00:09:31.360 are animals I can dart, anesthetize, get blood, do whole workups on them. And essentially asking among

00:09:38.680 them, what does your social rank have to do with patterns of stress related disease? What does your

00:09:45.660 personality, what does your patterns of social affiliation? So it's been sort of a counterbalance

00:09:51.500 to the lab where, you know, we've been sticking artificial genes into neurons and fairly reductive

00:09:58.180 stuff like that. So I was actually about eight years old when I decided I wanted to be a primatologist.

00:10:04.360 So I was kind of planning on that for a long time and lucked out. I spent all of college brown nosing

00:10:12.080 the right person who shipped me off to a field site right after graduation. And I wound up sort

00:10:17.680 of inheriting that site. And those have been my, my baboons ever since.

00:10:22.940 Did you spend the whole time in Kenya? I remember reading that you also were in Uganda and obviously

00:10:27.860 they're, I think if my geography is correct, they're neighbors. So that's a pretty easy switch.

00:10:32.720 Where do the actual baboons, like what is their scope of their residence? How broadly?

00:10:36.600 Oh, they're spread actually all over Africa. They're one of the most ubiquitous primates

00:10:41.780 for a lot of the same reasons that we are, which is they'll eat anything. They're carnivores,

00:10:47.900 but they're also herbivores. They're omnivores. They scavenge dead stuff. They eat insects. They'll,

00:10:54.380 they'll eat most anything so they can fill a lot of niches. So they're scattered everywhere. But

00:10:59.300 my main work over the years has been this one troop in the Serengeti and Southwest Kenya,

00:11:06.080 you know, for about 25 years, I camped under the same tree. So it's really,

00:11:10.120 it's been a continuity with the same population of animals.

00:11:14.680 What is their natural predator besides man?

00:11:17.620 Leopards, lions, hyenas. Nonetheless, if you're a male baboon, the most likely thing to kill you

00:11:23.480 violently is another male. Yeah, exactly. Sort of like humans.

00:11:28.040 Yes, indeed. Did you say it's every summer or every other summer?

00:11:32.120 Well, it was initially for about 25 straight summers and then parenthood and all those

00:11:38.400 complications came in. So wound up being every other summer. And then our kids were old enough

00:11:44.680 to go with us one summer. But unfortunately, the field work ended about eight years ago. So

00:11:50.360 why is that?

00:11:51.660 My Kenyan field assistant of 30 years, we, we started together when we were 20. He died of AIDS,

00:12:00.600 political issues. There are some game park issues that made it harder and harder to

00:12:05.180 sort of get research done. And kind of that middle-aged realization that I could find some

00:12:11.100 new game park or new country or something and start all over, but it was kind of time to pack

00:12:16.020 it in instead. So after you did your PhD, which you did it in North New York, right?

00:12:20.640 Yeah. Rockefeller University.

00:12:22.820 Did you come straight out to Stanford for a postdoc or?

00:12:25.480 Postdoc to the Salk Institute down in San Diego, spent a couple of years there. If people are sort of

00:12:32.480 familiar with the hypothalamic hormone that runs the stress response, a hormone CRH, CRF,

00:12:39.940 corticotropin releasing hormone, I went and post-talked with this guy, Wiley Vale, who had

00:12:45.440 discovered it in like two years before. So that was a pretty exciting time to be there. So spent a

00:12:51.160 couple of years there. Stanford hired me and I've been there for 31 years since.

00:12:58.780 That's kind of amazing. I keep coming back to people at Stanford that, you know, would have been

00:13:04.780 there when I was there in medical school, but if it wasn't in the medical school, like you just

00:13:08.560 weren't paying as close attention. And I honestly don't recall if you ever gave us a lecture in

00:13:13.080 med school. Do you remember giving lectures in med school 20 plus years ago?

00:13:16.200 I did. Almost certainly the students were paying as little attention as I was. So

00:13:20.460 I was about to say, it certainly seems like something we should have been,

00:13:24.740 you know, learning in medical school. And yet I feel ashamed to say, I don't know if I recall it.

00:13:29.220 It was not much of an emphasis and it was sort of snuck in embarrassedly.

00:13:32.600 Like a lunchtime seminar or something. Yeah, exactly. So that-

00:13:36.600 Thrive them with free food.

00:13:39.100 Yes. And even still only about five people would stay past the cookies.

00:13:42.840 That's a much bigger issue we can come to. So you wrote a book, gosh, how many years ago was

00:13:48.160 Why Zebras Don't Get Ulcers? Is that 20 years ago?

00:13:50.380 Let's see. First edition was 94. It's gone through three editions now. Most recent one was 2004. So

00:13:58.060 at some point I got to do another one. As we talk about that, and you've written a book more

00:14:03.620 recently that I want to talk about as well, let's back up and explain something you touched on a

00:14:09.060 second ago, which is sort of the physiology of a stress response. So walk us through the

00:14:14.060 relationship between the hypothalamus, the pituitary, and the adrenal glands.

00:14:18.200 So when we're under stress, levels of 11D different hormones change in our body. Most of them are

00:14:25.300 relatively minor players. The two workhorses overwhelmingly, first one, famously adrenaline,

00:14:33.040 a British term, epinephrine, sort of North American term, output from the sympathetic nervous

00:14:38.920 system. It's on the scene in your bloodstream within one, two seconds or so after all hell breaks

00:14:45.160 loose. And I just want to explain what sympathetic means to the listener. We've had this discussion

00:14:49.160 before. It's not to say it's a nervous system that is kind. It just means it's one of the two

00:14:54.700 branches of these so-called autonomic or immediate, not under your conscious control, right? So the

00:15:00.720 fight or flight. Exactly. And the other half being parasympathetic, sympathetic fight or flight,

00:15:06.240 all hell breaking loose alarms going off, parasympathetic calm vegetative function. So

00:15:12.800 not only do you turn on the sympathetic during stress, you very emphatically turn off the parasympathetic.

00:15:19.520 Second main workhorse, which has already been alluded to, the steroid hormone class of hormones

00:15:25.760 called glucocorticoids, human version, cortisol, also known as hydrocortisone, rat version,

00:15:33.100 corticosterone, synthetic versions, prednisone, dexamethasone and such. These come out of the

00:15:38.740 adrenal glands. Your brain notes something stressful is happening within two seconds. Your hypothalamus is

00:15:45.480 secreting that CRH, which within about 10 seconds is getting your pituitary to release a hormone called

00:15:52.340 ACTH, which within about 30 seconds has gotten to your adrenals and you are slowly starting the

00:15:59.560 glucocorticoid component of your stress response. And in lots of ways, the adrenaline, the sympathetic

00:16:06.420 response, the glucocorticoid response, they work on hand in hand, they synergize.

00:16:11.380 You want to metaphor adrenaline in two seconds as handing guns out of the gun locker to whatever

00:16:19.220 is going to defend you. Glucocorticoids are building the aircraft carriers that a year from

00:16:25.100 now are going to be essential. It does some of the slower components of the stress response

00:16:29.500 stretching out over minutes to hours. Because I was just about to ask you, and I think your question

00:16:35.520 basically answers it, was why would we have evolved these two separate systems? One can only speculate on

00:16:41.160 such things, but it's basically that certainly norepinephrine, epinephrine, they stick around

00:16:45.780 for such a short period of time. I mean, we don't even measure these things clinically. I can't

00:16:49.340 poke your arm and measure your norepinephrine or epinephrine level. The best I can do is collect its

00:16:55.020 metabolites in your urine for evidence that it's been around. So I guess we have this hormone or pair of

00:17:01.300 hormones that are on the scene in seconds, gone in seconds, and really deal with the, I guess from an

00:17:08.620 evolutionary perspective, when the tiger is there, this is what gets you to jump into the tree.

00:17:13.300 Is it doing much beyond that? And is there some evidence of chronic low levels of those hormones,

00:17:20.080 which, which come out of a totally different part of the adrenal gland? I mean, that's the other thing

00:17:23.120 that's sort of interesting is you have two separate pieces, the cortex, the medulla that secrete these

00:17:28.760 hormones separately. And embryologically, they're two very different tissues. They start off separately.

00:17:34.680 It could have just as randomly wound up that your adrenaline comes from your big toe and glucorticoids

00:17:41.360 from your thumbs. Why they wound up being in the same organ is in fact, somewhat just, I think,

00:17:47.160 serendipitous. Probably because you're more likely to have your toes and fingers lopped off and we

00:17:51.180 wouldn't want to have incidental adrenalectomies happening. You're right. That's certainly why they

00:17:55.720 didn't wind up out there. What about in lower species? Is one of these considered more primitive?

00:18:00.800 Is the epinephrine arm something that began earlier and the cortisol arm more recent?

00:18:06.820 Yep. Nonetheless, the cortisol arm is just ancient. When you get stressed and you're secreting

00:18:13.020 glucorticoids, it's basically the exact same class of molecules as if you were a fish or bird or a

00:18:20.520 reptile. Nonetheless, it's a very ancient wiring and that's part of what winds up getting us in trouble.

00:18:25.960 Well, it's a system that's been serving vertebrates, doing a lot of help for them for an awful long

00:18:32.700 time. And it's been a very recent modification to instead secrete them in response to thinking

00:18:38.780 about taxes. This basic dichotomy between the very human domains where we activate the stress

00:18:45.320 response and the more typical domains of animals.

00:18:48.800 So if you and I were sitting here 10,000 years ago, I can think of lots of things that we would

00:18:55.680 want an adrenaline response for, the tiger jumps out of the thing, whatever. What are some of the

00:19:01.380 things that would result in that cortisol response? Because you described it as building the aircraft

00:19:06.360 carrier. Well, gosh, if the tiger's there, either I'm dead or I'm not, but I don't need a stress

00:19:11.380 response a day from now or the next day. So what is it that cortisol was doing 10,000 years ago that

00:19:17.540 was serving our interests? I want to certainly talk about what it's not doing today.

00:19:21.700 When you look at what it does, it actually makes perfect sense. As long as you're being stressed

00:19:26.500 like a normal mammal, running for your life, running after a meal where if you don't catch something,

00:19:32.940 you're going to be dead by tomorrow, a short-term physical crisis. The first five seconds of doing

00:19:39.060 that, which epinephrine is critical for, that's great. If we're heading into a couple of minutes of

00:19:46.500 evading a predator, being vigilant, thinking there might be, if you're getting into the realm of a

00:19:52.800 couple of minutes worth of the stress response, cortisol related glucorticoid hormones are

00:19:58.300 absolutely essential. So the glucose that's coming rushing out of your liver, pretty important in that

00:20:04.100 situation. Exactly. So it takes you about one second to decide you're going to use your thigh muscles

00:20:09.740 and run like mad. You need energy for them. And the main thing glucorticoids are doing in the metabolic

00:20:16.100 realm is glucocorticoids. They're increasing glucose levels in your bloodstream. They're going to

00:20:23.900 storage sites throughout your body, your liver, your muscle and breaking stuff down. What they do is they

00:20:29.780 go to the bank, they empty out your savings accounts and turn it into cash, glucose in the bloodstream

00:20:35.260 to hand to whichever muscles are going to save your neck. What they also do makes perfect sense,

00:20:41.740 whether you were running for your life or running for a meal, which is they increase cardiovascular

00:20:46.760 tone. Epinephrine is doing the first five seconds of it by 30 seconds in glucocorticoids. You're

00:20:54.640 bolstering it as well. And it's that same logic. You're running like crazy. You want to deliver that

00:20:59.980 glucose to your thigh muscles as quickly as possible. You increase your heart rate. You increase

00:21:05.180 your breathing rate, your blood pressure. You alter your vasculature. So you're preferentially

00:21:10.820 shunting to the exercising muscle. So that makes perfect sense. Also, it turns out some of the most

00:21:16.960 interesting stuff glucocorticoids do in those circumstances is basically run a triage program.

00:21:23.380 They shut down everything that's not essential, not essential to surviving the next five minutes of this

00:21:30.460 massive physical challenge. So digestion would be a mission. Exactly. You got better

00:21:35.140 things to do than digest breakfast when you're trying to avoid being somebody's lunch. And you're

00:21:40.380 sure not going to get any metabolic benefits of digestion during this five minutes. It's slow,

00:21:45.740 expensive. The energy you're getting, you're getting from your liver, you're getting from your fat cells.

00:21:50.680 It shuts down growth. Obvious logic there, you know, grow antlers tomorrow. If you're still around,

00:21:57.920 don't bother right now. Shuts off reproduction. Same logic there. It shuts off all the long-term

00:22:04.480 building projects and just focuses your energies on what's immediately there. And this makes perfect

00:22:11.020 sense. If you are running for your life, running after a meal, and all you need to do is look at a

00:22:16.340 couple of diseases where people don't turn on the endocrine stress response. Addison's disease,

00:22:22.480 Shy Draker syndrome, whatever. These are not diseases where somebody who now is more at risks for

00:22:29.120 adult onset diabetes eight months from now. These were diseases where somebody goes running after

00:22:34.780 their commuter bus and they drop dead from hypoglycemic shock. JFK had this. Didn't JFK have

00:22:40.280 Addison's? He had Addison's and that greatly constrained the famed pictures of all those Kennedys

00:22:46.800 playing touch football out and, you know, Martha's Vineyard or stuff were mostly for the benefit of the

00:22:53.540 photographers. How did he survive World War II? Because he had done some pretty heroic things

00:22:59.380 in that war. Although I've seen, it's hard to tell if it's snarky revisionism as to how much that was

00:23:05.680 public relations stuff afterward, sort of orchestrated. But just to get through basic training even

00:23:11.200 strikes me as an accomplishment because most people, I guess, who don't have a medical background

00:23:15.400 wouldn't appreciate this, but the tan that seemed to be eternally on JFK is the result of the Addison's

00:23:24.080 disease because the hormone you alluded to earlier that is released by the pituitary ACTH in someone

00:23:30.680 who's not making cortisol is going to be very, very high. And ACTH stimulates the pigment producing

00:23:36.760 cells in the skin. And that's what would give someone with Addison's disease darker skin.

00:23:40.460 The fascinating thing with Kennedy is if it were this situation now, presumably his doctors would

00:23:47.140 be on the air somewhere 24-7. There's remarkably little known about when his onset was, what the

00:23:54.160 course of it was, how severe it was. So it's not quite clear, but what little is known is it had a

00:24:00.080 hell of an impact on his functioning. You really do need a hormone if you, like glucocorticoids, if you

00:24:06.400 were going to be physically activated in a moment of crisis.

00:24:11.660 This is sort of the amazing thing with hormones like insulin and cortisol. I'm always impressed by

00:24:18.060 how tight the U-shape is on those curves. Thyroid hormone would be another example, certainly less so

00:24:24.560 with something like testosterone. You have just a much wider range that you can function in, and the

00:24:30.420 benefit is largely monotonically increasing. Sometimes if my patients will tolerate me going

00:24:36.720 on and on about this, I love to draw the pictures of which of these hormones can you, you know, but to

00:24:42.320 me, cortisol probably, if you were thought of it as a drug, it has the narrowest therapeutic index.

00:24:48.480 To your point, too much of it will kill you eventually and make you miserable as hell on the way,

00:24:55.220 and too little of it will kill you quite quickly.

