Dr. Peter Attia: Improve Vitality, Emotional & Physical Health & Lifespan

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.160 | and I'm a professor of neurobiology and ophthalmology

00:00:13.140 | at Stanford School of Medicine.

00:00:14.980 | Today, my guest is Dr. Peter Attia,

00:00:17.160 | his second time on the podcast.

00:00:19.460 | Dr. Peter Attia is a medical doctor

00:00:21.800 | who did his training at Stanford School of Medicine,

00:00:24.300 | Johns Hopkins School of Medicine,

00:00:25.880 | and the National Institutes of Health.

00:00:27.880 | He is a world expert in all things related to healthspan,

00:00:31.400 | vitality, and longevity.

00:00:33.380 | In this episode, we focused on many topics,

00:00:36.000 | focusing mainly, however,

00:00:37.600 | on healthspan and longevity and mental health.

00:00:40.960 | Healthspan and longevity, of course,

00:00:42.600 | relate to how long one lives,

00:00:45.120 | and Dr. Attia goes systematically

00:00:47.120 | through the seven major causes of death worldwide,

00:00:50.180 | beginning with cardiovascular disease

00:00:52.040 | and cerebrovascular disease,

00:00:54.040 | also cancer, also accident-related deaths,

00:00:57.040 | dementia, deaths of despair,

00:00:59.520 | and in every case,

00:01:01.220 | explains the three or four major levers

00:01:04.460 | that one can employ in order to offset,

00:01:06.720 | that is to prevent those major causes of death.

00:01:09.720 | What follows is an incredibly informative

00:01:11.720 | and actionable set of tools for anyone,

00:01:14.580 | male, female, young, or old.

00:01:16.740 | He explains the behavioral, nutritional,

00:01:19.160 | supplementation-based and prescription drug-based approaches

00:01:22.280 | that one can use in order to extend healthspan and longevity.

00:01:25.800 | Dr. Attia explains the key tests and markers

00:01:28.400 | that we should all pay attention to

00:01:30.200 | if our goal is to extend our healthspan

00:01:32.360 | and how to do so while maximizing our vitality.

00:01:36.240 | This is something that not a lot of people think about

00:01:38.440 | when they think about healthspan and longevity,

00:01:41.400 | but as Dr. Attia illustrates for us,

00:01:43.520 | emotional health has everything to do

00:01:45.620 | with our physical health and vice versa,

00:01:47.960 | and he shares quite openly about his own experiences

00:01:51.080 | in pursuing ways to improve emotional health

00:01:53.780 | and thereby healthspan, lifespan, and vitality.

00:01:57.280 | Dr. Attia is quite open about his own experiences,

00:02:00.120 | exploring different practices to improve emotional health

00:02:03.160 | as ways not just to improve healthspan, longevity,

00:02:05.860 | and vitality, but of course,

00:02:07.360 | also to derive the most meaning and satisfaction from life.

00:02:10.780 | Throughout today's discussion,

00:02:12.000 | we also discussed Dr. Attia's newly released book,

00:02:14.880 | which is entitled "Outlive,

00:02:16.400 | the Science and Art of Longevity."

00:02:18.800 | This is a phenomenal book.

00:02:20.200 | I've read it cover to cover now three times.

00:02:23.060 | I have extensive notes written throughout,

00:02:25.400 | and the book of course focuses on longevity and healthspan,

00:02:28.340 | and also has an extensive section on emotional health.

00:02:31.860 | It gets quite detailed into Dr. Attia's

00:02:33.780 | personal experiences with emotional health

00:02:36.320 | and tools to improve emotional health

00:02:38.360 | that are very actionable for anybody to use.

00:02:41.440 | I think the best way for me to summarize my feelings

00:02:43.500 | about the book would simply be to read

00:02:45.120 | the backjacket quote, which I provided.

00:02:47.400 | So I read quote, "Finally, there is a modern, thorough,

00:02:50.480 | clear, and actionable manual for how to maximize

00:02:53.820 | our immediate and long-term health.

00:02:55.700 | Firmly grounded in data and real life conditions,

00:02:58.500 | this is the most accurate and comprehensive

00:03:00.380 | health guide published to date.

00:03:02.020 | Outlive is not just informative, it is important."

00:03:05.200 | And indeed, "Outlive" is an important book,

00:03:07.760 | as is the discussion that Dr. Attia

00:03:09.580 | so graciously provided us in today's episode.

00:03:12.560 | "Outlive" is released on March 28th, 2023,

00:03:16.220 | and is available for pre-order prior to that date.

00:03:18.700 | You can find a link to where it's sold

00:03:20.580 | in the show note captions.

00:03:22.260 | Before we begin, I'd like to emphasize that this podcast

00:03:25.300 | is separate from my teaching and research roles at Stanford.

00:03:28.060 | It is, however, part of my desire and effort

00:03:30.400 | to bring zero cost to consumer information about science

00:03:33.060 | and science-related tools to the general public.

00:03:35.800 | In keeping with that theme,

00:03:36.980 | I'd like to thank the sponsors of today's podcast.

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00:05:21.020 | I consume one packet of Element

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00:07:30.560 | And now for my discussion with Dr. Peter Attia.

00:07:33.940 | Dr. Attia, Peter, welcome back.

00:07:36.680 | - Thanks, man.

00:07:37.520 | Good to be back and sounding better this time.

00:07:39.840 | - Looking forward to talking about a number

00:07:42.000 | of important topics with you that you cover in your book.

00:07:46.380 | Maybe we could start off by trying to set the frame

00:07:49.520 | for what people should be thinking about

00:07:52.320 | in terms of vitality and especially longevity.

00:07:56.800 | - So I mean, I think you have to be mindful

00:08:02.840 | of how you define these terms.

00:08:04.600 | And I'm not gonna suggest that the way I define them

00:08:07.940 | is the only way or necessarily the best way.

00:08:10.900 | But I think from a clinical perspective,

00:08:12.740 | it's the way that makes the most sense to me,

00:08:14.740 | having thought about this for the better part of a decade.

00:08:17.640 | So it involves some bifurcation

00:08:20.960 | between lifespan and healthspan.

00:08:23.060 | Lifespan is very easy for people to understand.

00:08:26.340 | It is binary, you are alive or you are not alive.

00:08:30.580 | And clearly part of longevity is about how long you live.

00:08:35.580 | Now I think for a lot of people,

00:08:38.480 | that tends to be where the discussion ends.

00:08:40.820 | That tends to be the focus of it, right?

00:08:42.360 | It's sort of like longevity somehow implies living

00:08:46.480 | for 100 years, 120 years, something to that extent.

00:08:49.720 | We talk a lot about maximum lifespan.

00:08:52.360 | Even in laboratory experiments with mice,

00:08:56.320 | that's sort of one of the metrics that's discussed

00:08:59.000 | is what's maximal lifespan of the animals.

00:09:01.500 | But there's an equally, if not slightly,

00:09:05.740 | I think potentially more important part of longevity,

00:09:07.860 | which is healthspan.

00:09:09.500 | And healthspan is squishier

00:09:13.140 | and I think it requires some definition.

00:09:16.120 | Now the medical definition of healthspan

00:09:18.340 | is the period of time by which you are free

00:09:22.340 | from disability and disease.

00:09:25.340 | I find that to be a not particularly helpful definition

00:09:29.420 | because by that definition,

00:09:31.060 | you and I have the same healthspan today

00:09:34.280 | that we did 30 years ago.

00:09:37.140 | But I know you pretty well, you know me pretty well.

00:09:39.540 | 30 years ago, we were twice the men we are now

00:09:42.060 | based on what we believe our healthspan is, right?

00:09:44.980 | In terms of our cognitive function,

00:09:46.340 | our physical performance and things like that.

00:09:48.560 | So I've clearly experienced the deterioration

00:09:52.060 | of my physical function as I'm sure you have

00:09:53.840 | going back to when you were a teenager,

00:09:55.620 | late teenager, early 20s.

00:09:57.080 | And I think that needs to be captured somehow in healthspan.

00:10:01.080 | So the way I think of healthspan really

00:10:04.300 | is along these three dimensions,

00:10:06.400 | physical, cognitive, and emotional.

00:10:08.320 | Again, not necessarily suggesting

00:10:09.960 | that that's the only way to do it,

00:10:11.520 | but I do think that clinically it makes the most sense.

00:10:15.160 | And so therefore, anything that really becomes

00:10:19.240 | a question of longevity has to address all of these issues.

00:10:23.400 | Lifespan, physical health beyond that

00:10:27.140 | of just straight up disability and disease,

00:10:29.580 | cognitive health independent of and separate

00:10:33.720 | from pathology such as dementia,

00:10:36.740 | and emotional health which of course

00:10:38.300 | is by far the most complicated of all of these

00:10:41.120 | because we have no biomarkers for it.

00:10:42.940 | We have no, you know, it's not like you can get a scan

00:10:46.780 | on somebody and determine the state of this.

00:10:49.100 | But nevertheless, it's important, right?

00:10:51.920 | And it dramatically factors into quality of life.

00:10:54.900 | - So with all of that in mind,

00:10:56.660 | what are the major exit points

00:10:59.660 | for people along the lifespan route?

00:11:03.080 | Let's just start with the binary one, dead or alive, right?

00:11:06.240 | I think most everyone who's healthy

00:11:08.440 | would like to be alive rather than dead.

00:11:10.720 | So what are the typical ways that people exit

00:11:13.320 | from alive to dead and how can people stay

00:11:16.320 | on the free way of life, so to speak?

00:11:19.080 | - So this is again a great analysis.

00:11:20.640 | We internally in our practice call this

00:11:23.080 | the death bar analysis.

00:11:24.560 | And it's a surprisingly trivial analysis

00:11:27.880 | that I'm just surprised the death bars

00:11:30.560 | aren't plastered front and center on every doctor's office.

00:11:33.880 | So if you simply just look at actuarial data

00:11:37.360 | which are readily available through the CDC

00:11:39.560 | and do a little bit of data, you know,

00:11:41.280 | manipulation and analysis, you can pretty quickly realize

00:11:45.520 | what the horsemen of death are.

00:11:47.840 | 'Cause there's largely speaking kind of four horsemen of death.

00:11:51.760 | The first and most consequential in terms of the numbers

00:11:56.280 | is the diseases of atherosclerosis.

00:11:58.640 | So that's cardiovascular disease

00:12:01.600 | being the lion's share of that,

00:12:03.060 | but also cerebrovascular disease.

00:12:05.480 | So anything that has to do with atherosclerosis

00:12:08.420 | rises to the top.

00:12:10.140 | Now that's true in the United States,

00:12:12.260 | but it's even more true outside of the United States.

00:12:14.480 | It's even more true globally.

00:12:16.140 | So in other words, when you look at the relative difference

00:12:19.460 | between the number one cause of death in the US

00:12:22.520 | and number two, which is cancer,

00:12:24.480 | the gap is actually smaller in the US than globally.

00:12:28.560 | Globally, it's enormous.

00:12:29.720 | We're talking about 18 to 19 million people a year

00:12:33.560 | that are dying of atherosclerotic cardiovascular disease

00:12:36.680 | in the world.

00:12:37.980 | Whereas number two is cancer at about 11 million.

00:12:41.720 | - How does the number change

00:12:42.840 | when you include cerebrovascular disease?

00:12:46.040 | - Yeah, it adds a bit to it.

00:12:48.280 | Cerebrovascular disease, largely speaking,

00:12:50.880 | you can die sort of through embolic events,

00:12:53.080 | which are the majority of them.

00:12:54.580 | - Can you explain for people what embolic events are?

00:12:57.220 | - Yeah, so taking a step back,

00:12:59.600 | what does the brain need more than anything?

00:13:02.280 | It needs blood flow.

00:13:03.420 | Anything that interrupts blood flow to the brain

00:13:05.900 | that results in ischemia is devastating.

00:13:08.560 | And it's devastating in a more readily apparent fashion

00:13:11.760 | than virtually any other organ.

00:13:14.260 | So one way that that can happen is if a clot

00:13:17.680 | or disruption of blood flow occurs

00:13:20.400 | through obstruction of blood flow.

00:13:22.820 | So that can occur through a clot.

00:13:24.160 | So for example, if a person has atrial fibrillation

00:13:26.400 | and a blood clot gets festering in the right atrium

00:13:29.680 | and they happen to have a hole

00:13:31.900 | between the atria of their hearts,

00:13:34.640 | called a patent foramen ovale,

00:13:36.140 | and a clot goes from right to left,

00:13:38.020 | it can make its way up into the arterial circulation

00:13:42.000 | and happen that way where you include blood flow.

00:13:44.500 | The much more common way it occurs

00:13:46.120 | is the same way it occurs in the heart,

00:13:48.620 | which is you have plaque buildup

00:13:51.180 | and that plaque becomes unstable, that plaque ruptures.

00:13:54.320 | And the rupture of that plaque results

00:13:56.460 | in an immediate attempt by the body to fix the problem.

00:13:59.980 | But in doing so, it walls off the artery,

00:14:03.480 | meaning the blood flow distal to that point

00:14:05.340 | so that now blood is acutely being robbed of that.

00:14:09.660 | However, there are other ways that people can

00:14:12.460 | have this problem.

00:14:13.380 | And so you have the whole hemorrhagic side of this.

00:14:15.820 | So you can have blood vessels that,

00:14:18.260 | small blood vessels in the brain that will rupture

00:14:20.540 | as a result of high blood pressure, for example.

00:14:22.420 | So hypertension factors into both sides of this equation,

00:14:27.260 | both in the heart and in the brain.

00:14:29.100 | The majority of these are embolic, however.

00:14:31.260 | So don't quote me on this exactly,

00:14:33.660 | but call it four or five to one strokes

00:14:37.720 | result from an embolic phenomenon

00:14:39.760 | as opposed to a hemorrhagic phenomenon,

00:14:42.840 | a bleeding phenomenon.

00:14:44.320 | - I don't want to take us too far off on a tangent,

00:14:46.340 | but as long as we're here talking about bleeds versus clots,

00:14:50.060 | what are some of the major risks for bleeds?

00:14:53.020 | I mean, I know some people out there

00:14:54.420 | have genetic predispositions for being bleeders,

00:14:57.780 | as they're sometimes called, or clotters.

00:14:59.460 | So things like factor V Leiden mutations,

00:15:02.780 | which can be exacerbated in women, for instance,

00:15:04.980 | by taking certain oral contraceptives.

00:15:06.820 | I mean, and there's a huge list.

00:15:08.200 | If people are interested in them, they can look up,

00:15:10.620 | what are the factors controlling bleeding

00:15:13.500 | and predispose people to be in a clotter?

00:15:16.040 | But for the typical person out there who feels healthy,

00:15:19.340 | but might do well to know whether or not

00:15:23.640 | they are predisposed to be a bleeder or a clotter,

00:15:26.620 | what sorts of things rise to the top of that list

00:15:31.140 | and that people might want to check into?

00:15:32.960 | - Well, I mean, there might be sort of

00:15:34.720 | two different things going on in that question,

00:15:36.700 | but I think if your question is,

00:15:39.100 | when we look at the subset of people

00:15:40.820 | who are at highest risk for hemorrhagic strokes,

00:15:43.780 | the far more germane question

00:15:45.940 | is not underlying coagulopathy.

00:15:48.500 | The far more germane question

00:15:50.060 | really comes down to blood pressure.

00:15:51.780 | Blood pressure would be the first, second,

00:15:53.700 | and third driver of that.

00:15:55.600 | So hypertension is, hands down,

00:15:58.380 | the leading driver of hemorrhagic stroke phenomenon.

00:16:01.180 | - Okay, so I'll just briefly interrupt and ask,

00:16:04.140 | since sometimes your recommendations

00:16:05.820 | deviate from the standards that one would find online

00:16:08.900 | or in the typical doctor's office,

00:16:10.860 | at what point do you get concerned?

00:16:12.940 | - Well, I actually find myself quite in line

00:16:16.460 | with the most recent available data on blood pressure.

00:16:19.560 | And this has been, obviously it's a topic

00:16:22.140 | that's of high concern to any doctor

00:16:24.140 | who's taken care of patients,

00:16:25.340 | who even pays a fraction of attention

00:16:27.640 | to the available literature,

00:16:28.700 | which is that basically

00:16:30.260 | with each subsequent blood pressure trial,

00:16:33.540 | the data are becoming clearer and clearer

00:16:36.060 | that the more aggressively you manage blood pressure

00:16:38.560 | to be within the 120 over 80 range, the better.

00:16:42.860 | So there's a recent study that even looked at going

00:16:46.420 | from what used to be considered acceptable,

00:16:48.300 | which was 130 to 135 over 80 to 85.

00:16:51.380 | We used to basically say

00:16:52.900 | that's kind of the first level of hypertension.

00:16:55.940 | And we would say, well,

00:16:58.020 | do you really need to be better than that?

00:17:00.020 | And the answer turns out to be, yes, you do.

00:17:02.180 | If you want to reduce heart attacks and strokes,

00:17:04.900 | it's better to be 120 over 80 than 135 over 85.

00:17:08.620 | Now, this is a whole other rabbit hole

00:17:09.940 | that we don't need to go down,

00:17:11.180 | but it's a total obsession of mine,

00:17:13.240 | which is how do you measure a person's blood pressure?

00:17:15.780 | I think this is potentially, I'd have to give it thought,

00:17:19.840 | but honestly, I could say top three

00:17:22.440 | under-diagnosed fixable problems in the United States today,

00:17:27.020 | and probably globally.

00:17:28.200 | In other words, there are too many people walking around

00:17:30.580 | with high blood pressure who don't know it.

00:17:33.420 | And I think part of the problem is it's something

00:17:36.580 | that is mostly done in the doctor's office,

00:17:38.860 | and the readings that you get in the doctor's office

00:17:40.920 | can be often misleading.

00:17:42.320 | You've heard of this phenomenon of white coat hypertension.

00:17:44.620 | So you go to the doctor,

00:17:45.820 | your blood pressure is virtually never measured correctly

00:17:50.120 | in the doctor's office.

00:17:51.180 | - That cuff they put on and that little squeeze bulb,

00:17:53.540 | that's not accurate. - Yeah, if you look

00:17:54.820 | at the rigor with which you need

00:17:56.720 | to measure a person's blood pressure,

00:17:58.060 | the right way to do it is the person has to be sitting

00:18:01.580 | like this for five minutes doing nothing.

00:18:05.200 | - Okay folks, so when you go to the doctor's now,

00:18:07.100 | you don't let them take your blood pressure

00:18:09.420 | until you've been sitting for five minutes,

00:18:10.700 | and that doesn't include in the waiting room,

00:18:12.420 | because if you walk from the waiting room--

00:18:13.260 | - Right, because then you get up and walk over, right.

00:18:14.860 | - Okay, so make them stand there.

00:18:16.260 | - Right, so you want to be sitting there like this.

00:18:19.540 | A manual cuff is better than an automated cuff,

00:18:22.820 | but not enough people use manual blood pressure.

00:18:25.860 | So a manual blood pressure means they put a cuff on you

00:18:28.780 | and they actually put a stethoscope on the brachial artery

00:18:31.700 | and they're using the human ear to listen,

00:18:34.240 | which, believe it or not, you would think a machine

00:18:36.500 | is better, but it's not.

00:18:37.820 | The machine can be misled by different sounds.

00:18:39.980 | Now, I don't want to suggest that automated cuffs

00:18:41.980 | are useless, they're not, but when an automated cuff

00:18:45.020 | gives you an answer that is potentially suspect,

00:18:49.260 | always back it up with a manual.

00:18:50.600 | I'm pretty relentless about checking my blood pressure,

00:18:53.500 | and so I'll do side-to-side manual versus automated

00:18:57.740 | every day, and there's easily a 10 to 15 point difference

00:19:01.380 | between them.

00:19:02.700 | - Maybe this is a silly question,

00:19:03.860 | but can people check their own blood pressure?

00:19:06.540 | - Meaning manually?

00:19:07.380 | - Yeah, just could I get a cuff and a bulb

00:19:10.140 | and learn how to do it?

00:19:11.900 | - Yeah, I think so.

00:19:12.740 | I mean, I can do it, but honestly,

00:19:13.940 | I usually have my wife do it, she's a nurse,

00:19:16.260 | but it's not rocket science to check blood pressure.

00:19:18.300 | I guarantee you there's a great video on YouTube

00:19:20.420 | that explains the physiology of it,

00:19:22.380 | if you're willing to splurge on a good enough stethoscope,

00:19:24.860 | and the cuff I have is really easy to use.

00:19:28.540 | Once you put it on, it's in a single thing,

00:19:31.340 | I'm squeezing the bulb and looking at the pressure gauge

00:19:33.740 | while I've got the stethoscope on my artery.

00:19:37.700 | - I mean, given the importance of blood pressure

00:19:39.940 | and this arterial sclerosis being at the top of the list

00:19:43.980 | of risks for dying, it seems to me

00:19:48.200 | it might be worth the expense.

00:19:49.180 | What's a typical range of costs for quality?

00:19:52.260 | - I don't, it's not inordinate.

00:19:54.220 | I feel like my blood pressure cuff is 40 bucks,

00:19:56.780 | and the stethoscope is a couple hundred bucks,

00:20:00.140 | if you're getting a good one.

00:20:01.580 | And a good automated cuff,

00:20:05.060 | I have no affiliation with any of these companies.

00:20:06.900 | I use two automated cuffs, one's called Withings,

00:20:10.140 | and the other one's made by a company called Omron, O-M-R-O-N.

00:20:14.620 | And they're both decent, but again, they tend to run high,

00:20:17.940 | and I have yet to find a credible explanation

00:20:20.860 | from cardiologists as to why.

00:20:22.260 | Everybody acknowledges that the manual one,

00:20:24.640 | when done correctly, is the answer,

00:20:27.460 | but I've heard wonky answers about why automated ones

00:20:31.860 | are sometimes incorrect.

00:20:34.080 | And again, it's just made me realize,

00:20:35.900 | we're not checking blood pressure often enough on people.

00:20:37.840 | We're overly relying on blood pressures

00:20:40.240 | in the doctor's office, which are not being done correctly.

00:20:42.040 | So we basically have our patients do this relentlessly.

00:20:45.580 | - So how often, let's say someone buys this,

00:20:48.260 | 'cause I think for $240, I mean,

00:20:50.100 | I realize that's prohibitive for some people,

00:20:51.820 | but given the cost of some of the other things

00:20:53.900 | that are discussed on this and many other podcasts--

00:20:56.140 | - First of all, I would just let people start

00:20:57.240 | with an automated cuff to begin with,

00:20:59.060 | and just start with there.

00:21:00.540 | We generally have people do it for two weeks.

00:21:02.900 | You know, we give our patients a little spreadsheet

00:21:04.920 | that automatically calculates averages and stuff like that,

00:21:07.180 | tells them what to record and where.

00:21:08.900 | And we just say, look, for two weeks,

00:21:10.420 | we want to see two recordings a day.

00:21:12.780 | And, you know, do a morning and an afternoon/PM recording

00:21:17.920 | twice a day for two weeks, and let us see those numbers,

00:21:22.920 | and we'll scrutinize them further.

00:21:24.400 | And if those numbers come in fine,

00:21:26.100 | let's revisit in a year.

00:21:28.600 | - Will a day ever come when a watch

00:21:31.320 | or a wristband can do this really well?

00:21:34.560 | - So I hope so, and I'm investigating it.

00:21:38.080 | I'm actually gonna be trying one out in a couple of weeks

00:21:43.080 | with a company that I tried two years ago,

00:21:47.100 | two years ago when I tried it, I was not impressed,

00:21:49.440 | so I kind of punted on it.

00:21:50.980 | The company, which I guess I'll not share the name

00:21:54.800 | of the company just yet, but they claim

00:21:57.320 | that it's significantly better,

00:21:59.340 | so I'm gonna put it to the test again.

00:22:01.800 | And it's basically a continuous monitor.

00:22:04.560 | So it's a wrist device that about every 15 minutes

00:22:08.440 | throughout the course of the day

00:22:09.480 | will check your blood pressure.

00:22:11.040 | To me, this would be, honestly, probably more important,

00:22:16.120 | you know how much emphasis I place on CGM

00:22:18.420 | as a great thing to be able to test.

00:22:19.940 | - Continuous glucose monitor.

00:22:20.780 | - Right, I would argue this would be more important.

00:22:22.640 | When the day comes that we can continuously

00:22:24.560 | assess people's blood pressure,

00:22:26.060 | it would be an integral part of a person's health checkup

00:22:30.460 | once a year is do two weeks

00:22:32.400 | of continuous blood pressure monitoring.

00:22:34.120 | Right now, to do that, which I've done as well,

00:22:37.020 | is so cumbersome that it borders on absurd.

00:22:39.720 | You actually have to wear a blood pressure cuff

00:22:42.200 | that is attached to a clumsy device

00:22:44.900 | that goes through the whole insufflation exercise

00:22:47.280 | every 15 minutes, including while you're sleeping.

00:22:49.920 | You know, it provides some insight,

00:22:51.720 | but it's so disruptive that it's not what we really want.

00:22:55.400 | The dream would be like a patch that you could put,

00:22:58.560 | I don't know, over your chest

00:23:00.680 | that can somehow impute changes in blood flow

00:23:04.120 | or something like that and regulate, but we'll see.

00:23:08.640 | Between optical sensors and things like that,

00:23:10.760 | I hope that we're getting closer to having something.

00:23:13.600 | - So I don't want a stroke.

00:23:15.720 | I don't want to bleed in the brain.

00:23:18.620 | I don't want to clot.

00:23:20.460 | As long as we're at this number one on the list,

00:23:23.120 | arthculosclerosis being the number one killer,

00:23:26.380 | what are the major ways to prevent it?

00:23:30.280 | - Yeah, so there's three big ones that stand out,

00:23:33.560 | you know, top and center.

00:23:35.020 | And then there's kind of a fourth one

00:23:36.340 | that I think is the foundational piece.

00:23:39.160 | So the three big ones we've talked about,

00:23:40.700 | one, blood pressure.

00:23:42.160 | So if your blood pressure is 120 over 80 or better,

00:23:46.000 | that's important.

00:23:47.340 | The second is not smoking.

00:23:49.900 | So it turns out that smoking and blood pressure

00:23:53.000 | are both devastating for arteries,

00:23:55.800 | but for different reasons, right?

00:23:57.040 | So smoking is devastating from a chemical perspective.

00:24:00.840 | So it's completely irritating to the endothelium.

00:24:04.520 | So the endothelium, as you know, is the single cell lining

00:24:07.680 | that is the innermost part of the arterial

00:24:11.200 | and arterial wall.

00:24:13.380 | So this is a pretty special organ.

00:24:16.060 | Again, it's a bit naive, but understandable

00:24:20.400 | that people just think of arteries as tubes.

00:24:23.180 | They're much more complicated than that.

00:24:24.680 | They have many layers to them.

00:24:26.380 | But this particular layer is unusually important.

00:24:29.800 | It has an outsized importance,

00:24:31.280 | because it is the one that's in contact

00:24:33.800 | with the luminal side, right,

00:24:35.420 | where the blood is flowing in the tube.

00:24:37.780 | And anything that injures that has significant consequences.

00:24:42.100 | So smoking is irritating to that in a chemical way,

00:24:46.440 | and blood pressure is irritating to that

00:24:48.640 | in a mechanical way.

00:24:50.240 | So those two things, basically, you just wanna,

00:24:53.700 | that's the low-hanging fruit in my world, right?

00:24:56.060 | You just don't wanna have those things

00:24:57.340 | causing irritation to the endothelium,

00:24:59.360 | because that renders you now susceptible

00:25:01.740 | to the third factor, which is ApoB-bearing lipoproteins.

00:25:05.820 | - I wanna talk about ApoB in depth,

00:25:08.540 | but as long as don't smoke

00:25:11.140 | is the second recommendation on the list,

00:25:13.880 | can we better define smoking and what's being smoked?

00:25:18.660 | So assume nicotine, what about cannabis?

00:25:23.020 | And what about vaping of nicotine and cannabis?

00:25:25.420 | Because vaping has become so much more common.

00:25:27.740 | - Yeah, it's a great question,

00:25:29.680 | and it's sadly something we don't have a great answer for.

00:25:32.940 | So I can certainly tell you that there's no reason

00:25:36.700 | to believe that smoking cannabis

00:25:40.140 | is somehow better than smoking cigarettes.

00:25:44.700 | But the dose seems to be significantly lower.

00:25:48.420 | In other words, let's consider a person

00:25:51.740 | who smokes a pack a day for 20 years.

00:25:54.780 | We call that a 20-pack year smoker.

00:25:57.260 | Someone who smokes two packs a day for 15 years

00:26:00.380 | is a 30-pack year smoker.

00:26:02.120 | That's a person who's dramatically increased

00:26:04.860 | their risk of many cancers, including lung cancer,

00:26:08.100 | and also their risk of cardiovascular

00:26:10.000 | and cerebrovascular disease.

00:26:11.660 | Again, I'm not a THC guy, so I can't necessarily speak

00:26:16.100 | for the habits of people that are smoking marijuana.

00:26:18.620 | I can't imagine they're smoking that much.

00:26:20.700 | - Probably not.

00:26:21.540 | - Yeah, so while on a joint to cigarette basis,

00:26:26.540 | they're probably equivalent in terms of harm,

00:26:30.900 | I don't know, let's say a person smokes a joint a day,

00:26:34.340 | that would be like smoking a cigarette a day.

00:26:37.700 | That's a 20th of a pack.

00:26:39.600 | Again, I don't wanna say that there's no downside to that,

00:26:42.980 | but it's probably significantly less.

00:26:45.580 | So I don't think the risk fully tracks.

00:26:48.440 | I think the same is probably true for vaping.

00:26:51.260 | And I wanna be clear, I don't think vaping's a good idea.

00:26:54.760 | The last time I looked at the data on this,

00:26:58.360 | it was surprisingly sparse, but to me,

00:27:02.880 | the only advantage I could see to vaping

00:27:05.720 | was if it was the only way a person would stop smoking.

00:27:08.660 | So there was, I sort of looked at it as,

00:27:11.480 | it was definitely the lesser of two evils,

00:27:14.680 | but by far the better scenario

00:27:18.280 | was not to do any of these things.

00:27:19.640 | If nicotine is what you're after,

00:27:21.780 | there are better ways to get nicotine, for example,

00:27:24.460 | through lozenges and gum and things like that.

00:27:26.800 | So you shouldn't be turning to those things to do it.

00:27:29.540 | But if it was like, if gum is here and cigarettes are here,

00:27:33.460 | vaping was probably here, but boy, I don't know.

00:27:36.540 | - For those listening, Peter spaced his hands

00:27:39.740 | far apart for gum and smoking and put vaping

00:27:43.320 | about a third of the way from gum toward smoking.

00:27:48.160 | In other words, vaping isn't good for you,

00:27:50.140 | but it's not as bad as smoking.

00:27:51.700 | - That would be my, I mean, do you have a,

00:27:53.980 | you've probably looked into this as well.

00:27:55.300 | What are your views on this? - Yeah, we did an episode

00:27:56.440 | about nicotine.

00:27:57.280 | I did an episode on cannabis and, you know,

00:28:00.300 | the discussion around cannabis gets a little contentious

00:28:02.700 | for reasons that aren't important.

