Dr. Peter Attia: Exercise, Nutrition, Hormones for Vitality & Longevity

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,

00:00:10.360 | and I'm a professor of neurobiology and ophthalmology

00:00:13.120 | at Stanford School of Medicine.

00:00:14.940 | Today, my guest is Dr. Peter Attia.

00:00:17.560 | Dr. Attia is a physician who's focused on nutritional,

00:00:20.720 | supplementation-based, behavioral, prescription drug,

00:00:24.160 | and other interventions that promote healthspan

00:00:26.640 | and lifespan.

00:00:28.020 | His expertise spans from exercise physiology

00:00:31.220 | to sleep physiology,

00:00:32.680 | emotional and mental health, and pharmacology.

00:00:35.700 | Today, we talk about all those areas of health,

00:00:37.940 | starting with the very basics,

00:00:39.440 | such as how to evaluate one's own health status

00:00:42.880 | and how to define one's health trajectory.

00:00:45.800 | We also talk about the various sorts of interventions

00:00:48.300 | that one can take in order to optimize vitality

00:00:51.660 | while also extending longevity, that is, lifespan.

00:00:55.080 | Dr. Attia is uniquely qualified

00:00:57.300 | to focus on the complete depth and breadth of topics

00:01:00.320 | that we cover.

00:01:01.240 | And indeed, these are the same topics

00:01:02.880 | that he works with his patients on in his clinic every day.

00:01:06.160 | Dr. Attia earned his Bachelor of Science

00:01:07.940 | in mechanical engineering and applied mathematics

00:01:10.360 | and his MD from Stanford University School of Medicine.

00:01:14.000 | He then went on to train at Johns Hopkins Hospital

00:01:16.560 | in general surgery,

00:01:17.480 | one of the premier hospitals in the world,

00:01:19.600 | where he was the recipient of several prestigious awards,

00:01:21.840 | including resident of the year.

00:01:23.600 | He's been an author on comprehensive reviews

00:01:25.560 | of general surgery.

00:01:26.800 | He spent two years at the National Institutes of Health

00:01:29.620 | as a surgical oncology fellow

00:01:31.560 | at the National Cancer Institute,

00:01:33.460 | where his work focused on immune-based therapies

00:01:35.540 | for melanoma.

00:01:36.740 | In the fields of science and medicine,

00:01:38.060 | it is well understood that we are much the product

00:01:40.060 | of our mentors and the mentoring we receive.

00:01:42.760 | Dr. Attia has trained with some of the best

00:01:44.820 | and most innovative lipidologists, endocrinologists,

00:01:47.380 | gynecologists, sleep physiologists,

00:01:48.940 | and longevity scientists in the United States and Canada.

00:01:52.520 | So the expertise that funnels through him

00:01:54.580 | and that he shares with us today

00:01:56.420 | is really harnessed from the best of the best

00:01:58.740 | and his extensive training and expertise.

00:02:01.100 | By the end of today's episode,

00:02:02.220 | you will have answers to important basic questions

00:02:05.180 | such as, should you have blood work?

00:02:07.140 | How often should you do blood work?

00:02:09.040 | What specific things should you be looking for

00:02:10.940 | on that blood work that are either counterintuitive

00:02:13.580 | or not often discussed,

00:02:15.300 | and yet that immediately and in the longterm influence

00:02:19.100 | your lifespan and health span?

00:02:20.940 | We talk about hormone health and hormone therapies

00:02:23.460 | for both men and women.

00:02:25.140 | We talk about drug therapies that can influence the mind

00:02:28.780 | as well as the body.

00:02:29.940 | And of course, we talk about supplementation, nutrition,

00:02:32.100 | exercise, and predictors of lifespan and health span.

00:02:35.840 | It is an episode rich with information.

00:02:38.340 | For some of you, you may want to get out a pen and paper

00:02:41.300 | in order to take notes.

00:02:42.580 | For others of you that learn better simply by listening,

00:02:45.820 | I just want to remind you

00:02:46.700 | that we have timestamped all this information

00:02:48.500 | so that you can go back to the specific topics

00:02:50.500 | most of interest to you.

00:02:52.320 | I'm pleased to announce that the Huberman Lab Podcast

00:02:54.200 | is now partnered with Momentous Supplements.

00:02:56.540 | We partnered with Momentous for several important reasons.

00:02:58.740 | First of all, they ship internationally

00:03:00.460 | because we know that many of you are located

00:03:02.360 | outside of the United States.

00:03:03.860 | Second of all, and perhaps most important,

00:03:05.880 | the quality of their supplements is second to none,

00:03:08.420 | both in terms of purity and precision

00:03:10.100 | of the amounts of the ingredients.

00:03:12.020 | Third, we've really emphasized supplements

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00:03:16.860 | and that are supplied in dosages

00:03:18.920 | that allow you to build a supplementation protocol

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00:03:25.620 | and that you can add things and remove things

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00:03:30.880 | If you'd like to see the supplements

00:03:32.040 | that we partner with Momentous on,

00:03:33.360 | you can go to livemomentous.com/huberman.

00:03:36.480 | There you'll see those supplements

00:03:37.600 | and just keep in mind that we are constantly expanding

00:03:40.080 | the library of supplements available through Momentous

00:03:42.760 | on a regular basis.

00:03:43.720 | Again, that's livemomentous.com/huberman.

00:03:46.320 | Before we begin, I'd like to emphasize that this podcast

00:03:48.860 | is separate from my teaching and research roles at Stanford.

00:03:51.620 | It is, however, part of my desire and effort

00:03:53.600 | to bring zero cost to consumer information about science

00:03:56.000 | and science-related tools to the general public.

00:03:58.680 | In keeping with that theme,

00:03:59.680 | I'd like to thank the sponsors of today's podcast.

00:04:02.400 | Our first sponsor is Thesis.

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00:04:54.320 | Today's episode is also brought to us by InsideTracker.

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00:05:02.080 | to help you better understand your body

00:05:03.640 | and help you reach your health goals.

00:05:05.600 | I've long been a believer in getting regular blood work done

00:05:08.120 | for the simple reason that many of the factors

00:05:10.220 | that impact your immediate and long-term health

00:05:12.240 | can only be assessed from a quality blood test.

00:05:14.560 | And nowadays with the advent of modern DNA tests,

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00:05:22.260 | And obviously it's your biological age that really matters.

00:05:25.760 | The challenge with a lot of blood tests and DNA tests,

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00:07:26.480 | And now for my discussion with Dr. Peter Attia.

00:07:29.620 | Peter, thanks for joining me today.

00:07:31.220 | - Thanks for having me, man.

00:07:32.180 | - I'm looking forward to this for a very long time.

00:07:34.780 | - That's fine.

00:07:35.620 | - I'm a huge fan of your podcast.

00:07:37.260 | I know that you went to Stanford

00:07:39.100 | and worked with a number of people

00:07:40.340 | that are colleagues of mine.

00:07:41.580 | So for me, this is already a thrill just to be doing this.

00:07:45.580 | - Yeah, well, likewise.

00:07:47.480 | - I have a ton of questions,

00:07:48.980 | but I want to start off with something

00:07:50.300 | that I wonder a lot about

00:07:51.700 | and that I know many other people wonder about,

00:07:54.780 | which is how to assess their current health

00:07:58.020 | and their trajectory in terms of health and wellbeing,

00:08:01.700 | specifically as it relates to blood work.

00:08:04.660 | So what are your thoughts on blood work?

00:08:05.860 | Is it necessary for the typical person?

00:08:08.860 | So this is somebody who's not dealing

00:08:10.140 | with some acute syndrome or illness,

00:08:12.740 | and at what age would you suggest

00:08:14.780 | people start getting blood work?

00:08:16.060 | How frequently should they get blood work?

00:08:18.520 | How often do you get blood work done, et cetera?

00:08:21.580 | - Yeah, there's a lot there.

00:08:22.420 | I mean, the way I talk about this with patients

00:08:23.940 | is first taking everything back to the objective.

00:08:27.380 | So what's the thing we're trying to optimize?

00:08:31.900 | So if a person says,

00:08:34.120 | "Look, I'm trying to break 10 hours for an Ironman.

00:08:38.000 | I don't know that blood work is going to be a game-changing

00:08:41.200 | aspect of their trajectory and their training."

00:08:44.280 | They're going to benefit much more

00:08:45.740 | from sort of functional analysis of performance.

00:08:48.760 | So I'm assuming, based on the question,

00:08:51.360 | that you're really coming at this through the lens

00:08:53.480 | of living longer and living better

00:08:55.540 | through the lifespan, healthspan lens?

00:08:58.560 | - Yeah, and just, I think most people have some sense

00:09:01.680 | of their vitality or lack of vitality,

00:09:03.940 | but I think everyone wonders whether or not

00:09:05.420 | they could feel better

00:09:06.260 | and whether or not blood work will give them a window

00:09:08.140 | into how they might go about feeling better.

00:09:11.020 | - Yeah, I think it does to some extent,

00:09:12.920 | but I also think that it has a lot of blind spots.

00:09:15.260 | So I kind of break things down into the two vectors

00:09:20.260 | that make up longevity, which are lifespan and healthspan.

00:09:23.560 | So lifespan is the easiest of those vectors to understand

00:09:26.620 | because it's pretty binary, right?