00:24:57.040 And what's most interesting about it is, okay, so there's an optimal level,

00:25:02.180 among other ways of translating that, that means we don't hate stress. We hate the wrong amount of

00:25:08.180 stress. When it's the right amount, we love it. We pay money to be stressed, to get on a roller

00:25:14.540 coaster, to go to a scary movie. When it's the right amount, when it's the optimal amount,

00:25:19.500 we call it stimulation. Okay, so exactly as you say, it's a narrow range, so that's a tough

00:25:25.200 biological problem, understanding a hormonal system that's pretty damn essential and where

00:25:32.240 an awful lot of the time you're walking on a knife edge where either side is bad news,

00:25:36.480 too much or too little. But when it comes to glucocorticoids and what counts as good stress

00:25:42.120 and stimulation, there's the added factor that there's incredible individual variation

00:25:48.140 as to what counts as the optimal level in between. And one person's like hair-raising

00:25:55.120 Audubon Society walk one Saturday morning looking for birds, while the other person goes and signs

00:26:01.360 up to be a mercenary in Yemen, because that's when they feel alive and awake and all of that.

00:26:06.660 Not only that it's a narrow range, but we differ so much as to what each person's optimum is.

00:26:12.020 Now, I want to make sure I understand that point, Robert. And this is probably overly simplistic,

00:26:17.140 so feel free to correct this. One of it would be the external scenario that is being perceived.

00:26:25.780 And I can see definitely how two people can have vastly different views on that. I mean,

00:26:31.440 it's the reason someone can voluntarily go and be a Navy SEAL and someone can say,

00:26:36.580 I'd feel much better not doing that, right? There's clearly a different appetite and or capacity

00:26:42.900 for distress. Is that what you're referring to? Or are you also referring to you and I could be

00:26:50.420 sitting here and have different levels of physiologic benefit and harm at the same level

00:26:56.000 of cortisol? Both.

00:26:58.400 I see. Absolutely.

00:26:59.200 So, I mean, the former, I think most people would acknowledge the latter is pretty new,

00:27:03.180 right? I mean, I shouldn't say pretty new. That's not intuitive to me.

00:27:05.820 Because there's centuries of endocrinology saying, what's the most important thing about hormones?

00:27:12.520 How much of the stuff there is in your bloodstream? What the levels are. And if you and I are sitting

00:27:17.560 here with the same circulating levels of whatever centuries of dogma was, that will translate into

00:27:23.360 the same biological effects. And then, I don't know, sort of endocrine revolution of 70s, 80s or so

00:27:30.400 turns out how loud someone is yelling at you counts what the hormone levels are, how sensitively you can

00:27:37.620 hear them. The levels of your receptors in target cells turn out to be essential as well. And there's

00:27:44.320 all sorts of endocrine domains where, in fact, screwy receptor levels are much more consequential

00:27:51.360 and impactful than our screwy levels of the hormone itself. And individual differences in levels of

00:27:59.840 receptors, what version you have, how well it works, how avidly it holds on to the hormone,

00:28:06.220 what it is then coupled with afterward downstream inside the cell. That whole world turns out to be

00:28:13.340 as central to understanding individual differences as are the levels of hormones themselves. And as

00:28:21.480 sensitive to all those things ranging from genes to prenatal environment, to early development,

00:28:29.100 to psychological factors, and so on. So yeah, that's a huge piece of the story now.

00:28:34.580 When I hear you say it like that, Robert, it seems pretty obvious because we would talk about

00:28:39.900 insulin in exactly that way. You could have two people with the exact same level of insulin,

00:28:44.420 completely different physiologic response because of insulin sensitivity. When insulin hits its

00:28:49.520 receptor, it leads to the phosphorylation of AKT, and that's what leads to the GLUT4 transporter

00:28:54.640 coming up to the surface. And different people with the same insulin can do that totally differently.

00:28:59.720 And different people will have a different insulin response to the same food, to the same meal.

00:29:03.680 That's the reason we do glucose tolerance tests. So you could basically say someone is

00:29:07.980 cortisol sensitive and cortisol resistant to make the analogy to insulin.

00:29:11.500 At the end product end, absolutely. If you're an obsessive with cortisol stuff in the 80s,

00:29:17.440 there was briefly this deep puzzle in that it turned out new world monkeys, monkeys in South

00:29:23.440 America, marmosets, tamarins, or whatever. When you compare them to traditional old world monkeys,

00:29:29.120 the Asian and the African ones, it turns out they have like an order of magnitude higher

00:29:33.680 glucocorticoid levels. Oh my God, that's crazy. What's that about? All sorts of theorizing about

00:29:40.200 how for some reason it's more stressful to be a new world primate than an old world,

00:29:44.520 which didn't make a whole lot of sense. And then there was this issue of these animals should

00:29:49.300 have been falling out of trees from their Cushing's disease. And finally, somebody found an

00:29:54.820 explanation. Oh, somewhere back when there was a mutation in the gene for the glucocorticoid receptor

00:30:00.380 in new world primates. And it has roughly one 10th the sensitivity. So the system just equilibrated

00:30:07.260 out at a different set point, but that's such a great example of just natural variation,

00:30:13.300 not only in how loudly you speak hormone, but how effectively your cells listen to hormone.

00:30:21.380 Do you have a sense in the human population today? I mean, a log full difference like you just

00:30:27.660 described sounds extreme, but do you have a sense of what the variability is in humans today? Is it a

00:30:32.940 twofold, threefold Delta on the receptor side? Gut feeling and reflecting the fact that my world,

00:30:40.600 the brain, you don't get to measure receptor levels anywhere near as easily as in a white blood cell,

00:30:45.940 well under an order of magnitude. We just acknowledged, or you just pointed out that

00:30:50.600 when a zebra sees a lion, everything that happens as far as the fast and what I would call the acute

00:30:58.540 and the subacute stress response is perfectly evolutionarily sound and completely in the best

00:31:04.380 interest of that zebra. We could also come up with a countless examples of 10,000 years ago,

00:31:09.960 or even today when the same thing is true in humans, when did that transition occur in our species

00:31:17.380 to where you started to see either something in the civilization or society that was unhealthy?

00:31:23.780 So today I could point to a thousand examples, social media, you name it. I mean, it's an infinite

00:31:29.040 number. When did that start to crop up? What does your research suggest is the arrival of that?

00:31:34.060 I think it predated us being humans and instead is a feature of smart social mammals because you see

00:31:44.440 indices of stress-related stuff, baboons, that's what I've spent my whole career on,

00:31:51.080 and other non-human primates, cetaceans, elephants, and such. Okay, so why study baboons if you're trying

00:31:58.240 to understand human stress? And it turns out they perfectly illustrate the point you just brought up.

00:32:03.260 If you're a baboon living in the Serengeti in East Africa, your life is pretty good. It's a fantastic

00:32:10.580 ecosystem. Baboons, they live in these big troops, 50 to 100 animals or so, so they really don't have

00:32:17.560 to worry about lions very often. The infant mortality rate is lower than among the neighboring Maasai

00:32:24.400 tribes people. And probably most importantly, unless it's a once a generation drought, if you're just a

00:32:31.880 baboon going about your everyday business, it takes you about three hours a day to get your day's

00:32:36.720 calories. And that has a critical implication, which is if you only need to spend three hours of sunlight

00:32:43.440 each day getting enough food to get by, you've got nine hours of free time every day to devote to being

00:32:51.120 miserable to some other baboon. And that's the key thing. They are well off enough in our westernized sense

00:33:01.100 that they can sit around and generate psychological stress for each other. Overwhelmingly, if you're a

00:33:08.320 baboon in the Serengeti and you're miserable, it's because another baboon has worked very hard to bring

00:33:13.800 that state about. They're wonderful models for westernized disease in that very few of us get

00:33:20.200 hypertensive because, you know, tigers are chasing us. Instead, it's psychosocial stuff that we invent

00:33:27.300 and that we can wallow in for hours every day. And that's exactly what baboons do. They're great

00:33:33.380 models for westernized stress. Do we have evidence? I mean, I'm sure it exists, but in the humans,

00:33:39.860 I would just be willing to bet that if you and I were subjected to the same external stressor,

00:33:46.800 I would probably internalize it more than you. That's my guess. So if we were both baboons and there

00:33:52.900 was a third baboon tormenting us, is it safe to say that you could be the baboon that would roll

00:33:59.120 with it more than me? Individual differences like that, absolutely. My guess is both of us would

00:34:04.360 respond to it by saying, I'm just going to get a longer and longer CV and then he's going to regret

00:34:08.800 it someday pushing me around. They'll be sorry when they see how many degrees I have. But yeah,

00:34:14.680 individual differences. One of the things that I focused on, you know, I spent my first 10 years

00:34:20.560 deciding rank and status, social statuses, everything. If you're a baboon and you got a

00:34:26.480 choice in the matter, you want to be high ranking because on the average, you have lower glucocorticoid

00:34:31.540 levels, you're arresting blood pressure is lower, all sorts of stuff works better. But what took me

00:34:37.580 some growing up out there to do was to realize that, yeah, social rank is important. Far more important

00:34:46.500 is the contextual meaning of your rank. Is that the same as your perception of your rank or is there,

00:34:52.800 there's more to it, right? Well, it's what the rank means in your particular troop. You can be a low

00:34:58.980 ranking guy in one of two different troops and one troop simply because of its culture. And that's a

00:35:05.300 perfectly scientific word to use for another species these days. In one troop, being low ranking

00:35:11.480 can be a whole lot crappier than in another troop in terms of how often somebody in a bad mood

00:35:18.060 displaces aggression on you, in terms of how often somebody actually grooms you and off terms of how

00:35:24.600 often you get to finish a meal before somebody steals it from you kind of thing. So the same exact

00:35:30.460 rank means different things in different sort of baboon cultures. So I'll take an extreme example.

00:35:35.580 In a prison, there's a clear hierarchy starting with the warden, the guards, the inmates. And of

00:35:42.560 course, within the inmates, there's a hierarchy. Presumably I'm making this up, but certainly the

00:35:47.140 pedophiles would be at the bottom of that list and a violent criminal would probably be at the top of

00:35:51.580 that list. So within that hierarchy, there's probably a manner in which you would be perceived

00:35:57.600 as a function of that unique environment, which is so artificial in its own way, but that wouldn't

00:36:04.220 necessarily be the same outside. Absolutely. And one of the most interesting things about us,

00:36:10.560 us humans, when we talk about across all sorts of primates being low ranking in general is bad for

00:36:18.760 your health. Well, what about humans? We don't have ranking in the same system that sort of other

00:36:23.860 primates do in a strict linear kind of way. But the other thing about us is we belong to multiple

00:36:29.600 hierarchies at once and we can have very different ranks in them.

00:36:34.320 So for example, family, work, sports team, hobby. Exactly. You've got some guy who's the

00:36:41.020 mailroom clerk in this giant corporation, and you could not possibly be lower status,

00:36:46.360 but he's the captain of the company softball team this year. And you better bet when you ask him

00:36:53.340 what's important in his life, nine to five, Monday to Friday is just a stupid way to pay the rent.

00:36:58.940 And what really matters is when the weekend comes around, you have somebody with a horrible low

00:37:05.200 status job who's the deacon of their church. We belong to multiple hierarchies and we are very

00:37:12.260 good psychologically at deciding that whichever hierarchy we're highest in, that's the one we

00:37:18.120 define ourselves by. Let's take another extreme example, which is you take people who are very

00:37:24.900 successful in what they do, whatever. They're the most famous hedge fund manager or an entrepreneur

00:37:30.140 that started some great company. You would argue, well, they seem to be pretty good on the food chain,

00:37:35.460 but yet many of them would say, or you could measure objectively, their hypercortisolemia is

00:37:42.700 problematic. So it seems like there's even more than just that ranking, right? Isn't there something

00:37:48.460 else? Cause they're at the top. If they were baboons, they're the alpha, but they're still

00:37:53.540 grossly stressed out. In other words, thank God we're more subtle than baboons, but it turns out

00:37:58.660 baboons are even more subtle than just rank. They have personality and you can be a high ranking baboon

00:38:05.320 and personality differences. And again, this is a scientific word as, as is culture. If you're a high

00:38:13.400 ranking baboon and your worst rival sneezing a hundred yards away as seen as a major provocation,

00:38:21.000 you're going to have much higher glucocorticoid levels than if you're a highest ranking baboon

00:38:25.740 for whom that's no big deal. And in fact, often you may have higher glucocorticoid cortisol levels

00:38:32.020 than if you're number 10 or number 20 in the hierarchy. There's lots of psychological filter

00:38:37.240 stuff. And I spent a ton of time studying that. Baboons differ as to how readily they see things

00:38:44.300 as being provocative or not, threatening or not. You're sitting there. And again, your worst rival

00:38:50.720 shows up and takes a nap a hundred yards away. There can be two baboons of the same rank. And one of them

00:38:57.520 keeps doing exactly what he's doing. And the other one is interrupted from whatever nice social thing is

00:39:04.240 happening. He's agitated and he's vigilant and he's got to look at the guy and lunge towards him a

00:39:08.680 couple of times before going back. If your worst rival taking a nap is as disruptive as the guy

00:39:14.560 threatening you in your face, you average about twice the cortisol levels in your bloodstream after

00:39:20.160 controlling for rank as a guy who can tell the difference between the big thing and the little

00:39:24.780 thing. Maybe this is too deep a question and the answer isn't known, but what is it that actually

00:39:32.700 transmits that information through the filter of your personality into the physiology that's very

00:39:41.040 well understood? So I understand the bookends, right? I understand how the visual cortex takes the guy

00:39:47.800 who's your enemy sleeping over there and transmits that to your cortex. And then I understand how the

00:39:54.560 sympathetic chain kicks off the response. Is there a link in between those, the processing link?

00:40:00.500 Here's one of those filters. You take people and you're flashing up faces at them, stick them in

00:40:06.680 a brain scanner, and you're looking at how jumpy their amygdala is. Their amygdala central to fear,

00:40:14.400 anxiety, aggression, and such. And what you see is tremendous individual differences in you show

00:40:21.140 somebody a face with kind of a neutral expression. Does this person look happy, sad, angry, threatening,

00:40:27.420 whatever, and lots of variability? And you look at the people who tend to view neutral expressions as

00:40:34.480 threatening. In other words, they see threats that most other people don't. What does that correlate

00:40:41.000 with? A bigger amygdala. Physically larger amygdala. A physically larger amygdala, amygdala with a higher

00:40:48.040 metabolic rate, an amygdala that is more electrophysiologically reactive than stuff.

00:40:54.420 Let's back up for a moment. I mean, tell people in case they don't know where the amygdala sits,

00:40:59.780 what part of the brain it evolved from, and why it's sort of referred to as this reptilian brain.

00:41:05.220 I think everybody's heard of the amygdala, but I think you could explain this in a more

00:41:08.920 interesting and accurate way. Okay. Amygdala is like one of the anchors of what's called the

00:41:15.260 limbic system in the brain. Limbic system, it's the part of the brain that's all about emotion.

00:41:21.480 Not surprisingly, mammals have a whole lot more limbic development than fish do. Fish are not

00:41:28.640 famous for their emotional lives. Limbic system is arousal, fear, anger, lust, love, maternal,

00:41:37.960 pair bonding, mother-infant bonding, all of that. And it's a whole series of structures. Not surprisingly,

00:41:44.440 ancient in mammals, not surprisingly, highly complex, interconnected, not surprisingly sitting

00:41:51.580 underneath the cortex, the cortex that more recently evolved part of the brain that does

00:41:57.080 your taxes, all of that. Limbic system underneath there, all the subterranean emotion stuff.