00:28:04.940 | It's kind of funny, the moment someone starts

00:28:07.900 | to confront cannabis as a potential health harm,

00:28:10.000 | people say it's not as nearly as bad as alcohol,

00:28:12.920 | which is a crazy argument, right?

00:28:14.560 | Getting hit by a bus isn't nearly as bad

00:28:16.140 | as getting hit by a motorcycle in most cases,

00:28:18.160 | but sometimes, you know, so that's just kind of silly.

00:28:21.000 | And clearly cannabis has medical applications, clearly.

00:28:26.820 | And then it becomes an issue of the ratio of THC to CBD,

00:28:29.740 | pure CBD forms actually being quite effective

00:28:31.660 | for the treatment of certain forms of epilepsy,

00:28:33.600 | so-called Charlotte's Web, that's actually what it's called.

00:28:36.200 | Very high THC containing cannabis clearly predisposes,

00:28:41.060 | especially young males, to later onset psychosis.

00:28:44.780 | Those data are starting to become clear,

00:28:47.240 | clear enough to me anyway,

00:28:48.420 | that people ought to be aware of them at least,

00:28:50.580 | and maybe make decisions on the basis of those.

00:28:53.020 | When it comes to the smoking versus vaping,

00:28:56.380 | it's just very, very apparent

00:28:58.740 | that the chemical constituents of the vape

00:29:02.220 | and what people are inhaling are terrible for people

00:29:07.900 | and are loaded with carcinogens and a bunch of other stuff,

00:29:10.820 | many of which cross the blood-brain barrier.

00:29:13.740 | So that's what worries me the most.

00:29:15.580 | Obviously I'm not a clinician,

00:29:16.620 | but anytime I hear about small molecules, you know,

00:29:19.400 | these small inorganic molecules

00:29:20.860 | getting across the blood-brain barrier

00:29:22.440 | and then being maintained in neurons for many, many years,

00:29:24.780 | I worry because the experiment is ongoing

00:29:26.820 | mostly in young people.

00:29:28.100 | So anyway, without going too far down that track,

00:29:30.360 | I think if people can avoid smoking and vaping, they should.

00:29:33.740 | And as you mentioned, there are other delivery devices

00:29:35.800 | for nicotine and cannabis, tinctures and patches and gums

00:29:40.180 | and things that, edibles that,

00:29:43.080 | if people choose to use those substances, they can offset.

00:29:46.780 | - I think sometimes people would benefit to imagine

00:29:50.260 | what the surface area of the lung is, right?

00:29:53.860 | If you took the alveolar air sacs of the lungs

00:29:57.560 | and spread them out, you would easily cover a tennis court.

00:30:01.420 | - Remarkable.

00:30:02.260 | - So just think about anytime you inhale something,

00:30:06.460 | you are exposing, your body is so adept at absorbing it.

00:30:11.040 | I mean, we have this unbelievable system for gas exchange

00:30:14.980 | that was designed for gas exchange.

00:30:16.700 | And anytime you're putting something else in that wake,

00:30:19.180 | you're doing a really good job of getting it into your body.

00:30:22.040 | So be mindful of what that is.

00:30:23.760 | And that, look, that applies to pollution too.

00:30:27.020 | I mean, the PM2.5 data is pretty good.

00:30:30.140 | I think once you, so particulates that are less

00:30:32.700 | than 2.5 microns are getting straight into the body,

00:30:36.420 | which is like a great argument for avoiding air pollution.

00:30:41.220 | I mean, I always find it funny,

00:30:42.680 | not to get off on this tangent, but to me,

00:30:45.900 | the most compelling arguments around cleaner energy

00:30:50.820 | have nothing to do with greenhouse gases.

00:30:52.940 | They have to do with air pollution.

00:30:54.740 | I promise you more people are dying

00:30:57.340 | from the particulate matters in air

00:31:00.040 | that result from burning coal than are ever going to die

00:31:05.040 | from the CO2 emissions that result from that.

00:31:07.900 | And I would argue that's gonna be two orders of magnitude.

00:31:10.900 | It's not even in the same zip code.

00:31:12.300 | - That makes sense.

00:31:13.140 | - During the fires, which seemed to follow me

00:31:16.300 | because when I was in Northern California,

00:31:17.740 | there were a bunch of fires and we were constantly looking.

00:31:20.640 | I mean, wake up in the morning,

00:31:21.700 | everything was covered with ash.

00:31:23.540 | My dog was having trouble breathing.

00:31:24.980 | I was having trouble breathing.

00:31:26.040 | Everyone was suffering.

00:31:27.740 | But there are websites that one can go.

00:31:30.100 | You can just look at air pollution.

00:31:31.500 | And we tend to only do this during fires.

00:31:33.580 | And then, you know, when I'm in Southern California,

00:31:35.460 | there tend to be fires here.

00:31:36.420 | So, you know, it's correlation, not causation,

00:31:39.560 | but for sure, I didn't set those fires, folks.

00:31:42.500 | But it's clear that it disrupts your breathing

00:31:45.440 | for a very long period of time.

00:31:46.900 | But it's the long tail of that

00:31:48.300 | that we're really talking about here.

00:31:49.560 | The very small particulate that we know firefighters,

00:31:52.100 | for instance, and certain industrial workers

00:31:55.100 | can end up with that stuff embedded in their brain tissue

00:31:57.320 | for extremely long periods.

00:31:58.860 | That's just not good.

00:32:00.520 | You make a really interesting point

00:32:01.760 | about the call for cleaner energy.

00:32:05.700 | Can we run that one up to Washington

00:32:08.700 | or settle some of the debates about climate change

00:32:10.820 | just by getting straight to help bypass all the garbage

00:32:14.620 | that's being spewed back and forth

00:32:16.800 | and basically get to the issue at hand, right?

00:32:19.700 | - Yeah, just make it better for people to not die

00:32:22.620 | from the direct consequence.

00:32:24.640 | - I'd like to take a quick break

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00:33:38.940 | So trying to avoid, such a difficult word to say,

00:33:44.640 | especially for a neuroscientist, arterial sclerosis.

00:33:47.840 | Did I get it right?

00:33:48.720 | - Well, it's athero, which is easier, 'cause yeah.

00:33:51.040 | - Atherosclerosis.

00:33:52.180 | Oh, there.

00:33:53.020 | I've been making life more complicated for myself.

00:33:54.980 | Typical of me.

00:33:55.980 | Okay, so blood pressure, keeping it 120 over 80 or better.

00:34:00.980 | Don't smoke.

00:34:04.140 | Let's just throw in don't vape.

00:34:05.600 | - Sure.

00:34:06.440 | - I'm gonna just plant my flag on it.

00:34:07.260 | Just don't vape.

00:34:08.100 | There are other ways to get those things in your system

00:34:09.760 | if you really wanna get nicotine

00:34:11.040 | or cannabis into your system.

00:34:13.200 | ApoB.

00:34:14.720 | What's the story with ApoB?

00:34:16.760 | - Okay, so to explain this,

00:34:18.440 | you have to tolerate a little bit of chemistry.

00:34:23.440 | So everybody's heard of cholesterol,

00:34:25.580 | and I certainly devote quite a bit of time in the book

00:34:29.600 | to explaining this, because it is so important.

00:34:32.480 | And it's definitely one of those areas

00:34:34.280 | where I initially received a lot of pushback from the editor,

00:34:39.000 | and there was a thought that hey,

00:34:40.160 | this is a bit more technical than it needs to be.

00:34:42.800 | But I think that sometimes you do need to resort

00:34:47.600 | to longer dissertations to dispel mythology.

00:34:51.680 | So cholesterol is a lipid.

00:34:55.320 | It is a molecule that the body synthesizes.

00:34:59.000 | It is a molecule that is essential for life.

00:35:01.640 | So if you cannot synthesize cholesterol, you can't live.

00:35:05.920 | You'll die in utero.

00:35:07.120 | So there are rare genetic conditions

00:35:09.520 | that prevent the successful synthesis of cholesterol.

00:35:12.880 | Embryos that have those mutations do not survive.

00:35:17.100 | Okay, so why do we need this stuff?

00:35:20.460 | So we need this stuff primarily for two reasons.

00:35:24.000 | First, it makes up a very important

00:35:26.880 | structural component of cell membranes.

00:35:29.700 | So as you know, a cell is a sphere.

00:35:33.140 | We look at them and think they're circles,

00:35:34.840 | but they're spheres, and they're fluid, right?

00:35:37.920 | They aren't just like little perfect big bowling balls

00:35:42.100 | or balloons.

00:35:43.700 | They actually morph and shape and move in these paths.

00:35:47.520 | And this is what allows cells to be next to each other

00:35:50.360 | and all sorts of things.

00:35:51.500 | They also have channels across all of them,

00:35:54.080 | and those channels are held in place by,

00:35:57.060 | among other things, cholesterol and phospholipids.

00:35:59.920 | The second thing that makes cholesterol so important,

00:36:03.440 | it is the precursor to some of the most important hormones

00:36:06.640 | in our body.

00:36:07.720 | So our sex hormones, testosterone, estrogen, progesterone,

00:36:10.640 | in addition to glucocorticoids.

00:36:12.620 | If you look at them, it's really funny.

00:36:14.140 | People, if you're looking at, if you Google,

00:36:16.040 | like give me the structure of these things,

00:36:17.600 | you're kind of like, wow, they're all basically the same.

00:36:19.600 | They all look really similar,

00:36:20.880 | and they're all pretty much just templates of cholesterol.

00:36:24.000 | So understandably, when it's something that's that important,

00:36:26.600 | the body would leave nothing to chance.

00:36:28.160 | We make all of our own cholesterol.

00:36:30.280 | The cholesterol that you eat in food, largely irrelevant.

00:36:34.060 | It's esterified cholesterol,

00:36:35.460 | so it means it has an ester side chain.

00:36:37.680 | It's too bulky to absorb in the gut.

00:36:39.700 | So most cholesterol that you eat in food

00:36:42.720 | just goes out your GI tract.

00:36:44.280 | Okay, so we have this super important molecule

00:36:47.800 | that every cell in the body makes,

00:36:50.260 | but there's a bit of a problem.

00:36:52.000 | There's actually two problems.

00:36:52.840 | The first problem is not every cell can make

00:36:55.640 | as much as it needs all the time.

00:36:58.680 | So you have this demand problem.

00:37:00.200 | So for example, if you're sick,

00:37:03.020 | you're gonna need to make far more glucocorticoids.

00:37:06.560 | Your body's response is going to be

00:37:08.120 | to ramp up cortisol production to mobilize fuel

00:37:11.160 | and do a whole bunch of other things,

00:37:13.000 | and certain cells, like the adrenal glands,

00:37:15.080 | are gonna be called on to rise

00:37:17.360 | to a higher level of performance,

00:37:19.320 | and they're not gonna be able to make enough cortisol.

00:37:22.160 | So they're going to have to borrow or take cholesterol

00:37:25.960 | from other cells in the body.

00:37:27.080 | In fact, one of the things we used to notice in the ICU,

00:37:29.240 | I never knew why it was happening, I now know,

00:37:33.640 | is the few times I would accidentally order

00:37:36.560 | the wrong set of labs on a patient in the ICU

00:37:38.960 | and also order like a lipid test or something,

00:37:41.600 | you would always notice their cholesterol levels

00:37:43.520 | were dropping, you know, serum cholesterol levels.

00:37:47.200 | And I now realize why, because they were basically

00:37:49.840 | just funneling cholesterol to the adrenals

00:37:53.120 | to make more of the cortisol that they needed

00:37:54.940 | to combat whatever they were in the ICU for,

00:37:57.080 | which is usually the most severe form of, you know,

00:37:59.400 | stress the body is under.

00:38:00.680 | So you have to be able to transport this stuff.

00:38:03.680 | And then the second problem is, as you know,

00:38:06.960 | cholesterol, being a lipid, is not water soluble.

00:38:10.840 | So the most dominant highway in the body

00:38:14.400 | is the circulatory system.

00:38:15.720 | We can use the lymphatic system and things like that,

00:38:17.720 | but for the most part, we use our circulatory system

00:38:20.480 | as the highway to move stuff around.

00:38:23.360 | And the highway is made up of water.

00:38:26.280 | Plasma, which is the liquid component of your blood,

00:38:29.440 | is water, and therefore things that are water soluble

00:38:32.960 | move easily, so glucose, sodium, electrolytes,

00:38:37.960 | all of those things are dissolvable in water,

00:38:40.420 | and therefore they don't need a carrier.

00:38:42.040 | You just dissolve them in the water and they can go.

00:38:44.240 | So that's why your liver can make glucose

00:38:46.740 | that your brain can easily get,

00:38:48.540 | and there doesn't need to be a carrier

00:38:50.100 | or an intermediary or anything like that.

00:38:52.460 | But unfortunately, with cholesterol being a lipid,

00:38:55.720 | we can't do that.

00:38:56.860 | Just as water and oil don't mix,

00:38:59.160 | cholesterol and plasma don't mix.

00:39:01.740 | So the body had to come up with a trick.

00:39:04.340 | And the trick was designing a vehicle

00:39:07.660 | that was water soluble on the outside

00:39:10.600 | and fat soluble on the inside,

00:39:13.280 | that you could bury the cholesterol inside,

00:39:16.060 | along with triglycerides.

00:39:18.260 | And on the outside, it was covered in protein,

00:39:19.920 | which is water soluble,

00:39:20.920 | and that's the thing that moves around.

00:39:23.660 | And that thing is called a lipoprotein.

00:39:25.440 | And as its name suggests, it's part lipid, part protein.

00:39:28.440 | Lipid on the inside, protein on the outside.

00:39:31.040 | And those lipoproteins come largely

00:39:36.040 | in two different families.

00:39:38.380 | So one family comes from a lineage called ApoB.

00:39:44.600 | So the ApoB family,

00:39:46.780 | which is short for Apolipoprotein B100,

00:39:51.300 | is a family that is derived from the liver.

00:39:54.140 | And each of those lipoproteins

00:39:56.780 | has one and only one Apolipoprotein B100 on it.

00:40:01.780 | We shorten it and just call it ApoB,

00:40:04.420 | 'cause we don't really worry about Apolipoprotein B48,

00:40:07.660 | which is attached to chylomicrons

00:40:09.900 | that are responsible for fat absorption in the gut.

00:40:12.400 | They're very short-lived.

00:40:13.900 | They don't really factor into atherosclerosis.

00:40:15.620 | So we're gonna just, for the purists out there,

00:40:17.820 | there's an ApoB48, we're not gonna talk about it.

00:40:20.620 | So when I say ApoB, what I'm talking about

00:40:23.860 | is a protein that wraps around

00:40:26.820 | a subset of these lipoproteins.

00:40:28.820 | There's another family of lipoproteins called ApoA,

00:40:31.980 | or Apolipoprotein A.

00:40:34.440 | This is a much more complicated family.

00:40:37.380 | And I'm not gonna talk about it here,

00:40:39.260 | 'cause we would take an hour to just explain

00:40:42.480 | how the Apolipoprotein A family works,

00:40:45.240 | but I'll give the punchline is,

00:40:48.360 | there are many Apolipoprotein As,

00:40:50.360 | there's variable numbers of ApoAs on those proteins,

00:40:53.200 | and they are all part of a family

00:40:54.660 | called high-density lipoproteins.

00:40:57.220 | Back to the ApoB guys,

00:40:59.120 | they are of the low-density lipoprotein lineage.

00:41:02.980 | So you've heard the term LDL and HDL.

00:41:05.480 | What is it referring to?

00:41:06.420 | It's basically referring to the relative concentrations

00:41:09.020 | of protein and lipids in the lipoproteins,

00:41:11.600 | and not surprisingly, based on their names,

00:41:13.620 | the HDLs are higher density, more protein, less lipid.

00:41:17.820 | The LDLs, low-density lipoproteins,

00:41:20.660 | and VLDLs, very low-density lipoproteins,

00:41:23.280 | and IDLs, intermediate-density lipoproteins,

00:41:26.500 | are all lower density, which means more lipid to protein.

00:41:31.020 | There are different sizes,

00:41:31.940 | there's a whole bunch of other things going on.

00:41:34.140 | Most important fact in all of this

00:41:36.600 | is that the ApoBs are atherogenic.

00:41:40.380 | So what we're about to talk about next

00:41:42.660 | is perpetuated by lipoproteins that have an ApoB on them.

00:41:47.260 | So everything in the story right now

00:41:49.160 | is just about how do you get cholesterol around the body.

00:41:53.920 | - And these proteins that have lipid in the middle.

00:41:59.780 | So let's just take ApoB for example.

00:42:03.420 | Many, many billions of them floating around in our body,

00:42:07.900 | even in the healthiest of people.

00:42:10.820 | And they're being shuttled to tissues that need them,

00:42:15.820 | like the adrenals, muscle, heart, et cetera.

00:42:20.740 | What sets the demand for these things?

00:42:24.740 | So for instance, could somebody have relatively high LDL,

00:42:29.100 | maybe even higher than sort of high end of chart,

00:42:35.120 | or even above high end ApoB,

00:42:39.120 | but there's some sort of demand, metabolic demand,

00:42:42.660 | or they're weight training a lot,

00:42:45.140 | or they're running marathons,

00:42:46.480 | and so they need a lot of LDL.

00:42:48.480 | The reason I ask this is because it's so easy

00:42:52.480 | for the uninformed person,

00:42:54.800 | which I include myself in that group,

00:42:56.560 | to just think here, oh, LDL bad, cholesterol bad, ApoB bad,

00:43:01.560 | when in fact you very graciously spelled out the fact

00:43:06.440 | that these things actually perform a functional role

00:43:10.460 | in the healthy body.

00:43:11.680 | So before we get into why they are or can be bad,

00:43:15.220 | why would you want a low density lipoprotein?

00:43:17.580 | What is that doing for somebody?

00:43:19.380 | And is there any circumstance

00:43:22.260 | where the way people are exercising,

00:43:25.100 | or thinking, or not sleeping, or sleeping too much,

00:43:28.380 | it's that a higher level actually reflects

00:43:30.680 | a healthy metabolic need?

00:43:32.500 | - We don't have any evidence of that to date.

00:43:35.480 | All of the functions that I described

00:43:39.400 | can be done by the HDL.

00:43:43.680 | So the high density lipoproteins,

00:43:45.500 | the ApoAs, can do all of it.

00:43:48.440 | - So ApoB and low density lipoproteins are just,

00:43:51.600 | they're just the necessary, the waste.

00:43:57.320 | - No, we don't understand why we have them, Andrew.

00:43:58.900 | This is the part that's really interesting to me.

00:44:01.960 | Most species do not even have ApoB.

00:44:05.680 | And as a result of that,

00:44:07.600 | most species are chemically incapable of atherosclerosis.

00:44:12.600 | - So if someone could zero out their ApoB and their LDL,

00:44:16.920 | we assume they would function just fine.

00:44:20.080 | - We know they would because we have certain people

00:44:22.660 | who walk around with genetic mutations

00:44:24.540 | that render them that way.

00:44:26.540 | - Wow.

00:44:27.380 | - Furthermore, we also know that,

00:44:30.000 | there's a bit of a myth out there that cholesterol,

00:44:32.440 | the cholesterol you measure in your blood is essential

00:44:35.440 | for brain health, for example.

00:44:36.800 | That's an understandable thing, right?

00:44:37.920 | You can speak to this very eloquently,

00:44:39.680 | the role of cholesterol in the brain.

00:44:41.640 | - Yeah, I wrote down when I was a postdoc at Stanford,

00:44:45.540 | so I always point out, I was born at Stanford,

00:44:48.400 | trained at Stanford, where he said I'd probably die

00:44:49.840 | at Stanford, hopefully a long time from now.

00:44:51.400 | You'll tell me how long from now.

00:44:52.240 | - Well, we're gonna do the Charlie Munger thing

00:44:54.480 | and make sure that you never go back to Stanford

00:44:56.720 | so that you can't die there.

00:44:58.280 | - There, exactly.

00:44:59.720 | We cured already.

00:45:02.200 | When I was a postdoc, I worked with a guy named Ben Baras,

00:45:06.320 | who I know you know, probably as a different person then,

00:45:10.440 | for reasons that people can look up Ben's name.

00:45:13.060 | Anyway, incredible scientist,

00:45:15.200 | but there was someone in his lab that discovered

00:45:17.400 | that cholesterol is a critical component

00:45:20.760 | of the synaptogenesis process,

00:45:23.560 | the formation of connections between neurons

00:45:25.360 | in the developing brain.

00:45:26.480 | And then that went on to lead to the discovery

00:45:29.720 | of things like thrombospondins being important

00:45:32.560 | for synaptogenesis, et cetera.

00:45:34.080 | But cholesterol sits central

00:45:35.560 | in the brain development mechanisms.

00:45:37.560 | You want cholesterol around for brain development.

00:45:40.580 | In fact, I think very low-fat diets

00:45:42.440 | and very low-cholesterol diets during early development

00:45:45.520 | can really impair brain development, as I understand.

00:45:47.960 | - Yeah, it's not entirely clear why,

00:45:49.640 | but here's what we know.

00:45:50.980 | When you're born, your serum cholesterol levels are very low.

00:45:55.860 | So children, infants and children, have very low levels

00:46:00.860 | of cholesterol.

00:46:01.920 | They would have, and I should explain one thing

00:46:04.900 | that's important.

00:46:05.740 | - Well, they're not myelinated yet, right?

00:46:07.240 | I mean, sorry to interrupt, but myelin, of course,

00:46:10.160 | the sheathing around neuronal axons,

00:46:13.860 | which accelerates the propagation of nerve signals

00:46:16.320 | and which is deficient in things like multiple sclerosis,

00:46:19.660 | is essentially fat made up of phospholipids

00:46:22.260 | and requires cholesterol for synthesis.

00:46:25.380 | But young children are not very well myelinated.

00:46:27.420 | I mean, the spinal cord is myelinated.

00:46:29.420 | Spinal tracts are myelinated.

00:46:30.420 | - So this is what's interesting, right?

00:46:31.860 | We would all agree that cholesterol is more important

00:46:35.980 | to infants and children than to anybody else, right?

00:46:39.180 | It would be the most important substrate

00:46:41.400 | for CNS development, and yet infants and children

00:46:45.920 | have virtually unmeasurable levels of cholesterol.

00:46:49.140 | It really starts to take off in your teenage years, right?

00:46:51.620 | So cholesterol basically, serum cholesterol levels rise

00:46:54.620 | basically monotonically throughout life.

00:46:56.760 | Women get a big bump at menopause,

00:47:00.720 | so it really goes up for them.

00:47:02.220 | But what's interesting is how is it,

00:47:07.240 | how do we reconcile the fact that infants and children

00:47:10.500 | have really low levels of serum cholesterol

00:47:13.320 | yet clearly undergo CNS maturation without any problems?

00:47:18.320 | And it basically comes down to the following.

00:47:21.380 | What you measure in the serum is but a fraction

00:47:25.920 | of the total body pool of cholesterol.

00:47:28.260 | So we get a little bit of the light under the,

00:47:31.920 | what's the street lamp under the--

00:47:34.560 | - The drunk under a--

00:47:35.400 | - The drunk under the street lamp problem.

00:47:37.100 | Just because we're looking there,

00:47:38.400 | we tend to think that that's what we're seeing.

00:47:39.980 | But if you took the entire circulatory pool of cholesterol,

00:47:44.980 | it's about 10% of your total body cholesterol.

00:47:48.500 | It's a tiny fraction of it.

00:47:50.180 | So it's what we measure 'cause that's all we have access to,

00:47:53.160 | but it really represents virtually none of it.

00:47:55.500 | I do wanna say something 'cause you mentioned LDL.

00:47:58.620 | I wanna tie this back to the reader, right,

00:48:00.420 | or the listener rather.

00:48:01.620 | ApoB refers to the lipoprotein, the singular lipoprotein

00:48:08.640 | wrapped around an LDL particle.

00:48:11.860 | So if you happen to be lucky enough

00:48:14.680 | that your doctor measures an ApoB level, it's a blood test.

00:48:18.860 | It says ApoB X number of milligrams per deciliter.

00:48:22.900 | That's measuring the concentration of that protein.

00:48:25.980 | It is a direct measurement of the concentration

00:48:29.340 | of LDL and VLDL particles.

00:48:33.080 | When you have a blood test that says LDL,

00:48:35.940 | it usually doesn't say LDL.

00:48:37.460 | It usually says LDL-C or LDL cholesterol

00:48:40.460 | because LDL is not a laboratory measurement.

00:48:43.220 | LDL cholesterol is a laboratory measurement.

00:48:46.040 | And it's just taking the total number of LDL particles,

00:48:49.740 | breaking them apart,

00:48:51.180 | and measuring how much cholesterol is in them.

00:48:53.740 | So LDL-C measures the total concentration of cholesterol

00:48:58.320 | in the LDLs.

00:49:00.120 | ApoB measures the number of them.

00:49:03.860 | And they're different, but one of them is far superior

00:49:07.280 | at predicting risk in its ApoB.

00:49:10.300 | The number of particles is much more predictive of risk

00:49:13.920 | than the amount of cholesterol contained within them.

00:49:16.520 | - Fascinating.

00:49:19.080 | First time I've understood HEL-LDL

00:49:22.160 | and these lipoproteins in a way that makes sense.

00:49:24.880 | So thank you.

00:49:26.140 | I'm sure others feel the same way.

00:49:28.780 | What ApoB level is your red flag cutoff, right?

00:49:33.780 | I actually had my ApoB measured recently

00:49:37.900 | and I'm definitely above the high end.

00:49:39.540 | - We'll be discussing this over dinner on Saturday night.

00:49:42.600 | And just to tie this back,

00:49:45.760 | I hope that's a steak dinner and that should be fine

00:49:47.960 | given the fact that dietary cholesterol

00:49:49.720 | has no direct link to ApoB and LDL.

00:49:51.840 | - That's true, but dietary saturated fat does.

00:49:54.500 | - Okay, so I'll-

00:49:55.340 | - Which is not to say we're not going to have a steak.

00:49:56.560 | We will, but-

00:49:57.880 | - Not necessarily one of the fattier cuts.

00:50:00.780 | Although probably will be for me.

00:50:03.040 | So what's the high end that you, high end flag?

00:50:08.440 | At what point do you start saying,

00:50:09.520 | "Ah, we need to do something."

00:50:10.720 | And then we'll talk about what people can do.

00:50:12.560 | - Yeah, so this is a complicated question

00:50:14.600 | because it depends on so many factors.

00:50:17.720 | The first factor it depends on is what is your objective?

00:50:20.960 | And I do pose this question directly to a patient, right?

00:50:24.080 | So I say, look, we've got this disease

00:50:26.600 | that's the number one cause of death.

00:50:29.000 | Now you can die with it or you can die from it.

00:50:32.460 | Those are your choices.

00:50:35.560 | Statistically speaking, more people will die from it

00:50:38.720 | than anything else.

00:50:39.920 | But if you live long enough,

00:50:40.880 | we will all die with it to some extent.

00:50:43.220 | So if you're me and I come from a family history,

00:50:48.320 | as you know, I write about this in the book,

00:50:50.040 | where basically every man in my family except one

00:50:52.920 | has died of atherosclerosis

00:50:54.160 | and they have all done so very prematurely.

00:50:56.940 | My dad's lost brothers in their 40s and 50s.

00:51:00.520 | By some miracle, my dad is still alive at 86,

00:51:04.800 | but I think that's in large part

00:51:06.720 | because he at least had the good sense to listen to doctors

00:51:11.320 | and take medication to lower his cholesterol

00:51:13.320 | and blood pressure.

00:51:14.320 | If your objective is to not die from heart disease

00:51:21.320 | and only to die with it,

00:51:24.040 | then you want ApoB as low as possible.

00:51:27.440 | Now, how low you go depends on when you start,

00:51:32.440 | because one way to think about this

00:51:34.960 | is it's an area under the curve problem.

00:51:37.680 | The longer you wait to start doing something about this,

00:51:42.460 | the more aggressively you need to do something about it.

00:51:45.660 | I think a better way to think about this though

00:51:50.320 | is to go back to what we talked about with smoking.

00:51:53.400 | So would you agree that smoking is causally related

00:51:58.400 | to lung cancer?

00:52:00.380 | - Yes.

00:52:01.220 | - So just to be clear, Andrew,

00:52:02.760 | you do not think that it's just an association

00:52:05.960 | that smokers get more lung cancer?

00:52:07.700 | - No, I do not.

00:52:09.560 | - In other words, you believe that smoking

00:52:12.720 | causes lung cancer then?

00:52:14.800 | - Yes.

00:52:15.880 | I mean, there are a number of mechanistic steps in between.

00:52:18.900 | I mean, if somebody was really wanting to drill

00:52:22.640 | into the logic, they could say,

00:52:23.840 | okay, it's not actually the smoking,

00:52:25.080 | it's some disruption of the endothelial cell lining that--

00:52:30.600 | - Smoking triggers that, it triggers that.

00:52:32.880 | - I assume so.

00:52:33.720 | - And I agree with you, by the way.

00:52:34.680 | I think the data are very clear.

00:52:35.840 | - I'm very relieved to hear that.

00:52:37.680 | - But I'm going someplace very important here

00:52:40.160 | because if there's one topic that doesn't get enough

00:52:44.120 | attention in medicine, it's causality.

00:52:46.960 | And causality is an obsession of mine.

00:52:51.460 | Like most of the day on some level,

00:52:55.000 | I sit around thinking about causality.

00:52:58.060 | And I think the hardest part about studying medicine

00:53:03.060 | with respect to human beings is how difficult it is

00:53:06.460 | to infer causality for most things that we do.

00:53:10.080 | So if you believe that smoking is causally related

00:53:16.180 | to lung cancer, then smoking cessation

00:53:22.660 | reduces the probability of lung cancer.

00:53:26.160 | That is a logical equivalency.

00:53:29.020 | There can be no debate about that.

00:53:31.060 | What if I said to you, Andrew, this is going to be

00:53:35.040 | our new philosophy around smoking cessation.

00:53:38.280 | You're gonna anoint you the czar of smoking cessation.

00:53:42.980 | So if people pick up smoking, no problem.

00:53:47.060 | We're gonna let them smoke.

00:53:48.640 | But we're going to assess their risk for lung cancer

00:53:53.260 | using a model that predicts when their 10-year risk

00:53:57.180 | of lung cancer gets above a certain level,

00:53:59.860 | we're gonna recommend that they stop smoking.

00:54:02.180 | So we're gonna look at their age, their sex,

00:54:04.140 | their family history, some biomarkers that might help us.

00:54:07.660 | We're gonna even do scans of their lungs.

00:54:10.380 | And once we think they cross a threshold

00:54:13.720 | where their risk of lung cancer is high enough,

00:54:15.620 | let's just say it's 25%, boom, you make them stop.

00:54:19.420 | You tell them it's time to stop.

00:54:21.340 | Is that a logical approach to treating smoking

00:54:25.460 | and lung cancer or would it be better to say,

00:54:28.340 | given that we know cigarettes are causally related to this,

00:54:32.860 | how about you never start smoking and the minute you do,

00:54:35.980 | we pull the cigarette out of your mouth

00:54:37.460 | and explain to you that you're doing something

00:54:39.660 | that is causally related.

00:54:41.660 | Of course it would be the latter, not the former.