00:09:28.200 | You're alive or you're not alive.

00:09:29.460 | You're respiring or you're not.

00:09:30.580 | You make ATP or you don't, end of story.

00:09:33.080 | So what gets in the way of lifespan

00:09:37.080 | is essentially the four horsemen of disease, right?

00:09:40.920 | So atherosclerotic disease, cancer, neurodegenerative disease

00:09:44.880 | and metabolic disease,

00:09:46.120 | which directly isn't the cause of many deaths,

00:09:49.140 | but basically creates the foundation

00:09:52.000 | to all of those other diseases.

00:09:53.600 | So if you're a non-smoker, what I just rattled off

00:09:58.420 | is about 80% of your death.

00:10:01.040 | So how does blood work help address those?

00:10:05.040 | It varies.

00:10:05.880 | So on the atherosclerotic standpoint,

00:10:07.600 | it's a very good predictor of risk

00:10:09.600 | if you know what to look for.

00:10:11.600 | So primarily ApoB would be the single most important

00:10:15.440 | lipoprotein that we care about.

00:10:17.200 | I gotta explain what that means in a second.

00:10:19.440 | And then also, you know, other markers of inflammation,

00:10:22.080 | endothelial health and metabolic health.

00:10:25.600 | When it comes to cancer, you know,

00:10:27.040 | blood testing in the sense of biomarkers

00:10:29.480 | is not particularly helpful.

00:10:30.560 | Outside of knowing that the second leading environmental

00:10:35.200 | or modifiable cause of cancer

00:10:36.920 | is metabolic ill health after smoking.

00:10:38.720 | So we don't actually know a lot about cancer

00:10:41.880 | in the sense of what causes it.

00:10:43.880 | It's really stochastic and it's a lot of bad luck.

00:10:46.520 | So we know that smoking drives it.

00:10:48.240 | And we know that even though epidemiologically,

00:10:51.680 | we say obesity drives it,

00:10:52.900 | what it really means is metabolic poor health.

00:10:54.880 | It's probably the hyperinsulinemia

00:10:56.560 | that comes with obesity that drives it.

00:10:58.740 | So biomarkers help with that,

00:11:00.820 | but there's still an enormous blind spot to cancer.

00:11:02.880 | We could talk about liquid biopsies aside

00:11:04.680 | 'cause those aren't really biomarker studies,

00:11:06.560 | but put that away.

00:11:08.380 | On the neurodegenerative side,

00:11:10.520 | you know, I don't think we have a lot of insight

00:11:12.160 | that comes to understanding Parkinson's disease.

00:11:14.640 | But when it comes to dementia,

00:11:15.860 | particularly the Alzheimer's disease,

00:11:17.160 | which is the most prevalent form of dementia,

00:11:18.740 | I think the biomarkers can be quite helpful.

00:11:20.940 | They overlap a lot with the atherosclerotic diseases.

00:11:23.500 | So the same things that, you know,

00:11:25.520 | drive the risk of heart disease

00:11:26.520 | or driving the risk of dementia.

00:11:29.160 | And then there's some novel stuff as well.

00:11:31.100 | If you include genetic testing,

00:11:32.420 | which you can get out of a blood test,

00:11:34.020 | we get a whole suite of genes,

00:11:35.960 | not just APOE, but far more, you know,

00:11:38.100 | nuanced stuff than that that can also play a role.

00:11:40.740 | So you can stratify risk in that sense.

00:11:42.920 | So in aggregate, I would say, you know,

00:11:45.480 | blood testing of biomarkers provides pretty good insight

00:11:49.620 | into lifespan.

00:11:51.800 | When you get into healthspan,

00:11:52.840 | you have kind of the cognitive, physical, emotional domains.

00:11:56.780 | I think here the biomarkers are far less helpful.

00:11:59.460 | And here we kind of rely more on functional testing.

00:12:03.260 | So when it comes to sort of the cognitive piece, you know,

00:12:06.340 | you can do cognitive testing.

00:12:08.300 | In terms of long-term risk,

00:12:09.640 | a lot of the things that imply good cognitive health

00:12:12.600 | as you age are in line with the same things

00:12:16.300 | that you would do to reduce the risk of dementia.

00:12:19.600 | So all the biomarkers that you would look to improve

00:12:22.800 | through dementia risk reduction,

00:12:24.180 | you would be improving through cognitive health.

00:12:26.740 | On the physical side, I mean,

00:12:27.900 | outside of looking at hormone levels and things,

00:12:29.420 | which we look at extensively

00:12:31.060 | and understanding how those might aid in

00:12:34.180 | or prevent some of the metrics that matter,

00:12:37.500 | it really is, this is a biomarker aside thing.

00:12:40.140 | I mean, I'd be much more interested in a person's DEXA,

00:12:42.660 | CPET testing, VO2 max testing, you know,

00:12:45.700 | Zone 2 lactate testing, fat oxidation,

00:12:48.780 | those what I would consider more functional tests

00:12:51.060 | that give me far more insight into that.

00:12:53.320 | And then of course the emotional piece,

00:12:54.560 | which depending on who you are,

00:12:56.900 | might be the single most important piece

00:12:58.360 | without which none of this other stuff matters, right?

00:12:59.920 | If you're a totally miserable human being,

00:13:01.940 | your relationships suck.

00:13:03.800 | I don't think any of this other stuff matters.

00:13:05.460 | And certainly there's nothing that I'm looking at

00:13:07.800 | in biomarkers that's giving me great insight into that.

00:13:10.820 | - Do you ask about emotional state

00:13:12.480 | or do you try and assess emotional state indirectly

00:13:14.640 | when you do an intake with one of your patients?

00:13:17.040 | - Probably not so much in the intake

00:13:19.420 | because I think it takes a while to form a relationship

00:13:21.660 | with a patient before that starts to become something

00:13:24.920 | that they're necessarily gonna wanna talk with you about.

00:13:27.420 | But I definitely think of it

00:13:29.340 | as an important part of what we do.

00:13:31.780 | And I think without it,

00:13:33.820 | none of this other stuff really matters.

00:13:35.560 | Again, the irony of thinking about how many years I spent

00:13:39.060 | sort of in pursuit of fully optimizing

00:13:42.280 | every detail of everything

00:13:43.620 | without any attention being paid to that dimension

00:13:46.580 | is not lost on me.

00:13:48.020 | And look, there are some patients who they,

00:13:50.680 | that's just not something that,

00:13:51.780 | that's something that's compartmentalized.

00:13:53.260 | Maybe they're doing well in that department

00:13:55.100 | or maybe they aren't,

00:13:55.940 | but they just aren't willing to engage on that yet.

00:13:58.820 | - In terms of frequency of blood testing,

00:14:00.820 | if somebody feels pretty good

00:14:03.220 | and is taking a number of steps,

00:14:05.380 | exercise, nutrition, et cetera,

00:14:07.280 | to try and extend lifespan and improve healthspan,

00:14:11.980 | is once a year frequent enough?

00:14:16.740 | And should a 20-year-old start getting blood work done

00:14:20.040 | just to get a window into what's going on,

00:14:21.740 | assuming that they can afford it

00:14:22.820 | or their insurance can cover it?

00:14:24.280 | - Yeah, I mean, look,

00:14:25.120 | I certainly think everybody should be screened early in life

00:14:27.580 | because if you look at,

00:14:28.580 | like what's the single most prevalent genetic driver

00:14:32.040 | of atherosclerosis is Lp little a.

00:14:34.540 | So unfortunately, most physicians don't know

00:14:36.100 | what Lp little a is,

00:14:37.080 | and yet somewhere between eight and 12% of the population

00:14:40.020 | has a high enough,

00:14:40.880 | and depending on who you, you know,

00:14:43.180 | I had a recent guest on my podcast

00:14:44.660 | who suggested it could be as high as 20%

00:14:46.740 | have a high enough Lp little a

00:14:48.120 | that it is contributing to atherosclerosis.

00:14:51.080 | So to not want to know that

00:14:52.900 | when it's genetically determined, right?

00:14:54.300 | This is something that, you know,

00:14:55.820 | you're born with this

00:14:56.680 | and you only need to really check it once.

00:14:59.220 | Why we wouldn't want to know that in a 20-year-old

00:15:01.500 | when it can contribute

00:15:02.700 | to a lot of the early atherosclerosis we see in people,

00:15:06.860 | you know, it just, you know,

00:15:08.200 | it's leaving money on the table in my opinion.

00:15:10.420 | The frequency with which you need to test

00:15:11.960 | really comes down to the state of interventions.

00:15:15.280 | You know, I don't think it makes sense

00:15:17.060 | to just do blood tests for the sake of doing blood tests.

00:15:19.200 | There has to be kind of a reason.

00:15:20.400 | Is something changing?

00:15:22.360 | You know, a blood test is for the most part

00:15:24.180 | a static intervention.

00:15:26.040 | It's a look at a window in time,

00:15:28.840 | and there's benefit in having, you know,

00:15:31.880 | a few of those over the course of a year

00:15:34.440 | if you're unsure about a level.

00:15:36.200 | So if something comes back and it doesn't look great,

00:15:38.600 | yeah, it might make sense just to recheck it

00:15:40.200 | without reacting to it.

