Hey everyone. Welcome to the Peter Atia drive. I'm your host Peter Atia. The drive is a result of my Hunger for optimizing Performance Health longevity critical thinking along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world. And this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality more fulfilling life. If you enjoyed this podcast, you can find more information on today's episode and other topics at Peter Atia MD.com. Hey everybody, welcome to this week's episode of the drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this you probably already know, but the two things I care most about professionally are how to live longer and how to
Better have a complete Fascination an obsession with this topic. I practice it professionally and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives curating and sharing this knowledge is not easy and even before starting the podcast that became clear to me the sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you to take one example. Our show notes are in A League of Their Own. In fact, we now have a full-time person that is dedicated to producing those and the feedback has mirrored this so all of this raises a natural question, how will we continue to fund the work necessary to support this as you probably know the tried and true way to do this is to sell ads, but after a lot of contemplation that model just doesn't feel right to me for a few reasons. Now the first and most important of these is trust. I'm not sure how you can trust me.
If I'm telling you about something when you know, I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for so if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads I've chosen to do what a handful of others have proved can work overtime and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest if you value what I'm doing, you can become a member and support us at whatever level works for you in exchange. You'll get the benefits above and beyond what's available for free. It's that simple it's my goal to ensure that no matter what level you choose to support us at you will get back more than you give.
So for example members will receive full access to the exclusive show notes, including other things that we plan to build upon such as the downloadable transcripts for each episode. These are useful Beyond just the podcast especially given the technical nature of many of our shows members also get exclusive access to listen to and participate in the regular ask me anything episodes. That means asking questions directly into the am a portal and also getting to hear these podcasts when they come out lastly in this is something I'm really excited about. I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking a dollars from anyone but instead what I'd like to do is work with companies who make the products that I already love and would already talked about for free and have them pass savings onto you again the podcast will remain free to all but my hope is that many of you will find enough value.
In one the podcast itself and to the additional content exclusive for members to support us at a level that makes sense for you want to thank you for taking a moment to listen to this. If you learn from and find Value in the content. I produce please consider supporting us directly by signing up for a monthly subscription. I guess today is Professor Robert sapolsky and many of you may recognize that name because Robert has written some incredible books. Probably the one that you would recognize the most is why zebras don't get ulcers a guide to stress stress related diseases and coping but he's also the author of a primates Memoir which grew out of work that he spent in his early years in Africa and he spent nearly 30 years in Africa for months at a time the trouble with testosterone and other essays on the biology of the human predicament and his most recent book behave the biology of humans at our best and worst. This is a book that Robert spent nearly four years researching and writing and the book is almost 800 pages long. This is a treat.
On the topic of human biology and behavior. Robert is a professor of biological sciences at Stanford where he's been, I believe since he completed his Ph.D and his postdoc which he did back on the East Coast. He spent a lot of time in Kenya right after college. He went to Kenya then Uganda where he studied for the next 30 Years the behavior of baboons and other primates. He is a MacArthur fellow in 1987. He was awarded the fellowship which many of you may recognize by its other name the genius Grant he is very modest and soft spoken about this and really doesn't doesn't like to be reminded of that. But Robert is a really impressive guy today is actually the first time we really met in person. I had seen him speak about a year and a half ago and after the talk, you know introduce myself and we spoke very briefly, but I remember during his talk thinking to myself. This is the first time I'm really being convinced at the true pathology of stress. I think I had certainly appreciated the benefits of meditation before when it came to being less.
Miserable but I think it was really Roberts work and in particular that presentation on that day that caught me to really start to think about the molecular and physiological harm of hypercortisolism Mia. So we talked a great deal about that in this discussion, but we also talked about things that go far outside of that. We talked about the role of depression. We talked about the impact of stress on the developing brain and also in the brain later in life and even some of the areas where the relationship between stress and disease is not as well understood and that clearly came across in our discussion of cancer. Overall. I found this discussion riveting and I could have continued this discussion for many hours longer on a personal level. I was also really kind of touched by the way. He spoke about this sort of change in heart. He had around the Relentless ambition and pursued and how over the past few years. He's really reevaluated that and that comes across at the end when we sort of get into more of a philosophical discussion about what one would do.
Given what he knows today, it was an honor to spend so much time with Robert today discussing this and I appreciated the confidence. He had in basically sight unseen sitting down with a stranger to have this discussion. So I hope you'll enjoy this discussion with Robert half as much as I
do
Robert. Thank you so much for making the time to meet with me today on a lovely. Rainy San Francisco afternoon.
Sure glad to be indoors here
as I was saying earlier. We had met once before really briefly soberly that you would not remember and of course only I would summer of 17. I believe you were giving a talk in Sun Valley and I was there and you gave a talk on stress now it was to a lay audience so you didn't really get to go into the depth and I remember sitting in the audience thinking. Oh, you know, a lot of what he's saying is really starting to make sense to me and I can't wait to get a little deeper into this stuff because truthfully and I'm just going to open with sort of my Mia culpa you
Always heard people say stress kills and I got to be honest with you. I always thought that was sort of nonsense. I was like come on. I mean stress kills stress is good. It builds resilience bubble. What is the mechanism by which stress quote-unquote kills, but of course, once you start to understand the endocrine system and of course training as a surgeon and not an endocrinologist. I sort of missed out on that you start to see it and in that talk you admittedly at a sort of high-level for the audience really walked through the danger of hypercortisolism Mia. And so in many ways, I guess, you know a year and a half ago was really when I became a fan of your work and then kind of said, you know what there is something to this. So anyway with that I appreciate you taking this time
sure and just to sort of back off a bit from that. I actually don't think stress kills you outright very often but it sure makes other things that kill you more effective a doing it.
Maybe it's semantics but you're right stress can amplify and accelerate the diseases of Aging you grew up in New York, right if I recall
You grew up in Brooklyn or in Brooklyn. I remember reading that after college. You actually went straight off to Kenya first. Is that right? Yep. What prompted that well I was
one of those I've sort of spend my career oscillating between being a lab neuroscientist studying the effects of cortisol on the brain punchline two decades of work is you don't want to have a whole lot of it marinating inside your head but also for more than 30 years. I've alternated spending my Summers studying a population of wild baboons and the national park in East Africa and it's the same animals I go back to each year. These are animals like and art and less the ties get blood to hold workups on them and essentially asking among them. What does your social rank have to do with patterns of stress-related disease? What does your personality? What does your patterns of social affiliation? So it's been sort of a counterbalance to the lab.
Are you know we've been sticking artificial genes into neurons and fairly reductive stuff like that. So I was actually about eight years old when I decided I wanted to be a primatologist. So I was kind of planning on that for a long time and lucked out. I spent all of college brown-nosing the right person who ship me off to a field site right after graduation and I wound up sort of inheriting that site and those have been my my baboon and 0 cents.
Did you spend the whole time in Kenya? I remember reading that you also were in Uganda and obviously there I think if my geography is correct their neighbors, so that's it pretty easy switch. Where do the actual baboons like what is their scope of their residents how broadly
oh, they're spread actually all over Africa. They're one of the most ubiquitous primates for a lot of the same reasons that we are which is they'll eat anything they're carnivores, but there are also purple boars are omnivores. They scavenge dead stuff.
He'd insects they'll they'll eat most anything so they can fill a lot of niches. So they're scattered everywhere. But my main work over the years has been this one troop in the Serengeti and Southwest Kenya for about 25 years. I camped under the same tree. So it's really it's been continuity with the same population of animals.
What is their natural predator besides man
leopards lions hyenas. Nonetheless. If you are male baboon the most likely thing to kill you violently is another male. Yeah, exactly
sort of like humans. Yes, indeed. Did you say it's every summer or every other summer?
Well, it was initially for about 25 straight Summers and then Parenthood and all those complications came in so wanted to being every other summer and then our kids were old enough to go with us one summer, but unfortunately the fieldwork ended about eight years ago. So
why is that
my
Onion Field assistant of 30 years we started together when we were 20. He died of AIDS political issues there some game Park issues that made it harder and harder to get research done and kind of that middle aged realization that I could find some new game park or new country or something and started all over but it was kind of time to pack it in instead.
So after you did your PhD which these it in north New York, right?
Yeah Rockefeller university. Did
you come straight out to Stanford for a postdoc or
postdoc to the Salk Institute, San Diego spent a couple of years there if people are sort of familiar with the hypothalamic hormone that runs the stress response to hormone. Crh CRF corticotropin-releasing hormone. I went and post talked with this guy Wiley Vale who had discovered its and like two years before so that was a pretty exciting time to be there. So spent a couple of years there.
Stanford hired me and I've been there for 31 years since
that's kind of amazing. I keep coming back to people at Stanford that you know would have been there when I was there in medical school, but if it wasn't in the medical school like you just weren't paying as close attention and I honestly don't recall if you ever gave us a lecture in med school. Do you remember giving lectures in med school 20 plus years ago.
I did almost certainly the students were paying as little attention as I was so like a
better chance to say it certainly seems like something we should have been learning in medical school and yet I feel ashamed to say I don't know if I recall it.
It was not much of an emphasis and was sort of snuck in and beerus idli
like a lunchtime seminar or
something exactly. So that thrive
them with free food
hasn't even still only about five people would stay past the
cookies. That's a much bigger issue we can come to so so you wrote a book - how many years ago is why zebras don't get ulcers that says that 20 years ago.
Let's see first edition was
94 it's gone through three editions. Now most recent one was 2004. So some point I got to do another one
as we talked about that and you've written a book more recently that I want to talk about as well. Let's back up and explain something you touched on a second ago, which is sort of the physiology of a stress response. So walk us through the relationship between the hypothalamus the pituitary and the adrenal
glands. So when we are under stress levels of 11d different hormones changing our body most of them are relatively minor players the to workhorses overwhelmingly first one famously adrenaline British term epinephrine certain North American term output from the sympathetic nervous system. It's on the scene in your bloodstream within 1-2 seconds or so after all hell breaks loose
and I just want to explain what sympathetic means to The Listener we've had this discussion before it's not to say it's a nervous
Damn, it is kind. It just means it's one of the two branches of these so-called autonomic or immediate not under your conscious control. Right? So the fighter
flight exactly and the other half being parasympathetic sympathetic fight-or-flight all hell breaking loose alarms going off parasympathetic calm vegetative function. So not only do you turn on the sympathetic during stress. You very emphatically turn off the parasympathetic second main Workhorse, which has already been alluded to the steroid hormone class of hormones called glucocorticoids human version cortisol also known as hydrocortisone rat version corticosteroids synthetic versions prednisone dexamethasone and such these come out of the adrenal glands your brain note. Something stressful is happening within two seconds. Your hypothalamus is secreting that crh, which wind at about 10 seconds is getting your pituitary to release a hormone called.
ACTH which within about 30 seconds has gotten to your adrenals on You are slowly starting the glucocorticoid component of your stress response and in lots of ways the adrenaline the sympathetic response glucocorticoid response, they work on head and hand. They synergize you want a metaphor adrenaline in 2 seconds is handing guns out of the Gun Locker. It's whatever is going to defend you glucocorticoids are building the aircraft carriers that a year from now, we're going to be essential it does some of the slower components of the stress response stretching stretching out over minutes to hours
because I was just about to ask you and I think your question basically answers. It was why would we have evolved these two separate systems one can only speculate on such things but it's basically that certainly norepinephrine epinephrine. They stick around for such a short period of time. I mean, we don't even measure these things. Clinically. I can't poke your arm and measure your norepinephrine or
Nephron level the best I can do is collect its metabolites in your urine for evidence that it's been around. So I guess we have this hormone or pair of hormones that are on the scene in seconds gone in seconds and really deal with the I guess from an evolutionary perspective when the tiger is there this is what gets you to jump into the tree. Is it doing much beyond that and is there some evidence of chronic low levels of those hormones which come out of a totally different part of the adrenal gland. I mean, that's the other thing that's sort of interesting is you have two separate pieces the cortex the medulla that secrete these hormones separately
and embryologically there are two very different tissues. They start off separately. It could have just as randomly wound up that your adrenaline comes from your big toe on glucocorticoids from your thumbs why they wound up being the same organ is in fact somewhat just I think
serendipitous probably because you're more likely to have your toes and fingers lopped off and we wouldn't want to have
Incidental adrenalectomy
happening. You're right. That's certainly why they didn't wind up out there in the what about
in lower species is one of these considered more primitive is the epinephrine arm something that began earlier and the cortisol are more recent.