00:54:43.580 | It would be idiotic to suggest that we endorse smoking

00:54:47.740 | until you cross a certain threshold.

00:54:50.720 | Well, this now becomes the germane question.

00:54:54.420 | There is no ambiguity that APOB

00:54:57.160 | is causally related to atherosclerosis.

00:55:00.340 | How can I tell you that?

00:55:03.460 | I can tell you that looking at

00:55:05.160 | all of the clinical trial literature,

00:55:07.060 | all of the epidemiologic literature,

00:55:09.680 | and perhaps even most importantly,

00:55:11.480 | the Mendelian randomizations.

00:55:13.860 | All of these things tell us, because by the way--

00:55:16.940 | - Mendelian randomizations meaning genetic mutants,

00:55:19.620 | humans out there that make very little APOB

00:55:21.960 | or excessive APOB. - And very much, exactly.

00:55:23.320 | So we have a whole gradient.

00:55:24.160 | - So you can say if you make very little,

00:55:25.980 | you aren't gonna die as quickly in your life

00:55:29.880 | as if you make too much.

00:55:30.980 | - That's right.

00:55:31.820 | So Mendelian randomization is such an elegant tool

00:55:33.880 | where you basically let genes do the randomization

00:55:37.900 | and as you said, there is a gradation of LDL concentration

00:55:42.020 | or APOB concentration that occurs from insanely low

00:55:45.640 | to insanely high and this is a wildly polygenic,

00:55:49.420 | polymorphic set of conditions

00:55:51.580 | and we can look at the outcomes of those people

00:55:55.260 | based on the random sorting of those genes

00:55:57.540 | and there's no ambiguity.

00:55:59.260 | LDL is causally related.

00:56:01.660 | LDL cholesterol or APOB,

00:56:03.340 | causally related to atherosclerosis.

00:56:05.900 | Well, if that's true,

00:56:09.380 | and I haven't seen a credible argument that it's not,

00:56:12.280 | there are people who argue that it's not, by the way,

00:56:15.420 | but they just don't have credibility in their arguments,

00:56:17.740 | then you have to say

00:56:20.380 | that what we're doing in medicine today is very backwards

00:56:23.300 | because what we're doing in medicine today is the following.

00:56:26.540 | We're saying, I'm coming at this in a long way,

00:56:29.780 | but your question is so important

00:56:31.300 | that I wanna answer it this way.

00:56:32.700 | We're answering your question today as follows.

00:56:35.080 | We're saying, Andrew, let's do a 10-year risk calculation

00:56:40.080 | of your risk of MACE.

00:56:42.900 | MACE stands for Major Adverse Cardiac Event.

00:56:45.820 | It is the metric we use in medicine.

00:56:48.780 | So a major adverse cardiac event is a heart attack,

00:56:51.340 | stroke, or death basically resulting from these things.

00:56:55.300 | And we have calculators that are pretty good

00:56:59.260 | at predicting your 10-year event risk.

00:57:02.860 | They'll look at your cholesterol levels,

00:57:05.040 | your blood pressure, they'll ask if you smoke,

00:57:07.540 | they'll ask some family history questions,

00:57:09.780 | and they'll spit out a number.

00:57:11.780 | Now, we should do yours after the fact.

00:57:15.620 | And I don't know, if we did it for a person

00:57:19.260 | who's is, you know, you're in your mid-40s,

00:57:21.280 | like it would probably spit out less than 5% risk

00:57:26.060 | for a major adverse cardiac event in the next 10 years.

00:57:28.860 | In fact, the models don't even work if age is below 40.

00:57:33.860 | So the first time I went to do one of these tests

00:57:37.420 | when I was in my mid-30s, I couldn't do it.

00:57:40.340 | Like, the algorithm breaks.

00:57:42.780 | That's sort of like, you know, just doesn't work.

00:57:44.460 | So the implication there is if you're,

00:57:48.040 | if your MACE risk is less than 5%,

00:57:52.940 | the thinking is you do not need to treat LDL or ApoB.

00:57:56.340 | I argue that that makes absolutely no sense.

00:58:00.340 | It's just as idiotic as the analogy I used around smoking.

00:58:04.560 | If a risk is causal and it is modifiable,

00:58:08.460 | it should be modified regardless

00:58:10.660 | of the risk tail in duration.

00:58:13.900 | So then the question becomes to what level?

00:58:17.460 | And again, the earlier you start,

00:58:19.100 | the less aggressive you need to be,

00:58:20.820 | the less damage that's there already.

00:58:22.900 | So for example, we do CT angiograms on our patients.

00:58:26.140 | If the CT angiogram shows no evidence of calcification,

00:58:29.260 | no evidence of soft plaque, that means grossly,

00:58:32.780 | their coronary arteries are still normal.

00:58:34.700 | Histologically, they're probably not

00:58:36.260 | because nobody probably makes it to our age

00:58:38.980 | with histologically perfect coronary arteries.

00:58:42.620 | You know, we might be satisfied with a person's ApoB

00:58:46.300 | being at the fifth percentile of the population,

00:58:48.420 | which would be about 60 milligrams per deciliter.

00:58:51.260 | But if we have any other factors,

00:58:55.020 | meaning we're starting later in life,

00:58:57.460 | or a person already has gross evidence of disease,

00:59:02.140 | calcification, soft plaque, family history is significant,

00:59:06.140 | any other risk factors are present,

00:59:08.740 | I mean, we'll treat ApoB to 30 to 40 milligrams per deciliter,

00:59:12.900 | which is, you know, probably the first percentile.

00:59:15.020 | - And if somebody's sitting up in the, say, low 130s,

00:59:18.200 | what kind of flag does that raise for you?

00:59:21.940 | And I realize it's highly contextual, age, et cetera.

00:59:24.820 | - No, no, it's a huge red flag.

00:59:26.380 | Again, just because something is causal

00:59:29.300 | doesn't mean you're guaranteed to get it.

00:59:31.300 | There are smokers who don't get lung cancer.

00:59:33.060 | So, you know, there's gonna be somebody listening to this

00:59:35.220 | who says, my grandmother's 95 years old,

00:59:39.100 | she's is, her cholesterol is sky high

00:59:41.620 | and she's alive and well, and I will say, absolutely,

00:59:44.300 | there are a lot of people walking around that way,

00:59:46.220 | just as there are a lot of smokers walking around

00:59:48.580 | who don't get lung cancer.

00:59:50.460 | You can't, you can't impute these things

00:59:55.480 | on an individual basis.

00:59:57.260 | You basically have to ask the question,

00:59:59.860 | how do I make the best judgment about an individual

01:00:04.060 | from heterogeneous population data

01:00:07.620 | and based on what are causal

01:00:09.800 | and non-causal inferences around risk?

01:00:12.300 | So, you know, to me, if a person has very high ApoB

01:00:17.300 | and they do not want to be treated for it,

01:00:21.460 | then the best we would do is say,

01:00:23.020 | let's at least establish that there are no other

01:00:25.220 | risk factors present and let's at least

01:00:28.000 | do the most investigation we can around the existing damage.

01:00:32.780 | And if that person has a perfect CT angiogram,

01:00:36.780 | I'm gonna push less hard than if they have

01:00:38.780 | a devastating angiogram.

01:00:40.460 | And by the way, devastating in my book

01:00:42.460 | is just any amount of calcification or soft plaque.

01:00:45.060 | Anything that shows up grossly that you can see

01:00:47.820 | on a CT scan means that you've got a decade plus

01:00:51.620 | of really bad histology building up to it.

01:00:53.940 | - This issue of causality, I think now,

01:00:58.060 | becomes very clear as to why that is so crucial

01:01:01.780 | and I really appreciate the way you spelled that out.

01:01:04.520 | So let's say somebody's ApoB is, you know, 80, 100,

01:01:09.520 | let's say 130, for example.

01:01:14.380 | What sorts of things can they do to reduce that number?

01:01:17.880 | Is this always going to be prescription medication?

01:01:19.940 | And if so, what are the more common forms

01:01:22.140 | of prescription medication that work best?

01:01:24.380 | What are their side effect profiles and so on?

01:01:27.700 | - So, yeah, usually once you want to start getting down

01:01:31.460 | into the 30 to 60 range,

01:01:33.260 | you're gonna require pharmacotherapy.

01:01:35.240 | But, you know, usually we want to see how far we can get

01:01:38.840 | with nutrition.

01:01:39.680 | So fixing insulin resistance in an insulin resistant person

01:01:44.040 | will bring this down, right?

01:01:46.060 | So one of the hallmarks of insulin resistance

01:01:47.940 | is elevated triglycerides.

01:01:50.020 | They haven't, we haven't talked about triglycerides,

01:01:51.660 | but they warrant some attention

01:01:54.220 | because I mentioned it earlier,

01:01:56.780 | but one of the other things that the lipoproteins carry

01:01:59.860 | is triglycerides.

01:02:01.040 | So they're, you're carrying fat and cholesterol.

01:02:03.500 | And if you recall, ApoB represents the number of particles.

01:02:09.640 | So the purpose of them is to be carrying around

01:02:12.940 | mostly cholesterol,

01:02:14.100 | but if you have a high amount of triglyceride,

01:02:16.760 | you're basically using up cargo space on the ships.

01:02:19.640 | And so you need more ships.

01:02:22.540 | So if a person has elevated triglycerides,

01:02:25.080 | and I consider anything over a hundred to be elevated,

01:02:28.300 | even though most laboratory tests would consider normal

01:02:30.820 | to be up to 150 milligrams per deciliter,

01:02:33.580 | we would want to fix their insulin resistance,

01:02:38.260 | bring the TRIGs way down.

01:02:40.640 | I would want to see TRIGs no more than two times

01:02:44.280 | the HDL cholesterol.

01:02:45.340 | So if their HDL cholesterol is, you know,

01:02:48.520 | 60 milligrams per deciliter,

01:02:51.080 | I consider 120 to be through the roof high.

01:02:54.920 | And ideally we want TRIGs at or below HDL cholesterol.

01:02:58.880 | - TRIGs being triglycerides.

01:02:59.960 | - That's right.

01:03:00.800 | - And does that mean lowering dietary fat?

01:03:04.240 | - No, actually it's most easily accomplished

01:03:06.840 | through carbohydrate restriction.

01:03:08.340 | Yeah, carbohydrate.

01:03:09.780 | Triglycerides in some ways are kind of an integral

01:03:11.960 | of carbohydrate consumption.

01:03:13.320 | Any energy restriction will get it for you,

01:03:17.340 | but it's most sensitive to restriction of,

01:03:22.000 | even under eucaloric conditions,

01:03:24.520 | carbohydrate restriction will lower triglycerides.

01:03:27.460 | So again, energy restriction would be kind of

01:03:29.880 | first order of business,

01:03:32.000 | but within that carbohydrate restriction

01:03:33.660 | will probably get you there quicker.

01:03:35.700 | So, you know, you sort of take the low-hanging fruit

01:03:38.840 | off the table.

01:03:39.680 | - And where does exercise play a role?

01:03:42.600 | - Minimal role.

01:03:43.520 | - For improving insulin sensitivity?

01:03:45.040 | - No, no, no, I'm sorry.

01:03:45.880 | For improving lipids in general, yeah.

01:03:48.920 | - But it can improve insulin sensitivity?

01:03:50.880 | - Absolutely, yeah.

01:03:51.720 | - Especially combinations of resistance training

01:03:53.600 | and cardiovascular exercise, correct?

01:03:55.360 | - Yeah.

01:03:56.180 | So once it comes down to pharmacotherapy,

01:03:59.800 | you basically have several classes of drugs.

01:04:01.640 | So the most obvious and the one that most people

01:04:03.200 | are aware of are called statins.

01:04:04.280 | So statins work both directly and indirectly on the problem.

01:04:08.280 | So directly they work by targeting an enzyme

01:04:11.700 | very high in the synthetic pathway of cholesterol production.

01:04:17.840 | Enzyme is called HMG-CoA reductase,

01:04:20.500 | and I think it's the second committed step.

01:04:23.160 | I could be wrong on that.

01:04:24.060 | I don't think it's the first committed step,

01:04:25.640 | but that enzyme gets targeted kind of ubiquitously

01:04:29.520 | throughout the body.

01:04:30.820 | And in response to that, the liver senses a reduction

01:04:35.400 | in the body's pool of cholesterol.

01:04:37.720 | And the liver really tries to regulate this.

01:04:39.640 | So the liver in response to that

01:04:41.840 | increases its expression of LDL receptors.

01:04:46.100 | So the liver itself has LDL receptors on its surface.

01:04:49.480 | And as the body's pool of cholesterol goes down,

01:04:52.840 | the liver senses this reduction and says,

01:04:54.820 | "I wanna bring more cholesterol in."

01:04:56.900 | More LDL receptors go up and more ApoB particles

01:05:00.260 | are coming out of circulation.

01:05:01.840 | So that's really the dominant way that they work.

01:05:04.420 | And in fact, that's kind of a dominant way

01:05:06.200 | that all of these drugs work.

01:05:07.580 | So another class of drug is called ezetimibe.

01:05:10.940 | It works by blocking,

01:05:13.660 | we could get as technical as you want on this.

01:05:15.160 | It's called the Nieman-Pix C1-Lyke-1 transporter

01:05:17.660 | in the enterocyte.

01:05:18.920 | I like to explain this.

01:05:21.140 | I borrowed this explanation from Tom Dayspring.

01:05:23.380 | But the enterocyte is obviously the luminal gut-side cell

01:05:28.380 | that is responsible for absorption of cholesterol.

01:05:32.620 | Remember I said earlier,

01:05:33.460 | most of the cholesterol you eat, you don't absorb.

01:05:36.020 | The reason you can't absorb it

01:05:37.540 | is an esterified cholesterol molecule

01:05:40.260 | cannot come in the Nieman-Pix C1-Lyke-1 transporter.

01:05:44.220 | It's physically too large.

01:05:46.300 | But the cholesterol that you synthesize,

01:05:48.540 | which once it makes its way back to the liver,

01:05:51.260 | gets secreted in bile down the intestine,

01:05:54.460 | that is unesterified and readily fits into that transporter.

01:05:58.480 | So I kind of describe that guy

01:06:00.060 | as the ticket taker at the bar.

01:06:02.140 | He lets everybody in as long as they fit through the door.

01:06:05.700 | There's a checkpoint inside the bar that basically says,

01:06:08.180 | do we have too much cholesterol?

01:06:09.660 | If so, spit it out.

01:06:10.880 | And there's another door that acts more like the bouncer,

01:06:14.120 | and he's called the ATP binding cassette G5-G8,

01:06:16.840 | and he spits excess cholesterol out.

01:06:19.300 | And if that system's working fine,

01:06:20.780 | everything is great, but in a lot of people,

01:06:22.940 | that ATP binding cassette doesn't work very well,

01:06:25.660 | and it can't properly regulate

01:06:27.220 | the total body pool of cholesterol.

01:06:29.180 | So there's a drug called ezetimibe

01:06:30.820 | that simply blocks the ticket taker.

01:06:33.380 | - Are there side effects to statins and ezetimibe?

01:06:36.820 | - Ezetimibe has virtually no side effects.

01:06:39.740 | You can think of it as a drug

01:06:40.620 | that's acting outside the body, right?

01:06:42.660 | It's sort of acting on a turnstile door in your gut.

01:06:48.140 | I have seen one patient get sort of loose stools from it

01:06:52.420 | that became enough of an issue that we discontinued it.

01:06:55.940 | I would say that when ezetimibe is combined with a statin,

01:06:59.140 | which is very commonly done, it's not unheard of.

01:07:04.140 | I can't give you a number, but it could be as high as 10%

01:07:07.980 | that you see an elevation in transaminases,

01:07:10.900 | which are enzymes that are made by the liver

01:07:12.640 | in response to some irritation.

01:07:14.300 | So this is where I think it's unclear

01:07:17.320 | what the clinical significance of that is.

01:07:19.040 | We tend to abort the strategy

01:07:21.060 | in the presence of elevated transaminases.

01:07:24.820 | Even though the literature says you don't need to,

01:07:28.080 | our view is we have other options.

01:07:29.860 | Why would we tolerate any inflammation if you don't need to?

01:07:33.780 | Statins do have side effects.

01:07:35.980 | So 5% of people genuinely and legitimately

01:07:39.980 | get a muscle soreness that can be debilitating.

01:07:43.480 | It could feel like kind of the worst workout

01:07:45.140 | you've ever had that, you know,

01:07:46.500 | like the day after you've,

01:07:47.980 | like imagine you hadn't lifted weights in six months

01:07:50.620 | and then you, you know, came over

01:07:52.800 | and I made you do the most brutal workout of your life.

01:07:54.980 | You know how you would feel the next day?

01:07:55.820 | - That happens every time I come over to,

01:07:56.820 | well, I work out often,

01:07:58.480 | but every time I come over to your house,

01:08:01.140 | you put me through the most brutal workout

01:08:02.940 | I've ever been through.

01:08:04.380 | I think you and Cam Haines are the two people

01:08:06.420 | who've managed to put me through workouts

01:08:08.000 | that kept me sore for at least two weeks after each visit.

01:08:12.180 | - So that soreness, imagine you would have that persisting

01:08:16.420 | 5% of people get that response from a statin.

01:08:19.020 | And obviously that's just non, you know,

01:08:20.500 | it's a non, it's a non, it's a non do.

01:08:23.680 | There's a narrower subset of people

01:08:26.140 | that do, do get brain fog

01:08:29.540 | and do experience brain fog from statins.

01:08:31.380 | And we don't really understand the why there.

01:08:33.900 | We have some theories as to why, you know,

01:08:35.840 | maybe they're, maybe they're getting too much of a reduction

01:08:40.260 | in central cholesterol synthesis.

01:08:44.920 | - Again, it's a subjective finding,

01:08:46.520 | but given that we have so many tools in the toolkit,

01:08:49.440 | like we don't have to tolerate side effects

01:08:51.240 | with these drugs anymore.

01:08:52.240 | There was a day when, you know,

01:08:53.960 | you had somebody who just had a heart attack

01:08:56.200 | and they're basically looking down the barrel

01:08:58.060 | of being on a statin for the rest of their life.

01:09:00.000 | And there were like two of them and they, you know,

01:09:01.720 | had tons of side effects and it didn't matter.

01:09:04.660 | Today, while there were probably nine statins out there,

01:09:08.000 | there were really only four that we even use.

01:09:10.600 | And at least two of them have such a low side effect profile.

01:09:13.980 | They're not as potent, but they have a,

01:09:15.360 | I mean, potent's a bit of the, potent's the wrong word.

01:09:18.360 | They don't have the same effect, but they're very potent

01:09:22.580 | because you're, at least one of them,

01:09:23.580 | you're taken at such a low dose

01:09:25.880 | that we've got lots of statin options.

01:09:27.900 | The third side effect of statins, which again, not common,

01:09:32.360 | but can't be ignored is insulin resistance.

01:09:35.780 | So it really, and this is one of the,

01:09:38.680 | I think one of the benefits of at least having

01:09:41.120 | periodic CGM tracking is we'll see this.

01:09:44.180 | We had a patient who happened to be wearing CGM in general,

01:09:47.860 | and then we started him on 10 milligrams of resuvastatin,

01:09:51.100 | which is probably the workhorse statin right now.

01:09:53.980 | That's a generic term for Crestor.

01:09:55.960 | And he pings us like a couple weeks later and he's like,

01:10:00.160 | man, my glucose is like 10 points up consistently

01:10:03.300 | from where it has normally been.

01:10:04.900 | Kind of hummed and hawed.

01:10:06.620 | We troubleshooted a few things.

01:10:09.620 | After two months we're like, let's just stop the Crestor

01:10:12.560 | and see if that fixes it, and it immediately fixed it.

01:10:15.520 | So we reintroduced the Crestor and it happened again.

01:10:18.460 | So there was no doubt in my mind that,

01:10:20.760 | or low doubt in my mind that Crestor

01:10:22.640 | was responsible for that.

01:10:24.680 | And again, you could say, well,

01:10:25.640 | maybe that's not that clinically significant,

01:10:27.340 | but I would argue, why bother?

01:10:28.960 | I have other choices.

01:10:30.300 | So those are your two big ones.

01:10:32.280 | The next one that is really the big one

01:10:34.120 | are PCSK9 inhibitors.

01:10:35.800 | So you know, gosh, coming up about 20 years ago maybe,

01:10:40.800 | a woman named Helen Hobbs made a discovery

01:10:45.380 | of a group of people that had a disease

01:10:48.520 | called familial hypercholesterolemia.

01:10:50.060 | So FH, or familial hypercholesterolemia,

01:10:52.840 | is a very genetic heterogeneous condition.

01:10:56.500 | Going back to that Mendelian randomization study,

01:10:58.420 | these are the people on the far end

01:10:59.960 | that show us how high lipid levels cause atherosclerosis.

01:11:04.280 | So these people have very high cholesterol levels,

01:11:06.460 | typically north of 300 milligrams per deciliter.

01:11:09.200 | Their LDL cholesterol alone is, by definition,

01:11:11.540 | at least 190 milligrams per deciliter.

01:11:14.000 | Very high incidence of atherosclerosis in these people,

01:11:17.800 | along with other sort of injuries.

01:11:20.120 | Like they have so much cholesterol,

01:11:21.640 | they accumulate it in their tendons, in their eyes.

01:11:24.920 | It's a really devastating condition,

01:11:27.120 | if not managed correctly.

01:11:28.840 | And she discovered this mutation in a gene

01:11:33.320 | for PCSK9 that codes for a protein

01:11:36.280 | that degrades LDL receptors.

01:11:38.680 | So these people had hyperfunctioning PCSK9 genes.

01:11:43.680 | So their genes were just chomping down

01:11:46.320 | all the LDL receptors in the liver,

01:11:47.760 | so these people weren't clearing LDL.

01:11:49.840 | About five years later, another subset of the population

01:11:54.040 | were discovered that were the exact opposite.

01:11:55.800 | These people had hypofunctioning PCSK9.

01:11:59.000 | They had virtually unmeasurable,

01:12:00.520 | these people had LDL cholesterol levels

01:12:02.560 | 10 to 20 milligrams per deciliter.

01:12:04.680 | And not surprisingly, they had no heart disease.

01:12:07.460 | So that led to the development of a couple of amazing drugs

01:12:10.400 | that are now used.

01:12:11.240 | So I take one of these drugs.

01:12:12.560 | I've been taking one of these drugs for,

01:12:14.560 | I don't know, I probably started in 2015.

01:12:16.520 | So it's an injectable drug.

01:12:17.880 | I take it every two weeks,

01:12:19.360 | and it's called a PCSK9 inhibitor.

01:12:22.320 | So the drug blocks the protein,

01:12:25.800 | and therefore gives me more LDL receptors,

01:12:28.480 | yanks more APOB out of circulation.

01:12:30.560 | - Interesting, when we were talking about side effects,

01:12:32.980 | I was thinking, are there any short-term benefits?

01:12:37.980 | So I guess we'd call this positive side effects,

01:12:40.300 | but let's think of it more directly in line

01:12:42.280 | with the underlying biology.

01:12:43.740 | Let's say my APOB is high,

01:12:47.920 | mid-range to high,

01:12:49.760 | let's say 100, 80 to 100.

01:12:53.640 | And I improve my insulin resistance through nutrition,

01:12:59.140 | but we decide it doesn't go down so much,

01:13:01.120 | so we're going to continue to try and knock this number down.

01:13:04.180 | And I take any number of different drugs to reduce it.

01:13:09.180 | Do I immediately start to feel better?

01:13:11.280 | - Nope.

01:13:12.120 | - So there's no-- - You feel nothing.

01:13:13.460 | - Okay. - You feel nothing.

01:13:14.300 | - And I think that's an important point

01:13:17.680 | because of the causality issue

01:13:19.160 | that we were talking about earlier.

01:13:20.360 | Because a lot of people are walking around out there

01:13:22.960 | feeling fine, their APOB might be a bit high.

01:13:26.500 | They either know it or don't know it,

01:13:28.100 | but they think, well, I'm feeling fine.

01:13:30.280 | And you gave a very rational argument earlier

01:13:33.040 | as to why because of the causality involved,

01:13:36.000 | it makes far more sense to intervene.

01:13:38.320 | - Yeah, we don't want to rely on feeling

01:13:40.320 | when it comes to atherosclerosis,

01:13:41.660 | just to put some perspective on this.

01:13:44.120 | When I was in medical school,

01:13:45.880 | we had a, and I think I even write about this in the book,

01:13:48.840 | we had a pathology lecture

01:13:50.560 | where the professor stands up there and he says,

01:13:54.840 | "What is the most common presentation of a heart attack?"

01:13:59.840 | And you know, us keener first year med students,

01:14:02.380 | hands shoot straight up, chest pain.

01:14:05.020 | No, that's not the most common.

01:14:06.820 | Oh, shoulder pain, arm radiating down the left arm, no.

01:14:10.540 | Nausea, shortness of breath, no, no, no.

01:14:12.660 | We rattled this off for a few minutes.

01:14:14.500 | And he goes, "Death."

01:14:15.940 | The single most common presentation

01:14:20.580 | for a myocardial infarction is death.

01:14:23.500 | More people, now, I would say today,

01:14:26.960 | that was 25 years ago.

01:14:28.760 | Today, it's probably not the most common

01:14:33.040 | because advanced cardiac life support is so much better,

01:14:37.480 | but it's still strikingly common.

01:14:39.960 | - Well, you could say that the best predictor

01:14:44.040 | of a heart attack is still a heart attack.

01:14:46.720 | I mean, not saying that the best underlying predictor.

01:14:49.860 | And actually, this hits home when I was a postdoc,

01:14:52.120 | I was living in San Francisco,

01:14:53.080 | and I'll never forget this,

01:14:54.140 | taking my coffee out on my porch in the morning.

01:14:57.020 | This is right near the UCSF Parnassus campus.

01:14:59.520 | And this guy's walking down the street,

01:15:00.640 | he's probably about my age.

01:15:02.000 | And I said, "Hello."

01:15:02.920 | And he said, "Hello."

01:15:03.760 | He walked a few more steps and boom,

01:15:05.340 | he just hit the concrete and died right in front of me.

01:15:07.260 | It took a minute or two to know that he was truly dead.

01:15:10.660 | I'll never forget it because that's a,

01:15:12.300 | for a non-surgent, it's an event, right?

01:15:15.720 | And I followed up on this and because it's family,

01:15:18.160 | you know, the whole thing, 'cause they wanted a report

01:15:21.360 | and no cocaine in his system,

01:15:23.840 | no prior history of any kind of health issues.

01:15:27.100 | But he was just strolling along and just boom,

01:15:29.400 | as if he'd been hit by a bus.

01:15:31.160 | It's crazy. - Yeah, so it's, I mean,

01:15:33.640 | again, this is just one of those things where we're gonna,

01:15:37.200 | he's spent a lot of time talking about things

01:15:38.640 | that feel good and feel bad when you change them, right?

01:15:40.840 | Like if you take a person who's not sleeping well,

01:15:43.680 | but who thinks they're sleeping well,

01:15:45.240 | and you ask them for a leap of faith,

01:15:46.980 | which is, hey, give me a month

01:15:48.360 | to help you sleep really well,

01:15:50.280 | yeah, you're gonna feel better.

01:15:51.700 | You might not know it now

01:15:53.000 | because you don't know how bad you're sleeping now.

01:15:54.760 | You've become acclimated to this.

01:15:56.800 | But this is not one of those domains.

01:15:58.360 | You know, exercise, nutrition, sleep, all those things,

01:16:01.280 | when you do those things better, you feel better.

01:16:04.240 | But you know, I don't wanna overpromise on this.

01:16:06.820 | You're not gonna feel better in the moment

01:16:09.400 | when you fix your lipids,

01:16:10.960 | but you'll feel better when you don't have a heart attack.

01:16:13.720 | - So by all this logic,

01:16:14.900 | everybody should get their ApoB measured.

01:16:16.780 | How early in life should people do that?

01:16:18.680 | Starting in their 20s, in their 30s?

01:16:22.560 | - Certainly if you have a family history

01:16:24.400 | that is of any concern.

01:16:25.960 | Like if I could live my life over again,

01:16:29.000 | if I knew everything then that I know today,

01:16:31.640 | yeah, I would have had mine measured in my 20s.

01:16:34.040 | I didn't get my ApoB measured for the first time

01:16:37.200 | probably till I was in my 40s because that's,

01:16:41.400 | well, yeah, maybe late 30s, early 40s, right?

01:16:44.040 | I had my first calcium scan when I was 35,

01:16:47.480 | and I had to beg Borrow Steel to get it done

01:16:49.720 | 'cause everyone was like,

01:16:51.220 | why does a 35-year-old wanna do this?

01:16:53.100 | But I just felt something was wrong

01:16:56.160 | given my family history, and I'm glad I did.

01:16:59.840 | I'm glad I did that 'cause I learned something

01:17:01.360 | that completely changed the direction of my life.

01:17:03.920 | - Okay, I know my ApoB numbers and that I might be that guy

01:17:06.640 | who's up in the, you know, above 100,

01:17:08.580 | so I'm gonna get this treated.

01:17:10.160 | That's a promise to myself.

01:17:12.320 | I'd like to just take a brief moment

01:17:13.880 | and thank one of our podcast sponsors,

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01:17:25.700 | I've long been a believer in getting regular blood work done

01:17:28.000 | for the simple reason that blood work is the only way

01:17:30.960 | that you can monitor the markers such as hormone markers,

01:17:33.320 | lipids, metabolic factors, et cetera,

01:17:35.440 | that impact your immediate and long-term health.

01:17:38.160 | One major challenge with blood work, however,

01:17:40.280 | is that most of the time,

01:17:41.800 | it does not come back with any information about what to do

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01:18:15.600 | and therefore, there's extreme value

01:18:17.360 | to knowing your ApoB levels.

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01:18:20.760 | you can go to insidetracker.com/huberman

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01:18:30.480 | We covered the three major risk factors,

01:18:33.760 | which were blood pressure, keeping that in check,

01:18:37.680 | don't smoke, and ApoB,

01:18:40.640 | and we've now talked about the things to adjust ApoB levels.

01:18:44.540 | We did not really talk about things

01:18:46.360 | to adjust blood pressure.

01:18:47.460 | I'm assuming exercise sits as one of the foremost--

01:18:50.380 | - Exercise and nutrition, yeah.

01:18:51.220 | Weight management is a huge one here.

01:18:53.240 | So, you know, you take a person who's blood,

01:18:55.620 | and this is one of those things

01:18:56.760 | where we don't immediately jump on the pharmacotherapy train

01:18:59.560 | with blood pressure,

01:19:01.020 | because here there are side effects sometimes,

01:19:03.800 | and you do have to worry about overshooting.

01:19:06.740 | You don't really have to worry

01:19:07.580 | about overshooting a person's lipids.

01:19:09.360 | We do back off if we overshoot,

01:19:11.480 | but it doesn't cause a symptom.

01:19:12.900 | There's not a short-term immediate risk from doing that.

01:19:16.240 | If you overshoot somebody's blood pressure medication,

01:19:19.000 | you trade one problem for another problem.

01:19:20.960 | They become lightheaded when they get up to pee at night.

01:19:22.820 | They fall and bang their head.

01:19:24.040 | That's a devastating consequence, totally unacceptable.

01:19:26.740 | So our goal is to see how much we can lower blood pressure

01:19:30.560 | without medication before we turn to medication.