00:42:03.220 And amygdala is one of the key limbic structures, and it's involved in fear. It's involved in anxiety.

00:42:09.600 It's involved in aggression. You learn to be afraid of something or somebody that didn't used to scare

00:42:16.840 you. And your amygdala does the exact same sort of cellular basis of learning that goes on in other

00:42:23.660 parts of your brain when you learn somebody's middle name and actually remember it. Your amygdala

00:42:28.340 learns to be afraid of new things. And when you manage to stop being afraid of something,

00:42:34.220 when you stop being afraid of thems, because it turns out, oh, they're actually more similar to

00:42:40.920 you than you thought. It's your amygdala that becomes less reactive to stimuli like that. So

00:42:47.300 your amygdala is absolutely central to some of our worst human moments.

00:42:53.160 It's so interesting because it's sandwiched between, you know, you can think of the human

00:42:56.560 brain as having sort of a very grossly three parts, right? This brainstem, this midbrain,

00:43:02.280 which the amygdala you could argue is the mare, and then the cortex that you described.

00:43:07.420 It's not an oversimplification, I think, to say that as the complexity of the organism evolved,

00:43:12.760 so too did that hierarchy, right? I mean, the brainstem basically handles everything we don't

00:43:17.500 have to think about ever, breathing and all of those autonomic and sympathetic, parasympathetic

00:43:22.260 functions. And then you layer on this midbrain that does everything that you said, which is still

00:43:27.240 kind of happening beneath consciousness. And then, of course, there's where most of us live in our

00:43:32.040 cortex where we're, or where we think we live, which is where we're thinking these thoughts, but

00:43:36.540 it seems we're maybe not as aware of how influenced the cortex is by what lies beneath it.

00:43:43.280 Exactly. Which is incredibly important. If you think of this kind of ancient reptilian brainstem

00:43:50.820 part of the brain, what does it do? It keeps track. It makes you breathe every now and then without

00:43:55.580 having to think about a boring sort of stuff. Then on top is the emotional limbic system. Then on top is

00:44:00.660 that cerebral thinking cognitive cortex thing. It's very easy to come up with a conceptualization

00:44:07.140 that what's fancy about humans is, for example, you're a lizard. And the only thing that's going

00:44:13.760 to change the functioning of that ancient brainstem stuff is if you're bleeding, if you're too hot,

00:44:19.600 if you're too cold, just like boring physiological states. Once you layer a mammalian emotional limbic

00:44:26.260 system on top, suddenly you can do something no lizard on earth can do. You're sitting there and

00:44:32.060 you're some wildebeest and some other scary wildebeest shows up and is peeing on some tree in your

00:44:39.320 territory and nothing regulatory has changed in your body, but your heart starts beating faster.

00:44:45.880 Aha! Your emotional brain can alter sort of the basic regulatory stuff down in the basement.

00:44:53.260 Now you go one step higher and you layer a cortex on top of it and now you could do amazing stuff.

00:45:00.560 You sit there and you think about the fact that your heart's going to stop beating someday

00:45:05.260 and you start breathing faster and your brainstem, the more ancient stuff, has altered as a result.

00:45:13.900 And you've just done something not only that no reptile can do, you've just done something that

00:45:18.220 no warthog can do, which is think, think about something that's scary or arousing or remember

00:45:26.580 the time that you would, and suddenly something changes down below there. So there's this easy

00:45:33.980 picture of sort of top-down complexity once you get to us and where the cortex can regulate your

00:45:43.000 emotional brain and that regulatory brain at the bottom, your emotional limbic brain can regulate.

00:45:48.560 What's far more interesting or underappreciated is exactly what you bring up, which is those lower

00:45:54.700 levels can influence what's going on up above. One example of this, this is like this classic great

00:46:01.640 study in sort of physiological psychology, social psych. You take people, and I think in this study,

00:46:08.000 they would take male volunteers, heterosexual male volunteers, and of course they were no doubt college

00:46:13.860 freshmen taking Psych 101, and they had these guys walk across this really scary suspended bridge.

00:46:22.220 And the deal was that either halfway across the bridge, you were met by, from the other side,

00:46:30.240 a researcher who happened to be an attractive female. And she would ask the volunteer some questions,

00:46:37.140 oh, what do you think of this bridge? Or how is it walking across this? Or whatever. The other half

00:46:42.100 of the time, you would not encounter this person until you were safely out at the other end.

00:46:48.060 Then they would ask you to evaluate the attractiveness of the person.

00:46:52.740 Same person.

00:46:53.340 That same person.

00:46:54.140 You're either seeing her in the middle of the bridge or at the far end.

00:46:56.240 Exactly. Saying, hey, remember while you were doing that, you, there was this, you know,

00:47:01.140 do you want to rate her attractiveness? Was she friendly? Did she seem smart? And what you would see is

00:47:06.540 guys in the middle of the bridge with their hearts racing because they're terrified would do some

00:47:12.880 misinterpretation. Why is my heart beating so much faster than if I was standing safely?

00:47:18.060 So they would rate her more attractively in the middle of the bridge.

00:47:21.200 Exactly. And then it's the sealing of detail is now you do the same experiment and you give the

00:47:26.900 person a beta blocker so that they don't have the accelerate and they don't rate the person as

00:47:33.540 attractive. Is it the same with the beta blocker you would treat? Yeah. You do nothing to their

00:47:38.100 ratings of them as how smart they seem, how kind they seem, whatever. It's just this. Okay. If my

00:47:43.300 heart's racing, it must be because, so that's a great example. Boring reptilian regulatory stuff

00:47:50.680 down there is helping influence what you think your emotions are.

00:47:56.220 That reminds me of that 1995-ish movie Speed with Keanu Reeves and I'm blanking our name.

00:48:03.440 Bullock.

00:48:03.920 That's right. Sandra Bullock. Where at the end of that movie, there's some cheesy line about how

00:48:08.740 relationships that start under this much distress, you know, it's dangerous. But, but of course the

00:48:14.180 other read on that now is, yeah, if you're on a bus that's about to blow up, like, I think you're

00:48:18.700 going to think the chair is attractive, right? Potentially.

00:48:21.540 Right. Yes. Wow. I haven't thought of that movie in years. Thanks.

00:48:27.220 I'm sorry. You can go home and I'm sure Netflix will stream that for you.

00:48:32.140 Right. So I read something you wrote. I can't remember where it might've been in another interview

00:48:37.020 that, and I didn't know this, and this is a great example of why I just love doing this podcast

00:48:43.260 because there's never an exception to how much I'm learning. It's like drinking from a fire hose.

00:48:47.040 And you'd think I would have remembered this from medical school. The neuron of a human and the

00:48:53.080 neuron of some other organism, when you look at it at the single cell level, can't really

00:48:58.580 differentiate it. If I showed you two Microsoft slides and here's a human and here's a fish.

00:49:04.620 So what is it about, and this is maybe getting us a little off topic, but I also think it feeds

00:49:09.200 into this broader issue of like the stew and the alchemy of how this stuff is put together. But

00:49:15.100 if we all have the same neurons, what is, is it the number of our neurons? Like what is it that

00:49:20.820 enables us to have all of this additional torture? Yeah. It's incredibly interesting because I mean,

00:49:29.000 there's, there's three and a half people on earth who have spent their entire careers being able to

00:49:34.020 tell the difference between like a tree shrew neuron and a human neuron and could recognize it in their

00:49:39.660 sleep. But yeah, for the most part, we are not humans because we have invented brain areas that

00:49:46.540 you don't find in other mammals or because we've invented neurotransmitters that you don't find in

00:49:51.780 other vertebrates or types of neurons. Here's a couple of types of neurons that people used to think

00:49:57.420 were specific to humans. And it turns out you find them in elephants and whales also. And that's

00:50:02.460 plenty interesting, but it's the same enzymes. It's the same gene regulation. It's the same,

00:50:09.500 you know, we're sharing 98% of our DNA with a chimp or a bonobo. So you say where a human has come

00:50:16.180 from. And I think it's exactly the issue you talk about. We have the same signal transduction pathways

00:50:22.580 and neurons as you see in a fruit fly. And what's the key difference? Isn't that, isn't that a bit

00:50:27.260 humbling? Yes, it is. When we just think we're that special. And it's the, where you can take one

00:50:33.500 of their genes or one of our genes and stick it in the other one and it functions just fine. Or you

00:50:40.220 could take it from a single cell organism, some genes related to programmed cell death. You can do

00:50:45.640 that. So what's the big difference for every neuron that a fruit fly has? We have a hundred million

00:50:50.360 and sort of the soundbite that I think summarizes all of that is with enough quantity, you invent

00:50:59.900 quality. And this is this whole world of emergent properties of complex systems. You take one ant

00:51:08.020 and you put it on a table and nothing that it does makes a huge amount of sense. And you put 10 ants

00:51:14.200 there and pretty much the same thing. And you put on, I don't know, a thousand and maybe they start

00:51:19.040 making a trail or something and you put 10,000 and they build a colony and they farm mushrooms and

00:51:25.880 they take aphids as slaves and they could keep the temperature in the colony plus or minus two degrees

00:51:31.540 and they have specialization of labor. And no ant has any more rules than he had when he was

00:51:38.660 wandering around on the table by himself. And you put enough of them together and complex adaptive stuff

00:51:46.240 emerges out of the very simple rules that each of those components has for dealing with another

00:51:52.200 component. It almost defies entropy, doesn't it? Like why does that happen? It's amazing that it does

00:51:58.420 that. And that's what our brains are. We've got more ants that are coming together in our heads than

00:52:03.960 does a fruit fly. And you get more complex emergent stuff happening. It blows my mind. So let's go back to

00:52:11.580 some of this stuff. Maybe about a year ago, I read something that really frightened me because the

00:52:16.400 implications were so significant. If a mother is under great stress, there was this critical window

00:52:23.840 in which her child could see something in her eyes that would communicate that stress to her. Or maybe it

00:52:32.120 wasn't in her eyes. It might've been just through her entire face, but it would imprint epigenetically

00:52:37.020 into the child and alter many features about them as they would age. For example, their propensity to

00:52:44.700 be depressed. I mean, I remember reading this in sort of a lay press thing. So I don't even think it

00:52:49.040 got into the description of epigenetics, but that was the only assumption I could make was that this

00:52:52.740 must be modulated through that mechanism. Do you see evidence of this in animals? I mean,

00:52:57.820 absolutely. And it's one of the trendiest topics around. I mean, like hooray,

00:53:03.940 science finally recognizes childhood matters. Like what your childhood is like has a lot to do with

00:53:11.240 what sort of adult you're going to wind up being. What do you know? And like lots of childhood

00:53:16.160 adversity versus childhood security and, you know, very different trajectories. And what's been the huge

00:53:22.480 mechanistic challenge for the field is understanding. So what is it about being in a scary neighborhood

00:53:29.800 or an unstable home or having a parent read to you? Or what is it about this whole world of

00:53:36.860 developmental individual differences? What are the nuts and bolts changes that occurs in a kid?

00:53:42.100 So that as an adult, they are now 30 fold more likely than the next person for this or that to happen

00:53:49.140 to them. And this, this whole trendy field of epigenetics, which is early experience doesn't change

00:53:56.900 your genes, doesn't change your DNA sequence with some like, you know, circus trick exceptions. You've

00:54:04.360 pretty much got your DNA sequence forever. What epigenetics is, is early experience changing the

00:54:10.760 regulation of your genes, how easily you turn certain genes on, how easily you turn others off

00:54:18.120 in different parts of your body, different parts of your brain, and so on. And that's exactly the sort

00:54:24.040 of domain where you see the sort of stuff that you outlined. So that, for example, if you're a fetal

00:54:32.260 rat and you, that rat have made a terrible decision, you've picked the wrong womb to be developing in,

00:54:39.800 and you happen to be inside a mother who's highly stressed, she's secreting a lot of rat glucocorticoids,

00:54:47.380 which get into the circulation through the placenta and to the fetal circulation into the kid's brain

00:54:53.120 brain. And one of the things that it does is it causes an epigenetic change in the amygdala.

00:55:00.200 So is that rat going to be born with a larger amygdala or is the phenotype more complicated than

00:55:05.040 just size? It's size and a bunch of other things. As an adult, it's going to have a bigger amygdala

00:55:09.800 and it's going to be more excitable and it's going to be more prone towards interpreting a neutral

00:55:15.760 situation as a threatening one. That's virtually the definition of rat anxiety disorder, seeing

00:55:22.300 menace that other people don't. And you see much the same evidence in humans by now. Early experience,

00:55:29.960 forget early experience, what kind of kindergarten teacher you had. This is fetal early experience.

00:55:36.600 And this is exactly a domain where you get potentially a lifelong epigenetic effect.

00:55:42.120 Okay. So that turns out to have a hell of an implication. That's just the most exciting

00:55:49.940 subfield around there by now. Okay. So you were fetus and got exposed to lots of mom's glucocorticoid

00:55:58.160 levels. And as a result, as an adult, you've gotten a large amygdala and you see threat all over the

00:56:05.480 place that other rats don't. And among other things, you secrete elevated levels of glucocorticoids

00:56:13.240 because the world is full of menace that only you are seeing. So you get pregnant and during your

00:56:21.500 pregnancy, as a result, your fetus is exposed to elevated glucocorticoid levels.

00:56:27.400 And to be clear, it's not because you have altered the germline genome. It's that you have changed the

00:56:34.680 expression of the gene, which has altered the phenotype. And now that phenotype is being passed

00:56:41.060 generation to generation through parallel expression. Exactly. Something termed non-genetic

00:56:46.640 transmission of traits, non-Mendelian. And people have now shown some of those traits. You see that ripple,

00:56:53.440 it gets smaller each generation, but it's there half a dozen generations later. And the exact

00:56:59.620 equivalent of some of these have been found in humans. In other words, individual differences are

00:57:06.880 arising not only from experience, but from the multi-generational transmission of some of the

00:57:12.300 consequences of experience, which is just mind boggling that that can work that way.

00:57:19.400 Let's go back a little bit to why this is problematic. So at the outset,

00:57:23.440 we alluded to this idea that it's a misnomer to say stress kills. I'd love to hear if you have

00:57:28.480 a particular definition of stress. I probably butcher this stuff, but I sort of think of stress

00:57:32.660 as the external thing. And I think about it as it's anything that is sort of emotionally or physically

00:57:39.320 either chronically or acutely distressing. I mean, that's sort of a dumb definition because it

00:57:44.280 contains the word stress, but I think people understand distress a little more than they understand

00:57:49.660 stress. But of course it's your response to that physiologic response, right? So we can quantify

00:57:57.360 this stuff in terms of what hormones are happening in the body and how the hormones are moving the body.

00:58:02.380 It's your response to that, that probably has a greater impact on your health. So let's go through

00:58:07.920 three things. Help me understand how hypercortisolemia and or its accompanying features

00:58:15.340 will impact the brain, especially, well, through any timeline you want. I'm obviously interested in

00:58:22.340 the aging brain, but I can't imagine this also doesn't impact the developing brain.

00:58:26.620 This is basically what I've spent my whole professional career thinking about. And historically,

00:58:33.200 the first place where people sort of realized something scary was happening was a brain region

00:58:39.000 called the hippocampus. Hippocampus is all about learning and memory. You want to have a hippocampus.