Yep. Nonetheless. The court of long arm is just ancient when you get stressed in the ER secreting glucocorticoids. It's basically the exact same class of molecules is if you were a fish or bird or reptile nonetheless, it's a very ancient wiring and that's part of what winds up getting us in trouble. It's a system that's been serving vertebrates doing a lot of help for them for an awful long time and it's been a very recent modification to instead secrete them in response to thinking about taxes this basic dichotomy between the very human domains where we activate the stress response in the more typical domains of
animals. So if you and I were sitting here,
Thousand years ago. I can think of lots of things that we would want an adrenaline response for you know, the tiger jumps out of the thing whatever what are some of the things that would result in that cortisol response because you know, you described it as building the aircraft carrier. Well, you know gosh if the Tigers their I either I'm dead or I'm not but I don't need a stress response a day from now or the next day. So what is it that cortisol was doing 10,000 years ago that was serving our interests. I want to certainly talk about what it's not doing today
when you look at what it does. It actually makes perfect sense as long as you're being stressed like a normal Mom. Oh running for your life running after a meal where if you don't catch something you're going to be dead by tomorrow a short-term physical crisis, the first five seconds of doing that which epinephrine is critical for that's great. If we're heading into a couple of minutes of evading a predator being vigilant thinking there might be if you were getting it.
Realm of a couple of minutes worth of the stress response cortisol related glucocorticoid hormones are absolutely essential.
So the glucose that's coming rushing out of your liver pretty important in that
situation. Exactly. So it takes you about one second to decide you're going to use your thigh muscles and run like mad you need energy for him. And the main thing glucocorticoids are doing in the metabolic realm is glucocorticoids. They're increasing glucose levels in your blood stream. You're going to storage sites throughout your body your liver your muscle and breaking stuff that what they do is they go to the bank they empty out your savings accounts and turned it into Cash glucose in the bloodstream to hand to whichever muscles are going to save your neck what they also do makes better perfect sense whether you were running for your life or running for Meal, which is they increase cardiovascular tone.
In epinephrine is doing the first five seconds of it by 30 seconds in glucocorticoids group bolstering that as well. And it's that same logic you're running like crazy. You want to deliver that glucose to your thigh muscles as quickly as possible you increase your heart rate you increase your breathing rate your blood pressure you alter your vasculature. So your preferentially shunting to the exercising muscle. So that makes perfect sense also turns out some of the most interesting stuff glucocorticoids do in those circumstances is basically run a triage program. They shut down everything that's not essential not essential to surviving the next five minutes of this massive physical
challenge. So digestion would be
impaired can exactly you got better things to do than digest breakfast when you're trying to avoid being somebody's lunch and you're sure not going to get any metabolic benefits of digestion during this five minute. It's slow expensive the energy you're getting your
From your liver you're getting from your fat cells. It shuts down growth obvious logic there, you know grow antlers tomorrow. If you're still around them all the right now shuts off reproduction. Same logic there. It shuts off all the long-term building projects and just focuses your energies on what's immediately there and this makes perfect sense. If you are running for your life running after a meal and all you need to do is look at a couple of diseases where people don't turn on the endocrine stress response Addison's disease shall I drink or syndrome? Whatever these were not diseases where somebody who now is more at risk for adult onset diabetes eight months from now, these are diseases where somebody goes running after their commuter bus and they drop dead from hypoglycemic shock
JFK had this didn't JFK have
Addison's he had Addison's and the greatly constrained the the famed pictures of all those Kennedy's playing touch football.
All out and you know Martha's Vineyard or stuff were mostly for the benefit of the photographers.
How did he survive World War Two because he had done some pretty heroic things in that war.
Although I've seen it's hard to tell if it's snarky revisionism as to how much that was Public Relation stuff afterward sort of
orchestrated, but just to get through basic training even strikes me as an accomplishment because most people I guess who don't have a medical background wouldn't appreciate this. But the tan that seemed to be eternally on JFK is the result of the Addison's disease because the hormone you alluded to earlier that is released by the pituitary ACTH in someone who's not making cortisol is going to be very very high and ACTH stimulates the pigment producing cells in the skin and that's what would give someone with Addison's disease darker
skin. The fascinating thing with Kennedy is if it were this situation now presumably his doctors would be on the are some
24/7 is there's remarkably little known about when is on set was when the course of it was how severe was so it's not quite clear. But what little is known as it had a hell of an impact on this functioning you really do need a hormone. If you like glucocorticoids, if you were going to be physically activated in a moment of Crisis,
this is sort of the amazing thing with hormones like insulin and cortisol. I'm always impressed by how tight the u-shape is on those curves thyroid hormone would be another example certainly less. So with something like testosterone you have just a much wider range that you can function in and the benefit is largely monotonically increasing sometimes if my patients will tolerate me going on and on about this. I love to draw the pictures of which of these hormones. Can you you know, but to me cortisol, probably if you thought of it as a drug, it has the narrowest therapeutic index
To your point too much of it will kill you eventually and make you miserable as hell on the way and too little of it will kill you quite quickly.
And what's most interesting about it is okay. So there's an optimal level among other ways of Translating that that means we don't hate stress. We hate the wrong amount of stress when it's the right amount. We love it. We pay money to be stressed to get on a roller coaster to go to a scary movie when it's the right amount when it's the optimal amount. We call it stimulation. Okay. So exactly as you say it's a narrow range, so that's a tough biological problem understanding a hormonal system. That's pretty damn essential and we're an awful lot of the time you're walking on a knife edge where either side is bad news too much or too little but when it comes to glucocorticoids and what counts as good stress and stimulation, there's the added factor that there's incredible individual.
In as to what counts is the optimal level in between and one person's like hair-raising Audubon Society walk one Saturday morning looking for Birds while the other person goes and signs up to be a mercenary in Yemen because that's when they feel alive and awake and all of that. Not only that it's a narrow range, but we differ so much as to what each person's Optimum
is now. I want to make sure I understand that point Robert and this is probably overly simplistic. So feel free to correct this one of it would be the external scenario that is being perceived and I can see definitely how two people can have vastly different views on that. I mean, it's the reason someone can voluntarily go and be a Navy SEAL and someone can say I feel much better not doing that right? There are clearly a different appetite and or capacity for distress.
Is that what you're referring to or are you also referring to you and I could be sitting here and have different levels of physiologic benefit and harm at the same level of cortisol. Both is absolutely the I mean the former I think most people would acknowledge. The ladder is pretty new. Right? I mean every I shouldn't say pretty new that's not intuitive to me because there's
centuries of Endocrinology saying what's the most important thing about hormones how much the stuff there is in your bloodstream what the levels are and if you and I are sitting here with the same circulating levels, whatever centuries of Dogma was that will translate into the same biological effects. And then I don't know sort of endocrine revolution of 70s 80s or so turns out how loud someone is yelling at you counts what the hormone levels are how sensitively you can hear them the levels of your receptors and target cells turn out to be essential as well and there's all sorts of
Different domains where in fact screwy receptor levels are much more consequential and impactful than our screwy levels of the hormone itself and individual differences in levels of receptors what version you have how well it works how avidly it holds onto the hormone what it is then coupled with afterward Downstream inside the cell that whole world turns out to be as Central to understanding individual differences are the levels of hormones themselves and as sensitive to all those things ranging from genes to prenatal environment early develop and to psychological factors and so on. So, yeah, that's a huge piece of the story. Now
when I hear you say it like that Robert, it seems pretty obvious because we would talk about insulin in exactly that way you could have two people with the exact same level of insulin.
From physiologic response because of insulin sensitivity when insulin hits its receptor, it leads to the phosphorylation of ETA KT and that's what leads to the glute for transporter coming up to the surface and different people with the same insulin can do that totally differently and different people will have a different insulin response to the same food to the same meal. That's the reason we do glucose tolerance tests. So you could basically say someone is cortisol sensitive and cortisol resistant to make the analogy to
insulin at the end product. And absolutely if you're an obsessive with cortisol stuff in the 80s, there was briefly this deep puzzle and that it turned out new world monkeys monkeys and South America marmosets tamarins or whatever when you compare them to traditional old world monkeys, the Asian the African ones turns out they have like an order of magnitude higher glucocorticoid levels. Oh my God, that's crazy. What's that about all sorts of theorizing about how for some reason it's more stressful to be a new world primate the middle. Row, which
Make a whole lot of sense. And then there was this issue of these animals should have been falling out of trees from their doctor Cushing's Disease and and finally somebody found an explanation. No somewhere back when there was a mutation in the gene for the glucocorticoid receptor in New World primates and it has roughly one-tenth the sensitivity. So the system just equal abraded out in a different set point, but that's such a great example of just natural variation not only in how loudly you speak hormone, but how effectively your cells listen to hormone.
Do you have a sense in the human population today? I mean a log fold difference that you just described sounds extreme, but you have a sense of what the variability is in humans today. Is it a twofold threefold Delta on the receptor side
gut feeling and reflecting the fact that my world the brain you don't get to measure receptor levels anywhere near as easily as in the
Blood cell well under an order of magnitude.
We just acknowledged or you just pointed out that when a zebra sees a lion everything that happens as far as the fast and what I would call the acute and the sub acute stress response is perfectly evolutionarily sound and completely in the best interest of that zebra.
We could also come up with a countless examples of 10,000 years ago or even today when the same thing is true in humans. When did that transition occur in our species to where you started to see either something in the civilization our society. That was unhealthy. So today I could point to a thousand examples social media. You name it? I mean, it's an infinite number. When did that start to crop up? What does your research suggests is the arrival of that?
I think it predated us being humans and instead is a feature of smart social mammals because you see indices of stress related stuff baboons. That's what I've spent my whole career on and other non-human primates cetaceans elephants and such. Okay, so why study baboons if you're trying to understand human stress and it turns out the perfectly illustrate the point you just brought up if you're a baboon living in the Serengeti in
East Africa your life is pretty good. It's a fantastic Echo System baboons. They live in these big troops fifty to a hundred animals or so, so they really don't have to worry about lions very often. The infant mortality rate is lower than among the neighboring Maasai tribes people and probably most importantly unless it's a Once a generation drought. If you're just a bad wound going about your everyday business takes you about three hours a day to get your days calories and that has a critical implication which is if you only need to spend three hours of sunlight each day getting enough food to get by you've got nine hours of free time every day to devote to being miserable to some other baboon. And that's the key thing. They are well off enough in our westernized sense that they can sit around and generate psychological stress for each
Overwhelmingly, if you're a baboon in the Serengeti and you're miserable, it's because another baboons worked very hard to bring that state about their wonderful models for westernize disease in that very few of us get hypertensive because you know Tigers were chasing us instead. It's psychosocial stuff that we invent and that we can wallow in four hours every day. And that's exactly what baboons do their great models for westernized stress.
Do we have evidence? I mean, I'm sure it exists, but in the humans, I would just be willing to bet that if you and I were subjected to the same external stressor.
I would probably internalize it more than you. That's my guess. So if we were both baboons and there was a third baboon tormenting us is it safe to say that you could be the baboon that would roll with it more than me
individual differences like that. Absolutely. My guess is both of us would respond to it by saying I'm just going to get a longer and longer CV and then he's going to regret it someday pushing me around they'll be sorry when they see how many degrees I have but yeah individual differences one of the things that I focused on, you know, I spent my first 10 years deciding Rank and Status social status is everything if you're a baboon and you got a choice in the matter you want to be high ranking because on the average you have lower glucocorticoid levels, you're resting blood pressure is lower all sorts of stuff works better. But what took me some growing up out there to do was to realize that yeah social rank is important far more important is
Is the contextual meaning of your rank,
is that the same as your perception of your Rancor is there's more to it. Right?