01:19:33.520 | And let's be clear, the meds today

01:19:36.080 | are so much better than they used to be.

01:19:39.240 | Again, there was a day

01:19:40.080 | when the side effects of these medicines were miserable.

01:19:43.160 | That's simply not the case today.

01:19:44.560 | I mean, ACE inhibitors, angiotensin receptor blockers,

01:19:47.720 | I mean, these things are very well tolerated,

01:19:50.160 | especially the ARBs.

01:19:51.560 | So again, almost anybody can be on these things,

01:19:56.000 | but if we could get a person to lose 10 pounds

01:19:58.600 | and exercise every day,

01:20:00.620 | we see great effects with zone two stuff, right?

01:20:02.840 | So kind of the low-intensity cardio.

01:20:04.800 | - And your recommendation there,

01:20:06.120 | I know you talk about this in the book,

01:20:07.360 | but I've thrown out numbers about 150 to 180 minutes per week

01:20:12.360 | you go a bit higher.

01:20:13.560 | - Yeah, we go 180 to 250, 240.

01:20:16.360 | Yeah, I'd like to see three to four hours a week

01:20:18.120 | of zone two.

01:20:18.960 | So that's an important piece,

01:20:21.560 | and sleep is an important piece.

01:20:23.800 | So get the sleep right, get the exercise right.

01:20:26.600 | If you're overnourished, let's correct that problem.

01:20:30.240 | And if all of that doesn't work,

01:20:32.400 | and by the way, that works a lot of the time,

01:20:34.880 | that works most of the time,

01:20:36.320 | if that doesn't work, then we've got pharmacotherapy.

01:20:38.320 | There is still a true phenomenon of essential hypertension,

01:20:41.160 | which is in individuals for whom all the fixable stuff

01:20:45.560 | has been fixed and they still have high blood pressure,

01:20:48.360 | we still have to medicate those folks.

01:20:50.520 | By the way, there's something that I want to mention here

01:20:52.080 | that doesn't get much attention, but it's so important,

01:20:55.480 | which is the effect of high blood pressure on the kidney

01:20:58.080 | and also the brain itself.

01:20:59.160 | We've talked about the brain, we've talked about the heart,

01:21:00.840 | but the kidney doesn't get enough attention.

01:21:02.960 | The kidney is a remarkable organ,

01:21:06.240 | and I think if you're really in this game

01:21:08.780 | of trying to live longer, right?

01:21:10.400 | If you think, hey, maybe we'll live 80, 85 years,

01:21:14.840 | but if we kind of start doing all of these other things

01:21:17.240 | and really optimizing our behaviors, that could be 95.

01:21:21.440 | Well, you have to start thinking

01:21:23.560 | about the capacity of the kidney.

01:21:26.040 | And once the glomerular filtration rate

01:21:29.240 | falls below a certain level,

01:21:32.000 | you have to be very careful with how you live your life.

01:21:35.520 | And unfortunately, this is one of those things

01:21:37.960 | that is another sort of mistake that's made

01:21:40.540 | in kind of modern medicine,

01:21:42.120 | which is we don't pay enough attention

01:21:44.040 | to how to measure kidney function correctly.

01:21:45.960 | We rely very heavily on something called creatinine

01:21:50.160 | as opposed to looking at another biomarker

01:21:51.920 | called cystatin C, which is far more accurate.

01:21:54.320 | And we also tolerate too low of a kidney function

01:21:57.760 | for a person's age.

01:21:58.920 | So we look at, you know, we might look at someone who's 50,

01:22:02.280 | whose kidney function is at 65%

01:22:06.600 | and say, you're totally fine.

01:22:07.920 | Because it's true that at 65%, there is no problem.

01:22:11.120 | But you're not thinking, well,

01:22:12.000 | if this person has to live another 40 years

01:22:14.440 | and this continues to go down,

01:22:16.320 | they're going to potentially be staring down the barrel

01:22:19.360 | of needing dialysis the last five years of their life.

01:22:22.160 | Again, you want to die with compromised kidney function,

01:22:26.220 | but never from compromised kidney function.

01:22:28.800 | In fact, the hazard ratio of all-cause mortality

01:22:31.240 | associated with compromised kidney function

01:22:33.300 | is even greater than that of heart disease.

01:22:36.240 | Once you cross that threshold, I mean, lights out.

01:22:39.500 | Once you are needing dialysis,

01:22:41.340 | I mean, your risk of death is higher than that

01:22:45.360 | of someone with high blood pressure, smoking,

01:22:47.700 | even someone who has cancer.

01:22:49.060 | You have a higher risk of death

01:22:50.640 | having end-stage renal disease than you do having cancer.

01:22:53.080 | So the kidney is so sensitive to blood pressure.

01:22:57.960 | This is a tiny organ that on every pump of your heart

01:23:02.200 | is getting 20 to 25% of your blood.

01:23:04.260 | So just imagine how sensitive and susceptible it is

01:23:09.280 | to elevated blood pressure.

01:23:11.360 | - We've covered quite a few corners

01:23:15.160 | of avoiding the major killer, arthrosclerosis.

01:23:19.580 | Let's talk about cancer.

01:23:22.400 | Nobody wants cancer.

01:23:25.420 | Everybody seems to know somebody who has had

01:23:27.720 | or has died of cancer, and probably no surprise

01:23:30.320 | given that it's number two on the list.

01:23:32.180 | What are the numbers and what can people do to offset cancer?

01:23:37.180 | And of course, there are a huge number

01:23:41.360 | of different types of cancer.

01:23:43.760 | And inside of this conversation, I just want to earmark

01:23:47.820 | that it might be good to have a conversation about alcohol,

01:23:51.680 | which we didn't talk about in the last discussion.

01:23:55.520 | But if alcohol is involved or is a risk factor rather

01:24:00.400 | for a cardiovascular disease or cerebrovascular disease,

01:24:03.360 | now would probably be the time to mention it.

01:24:06.400 | - Yeah, this has been looked at in a number of ways.

01:24:10.440 | And so if you look at sort of top line epidemiology,

01:24:15.280 | and you've heard of these things called the French paradox,

01:24:17.740 | which is, oh, come on, like they eat all of this fatty stuff

01:24:21.040 | and drink all this wine and they have a slightly lower risk

01:24:23.260 | of cardiovascular disease, you just have to kind of throw

01:24:25.980 | that stuff out the window 'cause there's so many confounders

01:24:28.300 | there that it's kind of useless epidemiology.

01:24:30.980 | If you really look at the data clearly,

01:24:32.840 | and there was actually a really elegant analysis

01:24:35.380 | that included some genetic studies that came out of JAMA

01:24:38.460 | about a year ago, it's actually pretty clear

01:24:42.220 | that there is no dose of ethanol that is healthy.

01:24:45.220 | Okay, so there's no J curve.

01:24:48.700 | So it used to, there used to be kind of this literature

01:24:51.500 | that said there's a J curve associated with ethanol.

01:24:54.600 | So meaning at total abstinence,

01:24:58.720 | there's a slightly higher risk of death

01:25:01.480 | than if you're drinking one drink a day,

01:25:04.320 | and then if you go beyond one drink a day,

01:25:06.020 | the rate of death starts to climb.

01:25:08.760 | The problem with that analysis,

01:25:10.000 | so there's just been a lot of consternation around that,

01:25:12.180 | but the problem with those analyses are multiple,

01:25:16.200 | but the most important of these are that the abstainers

01:25:19.960 | have a reason for abstaining typically,

01:25:23.000 | and those reasons can't be extracted statistically

01:25:26.660 | from these analyses.

01:25:28.780 | So I'll leave it at that without,

01:25:31.440 | I mean, I've written many blog posts about this.

01:25:33.640 | If people are really interested,

01:25:35.320 | they can go and talk about that.

01:25:36.600 | I also do talk about this a little bit in the book,

01:25:38.360 | by the way, but the short answer is there is no dose

01:25:43.360 | of ethanol that is healthy.

01:25:45.320 | I would argue that it's not a straight line of risk,

01:25:48.440 | but it probably goes, I think from zero to one,

01:25:50.960 | there's probably no measurable harm for most people.

01:25:55.280 | - One per day or one per week?

01:25:57.120 | - Probably one per day, up to one per day.

01:26:00.280 | It's probably very difficult to discern the harm,

01:26:03.320 | but I'm gonna put a caveat on that that I'll come back to,

01:26:06.160 | and then I think the risk starts to climb

01:26:08.000 | pretty steeply after that,

01:26:09.000 | and I think it climbs non-linearly after that.

01:26:11.760 | That is my reading of the literature.

01:26:14.220 | Okay, so then how do you decide

01:26:16.760 | if you're gonna have up to one drink a day?

01:26:19.120 | And by the way, that's not the same as seven a week,

01:26:21.560 | because that doesn't mean seven in a day.

01:26:24.160 | - Right, which we know is really detrimental.

01:26:27.240 | - Right.

01:26:28.400 | - Especially for the brain,

01:26:29.960 | but also the cascades that result from disrupted sleep,

01:26:34.960 | not just for that one night, but multiple nights.

01:26:38.360 | Yeah, the literature I've seen on alcohol,

01:26:40.560 | the most, now again, this is an emerging literature

01:26:44.360 | because what you're describing is exactly right,

01:26:47.080 | but people are now, some more conservative folks

01:26:49.760 | are starting to place it at two drinks per week total,

01:26:54.400 | beyond which you start running into issues,

01:26:56.680 | especially for women in terms of breast cancer risk,

01:26:58.920 | which is something maybe we can circle back on.

01:27:00.720 | - Yeah, I mean, look, my view is

01:27:03.160 | if you can not drink at all,

01:27:05.040 | you're better off not drinking at all.

01:27:07.360 | And people always say to me,

01:27:08.200 | "Well, Peter, what's your view on this?"

01:27:09.600 | And my view is I do drink.

01:27:12.760 | I'll go weeks at a time without having a drink.

01:27:15.320 | I haven't had a drink, you know,

01:27:17.120 | I've had one drink since I saw you last a couple weeks ago

01:27:19.360 | because I've been sick, so I'm thinking,

01:27:20.640 | well, gosh, like, the deck is stacked against me right now.

01:27:23.400 | Why would I do anything to stack it more?

01:27:25.520 | But my philosophy, which is half tongue in cheek,

01:27:30.560 | but is true, is like, I just don't drink bad alcohol.

01:27:34.240 | You know, I sort of, my wife saw me do this the other day.

01:27:37.840 | We opened up a bottle of wine,

01:27:39.580 | and it was a very expensive bottle of wine,

01:27:41.640 | I took a sip and I was like, yeah, I just dumped my glass.

01:27:44.120 | I was like, I don't know, just doesn't taste right to me.

01:27:46.440 | And it tasted fine to her,

01:27:47.400 | so I don't think it was that the wine had spoiled,

01:27:49.040 | it was just, I didn't like the taste of it enough

01:27:51.080 | to justify drinking it.

01:27:52.720 | I was like, I don't feel like drinking it.

01:27:53.620 | - Yeah, fortunately, there were times in life,

01:27:56.440 | certainly college and portions of graduate school

01:27:58.480 | when I drank, but I've never really enjoyed

01:28:00.540 | the taste or experience of alcohol.

01:28:03.960 | So all the alcohol in the plant could disappear,

01:28:06.440 | I wouldn't even notice,

01:28:07.260 | but I'll have one every once in a while,

01:28:08.740 | I'm sort of of that mindset.

01:28:10.280 | But, great to hear that zero is better than any,

01:28:13.800 | 'cause I think everyone agrees on that.

01:28:16.920 | So, it doesn't appear that alcohol can be directly linked

01:28:22.320 | to cardiovascular disease and cerebral vascular disease,

01:28:24.920 | although there are these indirect effects

01:28:26.720 | through insulin, altering insulin sensitivity.

01:28:28.720 | - And through sleep, I think the impact of sleep

01:28:31.740 | on cardiovascular and cerebral vascular disease is profound,

01:28:34.000 | and I do think that the impact of ethanol on sleep

01:28:37.280 | is underappreciated.

01:28:39.320 | - Yeah, and here, I think we should do a little nod

01:28:44.080 | to Matt Walker, the great Matt Walker,

01:28:46.120 | because 10 years ago, if someone had a conversation

01:28:49.820 | about sleep and how critical it is

01:28:51.860 | and how not getting enough quality sleep is dangerous,

01:28:55.900 | people would have just kind of shake their heads

01:28:57.400 | and say, what's the evidence for that?

01:28:58.520 | I think Matt really deserves most of the credit

01:29:02.680 | for alerting people to these issues

01:29:05.200 | around not getting enough sleep.

01:29:06.380 | It's just remarkable what's happened in the last decade,

01:29:09.460 | thanks to Matt.

01:29:11.020 | - And while we're on that topic,

01:29:12.700 | we have the other next horseman of death,

01:29:14.460 | the neurodegenerative diseases,

01:29:15.760 | I think those are also heavily impacted,

01:29:17.340 | especially on the dementia side by ethanol.

01:29:20.500 | So, again, I wanna be careful when I say this stuff, right?

01:29:24.060 | I don't believe in fear mongering, okay?

01:29:26.980 | I just said a moment ago, I'll say it again,

01:29:28.720 | I drink alcohol and I'm gonna continue to drink alcohol,

01:29:31.420 | but I think that one has to make the trade-offs,

01:29:34.920 | which is like, if I really do love the taste

01:29:38.500 | of certain Spanish wines,

01:29:39.760 | I really do love the taste of certain tequilas,

01:29:42.420 | certain mezcals, and I really do love the taste

01:29:45.140 | of certain weird esoteric Belgian beers.

01:29:48.720 | And it really does give me pleasure to consume those things

01:29:53.060 | in the same way it gives me pleasure

01:29:54.960 | to consume certain foods that are quite vapid, right?

01:29:59.460 | You know, there's no upside in consuming a brownie

01:30:02.700 | that my kid just made, except for the fact

01:30:05.080 | that my kid just made it,

01:30:06.340 | and it's fun to eat the brownie with them, right?

01:30:08.440 | So, you know, we come back to this thing about,

01:30:12.680 | like, longevity is also about healthspan,

01:30:15.020 | and part of healthspan is quality of life.

01:30:17.820 | And, you know, I write about this in the book

01:30:20.220 | that I think there was a day when my approach to this

01:30:23.120 | was purely an engineering approach,

01:30:25.080 | which was we were going to optimize every molecule

01:30:29.440 | of my being for this.

01:30:31.700 | And if you go so far down that rabbit hole

01:30:34.520 | that the quality of your life deteriorates,

01:30:37.560 | what's the point?

01:30:39.160 | So that's why I think for somebody like you,

01:30:41.920 | who says, like, you could take all the alcohol

01:30:43.720 | off the face of the earth, I wouldn't even notice,

01:30:45.840 | then that's a great reason not to bother drinking.

01:30:48.720 | I wouldn't put myself at the opposite end of that spectrum,

01:30:51.040 | but I'm probably further to the spectrum, you know,

01:30:53.680 | where, yeah, if you told me I could never drink alcohol

01:30:57.960 | again, I would be fine with it,

01:30:59.800 | but I'd be giving something up that I enjoy.

01:31:02.000 | But at the same time, I know if I have two drinks

01:31:06.660 | with dinner, my sleep sucks, and therefore,

01:31:10.140 | that's just a threshold I rarely, rarely cross.

01:31:14.320 | - I certainly have my vices of alcohol,

01:31:17.580 | just doesn't happen to be one of them.

01:31:19.600 | What about cancer?

01:31:22.500 | Again, nobody wants cancer.

01:31:24.620 | We've all known people who have died of cancer

01:31:27.260 | or have had cancer.

01:31:29.120 | What can be done to reduce one's risk of cancer?

01:31:32.860 | - Well, you asked earlier about the numbers,

01:31:35.260 | so let's throw some numbers out there, right?

01:31:36.860 | So globally, we're talking about 11, 12 million deaths

01:31:39.860 | per year, about half the number of ASCVD,

01:31:43.580 | still a staggering number.

01:31:45.220 | At the individual level, put it this way,

01:31:49.260 | somewhere between one in three and one in four chance,

01:31:52.340 | anyone listening to this or watching,

01:31:53.860 | this is gonna get cancer in their lifetime.

01:31:55.900 | - But what's the probability they will die from that cancer?

01:31:59.380 | - Half of that, about a one in six chance of dying.

01:32:02.160 | - Okay, so is it true that every male gets prostate cancer?

01:32:06.240 | In other words, from their deathbed, then have--

01:32:08.400 | - Every man will die with prostate cancer

01:32:10.960 | and some will die from it.

01:32:12.300 | - Got it.

01:32:14.960 | - You and I have prostate cancer right now.

01:32:16.640 | - Thank you for informing me.

01:32:17.680 | - Yes.

01:32:19.200 | Hopefully, we will not die of it.

01:32:20.400 | We should not die of it.

01:32:21.240 | Prostate cancer, colon cancer are cancers

01:32:23.960 | that no one should ever die from

01:32:25.520 | because they're so easy to screen for,

01:32:28.040 | they're so easy to treat when they are in their infancy

01:32:31.960 | that it's totally unacceptable

01:32:33.160 | that people are dying from this.

01:32:34.160 | There are other cancers for which I can't really say that.

01:32:36.360 | Breast cancer, much more complicated.

01:32:38.320 | Pancreatic cancer, much more complicated.

01:32:40.780 | Glioblastomy multiforme, much more complicated.

01:32:42.960 | So as you said a second ago, cancer is not a disease,

01:32:47.080 | it is a category of diseases.

01:32:49.200 | Each, it's not just that each organ is different

01:32:51.880 | and breast differs from pancreatic,

01:32:53.940 | it's that within breast cancer, ERPR positive,

01:32:57.260 | HER2/neu positive is a totally different disease

01:32:59.940 | from the triple negative breast cancers.

01:33:01.660 | - Those with BRCA mutations or non-BRCA mutations.

01:33:04.300 | - Well, even putting that aside,

01:33:05.960 | just looking at the hormone profile

01:33:08.040 | of the individual breast cancers,

01:33:09.600 | they're totally different diseases.

01:33:11.580 | So it's not just that breast cancer

01:33:13.400 | is different from prostate cancer,

01:33:14.680 | it's that all breast cancers are quite different.

01:33:17.700 | - Maybe I should frame the question a little differently

01:33:19.500 | than given the vast number of different types of cancers

01:33:22.580 | and categories within those.

01:33:23.420 | - Your question is still a fair one.

01:33:25.240 | I just wanted to throw that caveat out there.

01:33:26.600 | So now to your question.

01:33:27.760 | Okay, so what do we know?

01:33:29.620 | It turns out that we can very comfortably speak

01:33:34.060 | to several things.

01:33:37.420 | One is the role that genes play.

01:33:40.260 | So maybe I'll just spend one second

01:33:44.600 | on a gene 101 thing for the viewer.

01:33:49.360 | We want to differentiate between

01:33:50.720 | what are called germline mutations and somatic mutations.

01:33:54.420 | So your germline and my germline are set.

01:33:59.320 | When we were born, our germline mutations,

01:34:03.340 | any mutations we have in germline genes

01:34:05.480 | are inherited from our parents.

01:34:07.240 | - They're non-negotiable.

01:34:09.720 | - They're non-negotiable, you got those things.

01:34:11.860 | So question one is how much of cancer results

01:34:16.540 | from those types of genetic mutations?

01:34:19.800 | And the answer is very little, less than 5%.

01:34:22.360 | So very, you mentioned one a moment ago, BRCA.

01:34:25.280 | Okay, so mutations in BRCA are germline mutations.

01:34:29.000 | A woman will get a BRCA mutation from one of her parents.

01:34:33.320 | And we will often have a sense of that

01:34:36.440 | just from the family history.

01:34:37.960 | When mom and sister and aunt and grandmother

01:34:41.480 | had breast cancer, you've got a breast cancer gene.

01:34:44.740 | Now it might be BRCA, it might be another gene

01:34:46.940 | that's not BRCA, but there's no ambiguity.

01:34:50.320 | And we test for these genes,

01:34:52.540 | mostly just for insurance purposes, frankly.

01:34:54.980 | But there's no ambiguity that that was a germline

01:34:57.980 | transmission of a gene that is driving cancer.

01:35:01.140 | But 95 plus percent of cancers are not arising

01:35:07.020 | from germline mutations.

01:35:08.340 | They are arising from somatic mutations

01:35:10.720 | or acquired mutations.

01:35:13.220 | So the question then becomes,

01:35:15.380 | what is driving somatic mutation?

01:35:17.760 | And the two clearest indications

01:35:23.840 | of drivers of somatic mutation are smoking and obesity.

01:35:28.200 | Smoking we've talked about.

01:35:30.400 | Let's put that aside for a moment.

01:35:31.720 | - I'm so surprised about obesity.

01:35:33.320 | I don't know why I'm surprised, but I've never heard this.

01:35:36.600 | I'm probably just naive to the literature.

01:35:38.360 | - Yeah, so obesity is now the second most prevalent

01:35:43.040 | environmental driver of cancer.

01:35:46.460 | Now I will argue, and I think I argue this in the book,

01:35:49.240 | hopefully pretty convincingly,

01:35:51.420 | I don't think it's obesity per se.

01:35:53.440 | I think obesity is just a masquerading proxy.

01:35:56.860 | What is obesity?

01:35:57.700 | Obesity simply is defined by body mass index.

01:36:01.780 | Well, first of all, I don't think I'm obese,

01:36:04.700 | but I'm way overweight on BMI.

01:36:07.380 | You probably are too.

01:36:08.600 | So let's just ignore--

01:36:10.260 | - I'm clinically diagnosable as obese.

01:36:12.580 | - Are you?

01:36:13.420 | - Oh, no.

01:36:14.240 | Well, not, well, clinically maybe--

01:36:15.080 | - That would be BMI over 30.

01:36:16.220 | I don't think you're probably there.

01:36:17.800 | - No, but if I measure my weight by height--

01:36:21.040 | - Yeah, yeah, yeah.

01:36:21.880 | Like my BMI is probably 27 or 28.

01:36:23.920 | - Okay, it's been a little while since I've checked.

01:36:25.720 | I can, I only know body fat percentages

01:36:27.920 | and things like that.

01:36:28.760 | - So basically like BMI is a far from perfect proxy,

01:36:32.060 | but at the population level, it's what we use.

01:36:35.660 | I wish we would get off it, by the way.

01:36:37.560 | I think it's really crap.

01:36:39.100 | - Because it doesn't take into account lean versus--

01:36:41.660 | - Yeah, I think we could get better data

01:36:45.260 | if we looked at waist to height ratio.

01:36:48.700 | That's a way better metric.

01:36:50.540 | So this is just a quick test for everybody.

01:36:52.900 | It's, I'm gonna argue your BMI is less relevant to me

01:36:57.620 | than your eye color, but if your waist circumference

01:37:02.060 | is more than 50% of your height, you should be concerned.

01:37:05.740 | - Okay, well then I'm okay.

01:37:06.940 | - Yeah, you're fine by that metric, right?

01:37:09.140 | But that's important.

01:37:09.980 | If you're six feet tall,

01:37:12.020 | your waist better be under 36 inches.

01:37:15.440 | And if it's over, I would argue that's the definition

01:37:17.900 | of obesity, not your BMI being over 30.

01:37:21.940 | So back to this issue,

01:37:24.900 | because we're using such a crude measurement,

01:37:28.180 | it basically is catching a whole bunch of stuff,

01:37:30.660 | but the question is, what's driving it?

01:37:33.620 | And I think if you really look at the physiology of cancer,

01:37:38.660 | I don't think it's obesity.

01:37:40.980 | I think it's two things that come with obesity.

01:37:44.780 | Insulin resistance, which is 2/3 to 3/4 of obese individuals

01:37:49.780 | are insulin resistant, and inflammation.

01:37:53.980 | And I think those two things, with the inflammation

01:37:56.460 | and the immune dysfunction, with the insulin resistance,

01:37:59.740 | and the hyper basically tonic growth stimulus that's coming,

01:38:04.740 | that's what's driving cancer.

01:38:06.700 | So again, is it because a person is storing extra fat,

01:38:10.780 | you know, and their love handles,

01:38:12.300 | that that's driving the risk of cancer?

01:38:13.780 | No, those are just two things

01:38:16.140 | that are coming along for the ride.

01:38:17.580 | So beyond those two things,

01:38:21.260 | and along with, there are also certain environmental toxins

01:38:25.300 | we absolutely know are doing this, right?

01:38:26.900 | So we understand that people who have exposure to asbestos

01:38:30.300 | have a much higher risk of certain types of lung cancers

01:38:32.420 | and things like that.

01:38:33.260 | But for the most part, those are our big risks.

01:38:36.300 | Beyond that, we talk about alcohol in certain cases,

01:38:39.300 | absolutely, alcohol is a carcinogen.

01:38:43.260 | The dose part still isn't clear to me.

01:38:45.460 | I don't know, is one drink a day

01:38:50.540 | moving the needle much on cancer risk per se?

01:38:53.060 | It's not clear.

01:38:53.900 | - And it might depend on those genetic predispositions.

01:38:57.140 | - Yes, so yeah, if step one is don't get cancer,

01:39:03.820 | you have no control over your genes,

01:39:06.380 | you have control over smoking,

01:39:08.700 | you have control over insulin sensitivity,

01:39:12.060 | I wish I could sit here and tell you

01:39:14.660 | that there is a proven anti-cancer diet

01:39:18.460 | or that if you do X amount of exercise per week,

01:39:23.900 | you're gonna not get cancer.

01:39:26.660 | We just don't have a fraction of the control over cancer

01:39:30.340 | that we have with cardiovascular disease.

01:39:32.820 | We don't understand the disease well enough,

01:39:35.660 | so we don't understand kind of the initiation process

01:39:38.700 | and the propagation process.

01:39:40.180 | And we have to rely much more on screening.

01:39:46.940 | - Are there good whole body screens for cancer?

01:39:51.540 | In other words, can I walk into a tube

01:39:54.820 | or a cylinder rather and get screened

01:39:59.860 | for the presence of tumors any and everywhere in the body?

01:40:03.340 | Outside the brain,

01:40:04.180 | 'cause the brain's a little harder to get to, right?

01:40:06.260 | - Believe it or not,

01:40:07.100 | the brain is actually pretty easy to screen for.

01:40:08.780 | - 'Cause it's so fatty and floating in water.

01:40:11.620 | - Well, and also the head,

01:40:13.220 | when you put the head into an MRI scanner,

01:40:14.900 | there's no movement.

01:40:16.640 | It's the least motion artifact is in the brain.

01:40:19.140 | So when you use something called diffusion weighted imaging

01:40:21.660 | with background subtraction in an MRI,

01:40:23.980 | a technology that was actually pioneered in the brain

01:40:26.700 | for stroke identification,

01:40:29.040 | it's also really good at looking for tumors as well.

01:40:31.800 | So let me make the argument for why screening matters,

01:40:37.940 | 'cause this is again kind of an area

01:40:40.120 | where I go far down a rabbit hole

01:40:43.860 | in a way that I think traditional medicine

01:40:45.420 | would argue against.

01:40:47.940 | So my argument for screening is an argument

01:40:51.820 | at the individual level, and it goes as follows.

01:40:56.220 | To my knowledge, there is not a single example

01:40:59.520 | of a cancer that is more effectively treated

01:41:03.480 | when the burden of cancer cells in the body

01:41:05.500 | is higher than when it is lower.

01:41:07.100 | So the two examples I think I talk about in the book

01:41:12.140 | are colon cancer and breast cancer.

01:41:14.680 | So when you take an individual with stage four colon cancer,

01:41:18.780 | that means that the cancer has left the colon

01:41:21.480 | and is now outside of the colon.

01:41:23.440 | So it's usually in the liver at a minimum,

01:41:25.680 | potentially in the lungs or in the brain.

01:41:27.740 | That person's five year survival is very low,

01:41:32.040 | their 10 year survival is zero.

01:41:33.640 | We will treat them with a very aggressive regimen

01:41:38.160 | of multiple drugs.

01:41:40.180 | And again, you'll get a five year survival

01:41:42.540 | of maybe 10 to 20%, and by 10 years nobody's alive.

01:41:46.820 | If you take a person with stage three colon cancer,

01:41:52.720 | so the colon cancer is big, and it's even in the lymph nodes

01:41:56.780 | around the colon, but at least grossly,

01:42:00.560 | you can't see colon cancer cell,

01:42:03.040 | you can't see those cells in the liver.

01:42:05.040 | Microscopically, of course, we know they're there,

01:42:07.240 | because if you don't treat those patients,

01:42:09.060 | they still die of colon cancer,

01:42:10.560 | but you whack them with the same chemo regimen

01:42:13.600 | that you were gonna give the metastatic patients,

01:42:16.240 | 80% of those people are alive in five years.

01:42:19.200 | So night and day difference in survival.

01:42:22.100 | What's the difference?

01:42:23.360 | In the person with metastatic cancer,

01:42:25.160 | you're treating a person with hundreds of billions of cells.

01:42:29.280 | In the adjuvant setting, which is what we call it adjuvant,

01:42:33.000 | when you treat people who have only microscopic disease,

01:42:36.520 | you're treating billions of cells.

01:42:39.480 | The same is true with breast cancer.

01:42:40.760 | So we have the clinical trial data to put them side by side.

01:42:43.040 | So rule number one is don't get cancer.

01:42:47.360 | Rule number two is catch cancer as early as possible

01:42:49.720 | if you're gonna get it.

01:42:51.500 | Which brings us to your question

01:42:52.480 | of how do you screen for it?

01:42:53.880 | We basically screen, the first line of screening is imaging,

01:42:59.820 | is a sort of visualization.

01:43:02.260 | So you have cancers that occur outside the body

01:43:04.460 | that you can look at directly.

01:43:06.240 | So skin cancer, you can look directly at the skin.

01:43:09.600 | Esophageal, gastric, colon cancer,

01:43:12.400 | those are outside the body, right?

01:43:13.460 | Mouth to anus, embryologically is outside the body.

01:43:16.520 | So you can put a scope in

01:43:17.760 | and you can look directly at the cancer.

01:43:21.160 | But for all other cancers that are inside the body,

01:43:23.100 | yeah, you have to rely on some sort of imaging modality.

01:43:26.360 | Although now we're starting to look at things,

01:43:28.080 | things called liquid biopsies.

01:43:29.220 | So blood tests that are looking for cell-free DNA.

01:43:31.960 | And the cell-free DNA gives us a sense of,

01:43:35.640 | based on the epigenetic signature of what you're looking at,

01:43:39.260 | hey, is there a cancer in the body?

01:43:41.020 | And if so, what tissue is it potentially coming from

01:43:43.440 | based on these epigenetic signatures?

01:43:46.280 | So the problem with relying on any one modality

01:43:50.520 | is a problem of sensitivity and specificity optimization.

01:43:55.040 | Now with MRI scanners,

01:43:56.880 | which are in some ways the best way to do this

01:43:59.680 | because they don't have radiation.

01:44:01.320 | So you don't wanna be incurring damage as you do this.

01:44:03.840 | The irony of doing a whole body CT scan,

01:44:06.200 | screening for cancer is your whole body CT scan

01:44:09.860 | would be close to 30 to 50 millisieverts of radiation.

01:44:14.640 | It's a staggering sum of radiation.