00:58:46.440 It's the main brain region that's damaged in Alzheimer's disease, and it's vulnerable in lots of

00:58:51.660 other ways. Turns out it's extremely sensitive to glucocorticoids, translated more reductively.

00:58:58.680 It's got extremely high levels of receptors for glucocorticoids by the standards of the rest of the

00:59:04.320 brain. And what's the evolutionary basis for that? Is that to have a feedback loop? There's two reasons.

00:59:09.560 One is to have a feedback loop, but the other is, okay, so the hippocampus remembers stuff for you.

00:59:16.420 You don't remember everything. You don't remember where you were on 9, 10, as opposed to 9, 11 kind

00:59:24.240 of thing. Your memory processes has to come with a filter saying, is this one important?

00:59:31.140 So you're saying that cortisol amplifies memory consolidation and that you use this to consolidate

00:59:36.020 stressful memories as a way of learning. Exactly. Along with epinephrine and norepinephrine

00:59:41.000 indirectly, they have some of the same effects. So cortisol crosses the blood brain barrier with no

00:59:44.960 difficulty. Exactly. I assume epi and norepi do the same.

00:59:48.660 They have to work more indirectly heavily through the vagal nerve because they don't get them as

00:59:53.140 readily. But some of it is also norepi being released within the brain during stress. So it

00:59:58.180 has some of its own memory enhancing effects. Again, a great example of evolution's got this

01:00:04.060 awesome system set up and it only gets out of whack when the stimulus becomes too much. You do want

01:00:11.960 that imprint, but you don't want that happening full-time. Or stated another way, this is the

01:00:16.400 reason why you don't get much out of a class if you're semi-comatose and you got two hours of sleep

01:00:22.720 last night. If you're like three-quarter, your glucocorticoid levels are low, you're not consolidating

01:00:28.700 stuff. If you are out of your mind terrified because there's a lion sitting next to you, you're not going

01:00:34.380 to absorb much either. Inverse U, optimal range, all of that. So it turns out the optimal amount of

01:00:40.520 glucocorticoids, something that is moderately stressful. In other words, something stimulating

01:00:47.000 does great stuff to your hippocampus. It increases blood delivery, their glucose, oxygen. It makes the

01:00:55.600 synapses, the connections between neurons more excitable in the hippocampus. It does great stuff.

01:01:01.740 A little bit of arousal, alertness is a good thing for learning and memory. Now instead,

01:01:07.120 transition to you are stressed 24-7 ever since you were like 10 years old kind of thing,

01:01:14.700 and you're in the range where glucocorticoids do exactly the opposite. They decrease oxygen and

01:01:20.500 glucose delivery to the hippocampus. They make neurons less excitable. They disconnect synapses.

01:01:27.400 They cause the processes in neurons to shrivel. They block the birth of new neurons there.

01:01:33.020 They make other insults more damaging to neurons in the hippocampus. What do you have there? That's

01:01:38.740 the world in which if you were stressed out of your mind, memory doesn't work so hot. And what we're

01:01:45.420 increasingly realizing is if you're exposed to excessive glucocorticoid levels, like on the scale

01:01:51.500 of years to decades, you're going to make this part of the brain get older faster.

01:01:56.300 Which speaks to something that I know you're quite passionate about, which is the differences in how

01:02:03.880 socioeconomic status can sort of affect generational changes in this manner. Because, you know,

01:02:12.000 use the example of a 10-year-old. Well, I did my residency in Baltimore. Let me tell you,

01:02:16.620 a 10-year-old in inner city Baltimore who's in the wrong house versus a 10-year-old in Palo Alto

01:02:21.380 who's in quote unquote the right house. And look, that's not to say that you could have a 10-year-old

01:02:25.260 in Baltimore that's got a great environment and 10-year-old in Palo Alto that's dealing with a

01:02:28.520 whole bunch of other different issues, which, you know, especially in the era of social media.

01:02:32.160 But all things considered, probabilistically, that 10-year-old in Baltimore is going to have

01:02:36.760 a much harder time given what you just said. Or, I don't know, stated the other way, I have a

01:02:43.760 friend who's a cardiologist who splits his time between a hospital in Oakland and a private

01:02:49.900 practice in San Francisco. Some of the time what he's doing is dealing with 80-year-olds who are

01:02:56.020 considering getting a pacemaker because the ski season is coming and they are wondering if they're

01:03:01.000 going to be in shape and time for that and maybe that. And then back in Oakland, he's dealing with

01:03:06.700 50-year-old elderly men who are having heart disease. Yeah. Socioeconomic disparities are,

01:03:13.320 I won't get on my soapbox now, when you look at the source of variability in health among humans on

01:03:21.100 this planet, socioeconomic differences, differences in absolute levels, differences in degrees of

01:03:27.560 inequality within cultures and within communities and so on, there's an enormous predictor of health.

01:03:34.020 You want to look at the most medically impacted, low-ranking primates you could find on Earth,

01:03:43.640 look at poor humans. Because when humans invented socioeconomic status and the capacity to be poor,

01:03:51.440 they invented a way to subordinate the have-nots like no chimp on Earth could ever dream of doing.

01:03:57.800 As you've alluded to, there's something else to it. You know, recently I interviewed an amazing

01:04:00.940 physician named Tom Katana who practices in the Nuba Mountains in the south of Sudan. So he's the

01:04:06.940 only physician to take care of one million people who, as you know, are being killed by their own

01:04:13.620 government. Bashir is sort of indiscriminately killing these people. So my discussion with Tom

01:04:19.440 was one of the most riveting discussions I've ever had with a human being. It just happened to be in

01:04:24.080 front of a microphone. But one of the things that just as an afterthought we were discussing that

01:04:29.180 surprised me, as we were going through all of the different things that people die of there,

01:04:33.900 you know, they don't have vaccines, you've got measles outbreaks that are killing people left,

01:04:37.500 right, and center, and the trauma, like, you know, the shrapnel blowing people apart.

01:04:42.560 Not surprisingly, they're just not getting the same chronic diseases, you know, and the cancers they

01:04:47.140 get are not the cancers we get, and they're not getting heart disease, and they're, you know,

01:04:50.840 almost unheard of to get type 2 diabetes. But what really surprised me is there was no suicide.

01:04:56.780 And I found that as the single most interesting thing I guess I learned from Tom, which was

01:05:03.280 we would look at their life and think that is an abysmal existence that I couldn't tolerate for one

01:05:10.660 second. And yet I would have to guess that their level of cortisol might be lower than ours, even

01:05:18.540 though they're in a much worse environment. So whether it's that sense of community that they have,

01:05:23.180 or the shared purpose, there's something about it. So in other words, my point is, even in the

01:05:28.020 presence of such great poverty, it seems that there's ways that this can be overcome, whether

01:05:33.900 it's through there's no comparison to anybody else. Because another point he made was most of the folks

01:05:38.860 there don't even know they're in Africa, like they don't necessarily know that Africa is the continent

01:05:42.800 in which their country resides. So is the bigger issue there, you think that there's no disparity?

01:05:47.640 So even though that's complete poverty, there's no real perceived disparity? Or do you think it's

01:05:53.220 the sense of community? Like what would you hypothesize explains that health, that mental health?

01:05:59.540 All the above. There's a whole world of people who study happiness, along with more traditional

01:06:05.760 public health people who study things like longevity. You look at the quarter poorest places on earth,

01:06:12.400 and indeed, people there don't live very long and are miserable. But once you get past sort of the

01:06:20.440 subsistence level, there's not a great relationship between the wealth of a country, GDP per capita,

01:06:29.360 anything, and levels of happiness or life expectancy. And you look at the fact that the US has a shorter

01:06:35.640 life expectancy than Cuba and Lebanon and Costa Rica. And it's like the shame of this country kind of

01:06:43.220 thing. Once you get past mere subsistence level, income is not a great predictor of any of this stuff.

01:06:49.720 And that's instead where you get into worlds of social capital and social support. And when you look

01:06:58.420 at the whole literature, and you look basically at every westernized country on earth, and it's now seen

01:07:04.100 as they become westernized. And what you see is the health socioeconomic gradient. The poorer you are,

01:07:11.020 the worse your health on the average. The more of a whole array of diseases you get, not all of them,

01:07:17.300 but a huge number, the more impactful they are. And when you look in the West, the United States is the

01:07:24.420 poster child for that. We've got the steepest curve of any country on earth. In the westernized world,

01:07:29.980 the least steep ones are, you bet, of course, the Scandinavian countries, ever reliable sort of utopias.

01:07:37.060 And then you begin to unpack why this relationship occurs. And like some incredibly smart people have spent

01:07:44.760 their careers looking at it. The most obvious one is, if you're not healthy, it's very hard to pull off being

01:07:51.740 the CEO of a company. Poor health precedes and gives rise to poor socioeconomic status.

01:07:58.600 Okay, that's plausible. That turns out to explain a tiny percentage of the variability. And you could

01:08:04.240 look at the status, socioeconomic status of the home in which a child is raised. And that's a predictor

01:08:11.640 of their likelihood of diabetes half a century later. So absolutely, the socioeconomic status comes first

01:08:18.700 in explaining the vast percentage of the variability. Okay, so next thing, maybe it's just that, well,

01:08:25.080 everybody's kind of equally healthy. It's just that the really poor people are very unhealthy. We have

01:08:30.560 a step function. No, you start with Jeff Bezos and Bill Gates and every step down there. And

01:08:37.420 statistically, the lower you go down every rung of the way, the poorer you are.

01:08:43.340 The poorer you are with respect to health, you mean?

01:08:44.680 The poorer your health. Yes, yes. Thanks. So now you unpack that. And what's the most obvious

01:08:49.960 explanation? And this is what people call a neomaterialist explanation, which is obvious.

01:08:54.880 The poorer you are, you don't have healthcare access. You don't have health insurance. You

01:08:59.920 can't go to the doctor as readily. Your care is more lousy. That's obviously, that explains everything.

01:09:05.440 That explains virtually none of the variability in the data. Because you see the gradient,

01:09:10.040 nonetheless, in countries with socialized medicine, universal healthcare. You see it for diseases where

01:09:17.560 it doesn't matter how often you get healthcare access. Juvenile diabetes. So it shows an SES gradient

01:09:25.880 kind of thing. So it's not healthcare access. You then look cross-culturally and you see wildly

01:09:33.620 different income levels and wildly different levels of healthcare access. And you see very

01:09:38.860 similar lifespans across these countries and very similar gradients. So what people spent like the

01:09:45.320 last 30 years doing is having this huge shift towards, it's got so little to do with the material

01:09:52.060 aspects of wealth or poverty. It's got to do with the psychological aspects. It's got to do with the

01:09:57.760 stress. First key finding, somebody at UCSF named Nancy Adler, who's done wonderful research showing,

01:10:06.340 okay, your socioeconomic status, your wealth, your objective measure of wealth is indeed a predictor

01:10:13.840 of your health. Turns out, at least as good of a predictor is your subjective socioeconomic status.

01:10:22.620 On the level, when you look at people around you, how are you doing compared to other people? Where

01:10:28.120 do you place yourself on this 10-step ladder in terms of what's your absolute SES? What's your

01:10:34.360 subjective one? And by asking it that way, you're asking the person to consider the community that's

01:10:39.420 most pertinent to them. Who's the comparison group? My next door neighbors, Warren Buffett,

01:10:44.660 in between, whatever. When you think of other people, how are you doing compared to them? And it turns

01:10:51.040 out your subjective SES is at least as good of a predictor of your health as is your objective.

01:10:57.260 In other words, if you took someone's income, which is quite objective, it would offer no more

01:11:03.740 prediction than asking that person in the Anuba Mountains, where do you rack up in this tribe?

01:11:09.740 And it's sort of like, eh, you know, sort of top two thirds.

01:11:13.780 Yeah, exactly. Or another way of stating that is you look in some bloated corporation,

01:11:20.120 and there's some guy who's the assistant manager of the mailroom, and that's an incredibly status-filled

01:11:26.680 position for that guy. And there's some other guy who's number two in the company who was just passed

01:11:32.580 over to be number one. And the only pertinent thing in his mind is not the 99,000 employees that he's

01:11:38.460 higher ranking in, that there's still somebody ahead of me. And you can see the same thing in

01:11:43.420 baboons. In other words, it's not being poor, it's feeling poor. The next critical piece in the

01:11:51.020 story is work from this guy, Richard Wilkinson in the UK, who shows what's the best, most like

01:11:57.820 effective way to make somebody feel poor, independent of their absolute levels of income,

01:12:03.620 surround them by inequality, surround them by reminders of all the people who are doing better

01:12:10.380 than them. I mean, this is where social media, it's the amplifier to all amplifiers of this,

01:12:15.780 right? You can't go 10 minutes if you're on it without looking at somebody who's obviously better

01:12:22.140 looking, obviously smarter, obviously richer, obviously having more fun. I think this has been

01:12:27.660 pretty well documented, right? I mean, lifestyle of the rich and famous, or you could be driving down

01:12:33.100 a freeway and somebody passes you, and I don't know what counts as a high status car these days,

01:12:38.780 that cost a fortune, but they come speeding past you, and you can feel crappy and diminished and

01:12:47.100 like a less successful human, and you never even saw that person's face. This is unheard of in the

01:12:54.580 history of humans or primates of being able to feel socially subordinated, and you don't even interact

01:13:00.780 with the person. Oh, there's people out there with, you know, at least if the next door neighbor has

01:13:06.700 more camels than you, that's a very like tangible, real thing in terms of like likelihood of surviving

01:13:13.820 that extract. Income inequality explains the mediating effect between objective socioeconomic

01:13:21.360 status, subjective socioeconomic status, and health outcome. What I'm hearing you also say,

01:13:27.700 though, that's a more subtle spin on this, is it's not necessarily global income inequality,

01:13:33.840 it's local income inequality that is much bigger. But what technology has allowed us to do is explain

01:13:39.960 what counts as low. That's right. That's exactly right. It's expanded what local means.

01:13:43.320 You can sit there and watch, I don't know, Lifestyles of the Rich and Famous, and back when,

01:13:48.820 you would never have gotten into like the head of your fiefdom's castle or whatever, and now you can

01:13:55.040 see all the crap they have that you're never going to get and feel less loved as a result.

01:14:02.840 It's so interesting to hear you talk about this. This is a topic that I think anybody listening to

01:14:06.640 this is well aware of, especially if you're a parent, because you also have to think about this

01:14:12.820 through a developmental lens, which is at least when you and I grew up, I didn't grow up with a lot,

01:14:18.940 but you really had no idea what was different, right? Everybody was the same. I mean, everybody's

01:14:25.640 parents bought used cars instead of new cars, and everybody had more or less the same sort of

01:14:31.360 clothing that wasn't exactly the best and whatever. So at least you could argue, well,

01:14:38.200 were we at least spared some of this difficulty during a critical window of development?

01:14:42.900 And what happens now to a 10-year-old that's got a smartphone and is subjected to this? Because

01:14:50.960 I remember that funny show, Lifestyles of the Rich and Famous. I can still sort of hear the goofy,

01:14:55.720 cheesy theme song. I think I even probably watched it once or twice as a kid, but it's a lot easier

01:15:01.840 when that's the one exposure you have to extreme wealth or disparity, and either you can watch it for

01:15:07.400 one hour or not. But it's quite a different thing if, not to pick on the Kardashians, I'm just,

01:15:12.460 but if you're inundated with, oh my God, look at how awesome the Kardashians are and what they're

01:15:17.300 doing and how great their life is, and multiply that by three log orders, do we have any data that

01:15:25.360 suggest that we are at a critical juncture? Because I was having this discussion with a friend yesterday,

01:15:30.960 which is, is there evidence of any greater transition in technology in both a positive and

01:15:40.700 negative way than this generation to the last? Is this truly the greatest step forward?