Well, it's what the rank means in your particular troop. You can be a low-ranking guy in one of two different troops and one troop simply because of its culture and that's a perfectly scientific world word to use for another species these days and one troop being low-ranking can be a whole lot crappier than another trip in terms of how often somebody in a bad mood displays has aggression on you in terms of how often somebody actually Grooms you and off terms of how often you get to finish a meal before somebody steals it from you kind of thing. So the same exact rank means different things in different sort of baboon
cultures. So I'll take an extreme example in a prison. There's a clear hierarchy starting with the warden the guards the inmates and of course within the inmates there's a hierarchy presumably by making this up, but it certainly
The pedophiles would be at the bottom of that list and violent criminal would probably be at the top of that list. So within that hierarchy there's probably a manner in which you would be perceived as a function of that unique environment, which is so artificial in its own way, but that wouldn't necessarily be the same outside.
Absolutely and one of the most interesting things about us us humans when we talk about across all sorts of primates being low ranking in general is bad for your health. Well what about humans we don't have ranking in the same system that sort of other primates do in a strict linear kind of way. But the other thing about us is we belong to multiple hierarchies at once and we can have very different ranks in them.
So for example family work
sports team, it's hobby. You've got some guy who's the mailroom clerk in this giant Corporation and you could not possibly be lower status.
But he's the captain of the company softball team this year and you better bet when you ask him. What's important in his life nine to five Monday to Friday is just a stupid way to pay the rent and would really matters is when the weekend comes around you have somebody with a horrible low-status job. Who's the Deacon of their Church you have some we belong to multiple hierarchies and we are very good psychologically at deciding that whichever hierarchy were highest in that's the one we Define ourselves by
let's take another extreme example, which is you take people who are very successful in what they do, you know, whatever. They're the most famous hedge fund manager or an entrepreneur that started some great company you would argue
Well, they seem to be pretty good on the food chain. But yet many of them would say or you could measure objectively there hypercortisolism Mia is problematic. So it seems like there's even more than just that ranking right isn't there something else because they're at the Top If they were baboons their the alpha but they're still grossly stressed out
in other words. Thank God, we're more subtle than baboons, but it turns out baboons or even more subtle than just drank they have personality and you can be a high-ranking baboon and personality differences. And again, this is a scientifical word as is culture. If you are a high-ranking baboon and your worst rival sneezing a hundred yards away is seen as a major provocation you are going to have much higher glucocorticoid levels then if you are highest-ranking baboon for whom that's no big deal. And in fact often you may have higher glucocorticoid cortisol levels than if you're number ten.
Number 20 in the hierarchy, there's lots of psychological filter stuff and I spent a ton of time studying that baboons differ as to how readily they see things as being provocative or not threatening or not. You're sitting there. And again your worst rival shows up and takes a nap a hundred yards away. There can be two baboons of the same Rank and one of them keeps doing exactly what he's doing and the other one is interrupted from whatever nice social thing is happening these agitate in these Vigilantes gotta look at the guy and lunge towards him a couple of times if we're going back. If your worst rival taking a nap is as disruptive as the guy threatening you and your face you averaged about twice the cortisol levels in your blood stream after controlling for rank as a guy who can tell the difference between the big thing in the little
thing. Maybe this is too deep a question in the answer isn't known but what is it that actually
Transmits that information through the filter of your personality into the physiology. That's very well understood. So I understand the bookends, right? I understand how the visual cortex takes the guy who's your enemy sleeping over there and transmits that to your cortex. And then I understand how the sympathetic chain kicks off the response. Is there a link in between those the processing link.
Here's one of those filters you take people and you're flashing up faces at them stick them in a brain scanner and you're looking at how jumpy their amygdala is their amygdala Central to fear anxiety aggression and such and what you see is tremendous individual differences in you show somebody a face with kind of a neutral expression. Does this person look happy sad angry threatening whatever and lots of variability and you look at the people who tend to view.
Neutral Expressions is threatening. In other words. They see threats that most other people don't what does that correlate with a bigger amygdala
physically larger
amygdala physically larger amygdala makes a loop with a higher metabolic rate and an amygdala that is more Electro physiologically react and
stuff. Let's back up for a moment. I mean tell people in case they don't know where the amygdala suits what part of the brain it evolved from and why it's sort of referred to as this Reptilian Brain like I think everybody's heard of the amygdala but I think you could explain this in a more interesting and accurate way.
Okay. Amygdala is like one of the the anchors of What's called the limbic system in the brain limbic system. It's the part of the brain that's all about emotion. Not surprisingly mammals have a whole lot more Olympic development than fish do fisher are not famous for their emotional lives limbic system is
Arousal fear anger lust love maternal pair-bonding mother-infant bonding all of that and it's a whole series of structures not surprisingly ancient in mammals not surprisingly highly complex interconnected not surprisingly sitting underneath the cortex the cortex that more recently evolved part of the brain that does your taxes all of that limbic system underneath there all the Subterranean emotion stuff and amygdala is one of the key limbic structures and it's involved in fear. It's involved in anxiety. It's involved in aggression. You learn to be afraid of something or somebody that didn't used to scare you and your amygdala does the exact same sort of cellular basis of learning that goes on in other parts of your brain when you learn somebody's middle name and actually remember it your amygdala learns to be afraid of new things and when you manage to stop
Being afraid of something when you stop being afraid of them's because it turns out oh, they're actually more similar to use than you thought or something. It's your amygdala that becomes less reactive to stimuli like that. So your amygdala is absolutely Central to some of our worst human
moments. It's so interesting because it's sandwiched between you know, you can think of the human brain as having sort of very grossly three parts right this brainstem this midbrain, which the amygdala You could argue as the mayor and then the cortex that you described. It's not an over simplification. I think to say that as the complexity of the organisms evolved so too did that hierarchy, right? I mean the brainstem basically handles everything we don't have to think about ever breathing and all of those autonomic and sympathetic parasympathetic functions. And then you layer on this midbrain that does everything that you said which is still kind of happening beneath Consciousness. And then of course, there's where most of us live in our cortex where
Or where we think we live which is we're thinking these thoughts but it seems we're maybe not as aware of how influenced the cortex is by What Lies Beneath
exactly which is incredibly important. If you think of this kind of ancient reptilian brain stem part of the brain, what is it do with keeps track? It makes you breathe every now and then without having to think about a boring sort of stuff then on tops the emotional limbic system that on top is that cerebal thinking cognitive cortex thing. It's very easy to come up with a conceptualization that what's fancy about humans is for example, you're a lizard and the only thing that's going to change the functioning of that ancient brain stem stuff. That is if you're bleeding if you're too hot if you're too cold just like boring physiological States once you layer a mammalian emotional limbic system on top suddenly, you can do something no lizard on earth can do you're sitting there and you're some will
Beast and some other scary will to be shows up and is peeing on some tree in your territory and nothing regulatory is changed in your body. But your heart starts beating faster, aha, your emotional brain can alter sort of the basic regulatory stuff down in the basement. Now you go one step higher and you layer cortex on top of it and now you could do amazing stuff you sit there and you think about the fact that your hearts going to stop beating someday and you start breathing faster and your brains than the more ancient stuff has altered as a result and you've just done something. Not only that no reptile can do you've just done something that no warthog can do which is think think about something that's scary or arousing or remember the time that you would and suddenly something changes down below there. So,
Is this easy picture of sort of top-down complexity once you get to us and where the cortex can regulate your emotional brain and the regulatory brain of the bottom your emotional limbic brain can regulate what's what's far more interesting or underappreciated is exactly what you bring up which is those lower levels can influence what's going on up above one example of this is like this classic great study and sort of physiological psychology social psych you take people and I think in this study, they would take male volunteers heterosexual male volunteers. And of course, they were no doubt College freshman taking psych 101 and they had these guys walk across this really scary suspended bridge and the deal was that either halfway across the bridge you were met by from the other side a researcher who happen to be an attractive.
Male and she would ask the volunteer some questions about what do you think of this bridge or how is it walking across the sir? Whatever the other half of the time you would not encounter this person until you were safely out of the other end. Then they would ask you to evaluate the attractiveness of the
person same person that's in purchasing her in the middle of the bridge or at the far
end. Exactly. Say, hey, remember while you were doing that you there was this, you know, you want to rate her attractiveness was she friendly we did she seem smart would and what you would see is guys in the middle of the bridge with their hearts racing because they're terrified would do some misinterpretation. Why is my heart beating so much faster than if I was standing safely
so they would rate her more attractively in the middle of the bridge
exactly. And then it's the ceiling a detail is now you do the same experiment and you give the person a beta blocker so that they don't have the accelerated and they don't
The person as
attractive, is it the same with the beta blocker? You wouldn't treat you
you do nothing to their ratings of them is how smart they seem how kind they seem whatever it's just this say okay if my heart's racing it must be because so that's a great example boring reptilian regulatory stuff down. There is helping influence what you think your emotions are that
rare coins. I reminds me of that 1995 ish movie Speed with Keanu Reeves and I'm blanking our name Bullock by that's right center by like we're at the end of that movie. There's some cheesy line about how relationships that start under this much distress, you know, it's dangerous. But but of course the other read on that now is yeah if you're on a bus that's about to blow up like I think you're going to think the chair is attractive, right? Potentially.
Yes. Wow. I haven't thought of that movie in years. Thanks to
go home and I'm sure Netflix will stream that were right.
So I read something you wrote. I can't remember where it might have been in another interview that and I didn't know this and this is a great example of why I just love doing this podcast because there's never an exception to how much I'm learning. It's like drinking from a fire hose and you'd think I would have remembered this from Medical School the neuron of a human and the neuron of some other organism when you look at it at the Single Cell level can't really differentiate it if I showed you to microscope slides and here's a human and here's a fish. So what is it about and this is maybe getting a little off-topic but I also think it feeds into this broader issue of like this stew and the Alchemy of how this stuff is put together. But if we all have the same neurons, what is it the number of our neurons like what is it that enables us to have all of this additional
torture? Yeah. It's incredibly interesting because I mean there's there's three and a half people on Earth who have spent their entire.
Career is being able to tell the difference between like a tree shrew neuron and a human neuron and could recognize it in their sleep. But for the most part we are not humans because we have invented brain areas that you don't find in other mammals or because we've invented neurotransmitters that you don't find in other vertebrates or types of neurons. There's a couple of types of neurons that people used to think we're specific to humans and turns out you find them in the elephants and whales also in that's plenty interesting but it's the same enzymes. It's the same gene regulation. It's the same, you know, we're sharing 98% of our DNA with a chimp or a bonobo. So you see we're going to humanist come from I think it's exactly the issue talking about we have the same signal transduction Pathways and neurons as you see in a fruit fly. And what's the key difference is
that it's not a bit humbling. Yes, when we when we just think we're that special
and it's the where you can
Take one of their genes or one of our genes and stick it in the other one and it functions just fine or you could take it from a single cell organism. Some genes related to program cell death you can do that. So what's the big difference for every neuron that a fruit fly has we have a hundred million and sort of the sound bite that I think summarizes all of that is with enough quantity you invent quality and this is this whole world of emergent properties of complex systems. You take one ant and you put it on a table and noting that it does makes a huge amount of sense and you put 10 answer there and pretty much the same thing and you put on a no a thousand and maybe they start making a trail or something and you put 10,000 and they build a colony and they Farm mushrooms and they take aphids as slaves and they could keep the temperature in the colony plus or minus two degrees in they have
Specialization of Labor and no Aunt has any more rules than he had when he was wandering around on the table by himself and you put enough of them together and complex adaptive stuff emerges out of the very simple rules that each of those components has for dealing with another component
it almost defies entropy. Doesn't it? Like why does that happen?