01:44:16.120 | So-

01:44:17.040 | - Does that mean that people should,

01:44:18.640 | sorry to pull you off this,

01:44:19.800 | but I was going to ask about this anyway,

01:44:24.280 | avoiding going through the whole body scanner

01:44:26.760 | at the airport.

01:44:28.320 | - Noise, solo, solo.

01:44:30.480 | Yeah, going through a whole body scanner at the airport

01:44:33.200 | or even getting a DEXA scan.

01:44:34.440 | I mean, these are trivial amounts of radiation.

01:44:36.920 | - What about flying?

01:44:37.920 | You hear that pilots get more cancer.

01:44:42.160 | - If you're a pilot who's flying over the North Pole

01:44:45.960 | back and forth and back and forth,

01:44:47.040 | you're probably getting five to 10 millisieverts a year.

01:44:51.280 | The NRC suggests that nobody should get

01:44:53.560 | more than 50 millisieverts a year.

01:44:55.360 | - So you and I both travel a fair amount,

01:44:58.760 | but typical travel for the busy person,

01:45:02.120 | let's say two round trip flights

01:45:05.200 | of more than two hours per month

01:45:08.020 | and an international trip every three months.

01:45:10.600 | - Probably still less than a millisievert a year.

01:45:13.320 | - Yeah, living at sea level, one millisievert a year,

01:45:16.320 | living at a mile elevation.

01:45:17.760 | If you lived in Denver,

01:45:18.600 | you're at two millisieverts a year basically.

01:45:20.160 | - I'd have to ask standing in front of the microwave.

01:45:22.520 | (laughing)

01:45:23.520 | I'm just, we've got friends, they ask.

01:45:26.680 | - With or without testes on the counter.

01:45:29.460 | - That's an inside joke that unfortunately,

01:45:33.180 | and fortunately deserves no description.

01:45:35.420 | And Peter's not referring to me.

01:45:37.880 | But people worry about other sources of radiation.

01:45:41.680 | So it doesn't sound like the microwave is a concern.

01:45:44.640 | What are the other major sources of radiation?

01:45:46.980 | - I mean, outside of sort of nuclear stuff

01:45:49.640 | where things go sadly wrong.

01:45:50.480 | - Yeah, if you live near a plant or there's been a--

01:45:52.280 | - Yeah, there's been a, it's mostly at the hands

01:45:55.160 | of medical professionals, right?

01:45:56.360 | It's the CT scanner and the PET scanner are hands down

01:45:58.880 | the biggest source of radiation.

01:46:00.300 | - What about the x-rays of the dentist when they scurry

01:46:03.060 | behind the wall, put me under the blanket?

01:46:05.360 | - They're very low, relatively speaking.

01:46:08.320 | Fluoroscopy is very high.

01:46:10.800 | They tend to try to cover up all of you.

01:46:14.120 | So for example, if they were doing a fluoroscopic study

01:46:17.160 | of your kidney because you had a stone

01:46:19.280 | or if you were getting an injection into,

01:46:22.400 | if they were doing a fluoroscopic guided injection

01:46:25.480 | of one of your discs in your neck,

01:46:27.320 | that would be a locally pretty high dose.

01:46:29.260 | But they're gonna cover the hell out of you elsewhere.

01:46:31.860 | And again, if you get one of these things,

01:46:33.960 | it's not the end of the world.

01:46:35.260 | But boy, I wouldn't wanna be getting one a month.

01:46:37.040 | And back to the point about screening,

01:46:39.840 | a chest, abdomen, pelvis CT scan is probably,

01:46:44.000 | I mean, look, there's probably a scanner out there now

01:46:47.140 | that's moving fast enough that it's much lower.

01:46:49.080 | But I'll give you an example, okay.

01:46:50.560 | Remember how I talked about we do CT angiograms

01:46:52.620 | on all of our patients for coronary artery disease?

01:46:55.560 | An off the shelf scanner for this

01:47:00.240 | is 20 millisieverts of radiation.

01:47:03.080 | - Okay, so calibrate me because--

01:47:05.120 | - That's 40% of your annual allotment.

01:47:08.020 | - Oh wow, so the medical practitioners

01:47:10.660 | really are the major culprits here.

01:47:13.740 | - That's right, so what we say is,

01:47:16.880 | and I think most doctors are now realizing this is,

01:47:20.520 | no, no, it behooves you to pay a little bit more

01:47:23.820 | to go to a really good place

01:47:25.800 | that can do that scan for two millisieverts.

01:47:28.580 | Meaning they have a much faster CT scanner,

01:47:31.460 | much better software, and they're better engineers.

01:47:34.960 | So they have better engineering

01:47:36.260 | that they can do on the scanner to get that done.

01:47:38.700 | So if someone's listening to this, here's my take.

01:47:41.780 | Do not get a CT scan or any imaging study

01:47:45.460 | without asking how much radiation am I seeing?

01:47:47.940 | And if a person can't tell you how many millisieverts

01:47:50.520 | of radiation you're being exposed to,

01:47:52.260 | then just say I'm gonna wait a minute

01:47:53.380 | until somebody can tell me that.

01:47:55.040 | And keep in mind, if 50 is the most

01:48:00.180 | you should ever be exposed to in a year,

01:48:02.840 | there better be a damn good reason

01:48:04.260 | why I'm gonna get 25 in a day.

01:48:05.740 | Now there are some people who have to do this.

01:48:07.740 | If you're a cancer patient and they're scanning you

01:48:11.460 | as a part of your treatment,

01:48:12.660 | I mean, you have to pick and choose

01:48:15.120 | between those two opportunities.

01:48:17.380 | So I don't also don't wanna create some fear-mongering

01:48:19.940 | where oh my God, if you hit 50 in a year, you're hosed.

01:48:22.020 | No, it's just I wouldn't wanna hit 50 a year

01:48:24.740 | every year for my whole life.

01:48:25.940 | And I certainly wouldn't wanna be hitting hundreds a year

01:48:28.940 | for any period of time.

01:48:30.380 | - I think we're just trying to raise awareness

01:48:32.140 | and also calibrate people to what the sources are

01:48:35.680 | and so they can make good choices

01:48:37.980 | not to place them into a chronic state of fear

01:48:42.020 | or even an acute state of fear.

01:48:42.860 | - So for that reason, we prefer MRI scanners

01:48:45.860 | 'cause there's no radiation.

01:48:47.460 | - I realize this might sound like a specialized circumstance

01:48:51.340 | but I'll just start off with my own,

01:48:54.280 | which is when I was a graduate student,

01:48:55.620 | I worked with fixatives of paraformaldehyde,

01:48:59.060 | paraformaldehyde, excuse me, glutaraldehyde.

01:49:01.700 | We know that these are mutagens.

01:49:03.260 | They mutate cells, not good.

01:49:04.860 | You do some molecular biology in the lab,

01:49:06.540 | you use DNA intercalating dye, those little bands and gels.

01:49:09.380 | The reason they label is 'cause they get between the DNA,

01:49:11.280 | not good to get into your own DNA.

01:49:14.920 | And that's a very specialized circumstance.

01:49:18.280 | I also injected radioactive proline into the animals

01:49:22.540 | and things of that sort.

01:49:23.840 | Again, very specialized.

01:49:24.840 | And yet most people I think will be exposed to pesticides.

01:49:29.840 | They'll put stuff on their lawn

01:49:33.480 | or they'll have paint thinners and things of that sort.

01:49:37.040 | Is there any sense of what the average, if one can,

01:49:40.640 | average risk is incurred in terms of carcinogens

01:49:44.720 | just through this interaction with weed killers,

01:49:48.820 | paint thinner, detergents around the house

01:49:52.960 | that we now know, there's some major lawsuits

01:49:56.100 | that have been successful against the manufacturers

01:49:59.660 | of these things.

01:50:00.640 | And what is the real cancer risk created

01:50:03.000 | by having those kinds of solvents and pesticides

01:50:06.560 | and things around?

01:50:08.220 | - I don't think I know, truthfully.

01:50:09.940 | I think it's very complicated to calculate such things

01:50:13.760 | when their ubiquity is so high.

01:50:17.460 | So one argument is, look, it's kind of baked into

01:50:22.520 | the baseline prevalence of cancer today

01:50:26.200 | because these things are so ubiquitous.

01:50:28.600 | - Asbestos, in California, for whatever reason,

01:50:31.280 | it seems that there's an asbestos warning

01:50:33.160 | on pretty much every building, if you look carefully enough,

01:50:36.240 | except maybe the ones built in the last five years.

01:50:38.600 | I don't think I've ever worked in a building

01:50:40.000 | where the elevator was updated in terms of the inspection.

01:50:44.320 | It was almost like 10 years back.

01:50:45.840 | You always see it while you're in the elevator.

01:50:47.160 | No one seems to worry about those.

01:50:48.720 | Or where there was not an asbestos warning or a lead warning.

01:50:53.720 | It seems like it's just kind of everywhere

01:50:56.000 | and they're noting it in these little flags.

01:50:58.140 | I don't walk around worried about it.

01:50:59.440 | I don't lose sleep over it.

01:51:01.000 | But it sounds like a real risk

01:51:02.360 | or else they wouldn't bother, right?

01:51:03.360 | Clearly they're just trying to cover their legal backs.

01:51:04.920 | - Yeah, it might be more CYA than anything at this point.

01:51:08.160 | I don't know how much of a risk asbestos poses

01:51:11.360 | when it's not being agitated.

01:51:14.360 | In other words, I don't know that the asbestos

01:51:16.820 | in the ceiling four layers up is really a problem.

01:51:20.800 | But if they had to come in here and rip this ceiling apart,

01:51:24.360 | I don't know that it'd want to be in here either.

01:51:25.920 | - It was like post-9/11, a lot of the workers

01:51:27.760 | selling the World Trade Center pits,

01:51:30.720 | 'cause that's what was left, sadly,

01:51:32.720 | were developed cancers, right?

01:51:34.920 | Probably from exposure and those kinds of things.

01:51:36.600 | - Well, I mean, I would argue it's also just the unbelievable

01:51:41.200 | amount of pollution, micropollution that was in the air

01:51:44.120 | following those things.

01:51:45.420 | I mean, that's devastating stuff.

01:51:46.440 | So yeah, those are fortunately the outlier events

01:51:49.640 | that are dramatic.

01:51:50.900 | But again, my focus is basically, look,

01:51:54.780 | I could hermetically seal myself somewhere in the world,

01:51:57.920 | maybe, and maybe that would reduce my risk by 1%.

01:52:02.920 | But I'm gonna focus my energy on what I control,

01:52:06.020 | 'cause that's really hard for me to control.

01:52:08.020 | I like focusing my energy on things I can control.

01:52:11.580 | What I can control is the timing

01:52:14.600 | and frequency of my screening.

01:52:16.100 | I can't control my genes anymore.

01:52:19.340 | They are what they are.

01:52:20.180 | I got whatever predisposing cancer genes I'm gonna get.

01:52:23.300 | I might be lucky in this regard in that I seem to get

01:52:26.120 | all these horrible heart disease genes,

01:52:27.640 | and maybe not as much.

01:52:28.600 | But you can also argue there are cancer bad genes in me

01:52:31.960 | that we don't really know about

01:52:33.280 | because everybody was dying of heart disease so young.

01:52:35.920 | But boy, am I gonna control the screening thing.

01:52:39.880 | - What source of genetic screening

01:52:41.880 | do you recommend to your patients?

01:52:43.760 | 'Cause there are a lot of them.

01:52:44.640 | There's 23andMe, there's whole genome sequencing

01:52:47.240 | in place available now in a variety of formats.

01:52:50.800 | - This is actually one of the questions

01:52:51.920 | our research team is working on as we speak.

01:52:53.960 | So we're trying to decide,

01:52:58.600 | so we do genetic screening for certain things.

01:53:00.360 | Like ApoE is a gene we wanna know in everybody.

01:53:02.760 | - For its role in neurodegenerative disease.

01:53:06.280 | - Correct, specifically in Alzheimer's disease.

01:53:09.360 | We are selectively using cancer screening in some patients.

01:53:14.360 | But in our practice, it's less important

01:53:19.000 | because we're generally so aggressive anyway

01:53:21.600 | that it turns out to be a little bit moot.

01:53:24.160 | We don't learn a lot in the genetic screening

01:53:26.560 | that's changing our screening practices

01:53:29.800 | because we're so thorough in our family history

01:53:32.120 | and we're so aggressive in everybody

01:53:34.480 | regardless of family history.

01:53:36.680 | But I think there's a place for these things.

01:53:38.760 | For example, if you're looking for reimbursement

01:53:40.560 | on certain tests, I'll give you an example.

01:53:43.400 | So colon cancer historically was not covered by,

01:53:47.800 | a colonoscopy screening for colon cancer

01:53:49.440 | was not covered until you were 50.

01:53:50.920 | That's been bumped to 45.

01:53:53.040 | We still think everybody should be screened

01:53:54.840 | no later than 40.

01:53:55.960 | - No, I haven't had one, so I suppose I should.

01:53:58.040 | - Yeah, I mean look, I'm 50 and I've had three already.

01:54:00.840 | So again, why?

01:54:03.160 | Because colon cancer is not just the third leading cause

01:54:06.720 | of cancer death, it's 100% preventable.

01:54:10.600 | Why?

01:54:11.440 | Because every colon cancer comes from a polyp

01:54:14.960 | and every polyp can be seen on a colonoscopy.

01:54:17.540 | So there's simply no reason to not know that.

01:54:21.460 | And that has to be weighed against the cost

01:54:23.620 | of the colonoscopy, both the financial cost and the risks,

01:54:27.540 | which are very low but not zero.

01:54:30.800 | There's a risk that comes from electrolyte abnormalities

01:54:35.160 | and hypotension from the bowel prep.

01:54:37.580 | There's a risk from the sedation.

01:54:39.420 | And there's obviously a risk of bleeding or perforation

01:54:42.220 | that comes from the colonoscopy itself.

01:54:43.500 | Again, in a generally healthy person,

01:54:46.560 | those risks are so low that they're almost difficult

01:54:49.360 | to quantify, as evidenced by a recent

01:54:51.560 | New England Journal of Medicine paper

01:54:52.940 | that was a very anti-colonoscopy paper,

01:54:55.540 | which I won't get into 'cause it's probably

01:54:59.060 | a little bit of a tangent.

01:55:00.520 | But what's interesting is, despite being

01:55:02.040 | a very anti-colonoscopy paper, this paper does

01:55:04.380 | a better job demonstrating the safety

01:55:06.160 | of colonoscopy than anything else.

01:55:07.820 | It just was an oddly designed experiment.

01:55:13.840 | So the biggest challenge with aggressive screening posture

01:55:18.840 | is the specificity problem, which is when you stack

01:55:23.440 | more and more modalities around these things,

01:55:26.280 | you're gonna start finding things that aren't cancer.

01:55:28.380 | So MRI has a very high sensitivity.

01:55:32.780 | In English, that just means if a cancer is present,

01:55:35.480 | an MRI is very likely to see it.

01:55:37.360 | But it has a very low specificity, which means in English,

01:55:43.180 | it will see a bunch of things and think

01:55:45.120 | they are cancer when they are not.

01:55:47.240 | And it's most troubled by glandular tissue.

01:55:51.080 | So glandular tissue is the Achilles heel of MRI.

01:55:56.040 | And therefore, when you use, as we do,

01:55:58.760 | whole body MRI for cancer screening,

01:56:01.640 | we tell our patients going in, it's like a 25% chance

01:56:05.440 | we're gonna find something that is not cancer

01:56:07.280 | but will require us to do further investigation.

01:56:10.240 | If you're not cool with that, which is totally fine,

01:56:12.320 | we probably shouldn't do this.

01:56:14.000 | And again, most people are okay with that,

01:56:16.560 | but it helps to set that expectation going in,

01:56:19.460 | that you're gonna probably be chasing your tail,

01:56:21.740 | looking at some stupid thyroid nodule

01:56:23.800 | that is absolutely nothing.

01:56:25.860 | I mean, I can't tell you how many useless thyroid nodules

01:56:28.980 | we've had to get ultrasounds on

01:56:30.840 | that prove to be absolutely nothing.

01:56:32.960 | But you have to follow them for a couple of years

01:56:34.380 | to make sure they're nothing.

01:56:35.440 | - What is the typical cost of a whole body MRI?

01:56:37.840 | And so for people who are not your patients,

01:56:39.920 | how would they go about getting those?

01:56:41.340 | Because I think most people's general practitioner

01:56:43.440 | is not going to script that out for them.

01:56:46.360 | - Correct.

01:56:47.200 | I don't know the short answer

01:56:49.960 | because I don't know how many different places are doing it.

01:56:51.960 | I can tell you that we use a couple of different facilities

01:56:55.720 | and I should disclose that I'm a founder of one of them.

01:56:58.500 | But we use a scanner that probably,

01:57:02.800 | we send our patients to anywhere they wanna go,

01:57:08.840 | but within a certain company that we like

01:57:11.920 | that's not a company I have an affiliation with.

01:57:14.260 | And I believe they're charging about $2,500.

01:57:16.960 | - Since you don't have an affiliation, can you mention that?

01:57:19.800 | 'Cause for instance, you are not my physician, sadly for me.

01:57:24.280 | And luckily for you.

01:57:26.700 | But I'd love to get a whole body MRI.

01:57:29.760 | So what is this company?

01:57:32.840 | - So the company that makes the MRI

01:57:36.300 | that we're using right now is called Pranuvo.

01:57:39.360 | I interviewed the chief technology officer

01:57:43.740 | and the head radiologist of that company

01:57:46.220 | on one of my podcasts.

01:57:47.840 | It's a super interesting technology based out of Vancouver.

01:57:53.240 | And for a long time that was the only scanner in the world.

01:57:57.000 | So I had my first scan back in 2015.

01:58:01.360 | I went up to Vancouver to get it done.

01:58:03.900 | I probably had my first two up there.

01:58:06.560 | They've now opened locations all over the country.

01:58:09.640 | So they've got one in the Bay Area,

01:58:12.160 | they've probably got one here in LA.

01:58:14.940 | I know they have one in Dallas.

01:58:17.680 | So they've got them all over the place.

01:58:18.880 | - Great.

01:58:19.720 | - And then the company that I'm affiliated with

01:58:23.440 | is a different type of company

01:58:24.880 | that does all sorts of diagnostics.

01:58:27.080 | But among them is we have a Pranuvo scanner in that company.

01:58:29.560 | That company's called Biograph and that's in the Bay Area.

01:58:31.520 | - Biograph. - Biograph, yeah.

01:58:33.000 | - Spelled as one would expect. - One word, yep.

01:58:35.340 | - That's very helpful in terms of understanding

01:58:38.880 | the general risk and ways to offset cancer

01:58:42.420 | to the extent that one can.

01:58:43.960 | And certainly what the consideration should be.

01:58:47.060 | Number three on the list of ways to die.

01:58:49.920 | We should just title this ways to die.

01:58:51.820 | Or we should title this how not to die.

01:58:53.920 | Too early.

01:58:56.140 | Neurodegenerative disease.

01:58:59.380 | This is an area I'm somewhat familiar with.

01:59:02.840 | Not because of my own experience, thankfully.

01:59:04.960 | But because of my relationship to the neuroscience community.

01:59:09.080 | And last time I checked,

01:59:10.840 | I was told that everyone experiences

01:59:16.440 | some age-related cognitive decline.

01:59:19.480 | So we all get less proficient at focus memory,

01:59:24.480 | complex context-dependent task switching, all that stuff.

01:59:32.240 | As we get older.

01:59:33.440 | But it's the slope of that line

01:59:36.320 | that really can be controlled to some extent.

01:59:38.880 | And that Alzheimer's dementia represents

01:59:41.600 | just a steep acceleration, downward acceleration

01:59:46.600 | of all of that.

01:59:47.500 | That was what I was told.

01:59:51.400 | I'm guessing that even though I reside in the,

01:59:54.160 | not kind of, but I reside in that community,

01:59:56.540 | that some of that is being revised.

01:59:58.380 | Especially with respect to the underlying causes

02:00:00.600 | of Alzheimer's 'cause there's a lot of controversy,

02:00:02.840 | even scandal around this whole APP, APOB,

02:00:07.840 | amyloid, plaque, tangle, stuff,

02:00:10.320 | which is the stuff of textbooks for medical students

02:00:12.960 | and neuroscience students.

02:00:14.400 | What is the story with neurodegenerative disease,

02:00:17.120 | Alzheimer's in particular?

02:00:19.200 | How can we offset it?

02:00:20.960 | And perhaps as importantly,

02:00:24.920 | how can we all slow our own cognitive decline,

02:00:28.820 | irrespective of whether or not we get

02:00:30.960 | what is called Alzheimer's dementia?

02:00:33.200 | - So Alzheimer's disease is both the most prevalent

02:00:38.200 | form of dementia and the most prevalent

02:00:41.600 | neurodegenerative disease.

02:00:43.360 | So it occupies that unique spot.

02:00:45.860 | We're talking about roughly six million people

02:00:49.680 | in the United States have Alzheimer's disease.

02:00:52.160 | - That's one in, let's see, I mean.

02:00:57.400 | - About 2% of the total population.

02:01:00.540 | But that doesn't include those with mild cognitive impairment

02:01:05.220 | or pre-dementia or other forms of dementia.

02:01:08.300 | And of course, the right metric is not what percent

02:01:10.960 | of the population, which of course includes children,

02:01:13.560 | things like that, it's, you know, so.

02:01:14.900 | - That's a function of age, right.

02:01:17.180 | Is age the major risk factor for getting Alzheimer's?

02:01:20.020 | We say with glaucoma, a disease I'm much more familiar with

02:01:22.700 | 'cause my lab worked on it for many years,

02:01:24.840 | the biggest risk factor for getting glaucoma is age.

02:01:27.600 | - Yeah, the greatest risk factor for cardiovascular disease

02:01:30.840 | is age, the greatest risk factor for cancer is age.

02:01:35.160 | We tend to not spend a lot of time talking about that

02:01:37.460 | because it's not a modifiable risk.

02:01:39.320 | So, you know, we tend to focus on modifiable risk factors.

02:01:44.620 | So what else can we tell you,

02:01:49.280 | just to give you kind of lay of the land?

02:01:50.740 | - So the second most prevalent neurodegenerative disease

02:01:55.380 | would probably be Lewy body dementia

02:01:57.380 | followed by Parkinson's disease.

02:01:59.300 | Although the rate of growth of Parkinson's disease

02:02:01.980 | is the highest, so I think we'd probably be most,

02:02:04.860 | you know, those three diseases we wanna really be paying

02:02:07.060 | a lot of attention to.

02:02:07.900 | As you know, there are a lot

02:02:08.740 | of other neurodegenerative diseases.

02:02:10.660 | Every one of these things is devastating, like--

02:02:12.540 | - Multiple sclerosis.

02:02:13.380 | - Yeah, multiple sclerosis, ALS, Huntington's disease.

02:02:17.300 | These are awful, awful diseases.

02:02:20.820 | There are also other kinds of dementia.

02:02:23.140 | Vascular dementia is not Alzheimer's dementia,

02:02:26.540 | but it is, it produces comparable symptoms.

02:02:30.520 | Each of these things, by the way, are slightly different.

02:02:32.060 | Lewy body is a dementia.

02:02:33.920 | It's a dementing disease,

02:02:35.700 | but it also has a movement component.

02:02:37.540 | So it sort of sits on a spectrum that's sort of, you know,

02:02:40.540 | I mean, loosely halfway between Alzheimer's disease

02:02:43.580 | and Parkinson's disease.

02:02:44.860 | We talked obviously about age being the number one

02:02:48.700 | risk factor, kind of not that interesting,

02:02:50.460 | 'cause you can't do anything about it.

02:02:51.580 | So the real goal is, as we age,

02:02:53.440 | what are we doing to reduce risk?

02:02:55.440 | Well, let's start with an important gene,

02:03:00.340 | the gene that everybody's heard of.

02:03:02.300 | Certainly came up a lot on the Limitless special

02:03:05.940 | where Chris Hemsworth was, you know,

02:03:08.500 | made the decision to reveal something

02:03:10.340 | that none of us expected when we started that whole series,

02:03:13.300 | which was that he ended up being homozygous

02:03:16.420 | for the APOE4 isoform.

02:03:19.780 | So maybe folks understand we have two copies of every gene.

02:03:24.660 | So for gene X, you have copy that you got from your mom

02:03:27.920 | and copy that you got from your dad.

02:03:29.980 | And the APOE gene is kind of a unique gene

02:03:33.300 | in that it really, it has three different isoforms

02:03:36.100 | that are all considered normal.

02:03:37.540 | None of them are mutations.

02:03:40.040 | So you have the E2 isoform, the E3 isoform,

02:03:43.460 | and the E4 isoform.

02:03:45.820 | The E4 isoform is the OG isoform.

02:03:49.180 | That's the one that we have historically had

02:03:52.300 | as far back as we can go.

02:03:54.860 | We actually think the E4 isoform

02:03:57.260 | offered a lot of advantages back in the day.

02:04:00.180 | It's a bit of a pro-inflammatory isoform,

02:04:03.780 | and it certainly offered protection against infections,

02:04:07.100 | especially parasitic infections in the CNS,

02:04:09.560 | which would have been a really important thing

02:04:11.460 | to select for 200,000 years ago.

02:04:14.260 | - How do parasites get into the CNS?

02:04:16.020 | I mean, you got a blood-brain barrier, you got a thick skull.

02:04:18.440 | I mean, you. - Trauma.

02:04:19.580 | - I'm not telling you you have a thick skull,

02:04:21.420 | but I mean, it just seems like parasites

02:04:24.620 | in other tissues would be an issue,

02:04:26.180 | 'cause what we're talking about here is brain disease.

02:04:27.740 | - Yeah, yeah, yeah.

02:04:28.680 | - Anyway, I don't want to take us off course.

02:04:30.180 | - But it also could have protected them.

02:04:31.320 | It probably offered some protection

02:04:32.740 | outside of the brain as well.

02:04:34.140 | Anyway, the E3 isoform I think showed up,

02:04:42.700 | God, I think 50,000 years ago,

02:04:45.340 | and the E2 isoform showed up very recently,

02:04:48.080 | about 10,000 years ago.

02:04:49.500 | Now, today, we realize that there's a clear stratification

02:04:55.820 | of risk when it comes to Alzheimer's disease

02:04:59.620 | that tracks with those isoforms.

02:05:01.960 | So because you have two copies,

02:05:04.020 | you basically have six combinations

02:05:05.920 | of how you can combine those genes.

02:05:07.260 | You could be 2/2, 2/3, 2/4, 3/3, 3/4, 4/4.

02:05:12.240 | The prevalence of them is basically as follows.

02:05:15.660 | 3/3 is now the most common.

02:05:17.660 | Three is the most common.

02:05:18.600 | So double three is 55-ish percent of the population.

02:05:23.600 | The next most common is the 3/4,

02:05:25.980 | which is about 25% of the population.

02:05:28.740 | And then after that, most things are kind of a rounding error.

02:05:31.440 | So 2/3s and 2/4s would be the next most common.

02:05:36.440 | 4/4s are very rare, and 2/2s are the rarest of them all.

02:05:41.740 | 2/2s are less than 1%.

02:05:43.740 | 4/4s are about one to 2%.

02:05:45.700 | Very important point here is that the E4 genes

02:05:52.620 | are not deterministic.

02:05:53.740 | So they're highly associated with the risk,

02:05:58.060 | but they're not deterministic.

02:05:58.980 | There are at least three deterministic genes

02:06:02.560 | in Alzheimer's disease.

02:06:04.880 | One is called PSEN1, another one is called PSEN2,

02:06:08.460 | and another one is called APP.

02:06:10.920 | Those genes collectively make up about 1% of cases

02:06:14.860 | of people with Alzheimer's disease.

02:06:16.860 | So they're fortunately very rare genes,

02:06:19.800 | but sadly they are deterministic.

02:06:21.640 | Meaning if you have those genes,

02:06:22.820 | you do get Alzheimer's disease.

02:06:24.680 | And what's perhaps most devastating about those genes

02:06:27.620 | is how early the onset is of the disease.

02:06:30.780 | These are people that are usually getting

02:06:32.360 | Alzheimer's disease in their 50s.

02:06:34.060 | So we do have a patient in our practice,

02:06:37.820 | actually she's spoken about this very openly,

02:06:40.540 | whose mom had one of these genes.

02:06:43.420 | And she got Alzheimer's disease in her early 50s,

02:06:48.420 | I think she might have made it into her 60s before she died.

02:06:52.300 | But absolutely devastating consequences here.

02:06:55.860 | - Why do people with Alzheimer's die?

02:06:57.740 | Because I know about the hippocampal degeneration,

02:06:59.900 | hippocampus of course being an area of the brain

02:07:01.480 | important for learning and memory.

02:07:03.560 | But is there brainstem degeneration?

02:07:05.560 | Do they lose breathing centers or cardiovascular control?

02:07:08.360 | - Usually what happens is it's sort of failure to thrive,

02:07:10.640 | aspiration, things like that.

02:07:13.140 | So it's usually they just stop eating.

02:07:15.780 | Or they can't control secretions,

02:07:18.340 | they aspirate, they get a pneumonia.

02:07:20.300 | Or they really lose the ability to even sense pain

02:07:25.100 | in their body and therefore they'll get an ulcer

02:07:28.060 | and they don't realize it and it'll become cellulitic

02:07:30.080 | and they'll develop a horrible infection in response to it.

02:07:33.460 | - I see, so it's a body vulnerability.

02:07:35.100 | The reason I ask is every once in a while

02:07:36.800 | a news report will come out based on a legitimate case study

02:07:40.660 | where they'll do a scan on some person

02:07:44.380 | and discover that they're missing literally

02:07:46.540 | half their cerebral cortex, like huge chunks of brain

02:07:49.100 | and they're functioning relatively normally.

02:07:50.900 | And so here we're talking about a neurodegenerative disease

02:07:52.860 | of relatively, it's widespread but there are a few hotspots

02:07:56.400 | of course in the brain that degenerate more profoundly

02:07:58.700 | than others and the people dying.

02:08:00.280 | So that makes sense.

02:08:01.120 | It extends to lack of peripheral awareness or control

02:08:04.220 | and then some acute injury or infection.

02:08:06.720 | Got it.

02:08:07.560 | - You mentioned earlier some of the controversy, right?

02:08:11.120 | So what are we talking about here?

02:08:12.560 | Well, it's, and I do write about this at length

02:08:16.460 | in the chapter on Alzheimer's disease

02:08:18.040 | because I think this is a very important point, right?

02:08:21.200 | Which is the index case for Alzheimer's disease,

02:08:25.800 | there's always an index case, right?

02:08:27.000 | You know, there's the quote unquote patient zero.

02:08:30.120 | The index case was a woman who 100 years later

02:08:35.120 | we realized had an APP mutation.

02:08:39.100 | These are APP or PSEN1.

02:08:40.700 | But she had one of these deterministic genes

02:08:43.120 | that led to a very early onset of disease,

02:08:45.600 | which by the way, without which we may not have come up

02:08:48.860 | with the diagnosis because had she just got

02:08:51.420 | Alzheimer's disease in her 70s,

02:08:53.500 | it would have just been referred to as senility,

02:08:55.400 | which is, you know, was not interesting enough

02:08:58.420 | to pay attention to.