01:15:47.340 I would assume so, but the things we worry about, people have been worrying about for centuries.

01:15:55.520 Oh my, kids, they don't go outside, they don't play, they don't have like meaningful relationships

01:16:01.960 because they spend all their time talking on the telephone. They spend all their time listening to

01:16:07.040 their transistor radio. So maybe we're blowing this up. Maybe this is just this generation's

01:16:11.660 version. I mean, I guess the one difference is when you're talking on the telephone, when you're

01:16:17.220 listening to the transistor radio, I don't know if it creates that global to local phenomenon quite as

01:16:24.040 easily or as quickly or with, with less resistance as we see, but maybe you're right. Maybe this has

01:16:29.520 always been one generation's struggle with the last. But what you get is an amplifier now,

01:16:36.040 because if you're an insecure, socially isolated, peri-adolescent kid who's vulnerable in all sorts

01:16:45.380 of ways, um, you know, no matter what decade or century it was, you're the last one picked for the

01:16:52.820 game. You're the one who's least popular or whatever. And that has all its corrosive effects.

01:16:57.920 Now, if you really set your mind to it and you're that kid, you could spend 24 seven, just wallowing

01:17:05.480 toxically in evidence of a gazillion other people who are better looking than you and more popular

01:17:12.680 and invited to parties. You'll never be in. It amplifies further in the, the technology does

01:17:19.160 absolutely that. What I think it does is it makes the vulnerable more damaged than in the past.

01:17:25.320 I think it's safe to say these amplifiers aren't going anywhere. So rather than wallow in their

01:17:34.380 harm, I guess the more relevant question is what do we do? If you're a parent today or not a parent

01:17:42.180 today, and you're thinking about this through the lens of yourself versus your kids, whatever,

01:17:45.980 what are the steps that one can take to become less susceptible to these forces that seem to drive

01:17:55.880 this? Because I want to step back for a moment. When I think about these areas that we've talked

01:18:01.720 about before, about the impact of nutrition and sleep and exercise and stress or distress to make

01:18:08.380 it more the term I use. When I think about this personally, the one I most worry about is the last

01:18:14.280 one. I think I've got a pretty good handle on nutrition and it's in many ways easier to control.

01:18:19.680 I feel like I'm more in control of what I eat. And when I make bad choices, I'm usually doing them

01:18:24.900 consciously. Like I've decided I'm going to eat this pizza versus I can't help myself. I'm going to eat

01:18:30.100 this pizza. Similarly with exercise, like, and again, I'm not saying this for anybody else, but this is just

01:18:34.660 my personal thing. And even with sleep, like once you commit to it, which is not something I did

01:18:40.500 until probably seven or eight years ago that I sort of committed to, wow, this really matters.

01:18:44.920 And to forego this thing, bad idea. It's this last one that really drives me crazy, which of course

01:18:52.620 doesn't help matters because the fact that it drives you crazy makes it worse. But I'll give you an

01:18:56.200 example. As a general rule, outside of the immediate postprandial period of a high glucose meal,

01:19:05.620 far and away, my highest blood glucose is always in the morning. Now I wear a 24 hour glucose meter.

01:19:11.840 So I'm kind of a weird guy for almost four years. I've been wearing a glucose monitor all the time.

01:19:17.680 So it measures my glucose 24 seven at one minute increments. And out of say 365 days in a year,

01:19:24.620 I'm easily wearing it 330 days of the year. So I've got a lot of data. And without a question,

01:19:31.220 when you look at a 24 hour period, if you stripped away the X axis of time, I could easily identify

01:19:38.960 morning for you without exception. I'll give you an example. This is not something I'd planned to do.

01:19:46.120 I had breakfast yesterday, yesterday being Sunday, really early because I woke up with my kids made

01:19:51.800 breakfast. I normally don't eat breakfast, but I did. So I had a breakfast, 730 in the morning,

01:19:56.220 did a workout, had to catch a flight, didn't have time to eat after, had a very, very busy day,

01:20:04.060 didn't eat a single thing, got to the hotel around 1030 or 11, didn't want to eat. So didn't,

01:20:11.180 you know, got up this morning. It's been almost 24 hours since a meal. And I looked at my glucose

01:20:17.460 meter and it was like said, you know, 110, 110 milligrams per deciliter. I was like, there's

01:20:21.340 no way that's right. Calibrated it. Sure enough, it was 110. Now there is no earthly reason I should

01:20:27.600 have had a glucose of 110 milligrams per deciliter 24 hours after my last meal, which by the way was

01:20:34.200 bacon and eggs. It's not like I was eating pancakes, right? Well, I promise you if I could spot check my

01:20:40.640 cortisol, it was high. And here's the thing before I went to bed, my glucose was quite low. You know,

01:20:47.720 my glucose was probably 80 when I went to bed and it slowly rose. And sure enough, as my day wore on

01:20:53.420 today, the glucose went lower, lower, lower, lower, lower. It was about 78 before you walked in here.

01:20:59.760 I'm not alone by the way. So I've seen this a lot clinically with patients. Once you start putting

01:21:04.420 these 24 hour glucose sensors on people, which a lot of my patients are now doing, you get this

01:21:10.140 insight into this horrible thing that's happening when we think we're sleeping and nothing else is

01:21:15.380 going on, but we're ruminating or God knows what else. And fits perfectly with morning wakening is

01:21:23.280 when you get your highest glucocorticoid levels, which is probably one of the main driving forces

01:21:29.060 on the increased blood glucose. When you think about it from a circadian standpoint, what's the most

01:21:34.740 challenging thing you have to do each day in the absence of any major tumult? Get up, start

01:21:40.940 functioning, all of that. It just seems like it's disproportionate. Certainly the Dawn effect has been

01:21:46.200 well described. It's more amplified in people with type 2 diabetes, which is another interesting point,

01:21:51.340 right? Which is, why is it that someone who already has glucose dysregulation would have an even

01:21:56.200 higher cortisol response in the morning? And yet you'll see, you know, enormous fluctuations in

01:22:02.320 glucose. I guess my point here is this seems like a harder problem to fix. And certainly meditation is

01:22:08.760 by far the best tool I have ever found to even approximate getting this under control, but it's

01:22:16.160 still hard because it's not like you have a pill. If your blood pressure is high, well, I think it's

01:22:21.240 probably best to fix it in any way possible, but we also have really great drugs that fix high blood

01:22:26.460 pressure that can at least mask these things. We don't have a pill to fix hypercortisolemia.

01:22:31.700 It's one of the most complicated endocrine situations. And yet, as you've described

01:22:37.020 eloquently, it's also so innately wired into us. And we have this miserable midbrain that's

01:22:44.920 just killing us. First of all, I'd love to hear your thoughts on meditation, but then also other

01:22:49.600 things that given how much time you've spent thinking about this problem, I'd love to know how

01:22:53.680 you would suggest someone who doesn't have quite the Zen mindset that I can tell you do, what should

01:22:59.800 someone else be thinking? Right off the bat, I'm delighted to see that I have a persona of a Zen.

01:23:05.700 I'm actually like one of the most type A stressed people you're ever going to run across. I've spent

01:23:11.260 40 years professionally studying how bad the outcome is going to be of all of these bad lifestyle

01:23:20.560 aspects without having anything insightful to say about how to actually fix it or prevent it. And I

01:23:27.540 certainly have learned personally absolutely nothing from my lifetime of work. I'm like incredibly

01:23:32.720 stressed. I'm mostly good at telling you what's going to happen if you don't get stuff under control

01:23:37.020 rather than how to get things under control. When I look at the stress management literature,

01:23:42.640 I don't do it very often because I tend to get sort of agitated at that point. But broadly,

01:23:49.860 it works. It works as in you can lower blood pressure, you can lower cholesterol levels,

01:23:56.840 you can lower subjective sense of health, objective measures as well with all sorts of

01:24:02.700 interventions. What you see when you look at the literature closely, first off is you can't do your

01:24:09.660 stress management on the weekends kind of thing. It needs to be a regular sort of thing. You can't do it

01:24:16.000 while you're on hold on the phone for 30 seconds. You need to set time out for it. The benefits of

01:24:22.040 aerobic exercise, I don't know what the magic number is these days, but 20 or 30 minute blocks

01:24:27.680 is a minimum to start getting the cardiovascular benefits. So it's got to be something like you

01:24:34.000 stop things to do. So that's important. Let's double click on that. What you're basically saying

01:24:38.040 is, because I think you're understating how much you know about this topic. Obviously,

01:24:42.100 it's something you know a lot about as seriously as we would take nutrition. And if you think about

01:24:47.940 how many hours a week do you put into eating? I mean, even if you're shoveling food down your throat,

01:24:51.980 it still takes quite a bit of time. If you're going to exercise to the levels that have demonstrated

01:24:56.520 benefit, we're talking about hours a week, not minutes a week. If you're going to make the difference

01:25:03.360 between getting by on sleep versus getting restorative sleep, I'm not talking about the absolute

01:25:09.100 amount of sleep. I'm just talking about the delta between those two. Think about how many hours that

01:25:13.320 is. In fact, for the average American, that would work out to be about an extra seven to eight hours

01:25:18.700 a week of sleep. And what you're basically saying is, if you want to combat this hypercortisolemia,

01:25:24.440 dude, guess what? It ain't a 20 minute a week thing. And in some ways that taps into one of the

01:25:31.060 80-20 rules of sort of mental health professionals. Okay. So you have this crazy stressful lifestyle.

01:25:38.580 And there's just a bazillion things you can't say no to, and you're just going 24 seven. And if you've gotten

01:25:46.020 to the point of saying, this is crazy, this is not a quality life, I want to live a healthy quality old age,

01:25:52.860 well, I got to get this stuff under control. I'm going to start doing something stress management-y.

01:25:59.920 And if you've gotten to the point where in this lifestyle where there's a billion things you can't say no to

01:26:05.620 each day, you're saying no to them enough that nonetheless, 20 minutes every single day you're

01:26:10.980 doing this, it almost doesn't matter what intervention you're doing. You're 80% of the

01:26:16.540 way there already if you're managing to do that. And that's very similar to this sort of amazing

01:26:22.340 classic finding. You get people who are clinically depressed and finally, finally, finally, they're

01:26:27.260 going to do something about it and merely making a first appointment. Even before you've seen the

01:26:33.380 person, people feel significantly better because you are finally saying, I matter enough to do

01:26:40.580 something about this, or I'm activated enough, or I'm optimistic enough to actually go. You're halfway

01:26:47.940 there at that point, merely by doing something on a near daily basis.

01:26:52.460 So just on that logic, even though I don't know that this has been done, you would argue that 10

01:26:56.960 minutes of deliberate mindful practice of meditation daily would probably be better than one hour once a

01:27:03.180 week. Absolutely. In part because if nothing else, if you do a daily seven times a week, you were

01:27:11.960 sitting in the aftermath of having done that versus only one time a week. And an awful lot of what's

01:27:18.780 most interesting about physiology and its impact on sort of mental health, things like that, is what's

01:27:24.440 happening in the recovery period after something like that. In the same way, one awful hour long stressor a

01:27:32.460 week versus punctuated episodes of it throughout the week without question. The latter is worse

01:27:38.380 because you've now got umpteen different times that you have to recover from having turned on the

01:27:44.520 stress response. And that's where a lot of the damage occurs. You know, I learned something about

01:27:48.940 myself that's going to sound so stupid because it's so obvious. Although I don't think it's true for

01:27:53.380 everybody. Email is a huge stress to me. To be blunt, I hate it. That would be the kindest thing

01:27:59.800 I could say about email. I really, a few months ago, hit a true nadir in my response. And I'm like

01:28:07.300 looking at these glucose levels going up and I'm looking at these morning glucose levels. So even

01:28:12.700 though my overall glucose levels still look great, I mean, this trend was upsetting to me. I'm watching my

01:28:17.580 resting heart rate in the morning go up. Over the course of four months, it had gone up like

01:28:22.800 six beats per minute. And if anything, I was in better shape, exercising more regularly.

01:28:28.980 I made this observation one day, which is how many times in a day do I stop to look at email,

01:28:34.540 even if it's just a check one or two? And the answer was like 50. And every time I do it,

01:28:40.580 to your point, even if it's very brief, the after effect is not that brief. So I could,

01:28:45.400 I could look at an email and see two stressful things, but it might sit with me for 20 minutes.

01:28:52.000 So I tried this experiment, which is, I'm going to just check email twice a day,

01:28:56.820 two 30 minute blocks of email. And I would say within two weeks, I just really felt better.

01:29:07.080 It seems to me like we just have to figure out ways to figure out what those triggers are for us

01:29:14.140 individually. There's probably some people for whom email doesn't trigger them at all, right?

01:29:16.920 There's probably, you know, for me, Twitter doesn't trigger anything because a, I have a very

01:29:22.880 narrow window that I pay attention to and it doesn't involve things that are aggravating like

01:29:27.960 politics or religion or whatever. It just sort of, I'm only really following science. So anytime I look

01:29:33.620 at Twitter, I'm actually learning something kind of new and there, but I'm sure there are many people

01:29:37.220 listening to this who would say, Oh my God, like if I spend an hour on Twitter, my blood pressure

01:29:41.100 could be through the roof. So it's like, everyone's got to kind of pick their thing.

01:29:44.900 You said you're type A, which obviously you are. I mean, you know what I didn't say at the outset

01:29:48.400 when we started speaking, but you've won one of the most prestigious awards imaginable, which is

01:29:52.260 the MacArthur award. And you won that about 30 years ago, right? That's impressive. They don't give

01:29:57.820 that award out lightly. So that's the one that's referred to as the genius award. And I know you're

01:30:02.000 probably like your skin is crawling when I say that. My point being is you're an incredibly

01:30:07.520 accomplished, successful guy. It's not surprising. You would describe yourself as a type A.

01:30:12.680 What have you learned about yourself over the past 30 years or even longer going back to your

01:30:17.480 first days in Kenya about what those triggers are for you and what you can do to lower your cortisol

01:30:22.600 levels? Not surprisingly, if you, you hang out with people who are field biologists of any sort. And

01:30:30.100 again, I've, I've only been a part-time annual one over the decades, but nonetheless,

01:30:35.600 I still think of myself as a field biologist. We're kind of a solitary tribe. I mean, during my

01:30:43.880 peak periods of doing field work, I'm spending three, four months a year alone living in a tent

01:30:49.280 where 12 hours a day, I wouldn't say a word to another person. Temperamentally, this is kind of

01:30:56.340 who I've been for a long time. And there was always this ironic thing because I was sitting there

01:31:01.680 studying these baboons because primate social behavior and I'm interested in primate social

01:31:07.460 behavior. And this big sort of epiphany I had in my work that, okay, yeah, your social rank as a

01:31:13.580 baboon has something to do with your health, but much more importantly is your patterns of

01:31:17.560 socialization and social networks. And how often do you groom and how often does somebody groom you and

01:31:23.820 how often do you sit in contact with another baboon or playing with an infant? And then I,

01:31:28.700 you know, finish the day's work and go back to my tent. So there was something ironic that I was

01:31:33.980 like studying the health benefits of sociality, living alone in a tent, a large part of the year.