It's amazing that it does that and that's what our brains are. We've got more ants that are coming together in our heads than does a fruit fly and you get more complex emergent stuff happening.
It blows my mind. So let's go back to some of this stuff maybe about a year ago. I read something that really frightened me because the implications were so significant. If a mother is under great stress. There was this critical window in which her child could see something in her eyes that would communicate that stress to her, or maybe it wasn't in her eye.
May have been just through her entire face, but it would imprint epigenetically into the child and altar.
Many features about them as they would age for example their propensity to be depressed. Our man. I remember reading this in sort of a lay, press things. I don't even think it got into the description of epigenetics. But that was the only assumption I could make was that this must be modulated through that mechanism. Do you see evidence of this in animals? I mean,
it's absolutely and it's one of the trendiest topics around. I mean like hooray science finally recognizes childhood matters, like what you want your child to just like has a lot to do with what sort of adult you're going to wind up being what do you know and like lots of childhood adversity versus childhood security and, you know, very different trajectories and what's been the huge mechanistic challenge for the field is understanding. So, what is it about being in a scary neighborhood or an unstable home or having a parent read to you or what? Is it about this whole world of Developmental individual differences? What are the nuts and bolts?
Changes that occurs in a kid, so that is an adult they are now 30 fold more likely than the next person for this or that to happen to them. And this this whole trendy field of Economics epigenetics, which is early experience doesn't change your genes doesn't change your DNA sequence with some like, you know, circus trick exceptions. You've pretty much got your DNA sequence forever. What epigenetics is is early experience changing the regulation of your jeans how easily you turn certain genes on how easily you turn others off in different parts of your body different parts of your brain and so on and that's exactly the sort of domain where you see the sort of stuff that you outlined so that for example, if you're a fetal rat and you that rat have made a terrible decision, you've picked the wrong womb to be developing in and you
Happened to be inside a mother who's highly stressed. She secreting a lot of rat glucocorticoids which get into the circulation through the placenta and to the fetal circulation into the kid's brain. And one of the things that it does is it causes an epigenetic change in the amygdala?
So is that going to be born with a larger? Amygdala or is the phenotype more complicated than just sighs
its size in a bunch of other things as an adult. It's going to have a bigger amygdala and it's going to be more excitable and it's going to be more prone towards interpreting the neutral situation as a threatening one. That's a virtually the definition of rat anxiety disorder seeing Menace that other people don't and you see much the same evidence in humans by now early experience forget early experience. What kind of kindergarten teacher you had? This is fetal early experience and this is exactly a domain where you get potentially
The lifelong epigenetic effect. Okay, so that turns out to have a hell of an implication. That's just the most exciting subfield around there by now. Okay, so you were fetus and got exposed to lots of moms glucocorticoid levels and as a result as an adult, you've got an enlarged amygdala and you see Threat all over the place at other rats don't and among other things you secrete elevated levels of glucocorticoids because the world is full of Menace that only you were seeing. So you get pregnant and during your pregnancy as a result. Your fetus is exposed to elevate a glucocorticoid levels
and to be clear it's not because you have altered the germline genome its that you have changed the expression of the gene, which is altered the phenotype. And now that phenotype is
Past generation to generation through parallel
expression exactly something term non-genetic transmission of traits non-mendelian and people have now shown some of those traits. You see that Ripple it gets smaller each generation, but it's their half a dozen Generations later and the exact equivalent of some of these have been found in humans in other words individual differences or arising not only from experience, but from the multi generational transmission of some of the consequences of experience, which is just mind-boggling that that can work that way.
Let's go back a little bit to Y this is problematic. So at the outset we alluded to this idea that it's a misnomer to say stress kills. I'd love to hear if you have a particular definition of stress. I probably butcher this stuff, but I sort of think of stress as the external thing and I think about it is
It's anything that is sort of emotionally or physically either chronically or acutely distressing. I mean that's sort of a dumb definition because it contains the word stress but I think people understand distress a little more than understand stress. But of course, it's your response to that physiologic response, right which was so lucky. We can quantify this stuff in terms of what hormones are happening in the body and what how the hormones are moving the body. It's your response to that that probably has a greater impact on your health. So let's go through three things help me understand how hypercortisolism Mia and or its accompanying features will impact the brain especially well through any timeline you want. I'm obviously interested in the Aging brain, but I can't imagine this also doesn't impact the developing brain.
This is basically what I've spent my whole professional career thinking about and historically the first place where people sort of realized something
Scary was happening was a brain region called the hippocampus hippocampus is all about learning and memory you want to have a hippocampus. It's the main brain region that's damaged in Alzheimer's disease and it's vulnerable. Lots of other ways turns out it's extremely sensitive to glucocorticoids translated more reductively. It's got extremely high levels of receptors glucocorticoids by the standards of the rest of the brain.
And what's the evolutionary basis for that is that to have a feedback loop
there's two reasons one is to have a feedback loop, but the other is okay. So the hippocampus remember stuff for you. You don't remember everything you don't remember where you were on 9 10 as opposed to 911 kind of thing. Your memory processes has to come with a filter saying is this one important.
So you're saying the cortisol amplifies memory consolidation and that you use this to consolidate.
For memories as a way of learning
exactly along with epinephrine and norepinephrine indirectly. They have some of the same
so cortisol crosses the blood-brain barrier with no difficulty. Exactly. I assume EPI and norepi do the same.
They have to work more indirectly heavily through the vagal nerve because they don't get in this readily, but some of it is also newer Epi being released within the brain during stress what has some of its own memory enhancing effects
again, a great example of Evolutions got this awesome system setup, and it only gets out of whack when the stimulus becomes too much you do want that imprint but you don't that happening full-time
or stated another way. This is the reason why you don't get much out of a class. If you are semi-comatose and you had two hours of sleep last night, you're if you're like 3/4 glucocorticoid levels are low, you're not consolidating stuff. If you are out of your mind terrified because there's a lion sitting next to you. You are not going to absorb much either inverse.
Optimal range all of that. So it turns out the optimal amount of glucocorticoids something that is moderately stressful. In other words. Something stimulating does great stuff to your hippocampus. It increases blood delivery their glucose oxygen and makes the synapses the connections between neurons more excitable and hippocampus does Great Stuff a little bit of arousal alertness is a good thing for learning and memory now instead transition to you are stressed 24/7 ever, since you were like 10 years old kind of thing and you're in the range where glucocorticoids do exactly the opposite they decrease oxygen and glucose delivery to the hippocampus. They make neurons less excitable. They disconnect synapses. They cause the processes and neurons to shrivel. They block the birth of new neurons there. They make other insults more damaging to neurons in
The campus what do you have there? That's the world in which if you were stressed out of your mind memory doesn't work so hot and what we're increasingly realizing is if you're exposed to excessive glucocorticoid levels, like on the scale of years to decades you're going to make this part of the brain get older
faster.
Which speaks to something that I know you're quite passionate about which is the difference is in how socioeconomic status can sort of effect generational changes in this manner because you know use the example of a ten-year-old. Well, I did my residency in Baltimore. Let me tell you a ten-year-old an inner-city Baltimore who's in the wrong house versus a ten-year-old in Palo Alto who's in quote unquote the right house and look that's not to say that you could have a ten-year-old in Baltimore that's got a great environment and ten-year-old in Palo Alto that's dealing with a whole bunch of other different issues which especially in the era of social media, but all things considered probabilistically that ten-year-old in Baltimore is going to have a much harder time given what you just said
or I don't know state of the other way. I have a friend who's a cardiologist who splits his time between a hospital in Oakland and Private Practice in San Francisco. Some of the time what he's doing is dealing with eight year olds who are considering getting a pacemaker because
Ski season is coming and they were wondering if they're going to be in shape and time for that and maybe and then back in Oakland. He's dealing with 50 year old elderly men who are having heart disease. Yeah, socio-economic disparities are I will get on my soapbox. Now when you look at the source of variability and health among humans on this planet socio-economic differences differences in absolute levels differences in degrees of inequality within cultures and within communities and so on has an enormous predictor of Health you want to look at the most medically impacted low-ranking primates, you could find on earth look at poor humans because when humans invented socioeconomic status and the capacity to be poor they invented a way to subordinate the have-nots like no Chimp on Earth could ever dream of doing
I've alluded to there something else to it, you know recently I interviewed an amazing physician named Tom Katina who practices in the nuba mountains in the south of Sudan. So he's the only physician to take care of 1 million people who as you know are being killed by their own government beshear is sort of indiscriminately killing these people so my discussion with Tom was one of the most riveting discussions I've ever had with a human being it just happened to be in front of a microphone but one of the things that just as an afterthought we were discussing that surprised me as we were going through all of the different things that people die of their you know, they don't have vaccines you've got measles outbreaks that are killing people left right and center and the trauma like, you know, the shrapnel blowing people apart not surprisingly. They're just not getting the same chronic diseases, you know, and the cancers they get or not the cancer as we get and they're not getting heart disease and then, you know, almost unheard of to get type 2 diabetes, but what really surprised me is there was no suicide.
And I found that as the single most interesting thing. I guess I learned from Tom which was we would look at their life and think that is an abysmal existence that I couldn't tolerate for one second and yet I would have to guess that their level of cortisol might be lower than ours even though they're in a much worse environment. So whether it's that sense of community that they have or the shared purpose there's something about it. So in other words, my point is even in the presence of such great poverty. It seems that there's ways that this can be overcome whether it's through there's no comparison to anybody else because another point he made was most of the folks there don't even know they're in Africa. Like they don't necessarily know that Africa is the continent in which their country resides so is the bigger issue there you think that there's no disparity. So even though that's complete poverty. There's no real perceived disparity or do you think it's the sense of community? Like what would you hypothesize explains that?
Health that mental health
all the above. There's a whole world of people who study happiness along with more traditional Public Health people who study things like longevity you look at the quarter poorest places on Earth and indeed people there don't live very long and are miserable. But once you get past sort of the subsistence level, there's not a great relationship between the wealth of a country GDP per capita anything and levels of happiness or life expectancy. And you look at the fact that you asked as a shorter life expectancy than Cuba and Lebanon in Costa Rica and it's like the shame of this country kind of thing. Once you get past me or subsistence level income is not a great predictor of any of this stuff and that's instead where you get into Worlds of social capital and social support and
When you look at the whole literature and you look basically at every westernized country on Earth and it's now seen as they become westernized and what you see is the health socio-economic gradient. The poorer you are the worse your health on the average the more of a whole array of diseases, you get not all of them but a huge number the more impactful they are and when you look in the Western United States is the poster child for that. We've got the steepest curve of any country on earth and the westernized world. The least steep ones. Are you bet of course the Scandinavian countries ever reliable sort of Utopias and then you begin to unpack why this relationship occurs and like some incredibly smart people have spent their careers looking at it the most obvious one is if you're not healthy, it's very hard to pull off being the CEO of a company poor health precedes and gives rise to poor.