00:15:41.800 | But typically, you know, in patients,

00:15:43.320 | we might check blood two to four times a year,

00:15:45.580 | but we're also probably doing things in there

00:15:47.640 | to now check like, hey, you know,

00:15:50.640 | we gave this drug, did it have the desired outcome?

00:15:54.180 | You know, you put on three pounds of muscle

00:15:56.640 | and lost three pounds of fat,

00:15:57.920 | did it have the desired outcome?

00:15:59.520 | - Speaking of tracking weight

00:16:02.880 | and fat lean mass percentages,

00:16:06.240 | is that something that you recommend

00:16:08.000 | your patients do pretty often?

00:16:09.500 | I know people that step on the scale every day,

00:16:11.000 | I know people like myself that, frankly,

00:16:12.960 | I might step on the scale three times a year.

00:16:14.720 | I don't really care.

00:16:16.280 | I pay attention to other things

00:16:17.640 | that are far more subjective.

00:16:19.640 | Maybe I'm making a huge mistake.

00:16:20.960 | What are your thoughts about quantitative measurements

00:16:24.200 | of weight BMI for the typical person?

00:16:29.200 | - I think they're pretty crude.

00:16:31.760 | I think a DEXA, I'd rather take a DEXA annually

00:16:35.960 | and then maybe follow weight a little bit more closely

00:16:40.400 | to get a sense of it.

00:16:41.400 | And so with a DEXA, you're getting,

00:16:43.920 | at least the way we look at the data,

00:16:45.460 | four pieces of information.

00:16:47.520 | Now, most people, when they do a DEXA,

00:16:49.520 | should I explain what that is?

00:16:50.800 | - Yeah, I think some people might not know what DEXA is.

00:16:53.080 | In fact, I confess I have a crude understanding

00:16:55.660 | of what it is.

00:16:56.500 | Tell me where I'm wrong

00:16:58.800 | and hopefully where I'm at least partially right.

00:17:02.040 | My understanding is that there are a number of different ways

00:17:03.760 | to measure lean mass to non-lean mass ratio.

00:17:07.080 | And there's one where they put you underwater.

00:17:09.520 | There's one where they put you

00:17:10.360 | into some sort of non-underwater chamber.

00:17:12.920 | There's calipering.

00:17:14.380 | And then there's the looking in the mirror

00:17:16.680 | and pinching and changing the lighting.

00:17:19.400 | - It's funny, if you've done it enough,

00:17:23.440 | I can sort of tell my body fat by my abs, right?

00:17:26.720 | So I can sort of tell by how good the six pack

00:17:29.440 | or how bad the six pack is, what the leanness is.

00:17:31.620 | And that's actually not a terrible way to do it.

00:17:34.480 | There are, a bodybuilder, for example,

00:17:35.880 | which I've never been, can tell you the difference

00:17:38.480 | between being 6%, 7%, 8%, 10%,

00:17:41.480 | just based on the degree of visibility within the abs.

00:17:46.480 | But basically a DEXA scan is an X-ray.

00:17:50.720 | So it's the same principle as just getting a chest X-ray

00:17:53.720 | where ionizing radiation is passed through the body

00:17:56.560 | and there's a plate behind the body

00:17:58.080 | that collects what comes through.

00:17:59.820 | And the denser the medium

00:18:02.720 | that the electrons are trying to go through,

00:18:05.420 | the less of them that are collected.

00:18:06.840 | So when you look at an X-ray, as everybody's probably seen,

00:18:09.020 | an X-ray, that which is white is most dense.

00:18:11.800 | So if you had a piece of metal in your pocket,

00:18:14.280 | it would show up as a bright white thing.

00:18:16.760 | That's why ribs and bones show up as white.

00:18:19.560 | And the things that are the least dense,

00:18:21.960 | like the lungs where it's just air, are the blackest.

00:18:25.320 | And everything is a shade of gray in between.

00:18:27.600 | So a DEXA is just doing that effectively,

00:18:30.560 | but it's a moving X-ray.

00:18:31.800 | So you lay down on a bed and it takes maybe 10 minutes

00:18:34.840 | and this little, very low power X-ray

00:18:37.320 | kind of goes over your body.

00:18:39.120 | And the plate beneath it is collecting information

00:18:43.400 | that is basically allowing it to differentiate

00:18:45.880 | between three things, bone mineral content, fat, other.

00:18:50.880 | And the other is quantified as lean body mass.

00:18:55.400 | So that's organs, muscles, everything else.

00:18:58.540 | So when most people do a DEXA, they get the report back,

00:19:01.640 | and the reports are horrible.

00:19:02.720 | I've yet to see one company that can do this

00:19:04.640 | in a way that isn't abjectly horrible.

00:19:06.760 | We've created our own templates.

00:19:08.240 | So we have our own dashboard for how we do this

00:19:09.940 | 'cause we've just given up on trying to use theirs.

00:19:12.340 | But the first thing most people look at

00:19:13.520 | is what's my body fat?

00:19:14.760 | And this is the gold standard outside of like MRI

00:19:17.960 | or something that's only used for research purposes.

00:19:20.000 | So a DEXA is going to produce a far better estimate

00:19:23.000 | of body fat than calipers or buoyancy testing

00:19:27.460 | or things like that, provided the machinery

00:19:29.760 | is well calibrated and the operator knows how to use it.

00:19:34.220 | I've heard some people argue that in the hands

00:19:36.200 | of the guy who's been doing calipers his whole life,

00:19:40.600 | it could probably be comparable with calipers.

00:19:42.460 | But nevertheless, for an off-the-shelf tech,

00:19:45.760 | DEXA is amazing.

00:19:46.680 | Of the four things that get spit out of the DEXA,

00:19:50.560 | we think that the body fat is the least interesting.

00:19:53.380 | And so I would rank that as fourth on the list

00:19:56.120 | of what's germane to your health.

00:19:58.020 | The other three things that you get spit out

00:19:59.920 | are bone mineral density, visceral fat,

00:20:03.960 | and then the metrics that allow you to basically compute

00:20:08.960 | what's called appendicular lean mass index

00:20:11.220 | and fat-free mass index.

00:20:12.940 | And so those three metrics are significantly more important

00:20:16.120 | than body fat.

00:20:17.480 | And the reason is as follows.

00:20:19.720 | So bone mineral density basically speaks

00:20:22.380 | to your risk of osteoporosis and osteopenia.

00:20:26.800 | And that doesn't sound very sexy to people our age.

00:20:30.220 | 50-year-old guy is listening to this.

00:20:31.780 | It's like, yeah, big deal.

00:20:32.760 | But for a 50-year-old woman, this is a huge deal, right?

00:20:35.840 | A woman who's just about to go through menopause

00:20:37.680 | or has just gone through menopause is at an enormous risk

00:20:40.780 | for osteopenia and then ultimately osteoporosis

00:20:43.940 | because estrogen is the single most important hormone

00:20:47.180 | in regulating bone mineral density.

00:20:50.100 | And we can come back and talk about why that's the case,

00:20:52.000 | but it's very interesting how the biomechanics

00:20:55.120 | of bones work and why estrogen specifically is so important.

00:21:00.120 | And this is a huge cause of morbidity, right?

00:21:02.480 | So if you're over the age of 65 and you fall

00:21:05.840 | and break your hip, your one-year morbidity

00:21:09.800 | is about 30 to 40%.

00:21:12.760 | Which again, just to put that in English,

00:21:14.800 | if you're 65 or older, you fall and break your hip,

00:21:17.120 | there's a 30 to 40% chance you're dead in a year.

00:21:20.440 | - Wow. - Bones matter.

00:21:22.020 | So we want to really get a sense of where you stack up

00:21:27.940 | for your age, for your sex, and if you're anywhere

00:21:31.440 | off the pace, we have to ramp up our strategy

00:21:34.920 | and be super aggressive about how to increase that

00:21:37.480 | or at a minimum, prevent any further decay.

00:21:41.400 | - And are there age-related charts for these sorts of things?

00:21:44.060 | - Yeah, this all gets spit out into what's called a z-score.

00:21:47.160 | So when you're looking at your BMD,

00:21:49.480 | it's gonna give you a z-score.

00:21:50.600 | So a z-score of zero means, and you understand this,

00:21:54.200 | but it's z-score referring to a probability distribution

00:21:56.800 | in a standard mode.

00:21:57.720 | So z-score of zero means you're at the 50th percentile

00:22:00.460 | for your age and sex.

00:22:01.460 | A z-score of plus one, you're one standard deviation above,

00:22:04.200 | minus one below, et cetera.

00:22:06.300 | There's also a t-score, which is doing the same thing,

00:22:08.800 | but comparing you to a young person.

00:22:11.600 | And so the t-score is technically used to make the diagnosis

00:22:14.200 | of osteopenia or osteoporosis.

00:22:15.800 | We tend to look more at the z-score and basically say,

00:22:18.180 | look, if your z-score right now is minus one in four years,

00:22:22.560 | I want your z-score to be zero.

00:22:24.120 | Not necessarily because you've increased that entire way,

00:22:27.460 | but maybe you've increased slightly

00:22:29.160 | while it's expected that you would have declined.

00:22:31.980 | - I see.

00:22:32.820 | What are some things that we can do

00:22:35.220 | to improve bone mineral density at any age?

00:22:38.900 | - So it turns out there's a real critical window

00:22:41.420 | in which we are malleable.