02:09:00.000 | But I think it probably set the field on the path

02:09:05.000 | towards an overemphasis on amyloid beta.

02:09:08.360 | And it's not really clear how important amyloid is,

02:09:15.860 | which is not to say it's not important, it is important.

02:09:21.040 | And there's no ambiguity that amyloid is responsible

02:09:25.840 | for the changes that we see in the brain.

02:09:30.340 | But it's not crystal clear because there are lots

02:09:32.900 | of autopsies that are done on people

02:09:35.620 | that are completely healthy and have died

02:09:37.660 | with no cognitive impairment

02:09:39.960 | and they're chock full of amyloid.

02:09:42.340 | So what we don't fully understand is exactly

02:09:47.340 | what does removing amyloid do.

02:09:50.140 | The other thing that complicates the story

02:09:52.800 | is there has been no shortage of drugs that target amyloid

02:09:56.780 | that have seemed unsuccessful.

02:09:58.700 | - And just to clarify, when you say amyloid,

02:10:01.460 | you mean people have died with their brains examined

02:10:04.900 | in autopsy and see that there are tons

02:10:06.240 | of so-called amyloid plaques?

02:10:07.780 | - Correct.

02:10:08.820 | - Different than arterial plaques, of course,

02:10:11.380 | but within the brain so that the two hallmarks

02:10:13.620 | of Alzheimer's histopathologically

02:10:16.420 | would be plaques and tangles.

02:10:18.560 | And even that now is, of course, coming under question.

02:10:23.040 | But it's what we teach every neuroscience graduate student,

02:10:26.940 | it's what we teach every undergraduate,

02:10:28.100 | it's also what we teach every medical student,

02:10:30.580 | and not just at Stanford, but everywhere.

02:10:33.260 | So I have heard that the link between APP

02:10:36.260 | and whether or not one develops genes related to APP,

02:10:39.960 | and whether or not it's cleaved at one side or another,

02:10:42.680 | which is what you were describing,

02:10:43.740 | and risk for Alzheimer's.

02:10:45.060 | - Yeah, so it's basically a cleavage question, right?

02:10:47.520 | So APP, people with the APP mutation,

02:10:49.900 | I think have one extra cleavage site.

02:10:51.820 | They result in one extra cleavage of amyloid,

02:10:55.860 | and then it misfolds.

02:10:57.340 | And the misfolding is what the plaque is that's being created

02:11:00.820 | that also then predisposes them

02:11:02.500 | to the neurofibrillary tangles, and again.

02:11:07.500 | - But all this is under question now, right?

02:11:09.700 | I mean, this is what I was told, and when I look,

02:11:12.060 | it sounds like there were some papers early

02:11:14.820 | in the chain of discovery and the research in Alzheimer's

02:11:18.680 | that were either wrong because they were falsified,

02:11:23.040 | intentionally falsified.

02:11:23.880 | - There was an intentionally falsified paper

02:11:25.720 | on one particular amyloid variant,

02:11:29.720 | and that clearly set the field back a decade,

02:11:32.460 | because a lot of people went down that rabbit hole

02:11:34.400 | based on deliberately falsified data.

02:11:36.940 | - So what happened to that guy?

02:11:40.120 | I don't know why I assume it was a guy,

02:11:41.160 | but what happened to that guy?

02:11:42.320 | - Yeah, it's a good question.

02:11:44.480 | I think I wrote one piece about it when it happened.

02:11:47.700 | I actually reached out to the person who broke the story,

02:11:50.660 | 'cause I wanted to have them on my podcast,

02:11:52.660 | and I forget why he didn't do it.

02:11:55.400 | I forget why he wouldn't commit to it

02:11:57.400 | or something like that, but I thought it was a little odd,

02:11:58.920 | 'cause I thought this would be a great way

02:12:01.020 | to talk about this.

02:12:01.980 | I do not know what came of that scandal.

02:12:06.260 | In other words, I haven't paid attention to it

02:12:08.040 | for probably nine months, so I don't know.

02:12:11.280 | Obviously, the paper's probably been recalled,

02:12:13.080 | but I don't know what disciplinary action was taken.

02:12:15.900 | The field is, I don't know.

02:12:22.460 | I don't wanna speak like I'm in the field, because I'm not,

02:12:24.920 | so I wanna be careful what I say,

02:12:27.400 | but I think the field is probably in a bit of a crisis,

02:12:32.400 | because there have been so many bets

02:12:37.240 | placed on anti-amyloid therapies and amyloid biomarkers

02:12:42.160 | and amyloid everything, and we just haven't seen efficacy.

02:12:47.160 | Contrast that with cardiovascular disease,

02:12:49.880 | where you have this ApoB biomarker,

02:12:54.060 | you understand the pathophysiology of how it works,

02:12:57.640 | you have drugs that target it, so you have a biomarker,

02:13:01.960 | so you give somebody a drug that lowers ApoB,

02:13:04.160 | you can measure ApoB.

02:13:05.320 | That's a really important and obvious thing

02:13:07.180 | to be able to do, and then you have clinical outcomes,

02:13:09.880 | which is, oh, when you take a bunch of people in primary

02:13:12.560 | prevention, it takes this long before you see an effect.

02:13:15.440 | In secondary prevention, it only takes this long

02:13:17.440 | to see an effect, right?

02:13:18.780 | Different risk stratifications, all these different things.

02:13:21.320 | We don't have any of that for Alzheimer's disease.

02:13:24.060 | So we do use, there are now serum amyloid biomarkers

02:13:27.480 | that we use, and we do track these

02:13:29.160 | in our highest-risk patients, but only because we believe,

02:13:33.680 | and I don't know if we're right, by the way,

02:13:35.520 | that lower is better, and therefore,

02:13:38.420 | if we make these changes to you,

02:13:40.660 | and your serum amyloid levels come down,

02:13:43.660 | that that tells us something about what's happening

02:13:45.500 | in your brain that's favorable.

02:13:47.140 | But I mean, I would hate to represent

02:13:50.220 | that we are practicing nearly the level

02:13:52.540 | of precision medicine there that we are

02:13:55.880 | in cardiovascular medicine.

02:13:58.080 | When it comes to Alzheimer's disease,

02:14:00.720 | maybe take a step back.

02:14:01.720 | When it comes to brain health, I think there are a handful

02:14:05.160 | of things that seem unequivocally true,

02:14:09.000 | and there's a lot of stuff that is signal-to-noise ratio

02:14:13.740 | that's really low.

02:14:14.960 | So the unequivocally true things

02:14:17.600 | for brain health are sleep matters.

02:14:21.020 | Another unequivocally true thing for brain health

02:14:25.800 | is that lower LDL cholesterol and ApoB is better than higher.

02:14:30.340 | Another thing that is unequivocally true

02:14:33.800 | is not having type 2 diabetes matters.

02:14:36.820 | - So having really good-- - Being in, yeah, but--

02:14:40.000 | - Be insulin-sensitive, not-- - Being insulin-sensitive

02:14:42.660 | matters, sleeping adequately matters,

02:14:46.840 | having lower lipids matters.

02:14:49.760 | Those three things are clear, and the fourth one

02:14:53.620 | that is unequivocally clear is exercise matters.

02:14:57.280 | More exercise-- - In a specific form

02:14:58.340 | of exercise?

02:14:59.520 | - Very, I mean, so I tried to answer this question

02:15:02.460 | in a recent AMA that I did, 'cause the answer is

02:15:05.920 | more is always better, but if you,

02:15:09.020 | if I tried to have one of our analysts look at it

02:15:12.300 | through the lens of if you could only exercise

02:15:14.140 | three hours a week, what would be the highest use case?

02:15:17.500 | And our interpretation of the literature was

02:15:21.020 | if you could only spend three hours a week exercising,

02:15:24.180 | you'd be best off doing one hour of low-intensity cardio,

02:15:28.820 | one hour of strength, and one hour of interval training.

02:15:32.620 | So if someone said I only want the minimum effective dose,

02:15:35.980 | you're gonna get a pretty good bang for your buck

02:15:37.540 | doing that, but I would argue if your brain

02:15:40.060 | really matters to you, do more.

02:15:41.660 | - One hour of interval training's no joke.

02:15:43.500 | - No, 'cause you're gonna spread that out

02:15:44.780 | over probably at least two workouts, yeah.

02:15:47.180 | But Andrew, those four things are basically

02:15:50.300 | the only thing where there's no ambiguity about the benefit.

02:15:55.180 | - What about head hits, like don't hit your head?

02:15:58.060 | - Seems almost assuredly true in a susceptible individual

02:16:01.540 | for sure.

02:16:02.460 | So I put that, yeah, maybe we could include that as well.

02:16:06.860 | - Well I just want to, one of the things I've been learning

02:16:08.980 | recently is I know you boxed for a number of years

02:16:13.300 | when you were younger, I boxed a little bit,

02:16:15.980 | hit my head a number of times skateboarding,

02:16:17.460 | but we think about sports injuries as the major cause

02:16:20.180 | of head injuries, but then I've got colleagues

02:16:22.060 | at Stanford that say-- - You have a car accident

02:16:22.900 | that's horrible. - Car accidents,

02:16:24.260 | bike accidents, I've got so many colleagues

02:16:27.740 | and children of colleagues growing up in and around campus

02:16:31.220 | that were hit by cars on Woodside Road,

02:16:34.140 | or a mere small object surrounded by three,

02:16:37.580 | was it a car weight, 3,000 pounds or something like that?

02:16:39.500 | - Jack Moore, yeah.

02:16:40.900 | - It's unbelievable the number of head injuries

02:16:43.780 | and then construction sites,

02:16:45.180 | 'cause those ridiculous little hard hats

02:16:46.700 | which don't protect against anything except, I don't know,

02:16:50.580 | maybe a windblown hair that they basically predisposed,

02:16:54.600 | the whole situation predisposed people to head injuries,

02:16:56.660 | very common on construction sites.

02:16:58.460 | And then say nothing of military, et cetera.

02:17:01.460 | So I think that I was told that the best thing to do

02:17:05.420 | if you get a head injury is to not get another one.

02:17:08.780 | In other words, if you can, stop doing the activity

02:17:11.800 | that leads to more head injury.

02:17:13.260 | - Yeah, the other thing that I think is emerging

02:17:15.780 | and I hope it is studied rigorously

02:17:18.140 | is the use of hyperbaric oxygen

02:17:20.380 | immediately following a TBI, a traumatic brain injury.

02:17:24.140 | I reached out to Dom D'Agostino a little while ago

02:17:27.380 | 'cause he knows a lot about this lit,

02:17:29.540 | to say, "Hey, is there anything out there

02:17:32.040 | that's really kind of turnkey convincing?"

02:17:34.620 | And he said, "Not yet."

02:17:35.820 | They're still doing it, right?

02:17:38.340 | So I would do this.

02:17:40.580 | If I was in a car accident tomorrow

02:17:42.300 | and sustained a concussion,

02:17:43.900 | and by the way, I'm not a proponent of hyperbaric oxygen.

02:17:46.220 | So we have an internal white paper

02:17:48.220 | that we wrote inside quite recently

02:17:50.780 | where I examined, when I say I examined,

02:17:53.900 | the analyst team examined and I pushed back and reviewed.

02:17:58.500 | And I came away very kind of bearish on hyperbaric oxygen.

02:18:03.060 | I don't think it's harmful,

02:18:04.940 | but I think all of the claims are nonsense.

02:18:07.620 | Telomere extension is totally irrelevant.

02:18:09.740 | And if you actually look at the studies,

02:18:11.200 | they're the worst done studies I've ever seen in my life.

02:18:13.860 | I'm sure you've seen some of these where it's like,

02:18:15.620 | you put these people in a hyperbaric chamber

02:18:17.040 | and then watch them do cognitive tasks,

02:18:18.560 | act after and they're so much better.

02:18:19.900 | Well, the fine print is

02:18:21.200 | they don't even have placebo groups here.

02:18:23.060 | Like, can you imagine doing a study without a placebo group

02:18:26.020 | or your placebo group doesn't go into a sham chamber?

02:18:29.180 | - Yeah, I mean, one of the big problems

02:18:30.540 | of the proliferation of all these pay-to-play journals,

02:18:33.660 | meaning journals that will basically publish a paper

02:18:36.040 | with minimal or poor peer review

02:18:39.000 | because they charge in order to publish

02:18:41.340 | and then offer free access.

02:18:43.340 | Free access sounds great,

02:18:44.420 | but when it's pay-to-play type journals,

02:18:46.180 | there's been a huge proliferation of papers,

02:18:48.200 | most of which you find on Twitter,

02:18:51.260 | in which the study design is beyond that.

02:18:54.720 | Like a ninth grader who woke up late for school

02:18:58.460 | and was partying all weekend could design a better study

02:19:01.540 | than most of these studies.

02:19:03.260 | And there's some excellent studies out there as well,

02:19:04.980 | of course, presumably and eventually

02:19:07.020 | on hyperbaric chamber too.

02:19:08.260 | So I'm not picking on hyperbaric chamber per se,

02:19:10.180 | but the proliferation of truly terrible science

02:19:14.500 | that's published in peer reviewed journals

02:19:17.260 | is just overwhelming.

02:19:19.060 | - Yeah, it's insane.

02:19:20.300 | And all of that is to say,

02:19:21.940 | I think there are places where hyperbaric oxygen

02:19:24.500 | makes sense, clearly in wound healing it does.

02:19:26.720 | It's a miracle treatment for wound healing.

02:19:29.700 | And I would absolutely use hyperbaric oxygen

02:19:33.660 | if I suffered a concussion.

02:19:35.020 | But beyond that, I think it's pretty tough

02:19:38.620 | to make the case.

02:19:39.460 | - Where do people go for that?

02:19:40.660 | I mean, their clinics?

02:19:42.380 | - Yeah, the clinics you basically go to.

02:19:44.300 | - 'Cause the protocols have to be very precise.

02:19:45.940 | I mean, this isn't something to cowboy at home.

02:19:48.480 | - No, no, no, you have to go into a real chamber.

02:19:51.300 | I think the TBI protocol that's most commonly used

02:19:55.840 | is, God, I wanna say it's pretty intense.

02:19:58.980 | It's like five 60 minute sessions a week

02:20:02.460 | at two atmospheres.

02:20:03.560 | - Oh boy.

02:20:04.400 | - Like it's no joke.

02:20:05.840 | So from a cost and time perspective, it's enormous.

02:20:08.900 | And the time and cost are reasons why I think

02:20:12.340 | when I see people doing hyperbaric oxygen

02:20:14.140 | just because they think it's gonna help them live longer,

02:20:16.740 | I'm like, dude, you know what you could do

02:20:19.740 | with five hours a week plus the commuting time

02:20:22.140 | that you put into that?

02:20:23.260 | Put that into exercise and I promise you

02:20:27.460 | you'll get a bigger benefit

02:20:28.780 | than you're getting out of hyperbaric oxygen.

02:20:31.640 | But there's a lot of other stuff that I just think

02:20:34.520 | is maybe helpful.

02:20:37.720 | There's tons of supplements that I think about

02:20:39.500 | when it comes to brain health.

02:20:41.180 | What about therecumin?

02:20:42.180 | What about magnesium with L-threonate, the transporter?

02:20:46.120 | What about methylated vitamins that lower homocysteine?

02:20:49.060 | What about EPA and DHA?

02:20:51.160 | And we've gone through all of the literature on that stuff

02:20:53.520 | and many of these things we still are recommending

02:20:55.940 | through a kind of basically like the potential benefits

02:21:00.160 | outweigh the potential costs.

02:21:02.120 | But the evidence is really unimpressive

02:21:04.860 | for most of those other interventions.

02:21:06.280 | So when you think about the big four or big five

02:21:08.260 | if you include not getting head injury,

02:21:10.520 | everything else is probably a rounding error

02:21:13.280 | compared to those big ones.

02:21:15.280 | - Maybe just for sake of thoroughness

02:21:17.900 | we can just list off those four again.

02:21:19.300 | Exercise.

02:21:20.140 | - Exercise, sleep, insulin sensitivity and lipid management.

02:21:25.140 | - Well along the lines of head injuries

02:21:29.060 | we should probably move to the next category

02:21:30.620 | of how not to die is to avoid accidental death.

02:21:35.540 | How common is accidental death

02:21:38.860 | and what are these accidental deaths?

02:21:40.580 | Because we are separating this out from automotive death.

02:21:43.740 | So is this people falling while hiking,

02:21:46.220 | selfies gone bad, you know what are we talking about here?

02:21:50.920 | I'm not chuckling because I like it.

02:21:52.500 | It's just I mean it seems like there's a near infinite

02:21:55.180 | ways to die accidentally.

02:21:57.880 | - So I think there's two ways to kind of look at this.

02:22:02.980 | And so here I kind of merge two categories.

02:22:06.800 | So I would call it that overlap in the way

02:22:12.660 | that they're characterized by the CDC

02:22:14.660 | but I would sort of, we'll talk about them separately

02:22:17.180 | and bring them together.

02:22:18.020 | So if you talk about true accidental deaths,

02:22:21.680 | automotive and falls and overdoses are the three.

02:22:26.680 | That's basically what it comes down to.

02:22:30.260 | So you know in our death bar analysis

02:22:33.220 | we kind of list all the stuff out.

02:22:34.340 | In fact I think that's actually one of the figures

02:22:35.780 | in the book is I have the accidental death figure

02:22:39.620 | that we've put together where we've adjusted by population.

02:22:43.700 | And you'll see a couple of things.

02:22:45.460 | If you look at it in absolute terms,

02:22:48.460 | it's basically a pretty constant.

02:22:50.940 | So regardless of what decade of life you're in,

02:22:53.220 | once you're above 20, accidental deaths

02:22:57.500 | are a pretty sizable number of deaths.

02:22:59.880 | Now car accidents seem to be pretty constant

02:23:02.760 | throughout life, little more common if you're under 60

02:23:06.380 | than over 60 but they never go away.

02:23:09.420 | - I was told that in teenage and boys in their early 20s,

02:23:14.420 | alcohol induced automotive fatalities

02:23:19.500 | place them at an astronomic risk.

02:23:22.180 | Is that just not true?

02:23:23.620 | - It's not true anymore compared to overdoses.

02:23:26.420 | - Is that because young people now

02:23:27.980 | aren't getting their driver's licenses?

02:23:29.380 | I've also heard that.

02:23:30.220 | - Yeah well I think it's also because we're seeing

02:23:32.180 | such an uptick in the deaths that come from fentanyl.

02:23:37.100 | So fentanyl related deaths have basically squashed

02:23:40.920 | all other deaths below 65 on the accidental front.

02:23:43.860 | - Really?

02:23:45.920 | - Oh yeah but it's not even close.

02:23:47.380 | - Because of the number of different substances

02:23:49.740 | that fentanyl is being woven into.

02:23:51.060 | - It's winding its way into everything.

02:23:53.460 | So all counterfeit drugs, all illicit drugs.

02:23:56.460 | And look, most of the time you're not getting a lethal dose

02:23:58.620 | so it's you know, but you're getting lethal doses

02:24:02.740 | so often now that, well you know I did a little analysis

02:24:07.740 | actually the other day when I looked at how are deaths

02:24:12.160 | of despair increasing over the last five years.

02:24:15.720 | So what did I define as a death of despair?

02:24:18.340 | Suicide, alcohol related death, or overdose.

02:24:22.700 | Accidental overdose.

02:24:23.620 | So we differentiate that from suicide

02:24:26.080 | where suicide is obviously deliberate

02:24:27.900 | and accidental is not.

02:24:29.540 | So if you just look at those three things.

02:24:30.860 | So accidental overdoses, suicides, and alcohol use

02:24:35.220 | or alcohol related death.

02:24:36.480 | Not including driving by the way.

02:24:41.100 | This is like cirrhosis of the liver that comes from.

02:24:44.020 | That number is going up at almost 20% per year since 2019.

02:24:49.020 | So I couldn't get 2022 numbers yet.

02:24:53.420 | So at the time I did this analysis which was last week,

02:24:59.400 | the 2021 numbers was about 210,000 Americans.

02:25:04.400 | - Goodness.

02:25:06.260 | - Up from 180,000 in 2020, up from like 150,000 in 2019.

02:25:11.260 | And that is driven almost entirely by fentanyl use.

02:25:21.980 | - So I'm trying to get a sense of how this would happen.

02:25:24.260 | A while back there was an article in the New York Times

02:25:26.660 | that some photographs of people that died

02:25:31.660 | of fentanyl overdose and said they went out to buy cocaine

02:25:35.120 | and died of fentanyl.

02:25:35.960 | And I thought to myself, this is a really kind of odd

02:25:39.040 | socio-biological phenomenon, right?

02:25:42.120 | Because I mean, here they're not demonizing

02:25:45.340 | these cocaine users.

02:25:46.260 | I mean, they went out to buy cocaine, right?

02:25:47.980 | This is not a, I know cocaine has one narrow clinical use

02:25:51.660 | as a prescription drug.

02:25:52.640 | But in general, when people buy cocaine,

02:25:54.100 | they're quote unquote partying with it

02:25:55.820 | or using it to work longer hours or something like that.

02:25:59.180 | So the whole nature of the article was a bit strange to me,

02:26:01.580 | but it clearly pointed to the fact

02:26:05.460 | that people are using cocaine, okay, that's no surprise.

02:26:08.660 | But people are going out and buying cocaine.

02:26:11.700 | They're presumably buying Valium.

02:26:13.160 | They're presumably buying-

02:26:14.000 | - Yeah, this is where it's really killing kids.

02:26:15.980 | - I mean, but this is online, this is in person.

02:26:18.580 | I mean, the reason I'm so baffled by this is,

02:26:21.700 | let me contextualize what I've said so far

02:26:25.440 | about this question.

02:26:27.000 | I was surprised that the Times would write a paper

02:26:30.160 | about the tragedy of cocaine users dying of fentanyl.

02:26:34.780 | And I think they did it to highlight this fentanyl problem

02:26:38.160 | because people have been using cocaine for a long time.

02:26:41.160 | And typically those are not the members of the population

02:26:43.920 | that we're really focused on since the mid '80s,

02:26:46.480 | the so-called cocaine and crack epidemic.

02:26:49.140 | So basically it tells me that people, like you said,

02:26:52.560 | illicit drugs, so cocaine, but also,

02:26:56.740 | what other sorts of drugs are people buying?

02:26:58.580 | - So where the majority of people are dying

02:27:00.240 | from fentanyl poisoning.

02:27:02.620 | And I had a guy on my podcast recently

02:27:04.160 | named Anthony Hippolito.

02:27:05.300 | And if anybody's interested in this topic,

02:27:06.740 | they really need to go listen to that.

02:27:08.140 | So Anthony-

02:27:08.980 | - I watched the YouTube version of this

02:27:10.300 | and your podcasts are excellent.

02:27:11.900 | So if you're interested in this,

02:27:13.240 | and I think everyone should be interested in this.

02:27:14.900 | - If you have a child or know somebody who has a child,

02:27:18.000 | you just got to get this podcast into their hands

02:27:20.200 | because it's the most important public service announcement

02:27:22.960 | I'll probably ever do

02:27:24.200 | in terms of saving more lives potentially.

02:27:26.760 | Where the majority of this is making its way

02:27:30.600 | into the accidental poisonings

02:27:33.880 | is through illicit counterfeit pills.

02:27:36.640 | So it's when kids are out there buying, you know,

02:27:40.180 | Oxy, they want Oxy.

02:27:41.500 | Well, they can't get real Oxy, right?

02:27:43.360 | 'Cause they're not gonna go to a doctor and get real Oxy.

02:27:45.700 | So they're gonna buy it through, you know, Snapchat, right?

02:27:48.560 | They're gonna buy it through some drug dealer

02:27:49.940 | that they're finding on social media.

02:27:52.140 | They're buying sleeping pills.

02:27:54.140 | They're buying all sorts of counterfeit stuff like Adderall.

02:27:58.080 | Any of these things are being laced with fentanyl.

02:28:00.860 | - Adderall.

02:28:01.700 | - Absolutely.

02:28:03.340 | - Well, I assume the fentanyl-

02:28:04.940 | - And again, the reasons are it's insanely cheap

02:28:07.740 | to use synthetic fentanyl.

02:28:09.720 | And secondly, and again-

02:28:11.360 | - But the effects of fentanyl are nothing like

02:28:12.920 | the effects of Adderall.

02:28:14.040 | So cocaine doesn't make sense for that reason either.

02:28:16.500 | - Cocaine doesn't make sense either.

02:28:17.720 | Yep, and yet it's still showing up in cocaine.

02:28:19.820 | Again, I don't think that's the dominant place

02:28:22.360 | it's showing up.

02:28:23.200 | I would guess that the dominant place it's showing up

02:28:26.940 | is in counterfeit opioids.

02:28:30.100 | - So any opioid, barbiturate, any sedative, depressant.

02:28:33.500 | - Let me tell you what I'm telling my daughter, right?

02:28:35.460 | 'Cause this is, to me, it's a frontline problem.

02:28:37.020 | I have a 14-year-old daughter.

02:28:38.580 | I'm like, listen, I don't care which friend of yours it is.

02:28:41.420 | I don't care how much she's amazing.

02:28:43.560 | If she tells you to try this sleeping pill

02:28:46.480 | because she took it the night before

02:28:47.860 | and it was really helpful,

02:28:49.180 | or this will help you study better,

02:28:50.660 | or this will help you do anything,

02:28:52.200 | I'm like, just come to us.

02:28:53.860 | We've got a better pill for you, right?

02:28:55.920 | Like in other words, you can't trust anything

02:28:59.260 | 'cause you don't know where she got it.

02:29:00.620 | She has the best of intentions, I'm sure,

02:29:02.100 | when she's giving it to you.

02:29:02.940 | And by the way, she probably took it the night before

02:29:04.440 | and was just fine.

02:29:05.760 | But the people who are making these pills

02:29:08.760 | are not exactly up to GMP standards.

02:29:11.580 | So you just have no idea

02:29:14.540 | which pill is getting what dose of fentanyl.

02:29:17.300 | One thing that Anthony Hippolito told me

02:29:18.760 | that I simply couldn't believe,

02:29:19.780 | I had to ask him six times,

02:29:21.520 | was that some of these pills

02:29:23.260 | have like one milligram of fentanyl in them.

02:29:27.340 | Now, I made the point on the podcast

02:29:29.640 | that 100 milligrams of fentanyl, for most people,

02:29:33.380 | is a hit, like I've had fentanyl before,

02:29:36.640 | I've been in the hospital and I've had fentanyl.

02:29:38.380 | 100 milligrams is like, wow, that is such a trip.

02:29:43.300 | - Why are people dying from one milligram intake?

02:29:45.660 | - Respiratory inhibition, you can't breathe.

02:29:48.140 | That shuts the brain stem off.

02:29:49.980 | - Well, I don't think we can highlight this enough.

02:29:52.900 | Adults are dying, kids are dying.

02:29:54.100 | I met someone just earlier this week

02:29:56.100 | who told me her 35-year-old son died

02:29:57.900 | of an accidental fentanyl overdose.

02:29:59.640 | And he wasn't, at least by her description,

02:30:02.660 | a drug addict or anything of that sort.

02:30:04.260 | - Yeah, we're talking about a different game now, right?

02:30:06.940 | So it's like, these are kids that have anxiety.

02:30:09.200 | These are kids that are sort of addressing another issue

02:30:14.200 | with these pills.

02:30:15.660 | And that's why I think this whole concept

02:30:17.520 | of deaths of despair is a really important one.

02:30:21.020 | But back to your question, what do accidental deaths

02:30:23.900 | primarily amount to for the aging population?

02:30:28.900 | Again, it is so clear that it is fall related.

02:30:33.100 | This is where once you hit 60, 65,

02:30:38.100 | the risk of a fall that results either immediately in death,

02:30:42.900 | you know, you hit your head and die,

02:30:44.900 | going back to like cerebral hemorrhage,

02:30:46.920 | or it is the straw that basically leads you down the path

02:30:51.620 | to death within the next 12 months is astonishingly high.

02:30:55.420 | It's so high that it's sort of hard

02:30:57.900 | to wrap your head around.

02:30:58.740 | But if you're over 65 and you fall

02:31:02.020 | and break your femur or hip,

02:31:05.420 | so you either crack the femoral neck or the femur itself,

02:31:08.580 | your 12-month mortality, the probability you will be dead

02:31:13.660 | in 12 months after that break, if you're 65 or older,

02:31:17.080 | depending on the study, is about 15 to 30%.

02:31:20.640 | - Wow.

02:31:22.240 | Wow, so in terms of offsetting the probability of falls,

02:31:26.280 | you talked a little bit about this before,

02:31:29.280 | but you and I have talked a little bit about this before,

02:31:31.940 | but maybe we could go a little bit deeper.

02:31:34.080 | People's ability to jump and land

02:31:38.240 | seems to be highly correlated with one's ability

02:31:40.980 | to not fall or at least fall and control the fall

02:31:45.560 | in a way that leads to no or less severe injury.

02:31:49.660 | - Yeah, so Andy Galpin talked about this on your podcast.

02:31:52.340 | He talked about it on my podcast.

02:31:54.080 | What is the hallmark of aging on the muscle?

02:31:59.060 | It is atrophy of the type two muscle fiber.

02:32:02.220 | That's the hallmark.

02:32:03.060 | - Fast twitch.

02:32:03.900 | - Fast twitch muscle fiber.

02:32:04.980 | So if you wanna understand what looks different

02:32:07.580 | in 50-year-old Peter versus 18-year-old Peter,

02:32:10.620 | it's not my type one fibers.

02:32:12.380 | It's my type two fibers.

02:32:13.540 | It's my fast twitch fibers.

02:32:14.500 | It's my explosive fibers.

02:32:15.860 | When I was 18 years old,

02:32:16.820 | I could vertical jump over 30 inches.

02:32:19.740 | Today, I'm lucky if I can vertical jump 24 inches.

02:32:23.860 | And when I'm 60, boy,

02:32:27.540 | my goal is to be able to vertical jump 20 inches

02:32:30.440 | when I'm 60, and I don't know if I'm gonna be able to do it.

02:32:32.300 | - I've seen some videos of some 80-year-old sprinters

02:32:35.620 | that are pretty impressive,

02:32:36.560 | and certainly 80-year-old gymnasts that are impressive.

02:32:39.460 | I have not seen very many videos

02:32:41.620 | of 80-year-olds dunking basketballs, for instance.

02:32:45.740 | - Yeah, it's--

02:32:46.580 | - Who are not more, who are not taller than six feet,

02:32:49.940 | five inches. - Right, yeah, yeah, yeah.

02:32:51.840 | So when we lose, you know, our,

02:32:55.460 | so again, if you just think about size, strength, speed,

02:33:00.460 | we lose speed first.

02:33:02.300 | We lose speed, then strength,

02:33:04.140 | and the last thing you lose is size.

02:33:06.180 | So again, size is agnostic to fiber, right?

02:33:09.900 | You could have big type one fibers

02:33:12.100 | and still have lots of size.

02:33:13.640 | They're not gonna be that strong,

02:33:14.540 | and they're certainly not gonna be fast.