01:31:40.460 Your wife is a scientist too, isn't she?

01:31:42.040 She was, she kind of decided she was sick of it. And she now directs a musical theater program,

01:31:47.120 which is much more fulfilling for her. But at one point my wife came along.

01:31:54.280 Yeah. Yeah. That's what I was going to ask.

01:31:55.320 And eventually family and, you know, kind of realizing, oh, I've missed out on an awful lot

01:32:02.780 of what are really like the wonderful, worth living for moments in life out of the sociality

01:32:09.700 stuff. And that is a refuge and a sanctuary from the world's madness. And I could not have predicted

01:32:18.580 as a 20 year old who had been planning to be a field biologist for a dozen years at that point,

01:32:23.780 sort of how much of my equilibrium at this point turns out to be due to interacting with the right

01:32:33.740 two or three other primates, like being in love with them and stuff. That one was kind of a

01:32:40.880 revelation for me. I am not the social being that I would have guessed I would have been back when.

01:32:46.400 Which is interesting because having this discussion with you today, I can sense much

01:32:52.560 more of your introversion than the first time we met when you were giving an unbelievably charismatic

01:32:59.280 animated talk. And I don't know how many of us were there, maybe a hundred people. And

01:33:04.040 which is so interesting, right? Because you would, I think anybody sitting in the audience would look

01:33:08.260 at this and say, oh, that's a, that's the life of the party. But it's interesting that we can

01:33:11.980 compartmentalize and separate those things, right? I mean, you couldn't get up there and you can do what

01:33:15.240 you need to do and you're at your happiest, I'm guessing, in the way you described it versus in

01:33:19.840 the aftermath of that talk when a hundred people run up to you to ask you four questions each.

01:33:24.140 Not to get too self-reflective or something, but I'm a fairly introverted person who does better with

01:33:30.640 scripts and giving a lecture is a pretty structured script and having sort of an academic persona or

01:33:40.580 whatever is another version of it as well.

01:33:43.000 What year did you become a full professor at Stanford?

01:33:45.600 It was 33 or something, early nineties.

01:33:50.900 I mean, you live in San Francisco, so you're not making that commute every day, I hope.

01:33:54.520 Nope. But I did for about a quarter century.

01:33:58.500 Yeah. That'll, that'll hurt the cortisol levels, won't it?

01:34:00.740 I used the commuter train, Cal train here.

01:34:03.760 So you could read and...

01:34:04.820 Oh, I loved it. I loved, this was much of it was before cell phones.

01:34:08.580 So you'd pick it up at 4th and King and you'd just go, yeah, I used to make that ride all

01:34:12.600 the time. I used to have a girlfriend that lived in San Francisco and I loved that train

01:34:17.000 ride. And then you'd get off on your bike at 4th and King and you could go anywhere in

01:34:20.620 the city.

01:34:21.140 Exactly. I wrote half my book writing was on the train there. It's pretty weird when you

01:34:27.040 realize that like one of your valid social communities or the conductors on Cal train sort

01:34:32.320 of as you're watching them grow up on you and things like that. But yeah, no, that was,

01:34:37.960 I was a big fan of train commuting.

01:34:41.600 So speaking about books, let's talk about your more recent book. It's about human behavior,

01:34:48.220 which, you know, I mean, I can see based on this discussion now how your interest would

01:34:54.060 shift to that. What was the impetus for that research?

01:34:56.840 Well, title is Behave the Biology of Humans at Our Best and Worst. And as we were talking

01:35:03.660 about before, I closed my lab four years ago and stopped active research to sit for four

01:35:09.560 years and write this book. And it's basically trying to make sense of the biology of what

01:35:18.480 is for me the most puzzling thing about us as a behaving species, which is we are simultaneously

01:35:25.200 the most miserably violent species on earth and the most altruistic and cooperative and empathic.

01:35:33.000 And any given human is capable, depending on the setting of incredible gyrations as to whether

01:35:43.180 they are being wonderful or awful or in between, or behaviors where whether that counts as good

01:35:49.060 or bad is incredibly dependent on what culture they happen to be doing it in.

01:35:53.420 So just trying to make sense of the biology, I mean, it's totally boring biology as to like

01:35:59.540 how your brain makes you do something like pull a trigger, like which muscle groups have

01:36:05.400 been told that's like studying cockroach neurobiology. What's totally interesting is the fact that we're

01:36:12.660 a species where sometimes pulling a trigger can be one of the most awful things a human can

01:36:17.560 do. And sometimes it could be one of the most wondrous ones. If you're suicidally drawing fire

01:36:24.620 from innocent people and you're sacrificing yourself, or in one setting, you put your hand

01:36:30.680 on somebody else's, and that could be a moment of incredible compassion. Or in another moment,

01:36:36.040 you do the exact same thing with your primate muscles. And that's the first step of betraying a loved

01:36:41.940 one of just making sense of this contextual stuff about human behavior, which is hugely complicated.

01:36:50.000 And the song and dance that I go through in nearly 800 agonizing pages in the book is,

01:36:56.800 you're going to understand nothing about that. If you've concluded, aha, we now know this is the

01:37:03.540 part of the brain that explains everything. Or this is the neurotransmitter or the hormone or the gene or

01:37:10.240 the child. Instead, to make sense of human behavior, you got to factor in what your neurons did one

01:37:16.700 second ago. But you got to factor in the environmental triggers of that 30 seconds ago. And you've got to

01:37:23.300 factor in what your hormone levels were like this morning, and what neuroplasticity you've done over

01:37:28.500 the last two seasons, and what your adolescence was like in your childhood and your fetal life and

01:37:33.980 your genes. And amazingly, what sort of culture were your ancestors inventing centuries ago,

01:37:40.540 because that influenced the way you were raised within minutes of birth and what things you value,

01:37:46.440 and what things your amygdala does or doesn't respond to and all the things of that. What sort of

01:37:52.880 ecosystems produce different types of cultures and then finally evolution. And why we're in some ways

01:38:01.260 like chimps and in some ways like bonobos, but we're not chimps. We're not bonobos. We've solved

01:38:06.240 our own special evolutionary. You've got to understand this stuff. It's everything from one

01:38:10.980 second before to a hundred million years before. And all these levels interact, and it's complicated

01:38:16.780 as hell. When people ask the question, which I'm sure you've heard this a hundred times, and you hear

01:38:21.680 people asking all the time, are we innately good or bad? That question doesn't really permit

01:38:26.740 the level of nuance you're describing. The answer is yes. Yes, exactly. And what's most startling about

01:38:34.780 us is most of us have the capacity to do something that we would be stunned and sickened that we were

01:38:41.580 capable of doing it. And most of us are capable in some circumstance of doing something that is so damn

01:38:47.600 heroic. And most of us spending most of our time doing things that instead are ambiguous and

01:38:53.200 multilayered and full of ulterior motives and what's really going on there. And you look at the

01:39:00.260 worst of us and the best of us, and there's not a whole lot of really reliable predictors beforehand.

01:39:06.740 And how much of this, like, you know, you wrote a little bit about PMS. So when I think about PMS,

01:39:12.400 I think about it purely through the lens of the endocrine system, right? I think of it purely through

01:39:18.160 the lens of when a woman is in her luteal phase, that progesterone level has to rise for the

01:39:26.220 placenta. And then of course, virtually every time it's a false alarm, you don't need it. You shed that

01:39:32.220 lining and that progesterone level comes crashing down. And it's this crashing down of progesterone that

01:39:38.320 has always interested me why two women could experience the same. We can measure progesterone

01:39:44.380 levels throughout the cycle. And we could know that at day 22, two women could have the exact

01:39:50.280 same progesterone. And on the first day of their menses, they could have the same progesterone. So

01:39:54.460 you know, they had the same peak to valley and yet two women can experience that in two totally

01:40:00.120 different ways. Now I've thought about that through the lens of progesterone receptors and, you know,

01:40:05.700 the way we sort of talked about the cortisol stuff. Is there something else to that, that you layer on top

01:40:10.760 of that, that is even more subtle about those differences? Yeah. Tons of this sort of additional

01:40:17.640 insights. Here's one example that comes completely out of left field. And this was actually my wife's

01:40:23.340 thesis research on baboons. So you're a female baboon and you're coming up on your period and we

01:40:31.440 could frame it as you just did. Here's two females who are both about to have their period and they have

01:40:37.180 the same exact progesterone levels. And as soon as they start menstruating, progesterone drops in

01:40:42.040 the exact same way. And one of them is a totally irritable, awful, like jerk to all the other females

01:40:49.680 around her for three days afterward. And the other one is not. The other one withdraws and becomes

01:40:55.720 socially isolated. Okay. What's the difference? It sure can't be progesterone levels. And it's probably

01:41:01.960 not going to be progesterone receptor levels. One of them's high ranking. She can afford to be a jerk

01:41:08.200 to everybody else and get away with it. The other one's low ranking. Oh, it's not just your hormone

01:41:14.420 levels. It's what sort of position in your society you have, even if you're a baboon. Or now you look

01:41:21.180 at humans and depending on what sort of culture you're in, are you in an individualist culture or a

01:41:28.460 collectivist one? Individualist, the United States poster child of individualist thinking,

01:41:34.140 collectivist. 99% of the research has been done on East Asian cultures. And how you somaticize

01:41:42.060 your mood shifts and your physical shifts during your period differs in collectivist versus

01:41:49.560 individualist cultures. How irritable you become. Not because there's a difference in how much of

01:41:56.200 negative affect you're feeling during the time. Are you in a culture where it's culturally acceptable

01:42:02.260 to bitch and moan to all your best friends when you're not feeling well? Or are you in a culture

01:42:06.980 where when you're feeling lousy, what you're supposed to do is reach out affiliatively and reify your like

01:42:12.920 social values. And how much of that do you think is also genetic? So for example, I mean, even though

01:42:20.480 I'm not a gynecologist and therefore don't see a lot of this, I see enough to realize that

01:42:26.480 women will often say my sister and my mother either go through or went through the same feelings. And of

01:42:33.200 course, as you described, there are so many different variants. The stereotypical one is the, you know,

01:42:38.760 the sort of the nasty phenotype. But actually the one that I think might be more prevalent is

01:42:43.900 the sadder phenotype, the more emotionally distraught, just emotionally labile, but in a

01:42:50.460 non-aggressive way. That's probably the phenotype I see more, easier to cry or something like that.

01:42:56.240 So how much of that do you think is heritable in the way that eye color or some other aspect of

01:43:02.760 body habitus or even depression is quite heritable versus the ecosystem you're in purely environmental?

01:43:09.840 Well, the answer is you really can't choose one or the other blah, blah, blah. But if you could only

01:43:14.400 manipulate one, which would be the first one, and I'm definitely of the school of genes get overrated

01:43:22.140 in terms of their impact. And, you know, a gene affecting your eye color, it's okay to use words

01:43:29.180 like determine, and it's probably not even 100% accurate. But when you get to genetic influences on

01:43:35.100 all the interesting stuff and behavior and our internal lives and all of that, yeah, genes are

01:43:41.780 important, but overwhelmingly, these are genes that modify vulnerability. Vulnerability to certain types

01:43:51.720 of environments. Okay. So for example, you bring up depression and catastrophic pandemic of that.

01:44:00.260 And, you know, there's a whole shopping list by now of genes that have been implicated and probably

01:44:06.000 the single most important one, it's called the gene for the serotonin transporter, serotonin,

01:44:12.980 SSRIs, Prozac, all of those serotonin is just like right in the middle of what we understand about

01:44:17.880 the neurochemistry of depression. And it turns out the serotonin transporter gene comes in a few

01:44:23.580 different flavors, a few different genetic variants, and a ton of basic research, rats, monkeys, et cetera,

01:44:32.380 suggested that if you had one particular variant, you were more at risk for major depression.

01:44:39.460 Okay. So this classic work, this guy at Duke, Avshalom Caspi, who's sort of a god in the field,

01:44:45.540 goes out and he follows like 17,000 people from birth up to age 25 or so. He's got genetic

01:44:51.360 information on them. And he's able to ask this critical question. Okay. If you have the quote

01:44:56.720 bad version of this gene by age 25, are you more likely to have a history of clinical depression?

01:45:02.640 And what's the prevalence of the gene approximately?

01:45:05.080 Depends on the population.

01:45:06.820 In his population?

01:45:08.020 His was a mixed one, but Westernized Western urine populations, I think it's got about a 20% incidence.

01:45:14.620 So the question then is of those 20%, how many go on to get depressed? Of the 80%,

01:45:19.740 how many go on to get depressed? The answer is very likely going to be, it's not a one-to-one mapping.

01:45:25.040 It might be an increase in risk by some factor.

01:45:28.640 And what they saw was overall, there was no increase in risk having the bad variant.

01:45:34.380 However, if it was coupled with a lot of childhood stress, you had about a 20-fold increase in the risk.

01:45:42.360 So just to be clear, on aggregate, there was no difference. The hazard ratio is one for with gene

01:45:49.000 versus without.

01:45:50.020 Because of a ton of variability.

01:45:52.080 But if you wanted to amplify it, take that gene and expose it to childhood stress or trauma,

01:45:57.700 and you almost assure depression.

01:45:59.980 You get a massive boost in predictability.

01:46:02.280 Look at people without the scariant vulnerability variant, and look at the same severity of childhood

01:46:08.500 stressors and loss, and you got a moderate increase in incidence of depression.

01:46:13.420 These folks, massive order of magnitude multiples of that, more increase there.

01:46:19.680 What that tells you is, this is a gene whose variants alter how readily you deal with

01:46:27.240 experiential kicks in the asses growing up.

01:46:30.680 And it turns out, these different variants are regulated in different ways by glucocorticoids.

01:46:36.600 Aha, so there's a stress angle of all of that.

01:46:39.200 The same way, there's another gene for the people who are interested in the genetics of aggression.

01:46:43.560 This gene, monoamine oxidase, and it comes in variants, and it's-

01:46:49.180 And there's a class of drugs that targets these receptors, yeah.

01:46:52.540 Again, a ton of basic research had suggested, ooh, there's a scary variant of it, which if you

01:46:58.800 have it, you are going to be more predisposed towards violence.

01:47:02.880 And in fact, the same group working with the same population, massive data set, winds up

01:47:08.100 showing just having that variant doesn't get you a higher risk of antisocial violent behavior

01:47:14.720 by age 25, if and only if it was coupled with abuse, childhood abuse growing up.

01:47:21.500 Oh, if you didn't have the scary variant, childhood abuse, a little bit of an increased risk, have

01:47:28.300 this variant with the abuse, and it was virtually the same figure as with the serotonin transporter

01:47:33.580 gene.

01:47:34.420 Huge boost and very-

01:47:36.500 Over and over the genes that are interesting when it comes to this stuff, these are all genes

01:47:41.800 about vulnerability and potentialities and tendencies that are emerging only in certain environments

01:47:49.940 and not in others.

01:47:50.940 The factors are inseparable.

01:47:52.680 It makes me think of the APOE genotype, which is linked to Alzheimer's disease, and there we

01:47:59.420 see that there is a difference.

01:48:01.860 About 25% of the population carries at least one copy of that gene, and they represent about

01:48:08.060 two-thirds of the cases of Alzheimer's disease.