00:22:43.100 | So depending on the age at which someone's listening to us

00:22:45.580 | discuss this, if you're under 20, 25,

00:22:50.400 | you are still in that time of your life

00:22:52.780 | when you are able to reach your potential.

00:22:55.560 | So it turns out that strength training is probably

00:23:00.060 | the single best thing you can do.

00:23:02.340 | And this was a surprise to me 'cause we did an AMA

00:23:05.660 | on this topic a little while ago,

00:23:07.420 | and that's when I got really deep on this with our analysts.

00:23:10.780 | My assumption was running must be the best.

00:23:13.300 | Some sort of impact must be the best thing you can do.

00:23:15.940 | I assumed running would be better than swimming and cycling,

00:23:18.680 | but it turned out that powerlifting

00:23:20.180 | was probably the best thing you could do.

00:23:22.820 | And I think once you understand how bones work,

00:23:25.220 | it became more clear, which is,

00:23:27.500 | powerlifting is really putting more of a shear force

00:23:30.460 | from the muscle via the tendon onto the bone.

00:23:33.120 | And that's what the bones are really sensing.

00:23:35.040 | They're sensing that shear force that's being applied

00:23:37.780 | through the bone in a compressive way,

00:23:39.720 | depending on the bone, of course.

00:23:41.420 | And that's what's basically activating the osteoblasts,

00:23:44.320 | which are the cells that are allowing bone to be built.

00:23:49.320 | So this turns out to be probably more important for females.

00:23:55.980 | Because how high you can get

00:23:59.280 | during that period of development,

00:24:00.740 | say till you're 20 or 25,

00:24:02.580 | basically sets your trajectory for the rest of your life.

00:24:05.660 | So where we get into real trouble

00:24:07.260 | is with patients who, for example,

00:24:09.780 | used large amounts of inhaled steroids

00:24:12.220 | during that period of their life,

00:24:13.100 | 'cause let's say they had really bad asthma.

00:24:15.340 | Or patients who needed large amounts of corticosteroids

00:24:18.220 | for some other immune-related condition.

00:24:20.260 | So during their critical window of development,

00:24:22.140 | they were taking a drug that was impairing this process.

00:24:25.660 | So we have some patients like that in our practice,

00:24:27.940 | and that's just an enormous liability

00:24:30.220 | that we're working really hard to overcome,

00:24:31.840 | with nutrition, with hormones, with drugs, with training.

00:24:35.900 | And it's just something you have to be aware of.

00:24:41.020 | - I wasn't aware that inhalants for asthma

00:24:45.660 | and things of that sort can impair bone mineral density.

00:24:48.460 | - Yeah, they're steroid-based.

00:24:50.060 | Some of them, of course, are just beta agonists,

00:24:51.780 | and they're fine.

00:24:52.620 | - So anything corticosterone-like?

00:24:54.780 | - Yep. - Interesting.

00:24:55.700 | And then I always get asked this question,

00:24:57.420 | and I always reflexively want to say no,

00:25:00.140 | but I don't really know the answer, so I don't reply.

00:25:02.780 | What about topical corticosterone?

00:25:05.540 | People will put cortisone cream.

00:25:06.740 | To me, it seems almost inconceivable

00:25:08.540 | that it would have a systemic effect,

00:25:09.900 | but then again, what do I know?

00:25:11.180 | - It's all dosing and time-related.

00:25:14.340 | So if you're talking about,

00:25:15.980 | I've got a little rash under my skin,

00:25:17.900 | I'm going to put corticosteroids on, probably not.

00:25:21.380 | But certainly with enough of it put on,

00:25:23.580 | I mean, it is absorbed, so it could be an issue.

00:25:26.880 | But that's not typically what we're concerned with.

00:25:29.060 | I mean, we're mostly concerned with people

00:25:30.520 | that are taking even modest amounts of prednisone

00:25:33.420 | for months, years at a time,

00:25:35.080 | or like I said, kids that are using steroid inhalers

00:25:39.860 | for years and years and years.

00:25:42.500 | Again, I'm not suggesting that if your kid's

00:25:44.080 | on a steroid inhaler, they shouldn't be.

00:25:45.580 | You have to solve the most important problem,

00:25:47.620 | and if asthma is the most important problem, so be it.

00:25:49.740 | I think you just want to turn that into,

00:25:51.620 | okay, well, how much more imperative is it

00:25:54.740 | that our kid is doing things

00:25:56.740 | that are putting a high amount of stress on their bones

00:25:59.880 | and via their muscles to make sure

00:26:01.680 | that they're in that maximal capacity to build?

00:26:04.940 | - Do you think that somebody in their 30s or 40s or 50s

00:26:08.180 | could still benefit from strength training

00:26:09.900 | in terms of bone mineral density and longevity

00:26:13.220 | as it relates to bone mineral density,

00:26:15.720 | given that there was this key window earlier,

00:26:18.260 | or they might've missed that window?

00:26:19.100 | - Oh yeah, no, no, this is essential for the rest of life

00:26:21.060 | because you're now trying to prevent the fall off.

00:26:23.300 | So basically the way it works is you're sort of,

00:26:25.680 | from birth to say 20, you're in growth.

00:26:28.820 | From 20 to 50, you plateau.

00:26:31.180 | At 50, men start to decline, but it's really small.

00:26:34.740 | Women start to decline, and it's precipitous.

00:26:36.860 | - And it's related to the drop in estrogen

00:26:38.720 | associated with menopause or pre-menopause.

00:26:40.820 | - Correct.

00:26:41.660 | - And can we get into any of the broad contours

00:26:46.120 | of what that strength training looks like?

00:26:47.860 | We had Dr. Andy Galpin on the show.

00:26:49.740 | He talked a lot about ways to build strength

00:26:51.300 | versus hypertrophy versus endurance, et cetera.

00:26:53.620 | I think there's pretty good agreement

00:26:55.340 | across the fields of physiotherapy, et cetera,

00:26:58.780 | of physiology and medicine in terms of how to do that.

00:27:01.460 | But my understanding is fairly low repetition ranges.

00:27:04.620 | So this is anywhere from one to six repetitions,

00:27:07.680 | typically not aiming for a pump hypertrophy,

00:27:11.940 | that sort of thing, but heavy loads that are hard to move,

00:27:14.640 | 80% of one repetition maximum or more

00:27:18.020 | done with long rest periods,

00:27:19.620 | two to three times a week type thing.

00:27:23.980 | Is that about right?

00:27:24.820 | - Yeah, if you look at the literature on this,

00:27:26.740 | it's going to tell you,

00:27:28.080 | it's going to differentiate powerlifting from weightlifting.

00:27:31.440 | In other words, yeah, you do need to be kind of moving

00:27:34.380 | against a very heavy load.

00:27:36.480 | Now, again, that can look very different

00:27:37.820 | depending on your level of experience.

00:27:39.840 | Like, I really like deadlifting.

00:27:42.280 | Now, I mean, I can count the number of days left in my life

00:27:45.300 | when I'm going to want to do sets over 400 pounds,

00:27:48.300 | but I'll pick and choose the days that I do.

00:27:51.280 | But I grew up doing those things.

00:27:54.000 | I'm comfortable with those movements.

00:27:55.580 | If I had a 60-year-old woman

00:27:57.580 | who's never lifted weights in her life

00:27:59.260 | who we now have to get lifting,

00:28:00.880 | I mean, we could get her to deadlift,

00:28:03.700 | but I think I wouldn't make perfect the enemy of good.

00:28:07.780 | I'd be happy to put her on a leg press machine

00:28:09.780 | and just get her doing that.

00:28:12.020 | You know, it's not as pure a movement as a deadlift,

00:28:15.120 | but who cares, right?

00:28:16.020 | We can still put her at a heavy load for her

00:28:18.600 | and do so safely.

00:28:20.060 | So, now, that said, I mean,

00:28:22.700 | there was a study that was done in Australia,

00:28:24.860 | and hopefully we can find a link to it.

00:28:27.640 | There's a video on YouTube that actually kind of has the PI

00:28:30.180 | sort of walking through the results.

00:28:31.540 | I could send it to you after, and it's just amazing.

00:28:34.380 | They took a group of older women.

00:28:36.060 | They looked like they were in their 60s or 70s

00:28:37.620 | who had never lifted weights in their life,

00:28:39.340 | who had osteopenia, and some probably already

00:28:41.900 | had osteoporosis, and they basically just put them

00:28:44.100 | on a strength training protocol.

00:28:45.680 | And it is remarkable to watch these women.

00:28:47.740 | They're doing good mornings.

00:28:48.980 | They're doing deadlifts.

00:28:49.820 | They're picking heavy things up off the ground.

00:28:51.940 | I think one woman was picking up,

00:28:53.660 | God, I wanna say she was like picking like 50,

00:28:57.560 | 60 kilos up off the ground.

00:28:59.860 | I mean, just staggering sums of weight

00:29:01.560 | for these women who have never done anything,

00:29:03.620 | and their bone health is improving at this age.

00:29:07.340 | So the goal, frankly, is to just never get to the point

00:29:12.340 | where you have to do this for the first time.

00:29:16.200 | Strength training is such an essential part

00:29:17.700 | of our existence that it's never too late to start,

00:29:22.420 | but you should never stop.

00:29:24.540 | - Love that advice.