02:33:16.480 | So what, I mean, like we could go through,

02:33:19.860 | we could spend hours on this particular topic,

02:33:21.820 | but I think the most important thing

02:33:23.060 | that people need to understand is you cannot age well

02:33:27.180 | if you are not doing the type of training

02:33:30.140 | that is there to strengthen and delay or minimize

02:33:34.020 | the hypertrophy of your type two fibers.

02:33:36.020 | So everything matters, right?

02:33:37.540 | You have to be doing your zone two.

02:33:39.340 | You have to be doing, you know, all of these other things,

02:33:42.300 | but some component of your training needs to be stressing

02:33:45.740 | the type two fibers.

02:33:46.620 | You have to be doing strength training

02:33:49.140 | that taxes those fibers.

02:33:50.500 | You have to be doing reactivity training.

02:33:52.780 | You have to be doing explosive training.

02:33:55.380 | - And ideally, some training that involves

02:33:57.460 | jumping and landing.

02:33:58.820 | - Well, jumping is a very big part of it,

02:34:00.300 | and landing is a very big part of another one

02:34:02.500 | of what I kind of think of as my four pillars

02:34:05.040 | of strength training.

02:34:06.180 | So one of the pillars of strength training

02:34:08.260 | is eccentric strength, which is breaks.

02:34:11.960 | So, you know, you're gonna hurt yourself 10 times

02:34:16.960 | more likely, I'm making that number up by the way,

02:34:19.680 | I don't know if it's 10 times,

02:34:20.540 | but experientially it seems to be you are 10 times

02:34:23.820 | more likely to hurt yourself stepping off something

02:34:27.060 | than stepping onto something, right?

02:34:29.260 | Stepping down versus stepping up.

02:34:31.420 | Because when you step up onto something,

02:34:34.600 | you are concentrically controlling muscle.

02:34:38.340 | When you step down, you have to apply the breaks,

02:34:42.060 | and that's where most people falter.

02:34:44.200 | Much harder to walk downhill than uphill.

02:34:46.260 | Uphill is taxing your cardiovascular system,

02:34:48.920 | but if you slow down enough, you're fine.

02:34:51.180 | But a lot of people don't have the ability

02:34:52.580 | to slow themselves down when they're walking downhill.

02:34:55.060 | And so when an older person steps off a curb

02:34:58.120 | and can't fully stop themselves,

02:35:00.700 | and that results in a fall.

02:35:02.520 | So, you know, I like doing things like a broad jump.

02:35:05.720 | Broad jump's a fun little test set

02:35:07.940 | I like to do every once in a while.

02:35:09.380 | I always wanna make sure I can broad jump six feet.

02:35:11.180 | That's kind of my arbitrary number that I've chosen.

02:35:13.620 | And the reason is on the takeoff,

02:35:15.540 | that's a very explosive movement.

02:35:18.040 | But the landing is just as important.

02:35:20.100 | If I can't stick that landing,

02:35:21.820 | it means I don't have the breaks.

02:35:23.420 | So those are kind of some of the tests

02:35:24.900 | I wanna be able to do to make sure

02:35:27.100 | that I'm utilizing that system.

02:35:29.160 | Because I do think, you know, look I've watched,

02:35:31.900 | I've watched my mom, my mom fell,

02:35:33.880 | gosh, probably been about four months ago,

02:35:37.380 | just fell in a typical way that people fall.

02:35:40.420 | By the way, it could have happened to anybody.

02:35:41.640 | It's not like, you know, my mom walks around

02:35:43.980 | and moves around just fine, but in this particular day,

02:35:46.620 | she just tripped on a uneven stone and fell

02:35:50.860 | and landed and broke her hand.

02:35:53.680 | And she's really lucky she didn't break her hip.

02:35:55.060 | And I told her that because my mom was, you know,

02:35:56.620 | probably in her mid 70s.

02:35:57.620 | And I said, look, you know, if that was your femur,

02:36:00.940 | I'd give you a 30% chance of dying in the next year.

02:36:04.940 | I mean, it's just an,

02:36:05.940 | those are such difficult to recover from injuries.

02:36:08.740 | Because first of all, you're dealing with the immobility

02:36:12.700 | of, you know, the hospitalization

02:36:14.660 | and immobility that follows that.

02:36:16.180 | And the amount of muscle loss that occurs

02:36:18.980 | could easily be, you know,

02:36:23.020 | four or five pounds of lean tissue lost

02:36:25.380 | that for most people that age

02:36:27.060 | becomes almost impossible to get back.

02:36:29.580 | And that says nothing about sort of the acute causes

02:36:31.780 | of death, like a fat embolism that results

02:36:33.500 | from a broken femur, a blood clot from laying in bed.

02:36:35.940 | Those things are also catastrophic.

02:36:38.060 | But what happens is a lot of these patients

02:36:39.780 | just never get back to the same level of mobility.

02:36:43.180 | And, you know, now I think in many ways,

02:36:45.220 | we're kind of pivoting from what kills you

02:36:47.600 | to what ruins your quality of life.

02:36:50.020 | And we've spent so much time talking about what kills you,

02:36:53.380 | but I think you might as well be dead in some ways

02:36:57.660 | if you can't do the things you want to do.

02:36:59.920 | And if playing with your grandkids or gardening

02:37:03.260 | or playing golf or going for a walk with your spouse

02:37:05.840 | or think of any of the things that we all do today

02:37:08.100 | and take for granted, if you can't do those things,

02:37:11.140 | I don't know, you sort of lose the reason to be around.

02:37:15.300 | - And oftentimes the inability to do those things

02:37:18.380 | is associated with pain, you know,

02:37:21.580 | which is psychologically and obviously physiologically

02:37:25.100 | so distressing.

02:37:27.060 | You mentioned the four pillars of health,

02:37:28.580 | maybe just list those off for people.

02:37:30.500 | - Of lifting?

02:37:31.700 | - Well, the four pillars of longevity through physical.

02:37:35.680 | - Oh, yeah, yeah, yeah.

02:37:38.000 | Sort of the exercise pieces of them.

02:37:40.020 | - Yes.

02:37:40.860 | - Yeah, so strength, stability, aerobic efficiency,

02:37:44.040 | and aerobic peak output.

02:37:47.300 | - Okay, so aerobic peak would be--

02:37:48.340 | - So VO2 max. - VO2 max, yep.

02:37:50.020 | - And zone two.

02:37:50.980 | That's, in my analogy, your zone two is how wide

02:37:56.080 | the base of your pyramid is,

02:37:58.020 | and your VO2 max is how tall the peak of the pyramid is.

02:38:01.100 | So the best pyramid has a wide base and a high peak.

02:38:05.420 | So you could have a reasonably wide base and a shallow peak.

02:38:09.100 | If you just did zone two training,

02:38:10.580 | you're gonna get a reasonable peak,

02:38:12.140 | but it's not gonna be that high.

02:38:12.980 | You have to do some of that specific training.

02:38:14.860 | If you just focus on high intensity,

02:38:16.560 | you might drive up that VO2 max,

02:38:18.540 | but you're actually gonna have a relatively wide,

02:38:20.460 | a narrow aerobic base.

02:38:21.660 | So think about just maximizing the area of that triangle,

02:38:24.700 | widest, tallest.

02:38:26.520 | Stability and strength.

02:38:28.580 | Stability, of course, encompasses everything

02:38:30.600 | we're talking about in terms of reactivity.

02:38:32.840 | I dedicate a chapter in the book to this concept

02:38:37.660 | because it is so foreign to most people,

02:38:40.340 | and for understandable reasons.

02:38:42.600 | It's just, it's not sexy, it's not,

02:38:45.800 | it's the hardest one to train,

02:38:47.100 | it's the hardest one to understand,

02:38:49.060 | but it's so important because it's the thing

02:38:50.840 | that I think differentiates people who age well

02:38:53.100 | and people who don't age well.

02:38:54.940 | - And I should perhaps throw in there,

02:38:57.260 | please correct me if I'm wrong,

02:38:58.400 | but also most of the machines

02:39:00.700 | that are in typical commercial gyms

02:39:03.220 | that allow people who are not very experienced

02:39:05.740 | to start doing some resistance training

02:39:07.700 | don't really tap into the stability factor terribly much.

02:39:11.300 | So while there's value to leg extensions and leg curls

02:39:14.180 | and chest presses and shoulder presses

02:39:16.380 | done with machines, certainly,

02:39:18.740 | for a number of reasons

02:39:19.620 | and can often be safer than free weights,

02:39:21.060 | especially for people who are approaching it at a later time

02:39:23.340 | or new to the whole thing,

02:39:25.020 | they don't really lend themselves to real life stability,

02:39:29.540 | walking down, as you mentioned, walking down stairs

02:39:32.700 | in the absence of a handrail or movements

02:39:36.160 | in kind of odd planes, having to step aside

02:39:40.500 | to avoid a bicycle at an angle

02:39:43.700 | as opposed to just moving linearly.

02:39:46.420 | - Yeah, and by the way,

02:39:47.460 | a lot of things that don't involve machines

02:39:50.740 | still don't give you that, right?

02:39:51.860 | Like, I mean, doing a deadlift,

02:39:53.780 | you have to be stable to lift a heavy weight

02:39:56.280 | like you would a deadlift without hurting yourself.

02:39:59.060 | That requires an unbelievable capacity

02:40:01.520 | to harness intra-abdominal pressure and to be connected,

02:40:04.900 | you know, if you're gonna lift 500 pounds off the ground,

02:40:07.060 | you're stable, but that still doesn't prepare you

02:40:10.220 | for what you just described.

02:40:11.480 | So stability is multifaceted

02:40:14.060 | and it involves doing a lot of things.

02:40:16.780 | You know, today, for example, I finished my,

02:40:18.580 | today was a cardio zone two day, so I did my cardio zone two

02:40:21.900 | and I, you know, had an extra 10 minutes

02:40:24.920 | before I needed to kind of get moving.

02:40:26.920 | And so all I did was step ups for 10 minutes.

02:40:29.500 | I just did single leg, very slow step up

02:40:34.500 | and insanely slow step downs off a box in a gym.

02:40:38.680 | So two second up, four second down,

02:40:41.380 | two second up, four second down with, you know,

02:40:43.980 | and I would do them with ipsilateral loads,

02:40:45.580 | contralateral loads, all sorts of different things.

02:40:48.300 | And, you know, basically that's just a stability game for me.

02:40:50.980 | It's like I'm building that concentric strength

02:40:54.500 | in a movement where it's easy to cheat,

02:40:58.020 | but can I do it without cheating?

02:41:01.060 | - That's terrific and it's terrific that you cover

02:41:03.300 | all of that in the book in addition to these other topics.

02:41:06.720 | So several times during our conversation today,

02:41:09.220 | you alluded to quality of life.

02:41:11.860 | And one of my favorite segments in your book,

02:41:15.020 | indeed the segment in your book that I believe could be

02:41:19.020 | its own entire book of tremendous value

02:41:22.620 | is the section on emotional health.

02:41:25.720 | If you could just share with us a bit

02:41:28.180 | of what inspired you to include that section.

02:41:31.300 | Was this, for instance, based on communication

02:41:34.980 | with your patients, to what extent it was based

02:41:37.260 | on your own life experience.

02:41:39.340 | And then maybe we can drill a little bit deeper

02:41:41.500 | into what's contained in those chapters

02:41:44.660 | and what really constitutes emotional health.

02:41:47.380 | - Well, I mean, I think that chapter of the book,

02:41:51.860 | which is a pretty long chapter,

02:41:52.980 | it's the final chapter as well,

02:41:55.060 | is certainly different from all of the others

02:41:59.140 | in that there is no confusion about expertise, right?

02:42:04.140 | I think in the other chapters I at least try to come across

02:42:08.940 | as having some knowledge on the subject matter

02:42:11.340 | and I'm writing them most often as, you know,

02:42:15.580 | quote unquote, the doctor, right?

02:42:17.540 | Whereas I think that last chapter is much more

02:42:20.020 | about an experiential side of my knowledge acquisition

02:42:25.020 | and therefore really it comes across more as a patient.

02:42:27.780 | And I think you're right.

02:42:29.880 | I think that that's a chapter that initially was resisted

02:42:34.880 | by all other parties involved in the book.

02:42:38.980 | So my co-author, my editor,

02:42:43.020 | everybody else sort of felt like this is interesting,

02:42:45.980 | but it's a separate topic.

02:42:47.740 | If you want to write about this,

02:42:48.700 | you should write another book about it,

02:42:50.740 | but it doesn't really belong in this book.

02:42:52.840 | I disagreed for two reasons

02:42:57.500 | and ultimately I guess my opinion prevailed.

02:43:00.620 | The first is I didn't want to write another book.

02:43:03.500 | So it just that, you know, not including this in this book

02:43:07.580 | to then write about it in another book

02:43:08.780 | was not something I was interested in doing.

02:43:10.700 | But I think more importantly,

02:43:12.460 | I do think that this book is about much more

02:43:15.600 | than how long you live.

02:43:17.540 | And while we have talked about and will talk about

02:43:21.740 | in the book that is, you know,

02:43:23.660 | how cognitive and physical health are just as germane

02:43:26.700 | to quality of life as they are to length of life,

02:43:29.520 | this other piece of emotional health,

02:43:32.140 | you know, it's potentially the most important of them all.

02:43:35.780 | It's also the hardest to define,

02:43:37.400 | but without it none of this other stuff matters, right?

02:43:40.080 | So there's, you know, infinite lifespan

02:43:43.640 | if you're miserable means nothing.

02:43:47.060 | - Maybe worse.

02:43:48.440 | - That would be a curse, right?

02:43:49.280 | You could argue, how could you punish somebody the most,

02:43:54.240 | allow them to live forever and be miserable?

02:43:56.420 | - Is there a Greek?

02:43:57.960 | - Yeah, there's a Greek god, Tithonus, yeah.

02:44:00.380 | - Tithonus? - Yeah.

02:44:01.440 | He was granted immortality, it's a bit different.

02:44:04.680 | He was granted immortality, but without a health span,

02:44:07.600 | basically, so he aged forever.

02:44:10.440 | - Dreadful. - Yeah.

02:44:12.320 | And this would be dreadful too, right?

02:44:14.880 | And then I feel like, why did I need to write about this?

02:44:17.800 | Well, I think that, you know,

02:44:19.500 | this is probably my greatest struggle, I think.

02:44:22.000 | You know, way at the outset of the podcast,

02:44:25.080 | you asked me kind of like,

02:44:26.000 | what are the obstacles to longevity?

02:44:29.000 | And that got us down a path of some very

02:44:33.500 | black and white things.

02:44:35.200 | But when I look at a patient, I create a dashboard.

02:44:40.200 | And the dashboard is, what are all the things

02:44:44.100 | that are a threat to every component of your longevity,

02:44:46.880 | both lifespan and health span?

02:44:48.660 | We talked about a bunch of those things.

02:44:49.660 | So what is your risk for atherosclerosis

02:44:53.320 | and what are we doing about it?

02:44:54.960 | What is your risk for cancer?

02:44:56.160 | What are we doing about it?

02:44:57.120 | What is your risk for neurodegeneration?

02:44:58.720 | What are we doing about it?

02:44:59.560 | What is your risk for accidental death?

02:45:01.880 | What are we doing about it?

02:45:03.280 | What is your risk for physical decline?

02:45:06.020 | What are we doing about it?

02:45:07.140 | And one of those things is,

02:45:08.220 | what is your risk of emotional health

02:45:11.620 | or poor emotional health and what are we doing about it?

02:45:14.420 | So when I do that exercise for me, which I do,

02:45:20.260 | I mean, I have that spreadsheet laid out for me

02:45:22.800 | and I know where my factors line up.

02:45:25.460 | And interestingly, despite my family history

02:45:27.860 | being horrible for atherosclerosis,

02:45:30.940 | it's like sixth on my list.

02:45:33.640 | Because, I mean, basically I intervened early,

02:45:37.840 | I have a clear understanding of the pathophysiology

02:45:40.160 | and I'm doing everything to the maximum.

02:45:42.860 | So I'm actually very confident I will die with

02:45:46.160 | and not from atherosclerosis.

02:45:48.940 | But the top thing on my list is actually emotional health.

02:45:52.900 | That's the one that is the hardest for me to manage.

02:45:56.440 | And it's the easiest to get out of balance

02:46:00.640 | and it creates the most pain in my life.

02:46:03.420 | So that's a long answer to why I felt

02:46:06.860 | this needed to be in here.

02:46:08.600 | - Well, in the book, you go into very honest detail

02:46:13.600 | about some of your journeys through and challenges

02:46:18.840 | with emotional health and paths to overcoming those.

02:46:23.580 | Maybe we'll get into those a bit, but before we do,

02:46:26.400 | how should we define emotional health?

02:46:29.480 | This to me seems like one of the most difficult areas

02:46:31.920 | to calibrate oneself, like even just measuring emotion

02:46:36.920 | is tricky, language is the dissection tool

02:46:40.440 | for psychologists, psychiatrists, and indeed for all of us,

02:46:44.900 | how are you doing today?

02:46:45.740 | Great, or I'm miserable or I'm depressed.

02:46:48.020 | I mean, it means such different things to different people.

02:46:50.260 | Obviously, suicide being the far end of,

02:46:53.920 | we presume misery and there are instances of manic suicide,

02:46:57.120 | but depressive misery.

02:47:00.320 | But setting that aside, how should we evaluate,

02:47:05.320 | think about, and communicate emotional health

02:47:10.880 | to ourselves and to the relevant people

02:47:14.040 | that could potentially help us?

02:47:16.600 | - Yeah, well, you're right, it's very difficult, right?

02:47:20.000 | And so much of what goes into this book

02:47:24.240 | is about things that are much easier to quantify.

02:47:27.580 | It's very, you know, I could sit here and talk for days

02:47:29.360 | about all the ways we quantify from the histologic

02:47:32.280 | to the gross of each of these diseases, you know,

02:47:34.980 | genetically, all of these other things.

02:47:36.880 | With emotional health, it's far more vague,

02:47:41.120 | and I don't even attempt to come up with a definition, right?

02:47:44.720 | I can tell you things that make up components of it.

02:47:48.080 | So connectivity with others just seems

02:47:52.680 | to be an inescapable part of this.

02:47:54.680 | So the ability to maintain healthy relationships

02:47:59.080 | and attachments to other people.

02:48:01.800 | Having, and by the way, these are in no particular order,

02:48:04.480 | having a sense of purpose, being able to regulate

02:48:09.480 | your emotions, experiencing fulfillment,

02:48:14.000 | experiencing satisfaction, all of these things matter,

02:48:20.800 | and I think that for many of us,

02:48:23.940 | if we're taking an honest appraisal of ourselves,

02:48:27.800 | we'll notice that we have deficits in these areas.

02:48:30.880 | Being present, by the way, that's something

02:48:35.120 | that may have been less of an issue 100 years ago

02:48:39.480 | than it is today.

02:48:40.720 | So I think, you know, certainly for me,

02:48:44.600 | being present is very difficult.

02:48:47.240 | It's not my default state.

02:48:49.520 | I don't know that it's the default state

02:48:50.820 | for most people, truthfully,

02:48:52.280 | but I'm very often predisposed with thoughts

02:48:56.440 | about the future, occasionally thoughts about the past,

02:48:58.720 | but it's much more often kind of thoughts about the future,

02:49:01.540 | and planning, and thinking about what I need to do,

02:49:04.720 | and what do I want to do next,

02:49:06.440 | and never really being satisfied

02:49:07.960 | with anything that's happening in the moment.

02:49:09.960 | So I have to work hard to kind of overcome those things,

02:49:13.060 | and I'm sure you can appreciate this,

02:49:15.920 | but when you are present,

02:49:18.160 | you generally are in a much better frame of mind.

02:49:21.240 | - Yeah, there's an interesting study,

02:49:22.840 | I think it was initially published by Dan Gilbert's lab,

02:49:25.500 | one of these long-term happiness studies

02:49:28.800 | that was published in Science Magazine

02:49:30.700 | that pinged people for their level of happiness,

02:49:36.000 | unhappiness, presence, or lack of presence

02:49:38.680 | multiple times throughout the day.

02:49:39.800 | This was in the early years of smartphones,

02:49:42.500 | so this is around 2010, 2011,

02:49:44.120 | so the technology wasn't as good as it is now,

02:49:46.060 | but it was good enough to do this in a very large number

02:49:49.240 | of people, I forget how many,

02:49:50.200 | but it's certainly more than 10,000,

02:49:52.400 | that number is, I'm stating it intentionally low.

02:49:56.040 | And what they found was regardless of whether or not

02:49:57.820 | people were doing something they enjoyed or not,

02:50:00.100 | boring to them or not,

02:50:02.780 | the degree of presence to what they were doing

02:50:05.220 | was a stronger predictor of their happiness in that moment,

02:50:09.500 | and overall, than was anything else.

02:50:13.180 | And also a fairly rare feature for most people.

02:50:16.740 | So seems like it's something that we do need to work at,

02:50:19.440 | perhaps nowadays, as you point out,

02:50:20.900 | more than we perhaps do in our ancestral past.

02:50:24.860 | I'm a little bit surprised that you say

02:50:29.980 | that you find it hard to be present,

02:50:31.500 | because you strike me as somebody that is not just willing,

02:50:34.660 | but has a strong, almost reflex toward drilling,

02:50:39.660 | observing the contour of something,

02:50:42.260 | and then really drilling into it,

02:50:43.740 | and really getting to the guts of most everything

02:50:47.560 | that interests you.

02:50:48.860 | So you strike me as somebody who's very present.

02:50:51.660 | And I guess maybe this gets back to this--

02:50:53.740 | - But they're not visually exclusive, right?

02:50:55.280 | I mean, I think, so for example,

02:50:57.940 | I'll notice that sometimes if I'm playing with my kids,

02:51:02.620 | especially my boys, 'cause they're younger, right?

02:51:04.660 | And playing with them is really being in their world.

02:51:09.340 | Like if I'm with my daughter,

02:51:10.860 | we can be doing things that are kind of mutually,

02:51:13.700 | like we'll do things together

02:51:15.540 | that I would probably do by myself,

02:51:17.260 | or she would do by herself.

02:51:18.160 | But with my boys, it's generally doing something

02:51:20.800 | I wouldn't otherwise be doing.

02:51:22.880 | And if I'm paying attention to it,

02:51:25.060 | I'm constantly amazed at how after five minutes

02:51:29.560 | of searching through a bin for just the right Lego piece

02:51:34.220 | that we wanna do to build this one little thing,

02:51:36.780 | like my mind will start thinking about something else.

02:51:38.900 | Like, oh my God, like I gotta go,

02:51:40.900 | ah, I didn't email that dude back.

02:51:42.660 | And I gotta do this, and I gotta do this,

02:51:44.460 | and I gotta do this, and I gotta do this.

02:51:45.660 | And I just get into the I gotta do, I gotta do, I gotta do.

02:51:48.900 | It's like, dude, you've only been here for five minutes.

02:51:52.180 | Why don't you just find the Lego piece

02:51:54.580 | that you need to finish building that thing over there

02:51:58.260 | that is this beautiful moment

02:52:00.440 | that you're not gonna have many of, right?

02:52:01.820 | There's a very finite number of these moments

02:52:04.180 | you're going to have.

02:52:05.220 | So you wanna savor every one of them.

02:52:08.300 | So again, I don't think I'm alone in that.

02:52:11.300 | I think a lot of parents, for example, can relate to that.

02:52:14.580 | And that's literally just one of many different things.

02:52:18.100 | And by the way, I wouldn't have said

02:52:19.020 | that that was my greatest challenge either.

02:52:22.020 | But it's something that requires,

02:52:24.820 | I think, deliberate attention.

02:52:26.360 | - What you're alluding to is a challenge

02:52:29.680 | with holding a single time perception,

02:52:34.680 | or perception of time.

02:52:36.740 | One of the most remarkable things to me

02:52:38.360 | about the human brain is our ability to be present

02:52:41.700 | or think about the past or the future

02:52:43.940 | or the present and the future.

02:52:45.080 | And we can occupy different time bins.

02:52:46.860 | And in a recent non-recorded conversation of ours,

02:52:50.700 | you showed me something that I've seen before,

02:52:53.420 | but for some reason this time it had a profound impact on me,

02:52:57.500 | which is that you have a chart of the number of weeks

02:53:00.300 | that you're going to live,

02:53:01.520 | and you mark them off one week at a time.

02:53:03.700 | We were talking about this

02:53:04.540 | in the context of major life decisions.

02:53:06.920 | And it illustrates the fact that we need such a chart

02:53:13.100 | that we can't really move through our day

02:53:15.900 | being present to the beauty of working on a Lego

02:53:19.180 | with our kid while also paying attention to the fact that,

02:53:22.480 | wow, this is week number whatever, 600 in the,

02:53:26.100 | or X number of weeks of one's life.

02:53:30.420 | So that ability to contract and dilate our time perception

02:53:35.420 | is marvelous, but it's also a double-edged sword

02:53:39.900 | 'cause it's what takes us out

02:53:41.540 | of what's meaningful in the moment.

02:53:43.340 | One sort of has to wonder then

02:53:47.820 | whether or not our challenges in being present,

02:53:51.200 | I guess the psychoanalyst, maybe we need to,

02:53:54.440 | or psychiatrist, maybe we need to ask Paul Conte,

02:53:59.260 | who you know and I know and respect greatly,

02:54:02.500 | whether or not this is some subconscious refusal

02:54:06.340 | of our own mortality or something, right?

02:54:08.440 | That if we were to really contemplate our mortality

02:54:10.740 | on a regular basis, not just when we're marking off

02:54:13.060 | the weeks of the poster, we wouldn't be able to be present

02:54:15.740 | because it's kind of overwhelming, right?

02:54:17.740 | - I don't know, I feel like the literature says

02:54:20.380 | that people who spend more time contemplating

02:54:23.500 | their own mortality are actually more at peace.

02:54:26.500 | Kind of a little bit of the exposure therapy idea.

02:54:29.380 | And so I'm not sure it's an unhealthy thing

02:54:35.820 | to be aware of your mortality.

02:54:38.760 | I suspect it's helpful in as much as you accept it, right?

02:54:43.660 | And you feel like you have some agency

02:54:45.420 | over parts of it, right?

02:54:46.460 | Like I don't think I have nearly enough agency

02:54:51.460 | over the length of my life.

02:54:54.340 | I think I've got five to 10 years of wiggle room

02:54:57.020 | that I can extract.

02:54:57.980 | If I do all of the things that I've written about

02:55:01.220 | in that book, I bet I can stretch my life out 10 to 15 years

02:55:05.580 | at the maximum, call it 10, over what would have happened

02:55:08.980 | if I didn't do those things.

02:55:10.740 | Maybe it's more.

02:55:11.580 | But it depends on what we're comparing it to, right?

02:55:15.680 | From being reasonable to maybe being a little bit

02:55:18.780 | hyper functioning, maybe it's 10 years.

02:55:21.580 | Where I know I have a much greater agency is on quality.

02:55:26.580 | And for me now a big part of that

02:55:29.740 | is in terms of quality of relationships.

02:55:32.960 | I think that's a big thing.

02:55:34.560 | And I think for most people that's what I hope

02:55:39.140 | this chapter does is it sort of allows more people

02:55:43.700 | to kind of take an appraisal of that

02:55:45.980 | and ask that question, which is before it's too late,

02:55:49.860 | am I living my life more for my resume virtues

02:55:54.860 | or for my eulogy virtues, to borrow from David Brooks' work,

02:56:01.420 | The Road to Character, which I talk about as being

02:56:04.060 | kind of one of the many aha moments

02:56:07.420 | that I had during this journey.

02:56:09.540 | - Yeah, and there again, thank you.

02:56:11.260 | You recommended The Road to Character.

02:56:12.980 | To me, I do an annual solo wilderness trip

02:56:16.460 | and I listen to it during the drive to that trip

02:56:18.560 | and on that trip and it's a, I would just say

02:56:22.440 | it's a truly important book for everyone to listen to.

02:56:25.580 | It's really quite impressive.

02:56:28.900 | What are the things that you do on a regular,

02:56:31.340 | let's say on a daily basis to try and enforce,

02:56:35.040 | forgive the word, but enforce emotional wellbeing

02:56:39.580 | and health in terms of relationships?

02:56:41.180 | Because as you point out, it's not reflexive for everybody

02:56:44.600 | and that doesn't make them bad people.

02:56:47.500 | I think it does have to do with this challenge

02:56:49.900 | in balancing expectations of work and other things

02:56:52.600 | and for some people, a more inherent selfishness

02:56:55.220 | and for some people, they aren't selfish enough.

02:56:58.580 | I know plenty of people that are running around

02:57:00.160 | trying to serve everybody and then their health is crashing

02:57:02.540 | or their mental health is crashing.

02:57:04.080 | So it can cut any which way or always.

02:57:06.760 | What sorts of practices do you incorporate

02:57:09.940 | or just even thoughts within your own mind?

02:57:12.140 | Do you use charts and lists?

02:57:13.600 | I mean, you're very regimented about your workouts,

02:57:16.400 | building grip strength, eccentric training zone two, et cetera.

02:57:21.400 | Why wouldn't we also script out the things

02:57:25.160 | to pay attention to each morning and day

02:57:27.220 | as a list of to-dos?

02:57:28.860 | - Well, I have done those things, right?

02:57:30.760 | So certainly, and I write about it in the book,

02:57:33.980 | I've gone away a couple of times, right?

02:57:36.060 | So in 2017, I spent two weeks at a facility in Kentucky.

02:57:41.060 | In 2020, I spent three weeks at a facility in Arizona.

02:57:45.660 | And on the back end of that facility three years ago

02:57:48.180 | when I got out, I mean, I had a very clear list

02:57:52.600 | of daily things I needed to do.

02:57:55.220 | And so at that point, for about six months following

02:57:59.300 | getting out of that stint of rehab, I mean, I was,

02:58:02.160 | I mean, God, the list of behaviors I was doing

02:58:06.520 | every single day.

02:58:07.420 | I mean, twice a day, standing in front of the mirror,

02:58:09.900 | reading my list of affirmations, writing in my journal

02:58:12.860 | every single day, I had therapy every single day.

02:58:15.400 | I mean, all of that stuff was highly regimented.

02:58:18.640 | You know, today, I would say there's no one single behavior

02:58:21.440 | that is "mandated" as part of my recovery.

02:58:24.740 | But perhaps the most important thing that does come up

02:58:28.660 | every day is being mindful of and acting on

02:58:33.660 | as quickly as possible every time I do something damaging

02:58:41.900 | to a relationship.

02:58:44.960 | So I would say that, like, if you compare Formula One,

02:58:49.960 | one of my favorites work by far, if you compare Formula One

02:58:56.860 | 40 years ago to Formula One today, the difference is not

02:59:01.540 | in the number of accidents that takes place.

02:59:04.340 | The difference is in the fatality of those accidents.

02:59:07.860 | There are just as many, if not more accidents

02:59:10.300 | in Formula One today.

02:59:12.380 | The difference is nobody dies in those accidents.

02:59:15.760 | The cars are so much safer.

02:59:18.280 | They're engineered first for safety, second for performance.

02:59:22.520 | It used to be the reverse.

02:59:24.380 | And that's why there was a day when every second

02:59:28.540 | or third weekend, a driver was killed.

02:59:31.280 | It's catastrophic to imagine what took place

02:59:34.820 | between the mid 60s and about the mid 80s in Formula One.