01:48:11.740 It's not a deterministic gene, but it does increase risk.

01:48:15.360 Now, of course, you could argue that maybe in a decade or more, we will be able to say

01:48:22.500 something very similar about APOE, which is it's not remotely deterministic.

01:48:26.980 It only gets turned on when X, Y, and Z happen before this period of time or in absolute.

01:48:34.940 And of course, we don't know what those things are right now.

01:48:37.200 At least in the examples you gave, you could say, well, trauma or childhood, some event

01:48:43.800 in childhood was the trigger.

01:48:46.400 And if you're seeing a 20-fold difference, it's pretty clear that you found the trigger.

01:48:50.320 Nonetheless, there's still variability to explain after that.

01:48:53.580 But yeah, pathetically, that counts as virtually state-of-the-art for understanding the modifying

01:49:00.440 factors.

01:49:01.260 And it's got to be that way.

01:49:03.000 I mean, anytime you do these like GWAS massive fishing expeditions and you come out with 300

01:49:10.800 genes or implicated in a trait that's as boring as height, 300 genes, which you put together

01:49:18.500 all of your knowledge of the variation of them in any given individual and you have like

01:49:22.460 4% predictability of their height, you know, Christ, if you're talking about genes for propensity

01:49:29.420 towards feeling poignancy or genes for like anything that's interesting.

01:49:36.020 Yeah, it's just not a chance.

01:49:37.460 Even if you just limit yourself to diseases, you know, of the 20,000 genes in our body, you

01:49:43.520 can really only point to about 100 that are directly this mutation means this disease.

01:49:50.980 And they're all pretty esoteric, right?

01:49:53.680 It's all like inborn errors of metabolism and certain things like that.

01:49:56.840 But when you start to talk about the complex diseases like Alzheimer's disease, even as

01:50:02.220 predictive as the APOE4 is, it's not even close to being enough to understand it.

01:50:07.120 And I think, yeah, it's funny when you talk about it through that lens, you realize the

01:50:10.900 importance of environment, which is, you know, at the risk of stating the obvious.

01:50:14.020 You said something a while ago that I made a note of because I wanted to come back to

01:50:17.080 it.

01:50:17.660 You talked about the effect of glucocorticoids on the hippocampus and not only how harmful

01:50:23.480 it was for memory consolidation, but overall cognitive impairment.

01:50:27.760 And listening to you talk about that was exactly the way Matthew Walker at Berkeley speaks about

01:50:34.220 sleep deprivation and its impact on the hippocampus, which then makes me wonder, I assume it's

01:50:40.680 been well-studied that, you know, when people are sleep deprived, we see greater elevations

01:50:45.420 of cortisol.

01:50:46.560 Do you have a sense of what the evolutionary basis of that is?

01:50:48.880 Because it seems counterintuitive.

01:50:50.620 You would think even evolution would want that to be in the opposite direction.

01:50:54.700 I mean, the only explanation I can come up with is if you're sleep deprived, you're

01:50:58.260 assuming that there's a reason for it that's good and therefore you want that.

01:51:01.960 Of course, not with any of the fact that higher cortisol will then prevent sleep.

01:51:05.020 I think that's probably the best sort of piece of teleology for that.

01:51:10.280 Yeah.

01:51:10.700 If you're like a basic mammal, which means either you are emphatically diurnal or emphatically

01:51:16.280 nocturnal.

01:51:17.020 And if instead you're wide awake eight hours into what should be the 12th, this does not

01:51:23.720 happen by chance.

01:51:24.880 The odds are you have something stressful going on.

01:51:27.800 I think that's the logic of it.

01:51:29.180 Turns out the stress, sleep, sleep quality, cortisol cluster of interactions, even more

01:51:38.880 subtle, incredibly cool study.

01:51:41.280 This was a science paper some years back that, okay, so as we talked about, the circadian peak

01:51:48.700 of glucocorticoids are around the time you wake up.

01:51:51.820 What's interesting is about an hour before you wake up, levels begin to rise, telling you

01:51:57.520 something, a subtle point, which is a lot of glucocorticoid actions are not for dealing

01:52:03.340 with a stressor that has already commenced, but can be preparatory.

01:52:08.200 So the preparatory stressor is having to actually get up and get out of bed and start functioning

01:52:13.520 and get dressed in an hour before people wake spontaneously.

01:52:17.300 Glucocorticoid levels are elevating.

01:52:19.300 Now in the study, what you do is you take a whole bunch of volunteers who are sleeping and

01:52:23.860 you see the preparatory rise, all of that, and you tell them, tonight we're doing something

01:52:28.360 different, I'm going to wake you up at four in the morning.

01:52:32.060 And what you see is around three o'clock, glucocorticoid levels start rising.

01:52:36.680 Okay, now you do something even more interesting.

01:52:40.220 You say, okay, tonight I'm not going to tell you when, but I'm going to wake you up at some

01:52:45.320 point during the night and that's the end of your night's sleep.

01:52:47.720 And the person's about 90 minutes into their sleep stage and all of that and cortisol rises

01:52:54.520 and stays high for the rest of the night.

01:52:57.040 You get one sleep cycle and then the adrenal gland says, that's it.

01:53:00.840 I'm on ready alert.

01:53:02.080 Yeah, exactly.

01:53:03.400 So not only is it bad not to get enough sleep, not only is it bad if the insufficient sleep

01:53:09.320 is fragmented, but the worst is if it's fragmented unpredictably.

01:53:13.420 And that's like every medical resident in history.

01:53:19.840 It's the first thought I had actually, when you said that, which was every night of call,

01:53:24.340 you have this pager and you're in this call room and you just want so desperately to sleep

01:53:28.740 for an hour, two hours, three hours.

01:53:30.820 I remember as my residency went on, the degree of sleep deprivation got greater and greater

01:53:35.820 that the steps I had to take to ensure I wouldn't sleep through a page got greater and greater.

01:53:41.000 And I'm not making this up.

01:53:42.080 I don't think I've ever told this story before.

01:53:43.620 It's so ridiculous.

01:53:45.120 I used to use this really heavy paper tape and tape the pager to my head, my forehead

01:53:50.580 at full volume because you would get both the sound to your ear and then you'd get the

01:53:57.020 transmission, you know, through the bone.

01:53:59.300 But imagine laying in bed with tape wrapped around your head, holding a pager on your forehead

01:54:05.680 in anticipation of what's coming, not knowing when it's coming.

01:54:09.580 It could be in five minutes or it could be in two hours.

01:54:12.960 You know, you're going to wake up.

01:54:15.120 Yeah.

01:54:15.620 I'm guessing that wasn't great sleep.

01:54:17.540 Oh, it's like wildly destructive.

01:54:19.960 And what do you know?

01:54:21.200 It turns out if you have elevated glucocorticoid levels while you're asleep, you have less delta

01:54:28.180 sleep time, which is the restorative stuff.

01:54:30.760 You make less adenosine stores in your brain during.

01:54:34.000 So even if you manage to go to sleep, if it's under the, I could be asleep for two hours

01:54:39.340 now or 30 seconds, the sleep quality is going to be horrible.

01:54:43.180 This interplay becomes more pronounced.

01:54:45.740 What about cancer?

01:54:46.940 What role do you think stress plays in cancer?

01:54:49.440 And do you think it's mostly mediated through the immune system?

01:54:52.660 I mean, cortisol can be quite damaging.

01:54:54.700 Yeah.

01:54:55.540 A hugely, hugely controversial subject.

01:54:59.260 There is a common perception that stress can play a very substantial role in the onset of

01:55:06.660 cancer, in coming out of remission and rates of tumor growth and such, sufficiently so that

01:55:12.800 there's been all sorts of studies where you ask cancer patients, what do you think is the

01:55:16.180 cause of your cancer?

01:55:17.180 And stress is invariably way up there.

01:55:19.080 The actual evidence for a role of stress in causing cancer, bringing it out of remission,

01:55:27.980 accelerating tumor growth is very, very minimal.

01:55:31.720 There's been a remarkably small number of good prospective studies of humans that have really,

01:55:38.320 truly ruled out all the confounding factors.

01:55:40.980 When you look at the animal studies, what they typically involve is you experimentally induce a

01:55:46.880 tumor, you inject transformed cells, you give a carcinogen, some such thing.

01:55:52.280 My lab back when did some of that work under those circumstances, you can accelerate the growth

01:55:57.600 of a tumor, but those are circumstances of cancer acquisition that are virtually irrelevant to human

01:56:03.740 cancer.

01:56:04.480 And the other question is, can you do it without perturbing other things?

01:56:07.380 So for example, if you go ahead and stick the tumor into the mouse and apply a stress to it,

01:56:13.600 it seems that that by definition will alter some other parameter, what it eats, how much it sleeps,

01:56:20.140 the quality of its sleep.

01:56:21.060 So it becomes difficult to disentangle cortisol.

01:56:23.880 I mean, I guess the only thing I can think of is what does the experiment look like where you take

01:56:27.400 the mouse that experimentally has the tumor and you just start injecting more glucocorticoid?

01:56:32.580 So in other words, you don't actually increase the stress level, you just increase the readout

01:56:37.360 state of stress.

01:56:38.640 You accelerate the tumor growth.

01:56:40.080 We did one study showing that as soon as cells become transformed, they upregulate the

01:56:45.900 GLUT4 glucose transporter.

01:56:48.780 And that's the one that's further upregulated by glucocorticoids and target cells.

01:56:52.920 So you're just shoveling energy over to those cells.

01:56:57.620 Yeah.

01:56:57.920 Which preferentially consume glucose anyway, just given the number of them that fall by the

01:57:02.440 Warburg effect.

01:57:02.980 So to me, even though that's very mechanistic and artificial, that strikes me as pretty reasonable

01:57:08.220 evidence that cortisol can play a role in cancer.

01:57:12.820 I mean, I guess it's going to be much more difficult to disentangle that in the real world.

01:57:17.160 Yep.

01:57:17.520 And again, these are types of cancers where this was virally induced transformation of cells

01:57:24.440 that are then transplanted in very artificial systems that turn out not to be terribly applicable

01:57:30.340 to human cancers.

01:57:32.840 And what you wind up seeing then, okay, yes, glucocorticoids can be potently immunosuppressive.

01:57:40.180 Usually by the time you have a tumor growing, that's long past the point where it's an immunological

01:57:45.680 problem.

01:57:47.580 It's now, can you keep the tumor from growing a whole bunch of capillaries that will feed

01:57:52.920 it?

01:57:53.180 Can you keep it from stealing all sorts of energy?

01:57:56.360 Can you keep it from turning off cell death programs?

01:58:00.160 It's no longer in the immune realm.

01:58:03.380 So it seems that there'd be hard to make the case that acute bouts of stress can really have

01:58:08.600 any impact because, you know, yeah, sure, you can acutely disrupt the immune system and maybe

01:58:13.440 get sick, right?

01:58:14.680 That, you know, I could explain why you might get a cold under a period of great stress, but

01:58:18.580 not necessarily cancer.

01:58:20.100 And what that winds meaning is that should be a massive, massive take-home message for anyone

01:58:26.340 who is predisposed towards thinking, ooh, stress caused my cancer.

01:58:31.540 Too bad I didn't have better priorities in life.

01:58:35.160 Now I know whose fault it is, that sort of thing.

01:58:37.620 And it should certainly make you damn cautious if there's some highly credentialed quack out

01:58:43.040 there who is selling a stress management will stop your tumor, will make it disappear entirely.

01:58:49.180 I mean, watch your wallet at that point.

01:58:51.320 All that being said, there's been some wonderful work.

01:58:56.160 And a lot of this was pioneered by a Stanford colleague of mine, David Spiegel, who showed

01:59:01.700 that things like supportive group therapy among cancer patients enhances survival.

01:59:08.640 So what do you think is the mechanism of that?

01:59:10.340 Okay.

01:59:10.660 This was when he first published this in the late 80s.

01:59:13.180 This was front page news.

01:59:14.700 I remember this.

01:59:15.600 I mean, I don't remember when it was published, but I remember learning about it in medical

01:59:18.440 It was a massive finding and one is immediately tempted to, at least as a biology type like

01:59:24.840 me, to come up with a biological explanation along the lines of what you proposed.

01:59:29.520 Okay.

01:59:30.340 Supportive group therapy, you're less stressed.

01:59:33.120 So you don't secrete as many glucocorticoids.

01:59:36.100 And therefore you're not having those adverse effects of it on your immune systems.

01:59:40.000 You're better able to fight the tumor.

01:59:41.340 You live longer.

01:59:42.100 Troll all that's wonderful.

01:59:42.740 And lower glucose levels and lower glucose and lower insulin and lower IgF.

01:59:46.240 If you could, yeah, you could come up with a complete biological.

01:59:48.840 And in general, those studies have shown that pathway does not occur.

01:59:53.060 Spiegel and I did some of those studies things.

01:59:55.380 So what's actually going on?

01:59:57.040 Something which if you're a nuts and bolts reductive bio type person is terribly disappointing,

02:00:03.800 but is so interesting and important people, when they have supportive cancer therapy with

02:00:11.960 other people going through the same hell, they become more compliant when they're medical

02:00:17.880 regimes.

02:00:19.040 They're more likely to go the extra round of chemo because everybody else is cheering them

02:00:24.260 on saying, I didn't want to do it either.

02:00:25.920 And they're more likely to take the meds that make them nauseous as hell.

02:00:30.840 Have you eaten today?

02:00:32.620 Me neither.

02:00:33.480 We're going to eat right after we're done with the group.

02:00:36.280 Have you taken your meds?

02:00:37.680 You're going to take them right now.

02:00:38.820 People become more compliant and that was very hard to demonstrate because what cancer

02:00:45.320 patient ever wants to admit to a researcher, actually, I skip about a third of my meds because

02:00:51.060 they make me feel so damn sick.

02:00:53.040 They're saving your life, Twitter.

02:00:55.480 It's in some ways a dark, dirty secret in cancer therapeutics how much people diverge from

02:01:03.640 their optimal treatment regime because the treatment regimes are sheer, utter hell.

02:01:07.800 When you're surrounded by people who are going through the same thing and understand, you're

02:01:13.140 more likely to be compliant.

02:01:14.620 I think that winds up explaining an awful lot of that effect.

02:01:18.420 So when you look at cancer, atherosclerosis, and neurodegenerative disease, it seems to me

02:01:25.980 that the direct lines of evidence for the damage of hypercortisolemia and the accelerated

02:01:32.800 stress response are probably most demonstrated in cardiovascular disease and atherosclerosis

02:01:38.140 vis-a-vis several mechanisms, not the least of which is hypertension, both macro and microvasculature,

02:01:44.700 but also through endothelial disruption.

02:01:46.820 Adhesion of cells and sludging and yeah, it's the best understood realm.

02:01:51.740 Cancer is probably the weakest realm.

02:01:53.660 I would expect that it's playing a role in dementia, but again, this probably gets to the

02:02:00.040 layer of susceptibility, right?

02:02:01.840 There's probably in isolation, maybe this wouldn't play a role, but in combination with

02:02:07.680 other factors, it would.

02:02:09.260 And it seems that, for example, we know that cortisol inhibits melatonin secretion.

02:02:15.180 So even if you take two people who have the same amount of blue light reduction, which

02:02:20.900 should therefore stimulate melatonin, the one with hypercortisolemia is going to, and we

02:02:25.180 actually measure this, right?