00:29:25.380 | Is it a systemic effect or a local effect?

00:29:27.460 | So for instance, let's say that,

00:29:30.660 | well, my mother's in her late 70s.

00:29:32.820 | She actually used to be really strong when we were kids.

00:29:35.780 | She could move this fish tank that was in my room

00:29:37.740 | long before I could move it, and she's really strong.

00:29:41.620 | Over the years, I wouldn't call her frail by any means,

00:29:44.920 | but I certainly think she could benefit

00:29:46.780 | from some strength training.

00:29:48.940 | Let's say she were to start doing some leg presses

00:29:51.200 | or start even with air squats

00:29:52.760 | and maybe work up to some pushups.

00:29:55.060 | Are the effects all local?

00:29:56.060 | Meaning if she were to just train her legs

00:29:58.340 | or just do pushups, would it only be the loads applied

00:30:01.940 | to the limbs and muscles and tissues that were involved?

00:30:05.060 | - I think that's where the bulk of it is, yeah.

00:30:06.420 | - Okay.

00:30:07.260 | So you need to train the whole body, essentially.

00:30:09.180 | - Yeah, now keep in mind,

00:30:10.300 | the diagnosis of osteopenia and osteoporosis

00:30:13.020 | is based on only three locations,

00:30:15.700 | the left hip, the right hip, and the lumbar spine.

00:30:18.220 | So that's just the convention

00:30:22.020 | by which we make the diagnosis.

00:30:24.300 | And I think part of that has to do with

00:30:25.920 | that's where the majority of the insults occur.

00:30:28.020 | Now, not all of the insults.

00:30:29.420 | I've seen people that have,

00:30:31.500 | because of horrible bone density,

00:30:33.180 | they're fracturing ankles and tibia, fibula,

00:30:36.820 | like they're having low tib fib fractures just walking.

00:30:40.000 | So clearly bone density outside of those regions

00:30:42.340 | does matter, but much of it is really focused on,

00:30:46.220 | and by the way, you know, you fall, you break a wrist.

00:30:48.020 | So this is a systemic issue,

00:30:51.060 | but the majority of the response is a local response

00:30:54.200 | 'cause it really comes down to

00:30:56.220 | putting a load directly on that bone

00:30:58.080 | and then having that bone in kind respond

00:31:01.140 | by laying down more bone.

00:31:03.140 | Before we continue with today's discussion,

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00:32:16.640 | - You mentioned falling and the problems with falling

00:32:18.800 | and breaking things and mortality related to that.

00:32:21.780 | I wonder whether or not there are also health-related

00:32:25.080 | effects of just having weak bones

00:32:26.920 | that are not just about falling and breaking a bone

00:32:29.480 | and dying a year later, even though that's obviously

00:32:32.480 | very severe, because I think when people hear about that,

00:32:35.000 | some people might think, well, I'll just be more careful.

00:32:37.360 | I'll just move more slowly.

00:32:38.300 | I'll sit in a wheelchair if I need to,

00:32:40.880 | even though I might be able to walk

00:32:42.280 | if it keeps me from falling.

00:32:43.440 | Some people I think adopt that mentality.

00:32:45.560 | What are some of the benefits of having

00:32:49.040 | high bone mineral density for men and women

00:32:51.800 | that are perhaps independent of risk of injury?

00:32:55.840 | - Well, I think it's actually the inverse

00:32:57.160 | of what you just said, right?

00:32:58.200 | It's sort of like, you have to sort of be able

00:33:02.280 | to articulate what it is you want in your marginal decade.

00:33:05.700 | So we use this thing in our practice

00:33:07.380 | called the marginal decade.

00:33:08.760 | Marginal decade is the last decade of your life.

00:33:10.840 | So everyone will have a marginal decade.

00:33:12.780 | That's the only thing I can tell you

00:33:13.960 | with absolute certainty, right?

00:33:16.400 | - I believe you.

00:33:17.240 | - There's no immortality, there's no hidden elixir

00:33:19.720 | that's gonna help us live to be, you know, whatever.

00:33:22.160 | I mean, we're all gonna be in our last decade at some point.

00:33:26.360 | And outside of people who die suddenly

00:33:28.240 | or through an accident, most of us know

00:33:31.280 | when we're in that marginal decade.

00:33:32.960 | You might not know the day you enter it,

00:33:34.480 | but most people, you know, who are old enough,

00:33:37.800 | if you tell them, are you in the last decade of your life,

00:33:39.780 | they probably have a sense that they are.

00:33:41.920 | So I think the exercise that we like to go through

00:33:44.920 | with our patients very early on is have them

00:33:49.600 | in exquisite detail, more detail than they've ever considered

00:33:53.280 | so we have to prompt them with like 50 questions,

00:33:56.980 | lay out what their marginal decade should look like.

00:34:00.580 | - Wow, that's a serious exercise.

00:34:02.680 | - It's a very serious exercise, right?

00:34:04.180 | Like what, tell me everything that is going to happen

00:34:06.800 | in your marginal decade.

00:34:07.640 | I don't know when it's gonna be, Andrew.

00:34:08.720 | It could be '87 to '97 if we're doing well, right?

00:34:12.400 | It might be '79 to '89, I don't know.

00:34:14.840 | But it would really be a very nuanced exploration

00:34:19.840 | of that topic.

00:34:21.620 | And I think until you do that, all of this other stuff

00:34:24.480 | is just abstract and kind of nonsense.

00:34:28.640 | You know, until a person can tell you what it is

00:34:31.640 | that they want to be doing in that last decade,

00:34:34.720 | you can't design a program to get them there.

00:34:37.900 | I mean, think about it.

00:34:38.960 | You know, someone wants to do an Ironman.

00:34:41.760 | We take it for granted that we know what the objective is.

00:34:44.840 | I have to be able to swim two and a half miles.

00:34:46.480 | I have to be able to get out, take my wetsuit off,

00:34:48.440 | hop on my bike, ride 112 miles, get off my bike,

00:34:51.740 | take the bike shoes off, put the run shoes on,

00:34:53.500 | run 26.2 miles, like we get it.

00:34:55.100 | We know what the objective is.

00:34:56.420 | And only by knowing that can you train.

00:34:58.940 | Can you imagine if I said to you,

00:35:01.420 | Andrew, I'm going to have you do an athletic event

00:35:03.580 | in a year, start training.

00:35:05.540 | I'm not gonna tell you what it is, just do it.

00:35:08.420 | It could be playing basketball.

00:35:10.400 | You know, it could be swimming to Catalina Island.

00:35:12.820 | It could be running a hundred miles.

00:35:15.140 | You wouldn't be able to do it.

00:35:16.260 | So similarly, if we don't know what our marginal decade

00:35:18.760 | is meant to be, there's no way to train for it.

00:35:22.200 | - Do you think this is a good exercise

00:35:23.520 | for anyone and everyone to do on their own

00:35:26.000 | regardless of age?

00:35:26.840 | Here I'm hearing this and I'm thinking,

00:35:28.600 | I need to think about when my last decade might be

00:35:31.320 | and what I want that to look like.

00:35:33.120 | - Absolutely.

00:35:33.960 | I mean, when I say we do it with our patients,

00:35:34.940 | that's only because that's the population I work with,

00:35:36.620 | but there's simply no reason everybody

00:35:38.360 | shouldn't be going through this exercise.

00:35:40.120 | - And then you sort of back script from there,

00:35:43.060 | figure out what people should be doing

00:35:44.200 | given their current health status.

00:35:45.560 | - That's exactly right.

00:35:46.400 | We call it back casting.

00:35:47.300 | So the first step we do is once we've really delineated

00:35:50.620 | what the objective function looks like,

00:35:52.780 | we then say, okay, how do you break down that

00:35:56.260 | into metrics that we can measure?

00:36:00.220 | So, you know, you described doing a whole bunch of things.

00:36:02.620 | Okay, just to let you know, to do that,

00:36:04.700 | we'll require a VO2 max of 30 milliliters

00:36:08.620 | of oxygen per minute per kilogram.

00:36:11.180 | And the person will say, okay, what does that mean?

00:36:14.120 | We'll say, well, that's a measure of your maximal uptake

00:36:16.700 | of oxygen, and that declines at about 8% to 10% per decade.

00:36:21.700 | So if you have to be at 30, and let's just assume

00:36:25.680 | you're gonna be doing that at 90,

00:36:27.700 | so what do you need to be at 80, 70, 60, 50?

00:36:31.020 | Okay, here's what it would need to be at 50.

00:36:33.220 | Okay, what are you now?

00:36:34.540 | Ah, there's a big gap.

00:36:36.060 | You're below where you need to be now.

00:36:37.320 | So you're obviously higher than 30 now,

00:36:40.720 | but if you're only at 42 now,

00:36:42.940 | and you need to be at 30 and 40 years,

00:36:45.940 | you're not gonna cut it.

00:36:47.140 | You have to be a lot fitter.

00:36:48.700 | Okay, now let's do the same exercise

00:36:50.660 | around strength and stability.

00:36:52.920 | And without exception, most people,

00:36:54.860 | when they do this exercise, will find out

00:36:56.500 | they're well below where they need to be.

00:36:58.900 | So the gravity of aging is more vicious than people realize,

00:37:03.900 | and therefore the height of your glider

00:37:06.400 | needs to be much higher than you think it is

00:37:08.900 | when you're our age.