Starbucks, okay, that's plausible that turns out to explain a tiny percentage of the variability and you could look at the status socioeconomic status of the home in which a child is raised and that's a predictor of their likelihood of diabetes half a century later. So absolutely the socioeconomic status comes first in explaining the vast percentage of the variability. Okay. So next thing maybe it's just that Well, everybody's kind of equally healthy. It's just that the really poor people are very unhealthy. We have a step function know you start with Jeff Bezos and Bill Gates and every step down there and statistically the lower you go down every rung of the way. The poorer you are
the poor you are with respect to helping
the poor your health. Yes. Yes. Thanks. So now you unpack that and what's the most obvious explanation and this is what people call a Neo materialist explanation, which is obvious the poorer you are you don't have health care and
Excess you don't have health insurance. You can't go to the doctor as readily your care is more lousy. That's obviously that explains everything that explains virtually none of the variability in the data because you see the gradient nonetheless in countries with socialized medicine you'd and universal healthcare. You see it for diseases where it doesn't matter how often you get Healthcare access juvenile diabetes so shows an SN SES gradient kind of thing. So it's not Health Care access you then look cross-culturally and you see wildly different income levels and wildly different levels of Health Care access and you see very similar life spans across these countries and very similar gradients. So what people spent like the last 30 years doing is having this huge shift towards it's got so little to do with the material aspects of wealth or poverty. It's got to do with the psychological aspects. It's got to do with
Stress first key finding somebody at UCSF named Nancy Adler who's done wonderful research showing. Okay, your socioeconomic status your wealth. Your objective measure of wealth is indeed a predictor of your health turns out at least as good of a predictor is your subjective socioeconomic status on the level. When you look at people around you, how do you are you doing compared to other people where you place yourself on this 10 step ladder in terms of what's your absolute SES? What's your subjective one? And by asking if that way you're asking the person to consider the community that's most important to them. Who's the comparison group? My next door. Neighbor's Warren Buffett in between whatever when you think of other people, how are you doing compared to them? And it turns out your subjective SES is at least as good of a predictor of your health as is your objective.
In
other words, if you took someone's income, which is quite objective, it would offer no more prediction than asking that person in the nuba mountains. Where do you reckon up in this tribe? And it's sort of like, uh, you know sort of the top two thirds. Yeah
exactly or another way of stating that is you look in some bloated Corporation and there's some guy who's the assistant manager of the mailroom and that's an incredibly status field position for that guy and there's some other guy who's number two in the company who was just passed over to be number one and the only pertinent thing in his mind is not the ninety-nine thousand employees that he's higher ranking and that there's still somebody ahead of me and he would see the same thing in baboons. In other words. It's not being poor. It's feeling poor.
The next critical piece in the story is work from this guy Richard Wilkinson in the UK who shows what's the best most like effective way to make somebody feel poor independent of their absolute levels of income surround them by any quality surround them by reminders of all the people who are doing better than
them. I mean, this is where social media it's the amplifier to all amplifiers of this right. It's you can't go ten minutes. If you're on it without looking at somebody who's obviously better-looking obviously smarter obviously richer obviously having more fun think this has been pretty well documented
right lifestyle of the Rich and Famous or you could be driving down a freeway and somebody passes you and I don't know what counts as a high-status car these days that cost a fortune, but they come speeding past you and you can feel crappy and diminished and like a less successful.
Human and you never even saw that person's face. This is unheard of in the history of humans or primate of being able to feel socially subordinated and you don't even interact with the person. Oh, there's people out there with you know, at least if the next door neighbor has more camels than you that's a very like tangible real thing in terms of like likelihood of surviving that extra income inequality explains, the mediating effect between objective socioeconomic status subject of socioeconomic status and health outcome
what I'm hearing. You also say though, that's a more subtle spin on this is it's not necessarily Global income inequality its local income inequality that is much bigger.
But what technology has allowed us to
do it makes the local councils. That's right. That's exactly right. It's expanded. What local means
you can sit there and watch on a no Lifestyles of the Rich and Famous and back.
You would never have gotten into like the heavier fiefdoms Castle or wood and now you can see all the crap. They have that you're never going again and feel the less loved as a result.
It's so interesting to hear you talk about this. This is a topic that I think anybody listening to this is well aware of especially if you're a parent because you also have to think about those through a developmental lens, which is at least when you and I grew up. I didn't grow up with a lot but you really had no idea what was different right? Like you simply we everybody was the same. I mean, everybody's parents bought used cars and that have new cars and everybody had more or less the same sort of, you know clothing that wasn't exactly the best and whatever. So at least you could argue well where we at least spared some of this difficulty during a critical window of development and what happens now to a ten-year-old that's got a smartphone.
And is subjected to this because I remember that funny show Lifestyles of the Rich and Famous. I can still sort of hear the goofy cheesy theme song. I think I'm even probably watched it once or twice as a kid, but it's a lot easier when that's the one exposure you have to extreme wealth or disparity and either you can watch it for one hour or not, but it's quite a different thing. If not to pick on the Kardashians. I'm just but if you're inundated with oh my god, look Whit. Look at how awesome the Kardashians are and what they're doing and how great their life is and multiply that by 3 log orders. Do we have any data that suggests that we are at a critical juncture because that was having this discussion with a friend yesterday, which is is there evidence of any greater transition in technology in both a positive and negative way than this generation to the last is this truly the greatest step
forward.
I would assume so but the things we worry about people have been worrying about for centuries only kids. They don't go outside. They don't play they don't have like meaningful relationships because they spend all their time talking on the telephone. They spend all their time listening to their transistor radio.
So maybe we're blowing this up. Maybe this is just this Generations version. I mean, I guess the one difference is when you're talking on the telephone when you're listening to the transistor radio, I don't know if it creates that Global to local phenomenon quite as easily or as quickly or with less resistance as we see it. Maybe you're right. Maybe this has always been one Generations struggle with the last
but what you get is an amplifier now because if you're an insecure socially isolated Perry adolescent kid who's vulnerable in all sorts of ways.
And you know no matter what decade or Century it was. You're the last one picked for the game. You're the one who is least popular whatever and that has all its corrosive effects. Now, if you really set your mind to it and you're that kid, you could spend 24/7 just wallowing toxically in evidence of a gazillion other people who are better looking than you and more popular and invited to parties. You'll never be in it amplifies further in the the technology does absolutely that what I think it does is it makes the vulnerable more damaged than in the past?
I think it's safe to say these amplifiers aren't going anywhere. So rather than wallow in their harm, I guess the more relevant question is what do we do? If you're a parent today or not a parent today and you're thinking about this through the lens of yourself versus your kids, whatever what are the steps that one can take to become less susceptible to these forces that seem to drive this because I want to take a step back for a moment when I think about these areas that we've talked about before about the impact of nutrition and sleep and exercise and stress or distress to make it more the term I use when I think about this personally the one I'm most worried about is the last one. I think I've got a pretty good handle on nutrition and it's in many ways easier to control. I feel like I'm more in control of what I eat and when I make bad choices, I'm usually doing them consciously like I've
Decided I'm going to eat this pizza versus I can't help myself. I'm going to eat this pizza similarly with exercise like and again, I'm not saying this for anybody else but this is just my personal thing and even with sleep like once you commit to it, which is not something I did until probably seven or eight years ago that I sort of committed to wow this really matters and to forgo this thing bad idea. It's this last one that really drives me crazy, which of course doesn't help matters because if I go to drives you crazy makes it worse, but I'll give you an example.
As a general rule outside of the immediate postprandial period of a high glucose meal Far and Away my highest blood glucose is always in the morning. Now, I wear a 24-hour glucose meter kind of a weird guy for almost 4 years. I've been wearing a glucose monitor all the time. So it measures my glucose 24/7 one minute increments and out of say 365 days in a year. I'm easily wearing it 330 days of the year. So I've got a lot of data and without a question when you look at a 24-hour period if you Stripped Away the x axis of time I could easily identify morning for you with out exception. I'll give you an example. This is not something I'd plan to do. I had breakfast yesterday yesterday being Sunday really early because I woke up with my kids made breakfast. I normally don't eat breakfast, but I did so I had a breakfast 7:30 in the morning did a workout
Had to catch a flight didn't have time to eat after it had a very very busy day didn't eat a single thing. Got to the hotel around 10:30 or 11:00 didn't want to eat. So didn't you know got up this morning? It's been almost 24 hours since Emile and I looked at my glucose meter and it was like said, you know one ten hundred ten milligrams or less like there's no way that's right calibrated it sure enough. It was 110 now, there is no earthly reason. I should have had a glucose of a hundred and ten milligrams per deciliter 24 hours after my last meal which by the way was bacon and eggs. It's not like I was eating pancakes, right?
Well, I promise you if I could spot check my cortisol. It was high. And here's the thing before I went to bed. My glucose was quite low in my glucose is probably 80 when I went to bed and it's slowly Rose and sure enough as my day wore on today. The glucose went lower lower lower lower lower. It was about 78 before you walked in here. I'm Not Alone by the way, so so I've seen this a lot clinically with patients. Once you start putting these 24-hour glucose sensors on people which a lot of my patients are now doing you get this insight into this horrible thing that's happening when we think we're sleeping and nothing else is going on, but we're ruminating or God knows what else
And fits perfectly with morning wakening is when you get your highest glucocorticoid levels, which is probably one of the main driving forces on the increased blood glucose is low and you think about it from a circadian standpoint. What's the most challenging thing you have to do each day in the absence of any major tumult get up start functioning all of that.
It just seems like it's disproportionate. Certainly the dawn effect has been well described. It's more Amplified in people with type 2 diabetes, which is another interesting point, right which is why is it that someone who already has glucose dysregulation would have an even higher cortisol response in the morning and you'll see enormous fluctuations in glucose. Guess my point here is this seems like a harder problem to fix and certainly meditation is by far the best tool I have ever found to even approximate getting this under control, but it's still hard because it's not like you have a pill if
Blood pressure is high. Well, I think it's probably best to fix it in any way possible. But we also have really great drugs that fix high blood pressure that can at least mask these things. We don't have a pill to fix hypercortisolism Mia. It's one of the most complicated endocrine situations and yet as you've described eloquently it's also so innately wired into us and we have this miserable midbrain. That's just killing us first. I'd love to hear your thoughts on meditation. But then also other things that given how much time you've spent thinking about this problem, I'd love to know how you would suggest someone who doesn't have quite the Zen mindset that I can tell you do. What should someone else be
thinking right off the bat. I'm delighted to see that. I have a Persona of a Zen. / I'm actually like one of the most high paced rest people you're ever going to run across. I've spent 40 years professionally studying.
How bad the outcome is going to be of all of these like bad lifestyle aspects without having anything insightful to say about how to actually fix it or prevent it and I certainly have learned personally. Absolutely nothing for my lifetime of work. I'm like incredibly stressed. I'm mostly good at telling you what's going to happen. If you don't get stuff under control rather than how to get things under control when I look at the Stress Management literature. I don't do it very often because I tend to get sort of agitated at that point, but broadly it works it works as in you can lower blood pressure. You can lower cholesterol levels. You can lose subjective sense of Health use of whom objective measures as well with all sorts of interventions. What do you see when you look at the literature closely? First off is you can't do your Stress Management on the weekends?
Kind of thing. It needs to be your regular sort of thing. You can't do it while you're on hold on the phone for 30 seconds. You need to set timeout for it, you know, the benefits of aerobic exercise. I don't know what the magic number is these days about 20 or 30 minute blocks is a minimum to start getting the cardiovascular benefits. So it's got to be something like you stop things to do.
So that's important. Let's double click on that what you're basically saying is because I think you're understating how much you know about this topic. Obviously. It's something you know a lot about is seriously as we would take nutrition and if you think about how many hours a week do you put into eating? I mean, even if you're shoveling food down your throat, it still takes quite a bit of time if you're going to exercise to the levels that have demonstrated benefit. We're talking about hours a week not minutes a week. If you're going to make the difference between getting by on sleep versus getting restorative sleep. I'm not talking about the absolute amount of sleep. I'm just talking about the Delta between those two.
Think about how many hours that is. In fact for the average American that would work out to be about an extra seven to eight hours a week of sleep and what you're basically saying is if you want to combat this hypercortisolism Iya, dude, guess what? It ain't a 20-minute a week
thing and in some ways that's have since of one of the 80/20 rules of sort of mental health professionals. Okay, so you have this crazy stressful lifestyle and it's just a bazillion things. You can't say no to and you're just going 24/7 and if you've gotten to the point of saying this is crazy. This is not a quality life. I want to live a healthy quality old age. Well, I got to get this stuff under control. I'm going to start doing something Stress Management to you. And if you've gotten to the point where in this lifestyle where there's a billion things you can't say no to each day you're saying no to them enough that nonetheless 20 minutes every single day you were doing this.