02:02:26.240 We can measure overnight urinary cortisol and overnight urinary melatonin.

02:02:30.560 You can see this association quite strongly.

02:02:33.280 Well, melatonin, it's a pro-neurogenic molecule.

02:02:37.000 So having less of that is less restorative to the brain, even beyond its important role, which

02:02:43.100 is sort of removing the brakes on being awake.

02:02:45.840 So what other lines of evidence do you see beyond what you've already described at the

02:02:50.880 developmental stage, now later in life?

02:02:53.460 Basically, everything we talked about with the hippocampus applies in the adult brain

02:02:58.140 as well.

02:02:58.920 And it's the first place we tend to see changes.

02:03:01.700 And it was the first area of research, first evidence for stress damaging the hippocampus

02:03:07.180 and hippocampal-dependent memory type stuff, late 70s.

02:03:10.940 I mean, that was really the first domain.

02:03:14.040 And superb studies from a number of groups, and I had my two cents in that literature also,

02:03:20.500 showing you could accelerate aspects of hippocampal aging with lots of stress, lots of glucocorticoids,

02:03:27.000 extent of neuron loss, extent of memory problem, extent of reactive gliosis, et cetera, et cetera.

02:03:33.380 Next big outpost that people began to appreciate in adult brains was derivative of what we talked

02:03:39.960 about before, which was the amygdala.

02:03:42.760 I was just about to say, is there a direct correlation, I guess, between amygdala size and

02:03:46.080 dementia?

02:03:47.260 What you see instead is that the syndrome where it's most demonstrated is PTSD.

02:03:53.540 You see expansion of the amygdala and you see atrophy of the hippocampus.

02:03:58.340 And glucocorticoids probably play the driving role in both.

02:04:02.100 So in the amygdala, like the hippocampal story is stress and glucocorticoids screw it up.

02:04:07.580 Neurons don't work as well.

02:04:08.780 Networks don't work as well.

02:04:09.860 The overall size decreases.

02:04:11.500 You get atrophy and the amygdala, it's the exact opposite story.

02:04:15.880 Neurons work better than they should.

02:04:18.960 Neurons become more excitable, form denser networks.

02:04:22.900 The amygdala gets bigger.

02:04:24.400 What's that about?

02:04:25.500 The problem with chronic stress is your memory goes down the tubes, hippocampus isn't working

02:04:30.320 as well as usual.

02:04:31.320 The problem with chronic stress in the amygdala is it works better than it's supposed to.

02:04:35.720 And this is the link between stress and anxiety disorders, stress and fear, stress and all

02:04:42.060 of that.

02:04:43.260 Next sort of outpost that people started looking at was the dopamine system in the brain.

02:04:48.700 And dopamine neurotransmitter most famously associated with reward, pleasure, cocaine works

02:04:55.120 on the dopamine system.

02:04:56.620 A much more accurate, subtle picture of it is dopamine is actually more about the anticipation

02:05:02.000 of pleasure than it is about pleasure itself.

02:05:05.220 And about goal-directed behavior you're willing to do in anticipation of reward.

02:05:11.180 But then a whole literature showing what distress and glucocorticoids do there, they mess with

02:05:16.940 the dopamine system.

02:05:18.040 It's less clean of a story than amygdala or hippocampus, but in ways that predispose towards the two

02:05:24.140 big psychiatric diseases of screwed up dopamine systems.

02:05:28.920 Number one, addiction.

02:05:30.220 Depression, more vulnerability to addiction, harder to get off of addictive substances.

02:05:36.160 Number two, depression.

02:05:37.960 Depression is a disease of on a certain level dopamine depletion.

02:05:41.520 It's a disease of inability to feel pleasure and hedonia.

02:05:46.160 And that's the neurochemistry of the link between chronic stress and why that increases the likelihood

02:05:51.980 of the first three, four episodes of major depression.

02:05:56.700 What for me is the most exciting area is one where if I was starting over, you know, forget

02:06:03.220 the hippocampus, who cares about like how many digits you could remember backwards or whatever.

02:06:08.620 The most interesting domain is turning out to be what stress and glucocorticoids do to the

02:06:13.000 frontal cortex, judgment, impulse control, executive function, long-term planning, strategizing.

02:06:23.700 And it turns out virtually every bad thing cellularly that stress and glucocorticoids do in the

02:06:30.480 hippocampus, they're turning out to do in the frontal cortex as well.

02:06:33.320 And what does that begin to explain in this entire world of why it is during moments of extreme

02:06:40.620 emotional arousal, especially aversive ones, why we make terrible, terrible decisions that

02:06:47.340 seem brilliant at the time and you spend the rest of your life regretting it because impulse

02:06:53.240 control, your amygdala overpowers your frontal cortex at those times.

02:06:57.880 Your amygdala has a lot more talking to your motor systems than your frontal cortex does.

02:07:03.320 It's the reason why judgments and impulse control become terrible when we're frazzled.

02:07:10.460 It's also looking like as a side story with that, it's one of the reasons why when we're

02:07:15.820 very stressed, it's hard for the frontal cortex to do one of its harder jobs, which is to take

02:07:24.240 the view of the world from somebody else's perspective.

02:07:27.560 Empathy.

02:07:27.960 Empathy.

02:07:28.840 Exactly.

02:07:29.380 Some research on animal models of empathy, and this was work with this guy at McGill named

02:07:36.280 Jeffrey Mogul, where I collaborated with him, showing in both rats and humans, you're less

02:07:42.640 empathic towards strangers when they're in pain.

02:07:45.720 And if you block glucocorticoid release, you don't get that effect anymore.

02:07:50.500 Glucocorticoids, the stressfulness of dealing with scary novel humans or scary novel mice,

02:07:58.520 if you're a rodent, glucocorticoids narrow your window as to who counts as an us and whose

02:08:06.700 pain registers and things of that sort.

02:08:09.040 So for me, you know, it's incredibly interesting if you're stressed and suddenly your SAT scores

02:08:14.340 plummet, the fact that stress makes people crappier to each other and less empathic and

02:08:21.200 more parochial and more xenophobic and more impulsive with the worst of our impulses, that's

02:08:27.000 the stuff that really interests me these days.

02:08:29.560 Everything you just said, Robert, is almost a call to action in criminal justice reform.

02:08:35.040 And I've done a podcast on this topic where, you know, I was very fortunate to go into a

02:08:40.000 maximum security prison with a program that is really there to do incredible rehabilitative

02:08:44.800 work led by this woman named Catherine Hoke.

02:08:47.820 It's a humbling experience.

02:08:49.700 There's a game that we played about halfway through the day called Step to the Line.

02:08:54.000 This is a game that's used to basically identify the vast difference between those of us who are

02:08:58.760 volunteers.

02:08:59.400 Like in other words, the role of luck in our lives versus the gentleman who two thirds of

02:09:05.400 these men are never going to get out of prison.

02:09:06.880 And one man had even spent more than half his life in solitary confinement, his total

02:09:12.020 life.

02:09:13.020 So it starts with these questions of step to the line if you grew up in a home that had

02:09:17.040 two parents.

02:09:17.720 And, you know, of the volunteers, you know, 60% step to the line of the inmates, five step

02:09:23.400 to the line, right?

02:09:24.140 Step to the line if you grew up in a home where there were more than four books.

02:09:27.680 You can imagine the disparity.

02:09:29.640 Step to the line if you saw someone die with your own eyes before this age.

02:09:34.040 Step, I mean, and it's, it's a very emotional thing to go through because as this game is

02:09:39.800 unfolding, you're just, you're feeling more and more fortunate on the one hand because

02:09:45.240 you realize if not for the grace of this luck and at the same time, the empathy you have

02:09:51.920 for these men who have done the most heinous things grows.

02:09:55.680 And you start to realize, boy, there's a fine line between those of us on the inside, those

02:10:02.640 of us on the outside.

02:10:04.500 Because everything you said really resonated when I was thinking about some of the stories

02:10:08.860 the men told us about the decisions that they made.

02:10:12.440 And there's this one part of the exercise that's incredibly emotional where you're partnered

02:10:15.920 with one, one guy.

02:10:17.820 So it's, it's one volunteer, one inmate, and you were each telling the other person

02:10:22.360 the greatest regret of your life, the biggest mistake you've made.

02:10:26.680 And hearing some of these stories, it's not to justify anything that's been done.

02:10:32.360 And it's not to say that there shouldn't be consequences for it.

02:10:36.900 But a lot of these things that people have wound up in prison for are really impulsive, horrible

02:10:43.640 decisions, as opposed to decades of sinister planning.

02:10:50.600 It's one thing to look at what, you know, like Hitler did.

02:10:53.860 It's hard to argue that anything that he did that was bad was impulsive.

02:10:57.000 It's quite another thing when you look at someone in a gang-related incident where, you

02:11:02.980 know, this guy gets shot and you're going to shoot this guy back, or this guy's about

02:11:06.300 to shoot you and you shoot him.

02:11:07.760 And yet that type of drug-related violence is disproportionately represented in, certainly

02:11:15.200 in the U.S. penal system.

02:11:17.440 And then to build on what you said, it's not clear that the environment in there is reducing

02:11:23.420 cortisol levels to the level that would enable rehabilitation, which is really the thesis

02:11:29.100 of, and a lot of people I'm sure listening to this are thinking, why would you feel empathy

02:11:34.180 for these folks that are in there?

02:11:35.600 And why should society care about them?

02:11:37.500 But the reality of it is, if they're going to get out, you should care.

02:11:42.060 That says nothing of maybe the higher level that you should care, which is the injustice

02:11:46.280 of it.

02:11:46.740 But even if you took a purely selfish view, a non-trivial number of these men and women

02:11:51.920 are going to get out.

02:11:53.060 So wouldn't you rather they get out and function better?

02:11:56.300 And yet it's really tragic to see this.

02:11:58.700 And I know two people actually very well who spent a great deal of time in prison.

02:12:02.780 One of whom I interviewed on this podcast, his name's Corey McCarthy.

02:12:05.580 And it really strikes me as the exception and not the rule that people are able to emerge

02:12:10.180 from that environment and go on to be successful outside.

02:12:13.460 It's a system that is so, so broken.

02:12:19.080 Any study the last century and a half's worth of neurobiology and genetics and child development

02:12:27.980 and all of that, and the notion that we are free agents of our action is so destructively

02:12:35.720 misplaced.

02:12:36.640 I'm sure you're familiar with the work of Sam Harris.

02:12:39.300 Sam has been one of the most interesting forces in my life at getting me to really even question

02:12:44.400 this notion of free will.

02:12:46.000 And once you realize that free will may not even be yours, it takes luck to a new level.

02:12:52.780 It's something I spent a lot of time thinking about now.

02:12:55.340 What advice would you offer somebody who is interested in the neurobiology of stress or

02:13:02.420 behavior and who wants to be able to look back when they're your age and be as, you know,

02:13:09.420 maybe accomplished is the wrong word.

02:13:10.800 I don't want to, I know you sort of bristle at that, but to have made as many contributions

02:13:14.700 as you've made.

02:13:15.360 I mean, what in retrospect was sort of the secret to being able to pursue your bliss and

02:13:19.340 be as successful as you've been?

02:13:20.420 And, and, and look, frankly, to be where you are and to still have the passion that you

02:13:24.140 have for what you're doing, which to me is really the marker of success.

02:13:27.000 It's that you're sitting here saying there's this other problem.

02:13:30.340 And I, you know, like I could spend, you know, the next 20 years just thinking about that.

02:13:34.820 How do you think about how you've done that?

02:13:36.740 Just damn luck.

02:13:39.420 Every bit of neurosis, every bit of affective instability I've got, every childhood trauma I've

02:13:46.200 got tucked away.

02:13:47.080 I, I've titrated in just the right way that I've turned it into more productivity and incredibly

02:13:54.680 lucky in that regard.

02:13:56.500 My capacity to sublimate emotion into intellectual pursuit, into really, really, really wanting

02:14:04.980 to understand something into, I've just been very lucky in that regard.

02:14:10.660 I've gotten just the right levels of all sorts of like tumult that, that have synergized most

02:14:18.760 productively.

02:14:19.540 In other words, just huge amounts of luck, huge amounts of luck.

02:14:25.220 And at least now coming later in life, an increasing capacity to more carefully try to analyze what

02:14:36.920 cost each type of ambition comes with.

02:14:40.400 Say more about that.

02:14:42.220 Oh, I don't know.

02:14:42.940 This had much to do with my closing my lab four years ago.

02:14:46.800 It was a big booming lab with lots of people in all sorts of labs around the world.

02:14:52.720 We were going to kick the asses of by getting the answer to this or that.

02:14:56.340 You know, if you're raised in the right sort of rarefied, ambitious world of biomedical research

02:15:06.620 at age 25, you've got a list down to the floor of the diseases you're going to vanquish and

02:15:13.040 the problems you're going to solve and all of that.

02:15:16.100 And, you know, getting to that point in life where you're realizing it's not going to happen.

02:15:20.240 Is that what actually happened four years ago?

02:15:22.060 Was it that much of a cerebral realization or was it combined with other factors?

02:15:29.600 You know, you've described obviously having this network of people around you who matter

02:15:32.840 the most.

02:15:33.540 And I mean, was part of it just thinking, I haven't spent enough time with them at the

02:15:37.560 expense of this?

02:15:38.380 Or was it the, this problem is enormous.

02:15:40.940 And when, you know, a thousand years from now, whether I worked this much harder or this

02:15:46.320 much less, it won't have altered the trajectory of X, Y, Z.

02:15:50.020 Like, I mean, how much of it is all of these?

02:15:52.240 All of you love.

02:15:53.080 Yeah.

02:15:53.760 Family growing up real fast as they tend to do.

02:15:59.120 Realizing your best work was decades behind you.

02:16:02.140 Realizing there's this book you want to write where the only way you can do it is to just

02:16:07.020 sit for really long stretches.

02:16:09.860 Kenyan field work having collapsed a few years before.

02:16:14.380 Body feeling older.

02:16:15.900 There are limits to how many 80 hours of work a week you can do.

02:16:19.980 All of them converging.

02:16:22.040 What advice, I mean, it's such a cliche question.

02:16:23.800 What advice would you give the, the 25 year old Robert as he was just finishing that PhD

02:16:29.760 at Rockefeller?

02:16:31.540 Be less ambitious.

02:16:34.900 Well, I think on that note, which by the way, I think is some of the greatest advice one could

02:16:39.480 ever get and receive.

02:16:40.440 Even those of us who are still on the climbing ambition curve should do everything to listen

02:16:45.420 to it.

02:16:45.720 I want to, I want to thank you so much for taking the time to sit down with me.

02:16:49.920 And more importantly, I think for just all of the work you've done and you're continuing

02:16:52.960 to do.

02:16:53.540 Thank you so much.

02:16:54.340 Well, thanks for having me on.

02:16:56.140 This has been fun is the wrong word, but stimulating good.

02:17:01.940 Glad we did this.

02:17:02.820 You can find all of this information and more at peteratiamd.com forward slash podcast.

02:17:10.000 There you'll find the show notes, readings, and links related to this episode.

02:17:14.120 You can also find my blog at peteratiamd.com.

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02:17:35.980 But usually Twitter is the best way to reach me to share your questions and comments.

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02:18:30.300 Thank you.

The Peter Attia Drive - April 29, 2019

#51 - Robert Sapolsky, Ph.D.： The pervasive effect of stress - is it killing you？

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