00:37:10.640 | If you wanna be able to do the things we probably

00:37:13.040 | wanna be able to do when we're 90.

00:37:15.140 | - I absolutely love this approach.

00:37:17.160 | I've never done it in terms of my health.

00:37:18.760 | I've always thought about what I wanna accomplish

00:37:20.240 | in the next three to six months or next year or so.

00:37:22.480 | - And by the way, that's a great approach.

00:37:23.980 | That's forecasting.

00:37:24.920 | Forecasting is fantastic.

00:37:26.200 | Forecasting is really good at short-term things.

00:37:29.300 | It doesn't work for long-term things.

00:37:31.380 | Long-term, you have to do backcasting.

00:37:33.860 | - This backcasting approach really appeals to me

00:37:35.760 | because in my career, well, I never anticipated,

00:37:37.960 | excuse me, I never anticipated I'd be podcasting,

00:37:41.280 | but that's what I did.

00:37:42.560 | At some point as an undergraduate, I looked,

00:37:44.440 | professors, I think that looks like a pretty good life.

00:37:46.440 | They seem pretty happy.

00:37:47.260 | I talked to a few of them and then I figured out

00:37:49.360 | what I need to do at each stage

00:37:50.560 | in order to get to that next rung on the ladder

00:37:53.760 | and just kind of figured it out

00:37:56.240 | in a backcasting kind of way as you refer to it.

00:37:59.240 | I think this is incredibly useful

00:38:00.920 | because it puts all the questions about blood work

00:38:03.340 | and how often to get blood work

00:38:04.440 | and what to measure in a really nice context

00:38:07.080 | that's highly individualized.

00:38:08.680 | I've never heard of this before, so.

00:38:10.960 | - And I should give a nod to Annie Duke.

00:38:12.740 | I used to always refer to this as reverse engineering,

00:38:15.800 | but in Annie Duke's book,

00:38:17.200 | she wrote about this exact thing and called it backcasting.

00:38:19.760 | And I was like, I like the term backcasting better.

00:38:22.320 | I think it's more intuitive than reverse engineering.

00:38:24.480 | - Yeah, there's a real genius to it.

00:38:25.960 | And I think it, 'cause it sets so many things

00:38:28.000 | into the appropriate bins and trajectories.

00:38:30.800 | I've heard you talk before about some of the prime movers

00:38:33.940 | for longevity and all risk mortality.

00:38:38.420 | And I'd love for you to review a little bit of that for us.

00:38:42.260 | I think we all know that we shouldn't smoke

00:38:44.060 | because it's very likely that we'll die earlier

00:38:46.540 | if we smoke nicotine.

00:38:48.500 | I'm neither a marijuana nor a nicotine smoker,

00:38:50.980 | so I feel unstable ground there.

00:38:52.920 | But anytime we see smoking nowadays,

00:38:54.780 | people really want to distinguish

00:38:56.400 | between cannabis and nicotine.

00:38:58.880 | So I am curious about any differences there

00:39:00.900 | in terms of impact on longevity.

00:39:04.220 | But in that context,

00:39:06.400 | what are the things that anyone and everyone can do,

00:39:09.960 | should do to live longer, basically?

00:39:13.800 | - How long you got?

00:39:14.760 | - Well, you tell me.

00:39:16.960 | (laughing)

00:39:18.160 | You tell me.

00:39:19.560 | I'd like to live to be,

00:39:20.660 | I'd like my final decade to be between 90 and 100.

00:39:23.400 | - Oh no, I meant how long do you, yeah, yeah, yeah.

00:39:25.120 | - I'm just kidding, I'm just kidding.

00:39:25.960 | - And will we spend from now until you're 90

00:39:27.460 | talking about this?

00:39:28.300 | - Well, there's a risk of that.

00:39:29.240 | But top contour is fine.

00:39:30.960 | I know you've done a lot of content on this

00:39:32.440 | and we will give people links

00:39:33.760 | to some of that more in-depth content.

00:39:35.640 | But let's say we were on a short flight

00:39:38.360 | from here to San Diego.

00:39:40.240 | We're in Los Angeles now.

00:39:42.260 | And we got takeoff and landing

00:39:43.940 | and we don't want to kink our neck too much

00:39:45.640 | by doing this thing.

00:39:46.480 | So if I just said, hey,

00:39:47.960 | give me the extended version of the three by five card.

00:39:52.340 | What does that look like?

00:39:53.540 | - So let's start with a couple of the things

00:39:56.840 | that you've already highlighted.

00:39:57.680 | So smoking, how much does smoking increase your risk

00:40:00.460 | of all-cause mortality?

00:40:01.840 | And the reason we like to talk about what's called ACM

00:40:04.180 | or all-cause mortality is it's really agnostic

00:40:07.480 | to how you die.

00:40:08.820 | And that doesn't always make sense.

00:40:10.700 | I mean, if you're talking about a very specific intervention

00:40:14.040 | like a anti-cancer therapeutic,

00:40:15.800 | you really care about cancer specific mortality

00:40:17.800 | or heart specific mortality.

00:40:19.880 | But when we talk about these sort of broad things,

00:40:21.460 | we like to talk about ACM.

00:40:22.840 | So using smoking, smoking is approximately a 40% increase

00:40:27.520 | in the risk of ACM.

00:40:29.280 | - What does that translate to?

00:40:30.540 | And that means I'm shortening my life by 40%.

00:40:35.040 | - No, it means at any point in time,

00:40:36.680 | there's a 40% greater risk that you're gonna die

00:40:39.720 | relative to a non-smoker and a never smoker.

00:40:42.040 | Yeah, so it's important to distinguish.

00:40:43.440 | It doesn't mean your lifespan is gonna be 40% less.

00:40:46.120 | It means at any point in time standing there,

00:40:47.720 | your risk of death is 40% higher.

00:40:50.560 | And by the way, that'll catch up with you, right?

00:40:52.340 | At some point that catches up.

00:40:54.720 | High blood pressure, it's about a 20 to 25% increase

00:40:59.040 | in all cause mortality.

00:41:01.180 | You take something really extreme

00:41:02.460 | like end stage kidney disease.

00:41:04.220 | So these are patients that are on dialysis

00:41:06.520 | waiting for an organ.

00:41:08.220 | And again, there's a confounder there

00:41:09.420 | because what's the underlying condition

00:41:11.780 | that leads you to that?

00:41:12.620 | It's profound hypertension,

00:41:14.780 | significant type two diabetes that's been uncontrolled.

00:41:17.840 | That's enormous.

00:41:18.680 | That's about 175% increase in ACM.

00:41:23.060 | So the hazard ratio is like 2.75.

00:41:26.860 | Type two diabetes is probably about a 1.25 as well.

00:41:30.480 | So a 25% increase.

00:41:32.280 | So now the question is like, how do you improve?

00:41:33.720 | So what are the things that improve those?

00:41:35.700 | So now here we do this by comparing low to high achievers

00:41:39.820 | and other metrics.

00:41:40.660 | So if you look at low muscle mass versus high muscle mass,

00:41:45.540 | what is the improvement?

00:41:47.840 | And it's pretty significant, it's about three X.

00:41:50.620 | So if you compare low muscle mass people

00:41:52.560 | to high muscle mass people as they age,

00:41:54.800 | the low muscle mass people have about a three X hazard ratio

00:41:58.120 | or a 200% increase in all cause mortality.

00:42:01.180 | Now, if you look at the data more carefully,

00:42:03.320 | you realize that it's probably less the muscle mass

00:42:07.640 | fully doing that,

00:42:09.320 | and it's more the high association with strength.

00:42:12.240 | And when you start to tease out strength,

00:42:15.380 | you can realize that strength could be

00:42:17.300 | probably three and a half X as a hazard ratio,

00:42:19.660 | meaning about 250% greater risk

00:42:24.220 | if you have low strength to high strength.

00:42:26.740 | - High strength is the ability to move loads

00:42:29.240 | at 80 to 90% of one repetition.

00:42:31.440 | - It's all defined by given studies.

00:42:32.940 | So the most common things that are used are actually,

00:42:36.740 | they're used for the purposes of experiments

00:42:39.300 | that make it easy to do.

00:42:40.400 | I don't even think they're the best metrics.

00:42:42.160 | So they're usually using like grip strength,

00:42:44.360 | leg extensions, and like wall sits, squats, things like that.

00:42:50.360 | So how long can you sit in a squatted position

00:42:53.020 | at 90 degrees without support

00:42:54.640 | would be a great demonstration of quad strength,

00:42:56.860 | a leg extension,

00:42:58.080 | how much weight can you hold for how long

00:43:00.900 | relative to body weight, things like that.

00:43:03.340 | We have a whole strength program

00:43:04.980 | that we do with our patients.

00:43:06.180 | We have something called the SMA.

00:43:07.260 | So it's the strength metrics assessment.

00:43:08.860 | And we put them through 11 tests that are really difficult,

00:43:13.860 | like a dead hang is one of them.

00:43:14.980 | Like how long can you dead hang your body weight,

00:43:16.660 | stuff like that.

00:43:17.660 | So we're trying to be more granular in that insight,

00:43:20.860 | but tie it back to these principles.