It almost doesn't matter what intervention you're doing your 80% of the way there or ready if you're managing to do that and that's very similar to the sort of amazing classic finding you get people were clinically depressed and finally finally finally we're going to do something about it and merely making a first appointment even before you've seen the person people feel significantly better because you are finally saying I matter enough to do something about this or I'm activated enough where I'm optimistic enough to actually go you're halfway there at that point merely by doing something on a near-daily basis.
So just on that logic, even though I don't know that this has been done you would argue that 10 minutes of deliberate mindful practice of meditation daily would probably be better than one hour once a week
absolutely in part because if nothing else if you do a daily seven times a week you were
Sitting in the aftermath of having done that versus only one time a week and an awful lot of what's most interesting about physiology and its impact on sort of mental health things like that is what's happening in the recovery period after something like that in the same way one awful hour-long stressor week versus punctuated episodes of the throughout the week without question. The ladder is worse because you've now got umpteen different times that you have to recover from having turned on the stress response. And that's where a lot of the damage occurs.
You know, I learned something about myself that's going to sound so stupid because it's so obvious, although I don't think it's true for everybody email is a huge stress to me to be blunt. I hate it. That would be the kindest thing I could say about email. I really a few months ago hit a true Nader in my response and I'm like looking at these glucose levels going up and I'm looking at these morning glucose levels.
Some even though my overall glucose level still look great. I mean this trend was upsetting to me. I'm watching my resting heart rate in the morning go up over the course of four months. It had gone up like six beats per minute. And if anything I was in better shape exercising more regular I made this observation one day, which is how many times in a day do I stop to look at email even if it's just to check one or two and the answer was like 50 and every time I do it to your point, even if it's very brief the after effect is not that brief so I could I could look at an email and see to stressful things, but it might sit with me for 20 minutes. So I tried this experiment which is I'm going to just check email twice a day to 30 minute blocks of email.
And I would say within two weeks. I just really felt better. It seems to me like we just have to figure out ways to figure out what those triggers are for us individually is probably some people for whom email doesn't trigger them at all. Right. There's probably you know for me Twitter doesn't trigger anything because a I have a very narrow window that I pay attention to and it doesn't involve things that are aggravating like politics or religion or whatever. It just sort of I'm only really following science. So any time I look at Twitter and actually learning something kind of new and there but I'm sure there are many people who listen to those who would say, oh my God if I spend an hour on Twitter, my blood pressure could be through the roof. So it's like everyone's got to kind of pick their thing. You said your type A which obviously you are me, you know what I didn't say at the outset we start seeing but you've won one of the most prestigious Awards imaginable, which is the MacArthur award Annette. Would you want that about 30 years ago, right that's impressive. They don't give that award out lightly. So that's the one that's
Referred to as the genius award and I know you're probably like your skin is crawling when I say that my point being is you're an incredibly accomplished successful guy. It's not surprising. You would describe yourself as a type A. What have you learned about yourself over the past 30 years or even longer going back to your first days in Kenya about what those triggers are for you and what you can do to lower your cortisol levels
not surprisingly if you hang out with people who were field biologists of any sort and again, I've only been a part time and it will one over the decades but nonetheless still think of myself as a feel while I just work kind of a solitary tribe mean during my Peak periods of doing field work. I'm spending three four months a year alone living in a tent where
12 hours a day, I wouldn't say a word to another person temperamentally. This is kind of who I've been for a long time and there was always this ironic thing because I was sitting there studying these baboons because primate social behavioral. I'm interested in primate social behavior. And this big sort of epiphany I had in my work that okay, here are your social rank as a baboon has something to do with your health, but much more importantly as your patterns of socialization and social networks, and how often do you groom and how often to somebody groom you and how often do you sit in a contact with another baboon or playing with an infant and then I you know finish the day's work and go back to my tent. So there was something ironic that I was like studying the health benefits of sociality living alone in a tent a large part of the year. Your
wife is a scientist who isn't she she was she kind of decided she was
sick of it and she now directs a musical theater program, which is much more fulfilling for her.
But at one point my wife came along. Yeah, that's always going to ask and eventually family and you know kind of realizing. Oh, I've missed out on an awful lot of water really like the wonderful worth living for moments in life out of the sociality stuff. And that is a refuge in a sanctuary from the world's Madness and I could not have predicted as a 20 year old who had been planning to be a field biologist for a dozen years at that point. I could not have predicted sort of how much of my equilibrium at this point turns out to be due to interacting with the right two or three other primates the like being in love with them and stuff. That one was kind of a revelation for me. I am not the social being that I would have guessed. I would have been back
when
It's interesting because having this discussion with you today, I can sense much more of your introversion. Then the first time we met when you were giving an unbelievably charismatic animated talk and I don't know how many of us were there maybe a hundred people and which is so interesting right? Because you would I think anybody sitting the audience would look at this and say oh that's a that's the life of the party but it's interesting that we can compartmentalize and separate those things. Right? I mean you couldn't get up there and you can do what you need to do. And you're at your happiest. I'm guessing in the way. You described it versus in the aftermath of that talk when a hundred people run up to you to ask you four questions each
not to get to self-reflective or something, but I'm a fairly introverted person who does better with scripts and giving a lecture is a pretty structured script and having sort of an academic Persona or whatever is a another version of it as well.
What year did you become a full professor at Stanford was?
33 or something really 90s.
I mean you live in San Francisco, so you're not making that commute every day. I hope
nope but I did for about a quarter Century.
Yeah, that'll that'll hurt. The cortisol levels won't it?
I use the commuter train Caltrain here so you could read and I love this was much of it was before cell
phones. You take it up at 4th and king and you just go. Yeah, I used to make that ride all the theis have a girlfriend that lived in San Francisco and I loved that train ride and then you get off on your bike at 4th and king and you could go anywhere in the city
exactly. I wrote half my book writing was on the train there. It's pretty weird when you realize that like one of your valid social communities or the conductor's on Caltrain sort of as you're watching them grow up on you and things like that. But yeah. No, that was I I was a big fan of train commuting
So speaking about books. Let's talk about your more recent book.
It's about human behavior, which you know, I mean I can see based on this discussion. Now how your interest would shift to that? What was the impetus for that
research? Well title is behave the biology of humans that are best and worst and sort of we were talking about before I closed my lab for years ago and stopped active research to sit for four years and write this book and it's basically trying to make sense of the biology of what is for me the most puzzling thing about us as a behaving species, which is we are simultaneously the most miserably violent species on earth and the most altruistic and cooperative and empathic and any given human is capable depending on the setting of incredible gyrations as to whether they are being wonderful or awful or in between where
Cave yours where whether that counts as good or bad is incredibly dependent on what culture they happen to be doing it in just trying to make sense of the biology. I mean, he's totally boring biology is to like how your brain makes you do something like pull a trigger like which muscle groups have been told that's that's like studying cockroach neurobiology, which totally interesting is the fact that we're a species were sometimes pulling a trigger can be one of the most awful things a human can do and sometimes it could be one of the most wondrous ones if your suicidally drawing fire from innocent people and you're sacrificing yourself for in one setting you put your hand on somebody else's and that could be a moment of incredible Compassion or in another moment. You do the exact same thing with your primate muscles and that's the first step of betraying a loved one of just making sense of this contextual stuff.
About human behavior, which is hugely complicated and the song and dance that I go through and nearly 800 agonizing pages in the book is you're going to understand nothing about that if you've concluded aha. We now know this is the part of the brain that explains everything or this is the neurotransmitter or the hormone or the gene or the childhood instead to make sense of human behavior. You got a factor in what your neurons did one second ago, but you got to factor in the environmental triggers of that 30 seconds ago and you've got a factor in what your hormone levels were like this morning and what neural plasticity you've done over the last two seasons and what your adolescence was like in your childhood and your fetal life and your jeans and amazingly what sort of culture were your ancestors inventing centuries ago because that influence the way you were raised within minutes of birth and what things you value
And what things you were Mick Thule does or doesn't respond to and I'll think of that what sort of Echo Systems produce different types of cultures and then finally Evolution and why we're in some ways like chimps and in some ways like bonobos, but we're not chimps. We're not bonobos. We've solved our own special evolutionary if you can understand the stuff, it's everything from one second before to a hundred million years before and all these levels interact and it's complicated as hell
when people ask the question, which I'm sure you've heard this a hundred times and you hear people asking all the time are we innately good or bad that question doesn't really permit the level of nuance you're describing. The answer is yes. Yes.
Exactly. And what's most startling about us is most of us have the capacity to do something that we would be stunned and sick and that we were capable of doing it and most of us are capable of in some circumstance of doing
Something that is so damn heroic and most of us spending most of our time doing things that are instead are ambiguous and multi-layered and full of ulterior motives. And what's really going on there and you look at the worst of us and the best of us and there's not a whole lot of really reliable predictors beforehand
and how much of this like, you know, you wrote a little bit about PMS. So when I think about PMS I think about it purely through the lens of the endocrine system, right? I think of it purely through the lens of when a woman is in her luteal phase that progesterone level has to rise for the placenta and then of course virtually every time it's a false alarm. You don't need it you shed that lining and that progesterone level comes crashing down and it's this crashing down a progesterone that has always interested me why two women could experience the same we can measure progesterone levels throughout the cycle and we could
No that day 22 two women could have the exact same progesterone and on the first day of their Menses, they could have the same progesterone. So, you know, they had the same Peak to Valley and yet two women can experience that in two totally different ways. Now, I've thought about that through the lens of progesterone receptors and you know, the way we sort of talked about the cortisol stuff. Is there something else to that that you layer on top of that that is even more subtle about those differences.
Yeah tons of this sort of additional insights. Here's one example that comes completely out of left field in this was actually my my wife's thesis research on baboons. So your female baboon and you're coming up on your period and we could frame it as you just did here's to two females who are both about to have their period of the same exact progesterone levels. And as soon as they start menstruating progesterone drops exact same way and one of them is a total lie.
Terrible awful like a jerk to all the other females around her for three days afterward. And the other one is not the other one withdraws and become socially isolated. Okay, what's the difference in sure can't be progesterone levels and was probably not going to be progesterone receptor levels. It's one of them's high-ranking she could afford to be a jerk to everybody else and get away with it. The other ones low-ranking. Oh, it's not just your hormone levels. It's what sort of position in your Society you have even if you're a baboon or now, you look at humans and depending on what sort of culture you're in. Are you in an individualist culture or a collectivist one individualist United States poster child of individualist thinking collectivist 99% of the research has been done on East Asian cultures and how you somatosensory eyes your mood shifts and your physical shifts during
. Differs in collectivist versus individualist cultures how irritable you become not because there's a difference in how much of negative affect your feeling during the time. Are you in a culture where it's culturally acceptable to bitch and moan to all your best friends when you're not feeling well or are you in a culture where when you're feeling lousy? What you're supposed to do is reach out affiliative Leandria fi you're like social
values and how much of that do you think is also genetic. So for example, I mean even though I'm not a gynecologist and therefore don't see a lot of this. I see enough to realize that women will often say my sister and my mother either go through or went through the same feelings. And of course as you described there are so many different variants. The stereotypical one is the, you know, the sort of the nasty phenotype, but actually the one that I think might be more prevalent is the sadder phenotype the
Or emotionally distraught just emotionally labile, but in a non-aggressive way, that's probably the phenotype. I see more easier to cry or something like that. So how much of that do you think is heritable in the way that I color or some other aspect of body habitus or even depression is quite heritable versus the ecosystem. You're in purely environmental.