02:59:39.060 | And similarly, I would say that the frequency

02:59:43.620 | with which I have an interaction with a person

02:59:48.620 | who matters to me that is not the best interaction

02:59:53.080 | it could be is only slightly less

02:59:56.300 | than what it was five years ago.

02:59:58.800 | The difference is the severity of that is much lower.

03:00:03.440 | And more importantly, and most importantly,

03:00:06.180 | the length of time between when I screw up

03:00:09.680 | and when I make amends is infinitely shorter, right?

03:00:14.680 | It went from being I would never make amends

03:00:17.700 | to if I'm a dick to my wife, I usually am trying

03:00:22.700 | to rectify it within a few minutes

03:00:26.100 | or at most a couple of hours.

03:00:28.020 | And so it's really, one thing I learned

03:00:32.380 | throughout this journey was if you hold yourself

03:00:37.100 | up to this goal of I have to be perfect,

03:00:38.940 | I have to be the perfect dad,

03:00:39.980 | I have to be the perfect husband,

03:00:40.960 | I have to be the perfect friend,

03:00:42.760 | you're gonna set yourself up for failure

03:00:44.260 | 'cause you're just not gonna be perfect.

03:00:47.260 | But if instead you can say what I'm gonna be perfect about

03:00:51.900 | is repairing damage when I cause it, that's what matters.

03:00:56.140 | The other day, I yelled at my son for something.

03:01:02.460 | It was a while ago, actually,

03:01:03.280 | 'cause it was before I lost my voice.

03:01:04.420 | So I don't know, he was just doing something,

03:01:07.720 | and he was wrong, he did something I told him 150 times

03:01:11.020 | not to do, and I yelled at him and punished him.

03:01:16.020 | But I was way too harsh, 'cause basically I basically,

03:01:21.340 | the first 27 times he did it, I didn't respond,

03:01:24.300 | and then when I finally did,

03:01:25.380 | it's like I blew a gasket, right?

03:01:26.980 | But what I realized is, yeah, you could say,

03:01:31.960 | well, maybe it hurts a child to do that,

03:01:33.880 | but I think it hurts them way less

03:01:36.580 | if you can immediately go and repair and say, hey, buddy.

03:01:39.720 | Daddy was a little harsh in that.

03:01:42.580 | I'm sorry, I didn't mean to yell at you like that,

03:01:44.120 | but what you did is wrong,

03:01:45.940 | and you're not gonna get to go out and play right now

03:01:48.100 | as a result of it, but I love you very much,

03:01:50.940 | and I want us to do better.

03:01:53.340 | I want you to do better in not doing this thing,

03:01:55.100 | and I wanna do better in not yelling at you

03:01:56.540 | when you do this thing.

03:01:57.700 | So it's not rocket science, right?

03:01:59.940 | But I just think I used to live my life in a way

03:02:03.040 | where all I did was break shit and never fix it.

03:02:08.040 | So you're living in a house where everything is broken,

03:02:10.960 | whereas now I still break things,

03:02:12.580 | but now I clean up the mess,

03:02:14.560 | and oh, like all of a sudden the house is better.

03:02:18.000 | - What is your process for when there's a need for repair,

03:02:25.120 | but you feel that it wasn't you,

03:02:28.980 | it was somebody else's error or potential error?

03:02:33.140 | So you very humbly express

03:02:37.500 | how you go about repairing your errors,

03:02:41.160 | but what about situations where a loved one, a coworker,

03:02:47.060 | you feel screwed up or wronged you, right?

03:02:50.640 | As many people do, we all do from time to time,

03:02:53.260 | feel this way, do you approach them

03:02:57.700 | and try and repair the situation?

03:03:00.720 | 'Cause there's a little bit less or far less control

03:03:02.980 | than the situation you described.

03:03:05.820 | And by the way, the situation you described I think

03:03:07.380 | is a perfect one because I think we all screw up.

03:03:12.340 | And so the answer to the second question

03:03:14.420 | is sort of the answer to the first,

03:03:15.700 | which is if everyone did what you were doing,

03:03:17.820 | the world would be truly a far better place,

03:03:20.260 | but not everyone's doing what you're doing.

03:03:22.620 | So if you feel wronged,

03:03:26.700 | assuming that wrong wasn't sociopathically motivated,

03:03:31.400 | what is your process for going about

03:03:33.220 | repairing a relationship fracture like that?

03:03:36.260 | - Again, this assumes that this is a relationship

03:03:37.980 | that matters, right?

03:03:38.820 | So in every interaction,

03:03:40.340 | you're only really able to optimize around one thing

03:03:44.060 | and you have to decide is this one thing

03:03:45.740 | that I'm optimizing around the relationship

03:03:47.980 | or is it the outcome?

03:03:49.780 | I mean, there are other things to optimize around,

03:03:51.300 | but you understand that those are different, right?

03:03:53.220 | - Maybe you could elaborate on that a little bit.

03:03:54.940 | I think I get it, but flesh that out a bit.

03:03:57.200 | - If I'm at the market and I'm trying to buy a new car

03:04:01.500 | and I'm sitting there talking to the car salesman,

03:04:05.220 | that's a relationship, that's an interaction.

03:04:09.220 | Now I want to buy this car for as little as possible

03:04:11.760 | and he wants to sell the car for as much as possible.

03:04:15.140 | Well, in that interaction,

03:04:16.640 | my relationship with him means nothing.

03:04:18.920 | Let's assume I don't know this guy

03:04:20.020 | and he's not like my best friend.

03:04:23.420 | I'm optimizing everything around the outcome.

03:04:25.800 | So everything I do in negotiating

03:04:28.340 | and in interacting with him personally

03:04:30.340 | is based on getting the best outcome for me.

03:04:34.400 | It's very selfish, right?

03:04:35.840 | Nothing wrong with that, by the way.

03:04:36.780 | He's doing the same thing. - Well, he's doing the same,

03:04:37.780 | right, exactly. - Absolutely.

03:04:39.220 | But now, for example, pretend that you are the car salesman

03:04:42.660 | and you're one of my closest friends

03:04:44.660 | and it's your dealership, like it's your money.

03:04:47.900 | You can't sell this thing to me at a loss.

03:04:49.420 | I don't want you to do that

03:04:50.700 | because I want you to be able to make money.

03:04:54.220 | And similarly, like you care about me

03:04:55.940 | and you don't want me to overpay for this.

03:04:57.900 | So now we're negotiating

03:05:00.860 | and we're both trying to optimize for an outcome,

03:05:02.820 | but our relationship also matters.

03:05:05.840 | It's a very different negotiation at that point.

03:05:08.300 | And so I think I always try to ask myself this question

03:05:13.020 | when I'm having some interpersonal conflict,

03:05:15.580 | which is what am I optimizing for?

03:05:18.420 | So if I'm having a quarrel with my wife,

03:05:23.420 | I have to remind myself that the outcome is,

03:05:27.980 | the objective or outcome is not necessarily the top priority.

03:05:32.000 | Being right all the time, which is my default state,

03:05:38.220 | it's just to be a bull in a China shop.

03:05:41.100 | It's to be authoritarian instead of authoritative.

03:05:46.300 | And that doesn't work if the relationship matters.

03:05:50.780 | So to answer your question,

03:05:52.560 | the first thing I'm gonna ask myself if I feel slighted

03:05:56.860 | is what is the nature of the relationship?

03:05:59.160 | Is it even worth trying to do something about this?

03:06:03.540 | And presumably you're asking the question

03:06:05.020 | because the lens is yes.

03:06:05.980 | This is someone who you care about more

03:06:09.100 | than in just a transactional way.

03:06:11.220 | Usually what I've realized is I can't try

03:06:15.160 | to approach the situation without fully understanding myself

03:06:19.340 | and that takes a while.

03:06:21.000 | So generally, and this is where I still,

03:06:25.780 | one to two times a week I'm still working with a therapist,

03:06:29.420 | I have to kind of try to figure it out on my own

03:06:32.180 | and then usually bounce it off a therapist and say,

03:06:33.840 | well, I think this is why I'm upset about this.

03:06:37.960 | I think that when this person did this or said this,

03:06:41.860 | I felt this, first of all, am I correct in what I felt?

03:06:46.620 | Because remember, sometimes you might,

03:06:49.660 | at least for me, this was the case.

03:06:51.380 | I would just feel anger in response to every interaction.

03:06:54.580 | But what I didn't realize was that anger

03:06:58.880 | was really just another emotion that was superimposed

03:07:02.300 | on top of hurt or superimposed on top of fear

03:07:05.660 | or superimposed on top of shame

03:07:08.060 | or superimposed on top of something else.

03:07:10.680 | But I didn't know how to articulate

03:07:12.320 | any of those other emotions.

03:07:13.540 | So the only thing I could really articulate was anger.

03:07:16.000 | So if anger is the only thing I know

03:07:17.980 | and anger is the only response I see, it's not very helpful.

03:07:21.240 | It's not very insightful.

03:07:23.460 | So that's a big part of it,

03:07:24.960 | is being able to deconstruct what I'm feeling.

03:07:28.180 | Oh, what I really feel is loss

03:07:31.760 | or what I really feel is abandonment right now.

03:07:35.180 | And that sometimes takes a while to figure out,

03:07:38.560 | at least for me, I'm still,

03:07:40.800 | I'm only a few years into this journey

03:07:44.620 | and maybe other people figured these things out

03:07:47.340 | when they were in their 20s and so they're veterans.

03:07:49.640 | They can do this more naturally.

03:07:52.800 | But that's step one.

03:07:53.820 | If I don't really understand what's going on,

03:07:56.340 | I can't even begin to try to approach this person

03:07:59.620 | to say, this is how I feel.

03:08:01.120 | This is, how do you feel

03:08:05.460 | and what are we optimizing for in this interaction?

03:08:08.860 | - I certainly know you are not alone in this sense.

03:08:14.680 | It's a process and it takes a lot of time

03:08:17.080 | and on a case-by-case basis can take a lot of time

03:08:20.920 | to figure out exactly what one is feeling.

03:08:23.060 | I think it really goes back to the coarseness of language

03:08:26.440 | as a way to sort one's feelings.

03:08:28.760 | It was actually your other,

03:08:30.180 | because we mentioned Paul Conti,

03:08:31.280 | who was one of your Stanford Medical School

03:08:35.080 | classmates, but another previous guest on this podcast

03:08:38.760 | who was also one of your medical school classmates,

03:08:41.580 | Dr. Carl Deisseroth, right?

03:08:44.400 | Psychiatrist and bioengineer of phenomenal stature

03:08:48.560 | and doing amazing things in the world who said,

03:08:51.120 | most of the time we have no idea how other people feel,

03:08:54.880 | even though we think we do.

03:08:56.400 | And most of the time we don't even know how we feel.

03:08:58.900 | I mean, our ability to really know

03:09:00.300 | what we're really feeling is terrible.

03:09:03.840 | And yet we recognize the broad bins.

03:09:08.420 | I'm pissed off, I'm super happy, I'm relaxed, I'm tired.

03:09:13.420 | I mean, just think about how coarse that language is

03:09:17.080 | for all the nuance and all the underlying things,

03:09:20.160 | conscious and subconscious,

03:09:21.240 | that could be driving an emotional state.

03:09:22.800 | It's really quite unbelievable.

03:09:25.000 | - Yeah, beyond the valence, positive versus negative,

03:09:28.200 | that was about the extent of my emotional language

03:09:31.600 | until somewhat recently.

03:09:34.120 | - Well, it strikes me you've come a very long way.

03:09:35.920 | Maybe you could share with us a little bit

03:09:38.040 | about what you learned on these,

03:09:41.000 | what you called retreats or,

03:09:42.800 | I mean, in the book chapter you describe

03:09:45.620 | deliberately going off to a treatment center,

03:09:49.640 | multiple treatment centers over time

03:09:51.720 | to really drill into this process

03:09:54.140 | of understanding oneself better

03:09:55.760 | and how one's current state of emotional processing

03:09:59.280 | and emotional stability are influencing relationships

03:10:01.840 | and the key importance of that.

03:10:03.920 | Was there any kind of overriding theme for you?

03:10:07.560 | For instance, could you trace back to specific events

03:10:12.480 | or themes of childhood that made a lot of it make sense?

03:10:16.920 | Or is it far more nuanced than that?

03:10:20.700 | - Well, the first thing I would say is

03:10:22.120 | I wish I could tell you that this was a very deliberate

03:10:26.400 | and wonderful choice that I just decided

03:10:29.560 | I'm gonna go on a little self-healing journey,

03:10:32.560 | but unfortunately that was not the case.

03:10:34.440 | In both cases, in 2017 and in 2020,

03:10:37.760 | I was as close to having no choice in the matter

03:10:42.400 | as one can have.

03:10:43.680 | So both of these experiences represented

03:10:47.320 | total rock bottom moments in my life.

03:10:51.400 | So these would have been the two lowest points in my life

03:10:54.780 | for different reasons, but they were nevertheless

03:10:57.320 | the two absolute low points in my life.

03:10:59.880 | And I would say in the first instance,

03:11:04.880 | I guess I could have chosen not to go,

03:11:09.320 | but I would have lost everything that mattered

03:11:14.280 | in my life at that point.

03:11:15.520 | And I had our good friend Paul Conte basically telling me

03:11:22.020 | that I needed to do this, that I really needed to do this.

03:11:26.980 | And in the second situation,

03:11:28.440 | though completely different circumstances,

03:11:31.140 | you might think how can one person

03:11:32.740 | in just a span of three years find themselves

03:11:35.220 | in a situation where they almost without having any choice

03:11:39.080 | in the matter have to go away to a place

03:11:42.500 | where you're basically locked up without a phone

03:11:46.340 | for three weeks and you're doing 12 to 13 hours

03:11:51.340 | of therapy a day.

03:11:54.120 | So nothing about this was something I wanted to do.

03:11:57.480 | Nothing about this was pleasant.

03:11:59.020 | I would describe these as the most difficult things

03:12:02.480 | I've ever done in my life, bar none.

03:12:05.520 | And I've done some difficult things in my life.

03:12:07.480 | But they've always been physically difficult.

03:12:09.480 | I love doing physically difficult things.

03:12:12.200 | But this was emotionally the equivalent of, for me,

03:12:16.340 | climbing K2 and swimming the English Channel

03:12:19.900 | in the same month.

03:12:21.160 | Something that you couldn't fathom.

03:12:24.100 | So with that said, yes, I learned a lot.

03:12:28.420 | And I learned that people like me can be overly analytical

03:12:33.420 | and that hyper-analytical nature can lead you astray

03:12:41.100 | when you think that your intellect is giving you

03:12:50.660 | a fact-based explanation for a set of circumstances

03:12:54.580 | and you rationalize them away.

03:12:58.120 | Well, this happened to me when I was a kid.

03:13:00.900 | But I get it and it's not really a problem.

03:13:05.220 | And as a result of that, these are actually

03:13:10.220 | some positive things that came out of that experience.

03:13:13.120 | And I think the real aha moment in my journey

03:13:18.300 | which occurred on a day that I remember very well

03:13:23.300 | was the day I finally dropped that.

03:13:27.260 | I dropped that rationalization.

03:13:31.860 | And I allowed myself to experience what a child

03:13:36.860 | would experience in that moment and then understood

03:13:41.380 | what the implications are for a child

03:13:47.620 | going through these things.

03:13:50.980 | And I think that was really the first time in my life

03:13:55.180 | I ever accepted emotionally something that I had

03:13:58.260 | intellectually always said, yeah, it doesn't really matter.

03:14:00.980 | I mean, it's just, you know, that's just life

03:14:02.620 | and those things happen and lots of worse things happen

03:14:06.060 | to lots of people and that's okay.

03:14:08.620 | And I think it's not that once I emotionally accepted this,

03:14:13.520 | I became a victim, it wasn't at all.

03:14:16.320 | It just finally allowed me to realize,

03:14:17.980 | oh, I can let that go now.

03:14:19.740 | I don't have to be a slave to the adaptations

03:14:24.740 | that came from that.

03:14:28.820 | I can surrender.

03:14:31.040 | - That's beautiful and inspiring to me.

03:14:37.820 | I think that, yeah, there's this incredible ability

03:14:44.000 | that the human brain has to script a story

03:14:47.500 | and to compare to other people's circumstances.

03:14:49.700 | And as you said, rationalize what are essentially

03:14:53.340 | emotional traumas or physical traumas

03:14:56.700 | from the perspective of the adult.

03:14:59.820 | But if I know one thing for sure, and I make it very clear,

03:15:03.880 | I'm not a clinician, but is that the brain doesn't discard

03:15:08.020 | of any circuitry.

03:15:08.860 | We repurpose the same circuitry we used as children,

03:15:11.940 | as adults and so the ability to go back to that

03:15:15.600 | and to parse it, but as you point out,

03:15:18.360 | not from an intellectual standpoint,

03:15:21.900 | but from an emotional standpoint,

03:15:23.700 | seems to be the really hard work.

03:15:26.080 | Do you do that on a regular basis?

03:15:29.620 | - No, not at all.

03:15:31.360 | It's been done a handful of times.

03:15:33.420 | It's been exhausting.

03:15:37.320 | It's very difficult.

03:15:38.920 | It's, I don't know if this is the right word.

03:15:43.680 | I would almost describe it as emotionally violent.

03:15:46.180 | And it's not something I need to revisit often truthfully.

03:15:52.840 | I think that, yeah, it's been done a finite number of times

03:15:57.860 | and I think I've captured so much value from it

03:16:04.520 | that there are lots of other things I continue to do.

03:16:07.100 | I mean, I use a system called dialectical behavioral therapy

03:16:12.100 | that is a regular part of the therapy that I do,

03:16:15.060 | but I don't have to go back to my childhood.

03:16:18.240 | I don't have to go back to uncovering

03:16:21.400 | and re-exploring a lot of that stuff.

03:16:24.080 | I've learned the lessons and now it's really

03:16:28.980 | about practicing the skills.

03:16:31.000 | I know what I want now and I know,

03:16:34.180 | you talk about plasticity.

03:16:35.440 | I'll share one example, which I know I wrote about

03:16:37.200 | in the book, but just for folks listening,

03:16:39.700 | that you'll appreciate.

03:16:41.600 | So I, just one of the hallmarks of my existence

03:16:46.480 | has always been just an insane amount of anger and rage.

03:16:51.480 | It's been there as long as I've known.

03:16:54.760 | So I don't have a conscious memory of not having rage, right?

03:16:59.040 | So earliest memories of life when I'm five years old,

03:17:03.160 | I have rage like you can't believe.

03:17:05.220 | And it's a problem all my life.

03:17:07.420 | So as a teenager, if I go more than two weeks

03:17:10.920 | without punching a hole in the wall of our house,

03:17:13.140 | it's a miracle.

03:17:14.460 | I mean, I am so good at drywall.

03:17:16.540 | You can't believe how good I am for all the stuff

03:17:20.100 | I have to repair around our house.

03:17:21.600 | Like I'm breaking windows, I'm breaking,

03:17:24.220 | it just doesn't matter, like I just,

03:17:26.220 | and so in a way, and of course I rationalized

03:17:28.940 | how much boxing saved my life

03:17:30.940 | because I had this amazing outlet for my rage, right?

03:17:34.380 | If you, I got to basically exercise six hours a day,

03:17:38.860 | I'm hitting punching bags and people all day long,

03:17:42.540 | and it's just a beautiful outlet that keeps me out of jail.

03:17:45.780 | And a big part of that rage was inward, right?

03:17:52.040 | So it's not rocket science to understand

03:17:54.900 | that a person who has that much hatred for everyone

03:17:58.940 | has an enormous amount for themselves.

03:18:02.040 | And so one of the things I didn't realize was happening

03:18:06.840 | was what my inner monologue was.

03:18:08.700 | Because as you can appreciate, your inner monologue

03:18:11.600 | is so frequent and ubiquitous and present

03:18:16.600 | that it's easy to almost forget that it's there.

03:18:20.480 | I mean, that's the sort of dangerous part about it, right?

03:18:25.480 | Is kind of the David Foster Wallace, this is water thing.

03:18:30.280 | The fish are swimming through water.

03:18:32.780 | The water's everywhere.

03:18:33.620 | They don't even realize they're in water.

03:18:35.360 | You don't realize the subconscious stream of thoughts

03:18:39.640 | that constantly flow.

03:18:40.780 | But eventually I became aware

03:18:44.100 | of just what that self-talk was.

03:18:46.800 | And it is, it was no longer the case.

03:18:50.960 | It was the angriest, the most violent self-talk

03:18:55.960 | you can imagine.

03:18:58.440 | I mean, it was like, there is no mistake that I could make

03:19:03.440 | that was anything other than my perfect, perfect standard

03:19:08.360 | that didn't result in what I would call

03:19:11.960 | my inner Bobby Knight going ballistic.

03:19:15.340 | So it just didn't matter.

03:19:17.320 | Like it sounds silly under, it didn't matter.

03:19:20.840 | If I didn't perfectly cook a steak,

03:19:23.720 | if I didn't perfectly nail something I was doing,

03:19:27.120 | if I didn't do anything that was perfect

03:19:30.080 | at what I described as match grade perfect,

03:19:32.760 | I mean, I would want to beat myself to a pulp

03:19:38.160 | and I would scream at myself.

03:19:40.440 | I mean, it just, again, it's hard to describe.

03:19:44.160 | And I hope that most people listening to this

03:19:46.160 | don't understand what that feels like.

03:19:48.020 | Well, it became very clear that that had to change

03:19:52.660 | because when you are that,

03:19:56.600 | when you hate yourself that much, by definition,

03:19:59.560 | you are going to be an insufferable prick to everybody else.

03:20:03.360 | 'Cause you're just, that's gonna spill

03:20:05.400 | into how you interact with the world.

03:20:07.240 | So I was working with a therapist who was one of the people

03:20:13.360 | who was sending me to this place in Arizona.

03:20:18.000 | And basically it became clear that they proposed

03:20:22.600 | that I could shed this trait if I was willing

03:20:26.580 | to do a certain amount of work.

03:20:29.000 | And I was like, there's no chance.

03:20:31.600 | Like I'm 47 years old.

03:20:34.020 | This is the only way I've ever interacted with myself.

03:20:36.440 | How in the world could this be undone?

03:20:39.200 | It would take another 40 years to undo this.

03:20:41.680 | And they're like, no, no,

03:20:42.820 | here's this exercise you're gonna do.

03:20:44.840 | So the exercise was every single time I did something

03:20:50.700 | where I would have that self-talk,

03:20:53.760 | I would have to immediately stop myself

03:20:56.080 | and pretend that it wasn't me that just did that,

03:21:01.860 | but it was one of my closest friends.

03:21:04.740 | And instead I would audibly speak to that person,

03:21:09.080 | there was nobody else there,

03:21:10.200 | but speak to that person as though they are the one

03:21:13.920 | that made the mistake.

03:21:14.760 | And I was to record that on my phone.

03:21:16.500 | So I'm out there shooting my bow and arrow

03:21:19.840 | and I don't get a bullseye.

03:21:21.960 | Instead of screaming at myself,

03:21:23.640 | I have to say, oh, imagine it's my buddy JR

03:21:26.200 | who just missed that shot.

03:21:27.440 | What would I say to him?

03:21:29.260 | Pick up the phone or pull out the phone

03:21:31.840 | and say, of course, something different.

03:21:34.380 | And of course, what I would say in that situation

03:21:36.360 | was much kinder, I mean, infinitely kinder.

03:21:38.840 | It's like from saying it to my closest friend,

03:21:41.660 | I'm gonna say it in a very kind way.

03:21:44.480 | And I had to take a copy of that audio

03:21:47.860 | and text it to my therapist.

03:21:49.520 | - Oh, wow.

03:21:50.360 | - Yeah.

03:21:51.180 | - Talk about vulnerabilities.

03:21:52.020 | - So can you imagine--

03:21:52.860 | - I was all on board this practice

03:21:53.800 | until you mentioned that at which point,

03:21:55.640 | and I trust my therapist to a very deep level,

03:21:59.520 | but I thought, wow, that's a mountain.

03:22:03.240 | - Well, this poor person got a lot of text messages,

03:22:06.680 | a lot of audio files.

03:22:08.180 | But here's the part that just blows my mind.

03:22:12.440 | It only took, I don't know, I can't remember exactly.

03:22:16.440 | I'd have to go back to look at my journals.

03:22:17.920 | It only took about four months to get rid of Bobby Knight.

03:22:21.040 | Again, we had kind of a mental model

03:22:25.200 | for what this looked like,

03:22:26.080 | which was Bobby Knight was the chairman of the board.

03:22:29.200 | He sat in the boardroom and nobody else got to talk.

03:22:31.840 | - And for those that don't know,

03:22:32.720 | Bobby Knight had a terrible temper.

03:22:35.140 | - Yeah.

03:22:35.980 | - Yeah, the worst.

03:22:36.800 | - Right, this is the guy that was throwing chairs

03:22:38.040 | across the basketball court.

03:22:39.120 | - Level 11 out of 10.

03:22:41.520 | - And all of a sudden, we got to the point

03:22:45.000 | where Bobby Knight is not even in the boardroom anymore.

03:22:49.080 | In fact, as I say this today,

03:22:52.000 | I don't really remember what he sounded like.

03:22:54.820 | I mean, it's amazing to me.

03:22:58.520 | And I've had some really amazing opportunities

03:23:02.040 | to bring him back.

03:23:03.120 | Like, it's not like I'm making fewer mistakes, right?

03:23:06.660 | It's not like I'm better today than I was three years ago

03:23:11.040 | at all the things that I do.

03:23:12.240 | I'm not, I'm actually probably worse in many regards.

03:23:15.640 | But the difference is, I can communicate with myself.

03:23:20.640 | I think I can say this, I think I can say lovingly, right?

03:23:25.480 | And maybe not as lovingly as some people can.

03:23:29.520 | I still think I'm probably,

03:23:31.560 | maybe just a little higher standard with myself

03:23:35.920 | than maybe I need to be at times.

03:23:38.260 | But I'm just not beating myself up like I used to.

03:23:42.200 | And I think by extension,

03:23:43.760 | I'm beating other people up a lot less.

03:23:46.200 | - Well, I don't know the extent

03:23:47.300 | to which your internal narrative reflects the narrative

03:23:51.640 | that others have about you.

03:23:52.920 | But first of all, I want to thank you

03:23:55.120 | for sharing what you just shared.

03:23:57.920 | I think as a practical step,

03:24:00.200 | first of all, it's one I've never heard of before,

03:24:03.660 | but certainly represents this incredible phenomenon

03:24:08.060 | of neuroplasticity.

03:24:09.000 | Because four months sounds like a bit of time,

03:24:10.640 | yet you're 47 years old.

03:24:12.360 | So that's 47 years of accumulated,

03:24:14.340 | just absolutely berating self-talk is what it sounds like.

03:24:18.740 | So it's something that people can think about

03:24:23.400 | for their own purposes and their own challenges.

03:24:28.160 | Also, I've read the book twice now and love it.

03:24:32.160 | As I put in my endorsement of it,

03:24:35.100 | I think it's not just informative,

03:24:37.860 | but it's indeed important

03:24:39.560 | because it centers on so many of the key actionable items

03:24:43.900 | related to healthspan and lifespan, vitality, longevity,

03:24:48.900 | whatever people want to call these things

03:24:50.400 | that are essential.

03:24:52.400 | But also the section on emotional health

03:24:54.560 | was absolutely profound for me.

03:24:57.560 | It inspired a huge number of changes.

03:24:59.440 | And the book as a whole represents

03:25:02.920 | a very important contribution to everybody.

03:25:06.640 | There are numerous points and I would say every chapter

03:25:10.880 | is applicable to everybody.

03:25:12.060 | And there are very few books out there like that.

03:25:14.580 | So I want to thank you for that.

03:25:17.040 | And especially for including the section

03:25:19.160 | on emotional health.

03:25:20.480 | And especially for sharing what you did today,

03:25:23.440 | because I think it doesn't just take a bit of vulnerability,

03:25:27.520 | but a ton of vulnerability and humility

03:25:29.800 | to be able to share what you just shared.

03:25:32.420 | And my only request or wish is that you also,

03:25:36.480 | hopefully internalize it,

03:25:37.600 | the tremendous gift that you're giving everybody

03:25:39.480 | through coming on podcasts like this,

03:25:41.980 | doing your own podcasts, writing the book.

03:25:45.200 | I look out on the landscape of front facing,

03:25:48.500 | public facing health out there.

03:25:51.660 | And you sit not alone, but in a unique stance

03:25:55.880 | as the medical doctor that I do believe

03:25:58.200 | that people trust the very most.

03:26:01.180 | Because of the fact that you have that intense rigor.

03:26:05.800 | I wouldn't even say your desire,

03:26:07.060 | your absolute obsession with measurement and precision.

03:26:11.520 | Many of the things that a moment ago you were pointing to

03:26:13.680 | as potentially hazards for your emotional life,

03:26:17.000 | but that serve all of us, the general public,

03:26:20.080 | so preciously and with just incalculable value.

03:26:25.800 | So I hope that internalizes as well.

03:26:27.720 | Maybe it'll even weave into your self-talk.

03:26:29.780 | Maybe I need to send you a script every day,

03:26:31.320 | but in all seriousness,

03:26:33.000 | I also want to thank you for taking the time today.

03:26:35.260 | And even though it's a personal thing,

03:26:37.480 | I really want to thank you

03:26:38.580 | for being an amazing colleague to me in the podcast space,

03:26:43.460 | in the health and medicine space, whatever that is.

03:26:47.680 | And also just an incredible friend.

03:26:50.460 | You've been a tremendous source of support and guidance

03:26:53.600 | in every one of the domains that we talked about today

03:26:56.220 | and many more.

03:26:57.540 | And again, I just want to say

03:26:58.700 | that this emotional health component, I agree with you.

03:27:01.100 | I think it's not just vital.

03:27:03.960 | I think it's the most vital of all of them.

03:27:06.960 | So you've just made numerous important contributions.

03:27:11.960 | And I just want to thank you for sharing

03:27:15.320 | that you clearly put everything you have

03:27:17.340 | into everything you do.

03:27:19.600 | Thank you, Peter.

03:27:20.520 | - Andrew, thank you.

03:27:21.360 | I really appreciate you making the time for us to sit down

03:27:23.840 | and talk in a long form way, which I enjoy.

03:27:25.720 | And yeah, it's an honor and it means a lot to me

03:27:30.300 | that you have read it twice and that you've appreciated it

03:27:33.340 | and praised it as you have.

03:27:36.360 | Thank you.

03:27:37.540 | - Thank you once again for joining me

03:27:38.840 | for today's discussion with Dr. Peter Attia.

03:27:41.560 | I hope you learned as much and enjoy the conversation

03:27:44.280 | as much as I did.

03:27:45.280 | Please also check out Dr. Attia's new book,

03:27:47.420 | which is releasing on March 28th, 2023,

03:27:50.760 | entitled "Outlive, the Science and Art of Longevity."

03:27:54.240 | If you're learning from and/or enjoying this podcast,

03:27:56.820 | please subscribe to our YouTube channel.

03:27:58.760 | That's a terrific zero cost way to support us.

03:28:01.000 | In addition, please subscribe to the podcast

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03:29:42.780 | Thank you once again for joining me

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Dr. Peter Attia: Improve Vitality, Emotional & Physical Health & Lifespan | Huberman Lab Podcast

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