00:43:23.340 | If you look at cardio respiratory fitness,

00:43:25.340 | it's even more profound.

00:43:26.900 | So if you look at people who are in the bottom 25%

00:43:30.660 | for their age and sex in terms of VO2 max,

00:43:33.620 | and you compare them to the people

00:43:36.240 | that are just at the 50th to 75th percentile,

00:43:40.660 | you're talking about a 2X difference roughly

00:43:43.020 | in the risk of ACM.

00:43:45.900 | If you compare the bottom 25% to the top 2.5%,

00:43:50.060 | so you're talking about bottom quarter to the elite

00:43:53.140 | for a given age, you're talking about 5X,

00:43:57.820 | 400% difference in all-cause mortality.

00:44:01.220 | That's probably the single strongest association I've seen

00:44:03.740 | for any modifiable behavior.

00:44:05.900 | - Incredible, so when you say elite,

00:44:07.940 | these are people that are running marathons

00:44:10.140 | at a pretty rapid clip?

00:44:11.220 | - Not necessarily, it's just like what the VO2 max is

00:44:13.420 | for that, like my VO2 max would be in the elite

00:44:15.820 | for my age group, my VO2 max.

00:44:18.420 | But again, I'm training very deliberately

00:44:20.580 | to make sure that it's in that.

00:44:21.660 | So I wouldn't consider myself elite at anything anymore,

00:44:24.840 | but I still maintain a VO2 max that is elite for my age.

00:44:28.500 | - I consider you an elite physician

00:44:30.280 | and podcast and guy all around.

00:44:33.540 | But true, but in terms of, okay, so--

00:44:38.540 | - But the point is you don't have to be

00:44:39.980 | a world-class athlete to be elite here, yeah.

00:44:41.940 | - Got it, so maybe we could talk a little bit

00:44:44.540 | about the specifics around the training

00:44:46.340 | to get into the top two tiers there,

00:44:49.740 | because it seems that those are enormous positive effects

00:44:52.700 | of cardiovascular exercise,

00:44:54.580 | far greater than the sorts of numbers that I see around,

00:44:58.280 | let's just say supplement A or supplement B.

00:45:00.220 | - Well, and that's, you know,

00:45:01.560 | like this is my whole pet peeve in life, right?

00:45:03.900 | It's like, I just can't get enough of the machinating

00:45:07.660 | and arguing about this supplement versus that supplement.

00:45:11.400 | And I feel like you shouldn't be having those arguments

00:45:15.260 | until you have your exercise house in order.

00:45:17.460 | You know, you shouldn't be arguing about your,

00:45:22.020 | this nuance of your carnivore diet

00:45:24.020 | versus this nuance of your paleo diet

00:45:25.940 | versus this nuance of your vegan diet,

00:45:28.380 | like until you can deadlift your body weight for 10 reps.

00:45:31.820 | Like then you can come and talk about those things

00:45:33.660 | or something like, let's just go up with some metrics.

00:45:35.240 | Like until your VO2 max is at least at the 75th percentile

00:45:39.700 | and you're able to dead hang for at least a minute

00:45:42.260 | and you're able to wall sit for at least two,

00:45:44.120 | like we could rattle off a bunch

00:45:45.260 | of relatively low hanging fruit.

00:45:47.720 | I wish there was a rule that said

00:45:49.800 | like you couldn't talk about anything else, health related.

00:45:52.460 | - We can make that rule.

00:45:53.820 | - No one will listen to it.

00:45:54.820 | - I don't know about that.

00:45:55.660 | We can make whatever rules we want.

00:45:56.780 | We can call it Atiyah's rule.

00:45:58.580 | One thing I've done before in this podcast

00:46:00.120 | and on social media is just borrowing

00:46:01.980 | from the tradition in science,

00:46:03.220 | which is it's inappropriate to name something

00:46:05.060 | after yourself unless you were a scientist before 1950.

00:46:08.780 | But it's totally appropriate to name things

00:46:10.300 | after other people's.

00:46:11.140 | I'm going to call it Atiyah's rule

00:46:12.460 | until you can do the following things.

00:46:15.320 | Don't talk about supplements.

00:46:16.160 | - Please refrain from talking about supplements

00:46:17.620 | and nutrition.

00:46:18.460 | - There it is.

00:46:19.280 | Hereafter, thought of, referred to,

00:46:20.980 | and referenced as Atiyah's rule.

00:46:23.300 | I coined the phrase, not him.

00:46:24.600 | So there's no ego involved, but it is now Atiyah's rule.

00:46:27.980 | Watch out, hashtag Atiyah's rule.

00:46:30.120 | - Oh God.

00:46:31.320 | - Wikipedia entered Atiyah's rule.

00:46:33.340 | In all seriousness, and I am serious about that,

00:46:36.240 | dead hang for about a minute.

00:46:37.820 | Seems like a really good goal for a lot of people,

00:46:40.420 | at least.

00:46:41.260 | - That's our goal.

00:46:42.080 | I think we have a minute and a half is the goal

00:46:43.860 | for a 40-year-old woman.

00:46:44.980 | Two minutes is the goal for a 40-year-old man.

00:46:46.780 | So we adjust them up and down based on age and gender.

00:46:51.420 | - Great.

00:46:52.260 | And then the wall sit, what are some numbers?

00:46:53.820 | - We don't use a wall sit.

00:46:54.660 | We do just a straight squat, air squat, at 90 degrees.

00:46:58.780 | And I believe two minutes is the standard

00:47:01.020 | for both men and women at 40.

00:47:02.620 | - Great.

00:47:03.460 | And then, because for some people,

00:47:05.100 | thinking in terms of EO2 max is a little more complicated.

00:47:07.340 | They might not have access to the equipment

00:47:08.740 | or to measure it, et cetera.

00:47:11.980 | What can we think about in terms of cardiovascular?

00:47:14.520 | So run a mile at seven minutes or less,

00:47:17.160 | eight minutes or less?

00:47:18.000 | - That's a good question.

00:47:18.840 | So there are really good VO2 max estimators online,

00:47:22.620 | and you can plug in your activity du jour,

00:47:26.160 | so be it a bike, run, or rowing machine,

00:47:29.300 | and it can give you a sense of that.

00:47:31.400 | And I used to know all of those,

00:47:34.420 | but now that I just actually do the testing,

00:47:36.260 | I don't recall them.

00:47:37.620 | But it's exactly that line of thinking,

00:47:39.360 | like, can you run a mile in this time if you can?

00:47:42.240 | Your VO2 max is approximately this.

00:47:44.160 | - Great.

00:47:45.000 | - And I think somewhere in my podcast realm,

00:47:49.400 | I've got all those charts posted of like,

00:47:52.700 | this is by age, by sex.

00:47:56.160 | This is what the VO2 max is in each of those buckets.

00:47:58.960 | - Terrific. We'll provide links to those.

00:48:01.040 | We'll have our people find those links.

00:48:02.840 | And then you mentioned deadlifting body weight 10 times.

00:48:05.640 | - I just made that one up.

00:48:06.880 | That's not one that we include, but something else.

00:48:09.280 | Something like that.

00:48:10.960 | - We use farmer carries.

00:48:12.420 | So we'll say for a male,

00:48:14.200 | you should be able to farmer carry your body weight for,

00:48:17.480 | I think we have two minutes.

00:48:19.280 | So that's half your body weight in each hand.

00:48:21.920 | You should be able to walk with that for two minutes.

00:48:24.860 | For women, I think we're doing 75% of body weight

00:48:27.240 | or something like that, yeah.

00:48:28.440 | - Great. I love it.

00:48:30.500 | As indirect measures of how healthy we are

00:48:33.880 | and how long we're going to live.

00:48:34.920 | - It's basically grip strength, it's mobility.

00:48:37.380 | I mean, again, walking with that much weight

00:48:39.080 | for some people initially is really hard.

00:48:42.280 | We use different things like vertical jump,

00:48:43.960 | ground contact time.

00:48:44.960 | If you're jumping off a box, things like that.

00:48:46.640 | So it's really trying to capture,

00:48:48.820 | and it's an evolution, right?

00:48:50.040 | I think the test is going to get only more and more involved

00:48:53.160 | as we get involved.

00:48:54.840 | 'Cause it took us about a year.

00:48:56.440 | Beth Lewis did the majority of the work to develop this.

00:48:59.720 | Beth runs our strength and stability program

00:49:01.920 | in the practice.

00:49:02.920 | And basically I just tasked her with like,

00:49:04.680 | hey, go out to the literature and come up with

00:49:07.140 | all of the best movements that we think are proxies

00:49:09.520 | for what you need to be like the most kick-ass,

00:49:12.820 | you know, what we call centenarian decathlete,

00:49:14.540 | which is the person living in their marginal decade

00:49:16.460 | at the best.

00:49:17.640 | - Well, what I'm about to say is certainly

00:49:19.120 | a mechanistic leap, but if you look at the literature

00:49:22.080 | on exercise-related neurogenesis in mice

00:49:26.280 | or brain atrophy or brain hypertrophy, et cetera,

00:49:30.880 | in animal models, it's very clear that the best way

00:49:33.340 | to get a nervous system to atrophy,

00:49:35.220 | to lose neurons, shrink neurons or lose connections

00:49:39.200 | between neurons is to stop that animal from moving

00:49:42.080 | or to de-enrich its environment,

00:49:44.600 | deprive it of some sensory input or multiple sensory inputs.