Well, the answer is you really can't choose one of the other blah blah, but if you could only manipulate one which would be the first one and I'm definitely the school of genes get overrated in terms of their impact. And you know what Gene affecting your eye color. It's okay to use words like determine and it's probably not even a hundred percent accurate, but when you get to genetic influences on all the interesting stuff and behavior and our internal lives and all of that yeah genes are important but overwhelmingly, these are jeans.
the modified vulnerability
vulnerability certain types of environments. Okay. So for example, you bring up depression and catastrophic pandemic of that and you know, there's a whole shopping list by now of genes that have been implicated and probably the single most important one. It's called the gene for the serotonin transporter and serotonin ssris Prozac. All those serotonin was just like we're right in the middle of what we understand about the neurochemistry of depression and it turns out the serotonin transporter gene comes in a few different flavors a few different genetic variants and a ton of basic research rats monkeys Etc suggested that if you had one particular variant, you were more at risk for major depression. Okay. So this classic work is going to do coughs alarm Cosby who sort of a God in the field goes out and he follows like 17,000 people from birth up to age.
25 or so. He's got genetic information on them and he's able to ask this critical question. Okay. If you have the quote bad version of this Gene by age 25, or are you more likely to have a history of clinical depression?
What's the prevalence of the gene approximately
depends on the population
in his population
his was a mixed one, but westernized Western Europe populations. I think it's got about a 20 percent incidence.
So the question then is of those 20% How many go on to get depressed of the 80% How many go on to get depressed? The answer is very likely going to be it's not a one-to-one mapping. It might be an increase in Risk by some factor
and what they saw was overall. There was no increase in Risk having the bad variant. However, if it was coupled with a lot of childhood stress you had about a 20-fold increase in the risk,
so just to be clear on aggregate there is no difference. The hazard ratio is 1 for with Jean versus
Out
because of the ton of variability,
but if you wanted to amplify it take that Gene and expose it to Childhood stress or trauma and you almost assure depression
you get a massive boost and predictability look at people without the scare and vulnerability variant and look at the same severity of childhood stressors and loss and you got a moderate increase in incidence of depression these folks massive order of magnitude multiples of that more increase their what that tells you is this is a gene whose variance alter how readily you deal with experiential kicks in the asses growing up and it turns out these different variants are regulated in different ways by glucocorticoids. Aha. So there's a stress angle all of that the same way there's another Gene to the people who are interested in the genetics of aggression. This Gene model would mean oxidase and it comes in two variants and
it's and there's a
Of drugs that targets these yep receptors here
again a ton of basic research had suggested. Ooh, there's a scary variant of it, which if you have it you are good at more be more predisposed towards violence. And in fact the same group working with the same population massive data set lines of showing just having that variant doesn't get you a higher risk of anti-social violent Behavior by age 25. If and only if it was coupled with abuse childhood abuse growing up. Oh, if you didn't have the scary variant childhood abuse a little bit of increased risk have this variant with the abuse and was virtually the same figure as with the certainly transporter gene huge boost in their over and over the genes that are interesting when it comes to the stuff. These are all genes about vulnerability and potentiality 's and tendencies that are emerging only in certain environments.
Hermanson on another's there. The factors are inseparable.
It makes me think of the apoe genotype which is linked to alzheimer's disease. And there we see that there is a difference about 25% of the population carries at least one copy of that Gene and they represent about two-thirds of the cases of Alzheimer's disease. It's not a deterministic gene, but it does increase risk. Now, of course, you could argue that maybe in a decade or more we will be able to say something very similar about apoe which is it's not remotely deterministic. It only gets turned on when X y&z happen before this period of time or in absolute and of course, we don't know what those things are right now at least in the examples you gave you could say well trauma or childhood, you know some event in try and childhood was was the trigger and if you're seeing a 20-fold difference, it's pretty clear that you found the
Trigger nonetheless, they're still very ability to explain after that. But yeah, it's pathetically that counts as virtually state-of-the-art for understanding the modifying factors and it's got to be that way. I mean anytime you do these like G wasps massive fishing Expeditions and you come out with 300 genes are implicated in a trait that's as boring as height 300 genes which you put together all of your knowledge of the variation in them in any given individual and you have like four percent predictability of their height our Christ few talking about genes for propensity towards feeling poignancy or genes for like anything that's interesting. It's just not a
chance even if you just limit yourself to diseases, you know of the 20,000 genes in our body you can really only point to about a hundred that are directly this mutation means this
Disease and they're all pretty esoteric right? It's all like inborn errors of metabolism and certain things like that. But when you start to talk about the complex diseases, like Alzheimer's disease even as productive as the apoe4 is it's not even close to being enough to understand it and I think yeah, it's funny when you talk about it through that lens you realize the importance of environment which is the risk of stating the obvious. You said something a while ago that I made a note of because I wanted to come back to it you talked about the effect of glucocorticoids on the hippocampus and not only how harmful it was for memory consolidation, but overall cognitive impairment and listen to you talk about that was exactly the way Matthew Walker Berkeley speaks about sleep deprivation and its impact on the hippocampus which then makes me wonder. I assume it's been well studied that you know, when people are sleep deprived we see greater elevations of cortisol. You have a sense of what the evolutionary basis of that is because it seems
Our intuitive we you would think even Evolution would want that to be in the opposite direction. I mean, the only explanation I can come up with is if you're sleep deprived you're assuming that there's a reason for it. That's good. And therefore you want that of course not with any the fact that higher cortisol. Will then I think that's probably the best
sort of piece of teleology for that. Yeah. If you're like a basic mammal which means either you are emphatically diurnal or emphatically nocturnal and if instead you are wide awake eight hours into what should be the 12x. This does not happen by Chance the odds. Are you have something stressful going on? I think that's the logic of it turns out in the stress sleep sleep quality cortisol cluster of interactions even more subtle incredibly cool study. This was a science paper some years back that okay. So as we talked about this circadian peak of glucose,
It's her around the time you wake up. What's interesting is about an hour before you wake up levels begin to rise telling you something a subtle point, which is a lot of glucocorticoid actions are not for dealing with a stressor that has already commenced but can be Preparatory. So the Preparatory stressor is having to actually get up and get out of bed and start functioning addressed in an hour before people wake spontaneously glucocorticoid levels are elevating. Now in this study. What you do is you take a whole bunch of volunteers who are sleeping and you see the Preparatory rise all of that and you tell them tonight we're doing something different. I'm going to wake you up at 4:00 in the morning and what you see is around 3 o'clock glucocorticoid levels start Rising. Okay. Now you do something even more interesting you say? Okay tonight. I'm not going to tell you when but I'm going to wake you up at some point during the night and that's the end of your night's sleep and the person is about
90 minutes into their sleep stage and all of that and cortisol Rises and stays high for the rest of the night.
You get one sleep cycle. And then the adrenal gland says that's it. I'm on ready alert.
Yeah, exactly. So not only is it bad not to get enough sleep. Not only is it bad if the insufficient sleep is fragmented, but the worst is if it's fragmented unpredictably and that's like every medical resident in history. It's
the first thought I had actually when you said that which was every night of call you have this pager and you're in this call room and you just want so desperately to sleep for an hour two hours three hours. I remember as my residency went on the degree of sleep deprivation got greater and greater that the steps I had to take to ensure. I wouldn't sleep through a page got greater and greater and I'm not making this up it I don't think I've ever told the story before it's so ridiculous. I used to use this really heavy paper tape and tape the pager tool.
I hit my forehead at full volume because you would get both the sound to your ear. And then you'd get the transmission, you know through the bone, but imagine laying in bed with tape wrapped around your head holding a pager on your forehead in anticipation of what's coming not knowing when it's coming. It could be in five minutes or it could be in two hours. You know, you're going to wake up. Yeah, I'm guessing that wasn't great sleep
like wildly destructive and what do you know it turns out if you have elevated glucose levels while you're asleep you have less Delta Sleep time, which is the restorative stuff. You make less adenosine stores in your brain during so even if you manage to go to sleep if it's under the I could be asleep for two hours now or 30 seconds. The Sleep Quality is going to be horrible.
This interplay becomes more pronounced. What about cancer? What role do you think stress plays in cancer? And do you think it's mostly mediated through the immune system? I mean cortisol can be quite damaging. Yeah. Alright,
hugely. Hugely controversial subject. There is a common perception that stress can play a very substantial role in the onset of cancer in coming out of remission and rates of tumor growth and such sufficiently so that there's been all sorts of studies where you ask cancer patients. What do you think is the cause of your accounts are in stress is invariably way up there the actual evidence for a role of stress in causing cancer bringing it out of remission accelerating tumor growth is very very minimal. There's been a remarkably small number of good prospective studies of humans that have really truly ruled out all the confounding factors when you look at the animal studies,
What they typically involve is you experimental induce a tumor you inject transform cells you give a carcinogen some such thing my lab back. When did some of that work under those circumstances? You can accelerate the growth of a tumor, but those are circumstances of cancer acquisition that are virtually irrelevant to human cancer.
And the other question is can you do it without perturbing other things? So for example, if you go ahead and stick the tumor into the mouse and apply a stress to it. It seems that that by definition will alter some other parameter what it eats how much it's sleeps the quality of its leaves so it becomes difficult to disentangle cortisol mean I guess. The only thing I can think of is what is the experiment look like where you take the mouse that experimental a has the tumor and you just start injecting more glucocorticoid. So in other words, you don't actually increase the stress level you just increase the readout state of stress
you accelerate the tumor growth. We did one study showing that assumes.
Become transformed they operate you late the glute for glucose transporter. And that's the one that's further up regulated by glucocorticoids and target cells. So you are just shoveling energy over those cells. Yeah, but
these are differentially consume glucose. Anyway, just given the number of Them Fall by the Warburg effect. So to me, even though that's very mechanistic in artificial that strikes me is pretty reasonable evidence that cortisol can play a role in cancer. I mean, I guess it's going to be much more difficult to disentangle that in the real world.
Yep. And again, these are types of cancers where this was virally induced transformation of cells that are then transplanted very artificial systems that turn out not to be terribly applicable to human Cancers and what you wind up seeing then okay. Yes glucocorticoids can be potently immunosuppressive usually by the time you have a tumor growing.
Long past the point where it's an immunological problem. It's now can you keep the tumor from growing a whole bunch of capillaries that will feed it. Can you keep it from stealing all sorts of energy. Can you keep it from turning off cell death programs? It's no longer in the immune
realm. So it seems that there would be hard to make the case that acute bouts of stress can really have any impact because you know, yes sure. You can acutely disrupt the immune system and maybe get sick right that you know, I could explain why you might get a cold under a period of great stress, but not necessarily cancer
and what the ones meaning is, that should be a massive massive take home message for anyone who's predisposed towards thinking who stress caused my cancer too bad. I didn't have better priorities in life. Now. I know whose fault it is that sort of thing and it should certainly make you damn cautious if there are some highly credentialed quack out.
Her who is selling a Stress Management will stalk your tumor will make it disappear entirely. We watch your wallet at that point. All that being said there's been some wonderful work and a lot of this was pioneered by a Stanford colleague of mine David Spiegel who showed that things like supportive group therapy among cancer patients enhances survival.
So what do you think is the mechanism of that?
Okay, this was when he first published this in the late 80s, this was front page news.
I remember this. I don't remember when it was published. But I remember learning about it in meta
gas at finding and one is immediately tempted to released as a biology type like me to come up with a biological explanation along the lines of what you proposed. Okay supportive group therapy, you're less stressed. So you don't secretes many glucocorticoids. And therefore you're not having those adverse effects of it on your immune systems. You're better able to fight the tumor. You live longer troll
on this lower.
Coast levels and lower glucose and lower insulin and lower IG. If you could you could come up with a complete biological
and in general those Studies have shown that path. We does not occur Spiegel and I did some of those studies things. So what's actually going on something which if you're a nuts-and-bolts productive biotype person is terribly disappointing but is so interesting and important people when they have supportive cancer therapy with other people going through the same. Hell they become more compliant with their medical regimes. They're more likely to go the extra round of chemo because everybody else is cheering them on saying I didn't want to do it either and they're more likely to take the meds that make them nauseous as hell. Have you eaten today? Me? Neither we're going to eat right after we're done with the group. Have you taken your meds? You're going to take them right in a people become more compliant and that was very hard to demonstrate.
Straight because what cancer patient ever wants to admit to a researcher, actually I skip about a third of my meds because they make me feel so damn sick. There are saving your life whether it's in some ways a dark dirty Secret in cancer Therapeutics how much people diverge from their optimal treatment regime because the treatment regimes are sheer utter hell when you're surrounded by people who are moving going through the same thing and understand you're more likely to be compliant. I think that one's up explaining an awful lot of that effect.
So when you look at cancer atherosclerosis and neurodegenerative disease, it seems to me that the direct lines of evidence for the damage of hypercortisolism Mia and the accelerated stress response are probably most demonstrated in cardiovascular disease and atherosclerosis vis-à-vis several mechanisms. Not the least of which is hypertension both.
Macro and micro vasculature but also through endothelial disruption
adhesion of cells and sludging and yeah, it's the best understood realm cancer is probably the weakest
realm I would expect that. It's playing a role in dementia. But again, this probably gets to the layer of susceptibility, right? There's probably an isolation. Maybe this wouldn't play a role but in combination with other factors it would and it seems that for example, we know that cortisol inhibits melatonin secretion. So even if you take two people who have the same amount of blue light reduction, which should therefore stimulate melatonin the one with hypercortisolism Mia is going to use and we actually measure this right we can measure overnight urinary cortisol and overnight. Urinary melatonin. You can see this Association quite strongly. Well melatonin. It's a pro neurogenic molecule. So having less of that is less restorative to the brain even Beyond its important role.
Is to removing the brakes on being awake. So what other lines of evidence do you see beyond what you've already described at the developmental stage now later in life,
basically everything we talked about with the hippocampus applies in the adult brain as well
as the first place we tend to see changes
and it was the first area researched first evidence for stress damaging the hippocampus and hippocampal dependent memory type stuff late 70s, and that was really the first domain and superb studies from a number of groups and I had my two cents in that would retire also showing you could accelerate aspects of hippocampal Aging with lots of stress. Lots of glucocorticoids extent of neuron law sixth sense of memory problem extent of reactive gliosis, etc. Etc. Next big Outpost that people began to appreciate in adult brains was derivative of what we talked about before which was the
amygdala I was
Is there a direct correlation, I guess between amygdala size and dementia
what you see instead. Is that the syndrome where its most demonstrated as PTSD you see expansion of the amygdala and you see atrophy of the hippocampus and glucocorticoids probably play the driving role in both. So in the amygdala like the hippocampal story is stress and glucocorticoids screw it up neurons don't work as well networks don't work as well the overall size decreases you and atrophy in the amygdala. It's the exact opposite story neurons work better than they should neurons become more excitable form denser networks. The amygdala gets bigger. What's that about? The problem with chronic stress is your memory goes down. The tubes hippocampus isn't working as well as usual the problem of chronic stress in the amygdala is it works better than its supposed to and this is the link between stress and anxiety disorders stress and fear stress and all of that.
Next sort of outpost the people started looking at was the dopamine system in the brain and dopamine neurotransmitter most famously associated with reward pleasure cocaine works on the dopamine system a much more accurate subtle picture of it is dopamine is actually more about the anticipation of pleasure than it is about pleasure itself and about goal-directed Behavior you're willing to do in anticipation of reward, but then a whole literature showing what distress and glucocorticoids do there they mess with the dopamine system. It's less clean of a story than amygdala hippocampus. But in ways that predisposed towards the two big psychiatric diseases of screwed up dopamine systems number one addiction more vulnerability to addiction harder to get off of addictive substances number to depression depression is a disease of on a certain level dopamine depletion. It's a disease of
Ability to feel pleasure and had oh Nia and that's the neurochemistry of the link between chronic stress and why that increases the likelihood of the first three four episodes of major depression. What for me is the most exciting area is one where if I were starting over, you know, forget the hippocampus who cares about like how many digits you could remember backwards or whatever the most interesting domain is turning out to be what's directly glucocorticoids to to the frontal cortex.
Judgment impulse control executive function long-term planning strategizing and turns out virtually every bad thing cellularly that stress and glucocorticoids doing that be campus to turning out to do with the frontal cortex as well. And what does that begin to explain this entire world of why it is during moments of extreme emotional arousal especially aversive ones why we make terrible terrible decisions that seem brilliant the time and you spend the rest of your life regretting it because impulse control your amygdala overpowers your frontal cortex at those times. Your amygdala has a lot more talking to your motor systems and your frontal cortex does it's the reason why judgments and impulse control become terrible when we're frazzled. It's also looking like as a side story with that. It's one of
Reasons why when were very stressed it's hard for the frontal cortex to do one of its harder jobs, which is to take the view the world from somebody else's perspective empathy empathy exactly some research on animal models of empathy and this was work with this guy at McGill named Jeffrey Mogul and we are by collaborated with him showing in both rats and humans, you're less empathic towards strangers when they're in pain. And if you block glucocorticoid release, you don't get that effect anymore glucocorticoids the stress fulness of dealing with scary novel humans or scary novel mice. If you are rodent glucocorticoids narrow your window as to who counts as an us and whose pain registers and things of that sort. So for me, you know, it's incredibly interesting if you're stressed and suddenly your SAT scores.
The fact that stress makes people crappy or to each other and less empathic and more parochial and more Zena phobic and more impulsive with the worst of our impulses. That's the stuff that really interests me these days
everything you just said Robert is almost call to action in Criminal Justice Reform and I've done a podcast on this topic where it was very fortunate to go into a Maximum Security Prison with a program that is really there to do incredible rehabilitative work led by this woman named Katherine Hoke. It's a humbling experience. There's a game that we played about halfway through the day called step to the Line This is a game that's used to basically identify the vast difference between those of us who are volunteers like in other words the role of luck in our lives versus the gentleman who two-thirds of these men are never going to get out of prison one man had even spent more than half. His life in solitary confinement is total life. So it starts with these questions of
Step to the line. If you grew up in a home that had two parents and you know of the volunteers 60% step to the line of the inmates five step to the line right step to the line. If you grew up in a home where there were more than four books, you can imagine the disparity step to the line. If you saw someone die with your own eyes before this age step. I mean and it's it's a very emotional thing to go through because is this game is unfolding. You're just you're feeling more and more fortunate on the one hand because you realize if not for the the grace of this luck and at the same time the empathy you have for these men who have done the most heinous things grows and you start to realize boy. There's a fine line between those of us on the inside those of us on the outside because everything you said really resonated when I was thinking about some of the stories the men told us about the decisions that they made and there's this one part of the exercise. That's incredibly
You know where you're partnered with one one guy. So it's one volunteer One inmate and you were each telling the other person the greatest regret of your life the biggest mistake you've made and hearing some of these stories. It's not to justify anything that's been done and it's not to say that there shouldn't be consequences for it.
But a lot of these things that people have wound up in prison for our really impulsive horrible decisions as opposed to Decades of sinister planning a it's one thing to look at what you know, like Hitler did it's hard to argue that anything that he did that was bad was impulsive. It's quite another thing when you look at someone in a gang-related incident where you know, this guy gets shot and you're going to shoot this guy back or this guy's about to shoot you and you shoot him. I mean and yet that type of drug related violence is disproportionately represented in certainly in the u.s. Penal system and then to build on what you said, it's not clear that the environment in there is reducing cortisol levels to the level that would enable Rehabilitation which is really the thesis of and a lot of people I'm sure listening to this or thinking
Why would you feel empathy for these folks that are in there? And why should Society care about them? But the reality of it is if they're going to get out you should care that says nothing of maybe the higher level that you should care which is the Injustice of it. But even if you took a purely selfish view a non-trivial number of these men and women are going to get out so wouldn't you rather they get out and function better and yet it's really tragic to see this and I know two people actually very well. We spent a great deal of time in prison one of whom I interviewed on this podcast is name is Corey McCarthy and it really strikes me as the exception and not the rule that people are able to emerge from that environment then go on to be successful outside.
It's a system. That is so so broken any study the last century and a half's worth of neural biology and genetics and Child Development and all of that and the notion that we are free agents of our
action is so destructively
misplaced I'm sure you're familiar with the work of Sam Harris Sam has been one of the most interesting forces in my life at getting me to really even questioned this notion of Free Will and once you realize that Free Will may not even be yours it takes luck to a new level
it's something I spent a lot of time thinking about now what
advice would you offer somebody who is interested in the neurobiology of stress or behavior and who wants to be able to look back when they're your age and be as may be accomplished is the wrong word I don't want I know you sort of bristle at that but to have made as many contributions as you made I mean what in retrospect was sort of the secret to being able to pursue your bliss and be as successful as you been and look frankly to be where you are and to still have the passion that you have for what you're doing which to me is really the marker of success it's that you're sitting here saying there's this other problem and I you know like I could spend you know
Next 20 years just thinking about that. How do you think about how you've done that
just damn luck every bit of the Neurosis every bit of affective instability. I've got every child trauma. I've got tucked away. I've titrated in just the right way that I've turned it into more productivity and Incredibly Lucky in that regard my capacity to sublimate emotion into intellectual Pursuit into really really really wanting to understand something into I've just been very lucky in that regard. I've gotten just the right levels of all sorts of like tumult that of synergized most productively in other words just huge amounts of luck huge amounts of luck and at least now coming later in life and increasing capacity.
City to more carefully try to analyze what cost each type of ambition comes
with hmm. Say more about that.
Oh, I don't know this had much to do with my closing my lab for years ago the big booming lab and a lots of people and all sorts of labs around the world. We were going to kick the asses of by getting the answer to this or that and you know, if you're raised in the right sort of rarefied ambitious world of biomedical research at age 25, you've got a list down to the floor of the disease's you're going to Vanquish and the problems you're going to solve and all of that and you know, you know that point in life where you realizing it's not going to happen is
that what actually happened four years ago. Was it that much of a cerebral realization or was it combined with other factors, you know, you've described obviously having this network of people around
Matter the most and mean was part of it. Just thinking I haven't spent enough time with them at the expense of this or was it the this problem is enormous and when you know a thousand years from now whether I worked this much harder or this much less it won't have altered the trajectory of XYZ. Like I mean how much of it is all of these?
Holy love family growing up real fast as they tend to do realizing your best work was decades behind you realizing there's this book you want to write where the only way you can do it is to just sit for really long stretches canyonfield work having collapsed a few years before body feeling older limits to how many 80 hours of work a week. You can do all of them converging
what have I mean, it's such a cliche question. What advice would you give the the 25 year-old Robert is he was just finishing that PhD at Rockefeller?
Be less ambitious.
Well, I think on that note which by the way I think is some of the greatest advice one could ever get in receiving those of us who are still on the climbing ambition curve should do everything to listen to it. I want to I want to thank you so much for taking the time to sit down with me and more importantly I think for just all of the work you've done in your continuing to do thank you so much.
Thanks for having me on this has been fun as the wrong word. But in relating good glad we did you
can find all of this information and more at Peter Atia m.com forward slash podcast there. You'll find the show notes readings and links related to this episode. You can also find my blog at Peter TMD.com. Maybe the simplest thing to do is to sign up for my subjectively non lame once a week email where I'll update you on what I've been up to the most interesting papers. I've read and all things related to longevity science performance sleep Etc on social.
Can find me on Twitter Instagram and Facebook all with the ID Peter at EF MD but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for General informational purposes only and does not constitute the practice of medicine nursing or other professional health care services, including the givings of medical advice and note no doctor-patient relationship is formed the use of this information and the materials link to the podcast is at the users own risk. The content of this podcast is not intended to be a substitute for professional medical advice diagnosis or treatment users should not disregard or delay in obtaining medical advice for any medical condition. They have and should seek the assistance of their Healthcare
Professionals for any such conditions
lastly and perhaps most importantly I take conflicts of interest very seriously for all of my disclosures the companies I invest in and or advise please visit Peter Atia m.com forward slash about