00:49:47.480 | And the best way to enhance the size of neurons,

00:49:50.920 | the number of connections between neurons,

00:49:52.120 | and maybe even the number of neurons

00:49:53.400 | is to enrich its environment and get it moving

00:49:55.240 | while enriching that environment.

00:49:56.840 | - You know, Andrew, I think it's very difficult for me

00:49:59.200 | to say that the same is not true in humans.

00:50:00.880 | And so the first time this became clear to me was in 2014.

00:50:05.000 | I had an analyst, Dan Pelichar, and I said,

00:50:08.460 | "Dan, I'm gonna give you a project

00:50:10.340 | "that is vexing me to no end, which is,

00:50:13.180 | "I want you to look at all of the literature that we have,

00:50:17.580 | "both mechanistic and clinical trial data

00:50:21.180 | "that talks about Alzheimer's prevention.

00:50:24.460 | "And I wanna know every single type of input,

00:50:27.940 | "and I wanna have a clear sense of via what mechanism

00:50:31.380 | "does it offer, what mode of protection?"

00:50:33.860 | And it took Dan, and this was obviously,

00:50:35.980 | we iterated a lot on this together,

00:50:38.380 | and he came back with kind of an amazing presentation

00:50:42.940 | that took, I don't know, nine months to a year of work.

00:50:46.900 | And what amazed me was when he came back to it,

00:50:49.540 | he said, "The single greatest efficacy

00:50:51.800 | "we can point to is exercise."

00:50:53.940 | And I was like, "Dan, that's gotta be nonsense, dude.

00:50:56.460 | "There's no way exercise is the single best thing

00:50:59.220 | "you can do for the brain.

00:51:00.240 | "There has to be some drug you've missed.

00:51:02.400 | "There has to be some other thing that you've missed."

00:51:06.380 | And he's like, "No, this is hands down the best thing,

00:51:09.920 | "'cause it's not just what it's doing to BDNF,

00:51:12.580 | "it's not just what it's doing to vascular endothelium,

00:51:14.980 | "it's not just what it's doing to glucose disposal

00:51:16.640 | "and insulin signaling, all these things.

00:51:18.120 | "It's just touching every aspect of the brain."

00:51:22.240 | And I was very skeptical for about six months,

00:51:24.500 | kind of really pushed on him, and I was like,

00:51:26.800 | "I think you're missing something, Dan,

00:51:28.060 | "I think you're missing something."

00:51:29.320 | And then finally in the end, looped in Richard Isaacson,

00:51:31.480 | who's a neurologist that we work with really closely

00:51:33.360 | on Alzheimer's prevention, and ultimately it turned

00:51:36.100 | into a paper that we wrote, basically, about this topic,

00:51:40.120 | and a few others, 'cause again, I thought,

00:51:42.380 | "Oh, are you sure it's not EPA and DHA?

00:51:44.520 | "That's gotta have a bigger impact."

00:51:46.000 | And again, there are a lot of things that I think do matter,

00:51:49.020 | and there's a whole host of things that we do

00:51:50.780 | for Alzheimer's prevention,

00:51:52.480 | but I think you're absolutely right.

00:51:53.980 | There's not one thing that I'll tell patients

00:51:55.980 | is more important than exercising.

00:51:58.240 | And by the way, it's not the sort of pathetic

00:52:01.920 | recommendations that are made.

00:52:03.400 | You have to exercise a lot more

00:52:06.200 | if you wanna get this maximum benefit.

00:52:07.720 | You will get, the maximum benefit comes

00:52:10.400 | going from nothing to something.

00:52:12.120 | So if you go from being completely sedentary

00:52:14.800 | to doing 15 met hours per week,

00:52:18.000 | you'll get probably a 50% reduction in risk.

00:52:22.440 | So a met hour, a met, just for people who don't know,

00:52:25.160 | is a metabolic equivalent.

00:52:26.560 | So we're exerting about 1.3 mets sitting here talking.

00:52:29.920 | If we were sitting here being quiet,

00:52:31.180 | it would be about one met.

00:52:33.080 | You know, walking really briskly would be about five mets.

00:52:36.840 | So 15 met hours per week would be three

00:52:40.720 | one-hour really brisk walks.

00:52:42.520 | That's not a lot of work.

00:52:44.440 | But just going from doing nothing to doing that

00:52:47.600 | would give you 50% of the benefit

00:52:50.320 | that you would get from going all the way.

00:52:53.040 | Now again, I think, I'm personally a little skeptical

00:52:56.920 | of how much that's, I think it's probably

00:52:59.380 | a bit less than that.

00:53:00.220 | I think there's more upside than people appreciate.

00:53:02.720 | But the studies I don't think can truly capture that.

00:53:05.160 | But look, you know, there's no reason

00:53:09.260 | to not be exercising more than that

00:53:11.160 | and capture more benefit, even though the rate

00:53:13.760 | at which you accrue it is less.

00:53:15.600 | And it also speaks to the healthspan side of this,

00:53:17.760 | which is not necessarily captured in those data.

00:53:19.840 | The healthspan gets back to the functional piece

00:53:21.600 | we opened with, which is what do you want to be doing

00:53:23.880 | in your marginal decade?

00:53:24.920 | Do you want to be able to pick up a great-grandkid

00:53:26.840 | if they come running at you?

00:53:28.160 | Do you want to be able to get up off the floor?

00:53:29.880 | Do you want to be able to play on the floor with a kid

00:53:31.520 | and then get up on your own?

00:53:33.780 | - Yeah, and I think most people are thinking

00:53:35.200 | final years of life, they're trying to think,

00:53:37.480 | how can they take themselves to the bathroom?

00:53:40.080 | They're thinking how can they sit up off the toilet?

00:53:43.040 | I mean, you've got really basic,

00:53:44.880 | vegetative-type functions, right, at some level.

00:53:48.760 | I love this, again, this idea of marginal decade

00:53:51.280 | and using that as a way to backcast

00:53:53.680 | to actual methods and behaviors and protocols

00:53:58.680 | that one should be doing on a daily basis.

00:54:01.200 | I'll use ANIC data, as it's now called,

00:54:05.160 | to cite just, I know, three Nobel Prize winners,

00:54:08.280 | which doesn't mean anything

00:54:09.520 | except that they did beautiful work,

00:54:10.800 | but the point is that they're all in their 90s,

00:54:12.880 | so I'll name them 'cause I'm complimenting them

00:54:15.800 | for what they've done, not just their work,

00:54:17.640 | but what I'm about to describe.

00:54:18.620 | So Eric Kandel at Columbia.

00:54:21.300 | Nobel Prize-winning for work on memory.

00:54:23.380 | Torrance and Wiesel, who work on neuroplasticity,

00:54:25.380 | and then Richard Axel, who's also at Columbia,

00:54:28.620 | Nobel Prize-winning work for molecular biology

00:54:30.420 | of smell and molecular biology generally.

00:54:33.420 | All three of them still alive.

00:54:35.780 | Richard's younger compared to the other two.

00:54:38.140 | All three of them either swim, jog, or play tennis,

00:54:41.500 | or racquetball, I think is Richard's thing,

00:54:43.780 | multiple times per week.

00:54:45.140 | Eric was, they're all cognitively still extremely sharp,

00:54:48.860 | still interested in the arts, doing science,

00:54:50.860 | curious about science, running laboratories,

00:54:52.740 | writing books, going on podcasts.

00:54:54.240 | I mean, it's incredible.

00:54:55.420 | Again, that's anecdotal, but I was kind of surprised

00:54:58.860 | to learn that colleagues that were so intellectually strong

00:55:01.940 | were also so obsessed with exercise.

00:55:03.980 | I mean, they really are obsessed

00:55:05.500 | with their exercise routine,

00:55:06.500 | and early on linked that to their,

00:55:09.960 | some of their intellectual vigor over time.

00:55:12.780 | I want to just also use it as a jumping off point

00:55:14.700 | to ask about one kind of niche thing, but it comes up.

00:55:17.980 | I don't think I'm going to out which one of those

00:55:19.380 | told me this, but one of those three individuals

00:55:21.980 | choose an excessive amount of Nicorette.

00:55:24.860 | Used to be a smoker and I asked him why.

00:55:27.340 | And he said, because in his estimation,

00:55:31.060 | it's protective against Parkinson's and Alzheimer's,

00:55:33.500 | or at least the nicotinic acetylcholine augmentation

00:55:38.500 | of nicotine, because nicotine is an acetylcholine receptor,

00:55:41.280 | obviously, is known to create a state of focus

00:55:45.440 | and neural enhancement.

00:55:47.060 | What are your thoughts about not smoking?

00:55:49.720 | Let's just, I want to be really clear.

00:55:51.060 | People don't smoke nicotine, vape nicotine,

00:55:53.860 | it's going to shorten your life.

00:55:54.680 | Just terrible idea, addictive, et cetera, in my opinion.

00:55:57.840 | But what are your thoughts about augmenting acetylcholine

00:56:02.540 | through the use of nicotine in order to keep the brain

00:56:04.780 | healthy and focused?

00:56:06.080 | Again, this is one Nobel Prize winner,

00:56:07.780 | so it's truly N of one, but he's so convinced

00:56:10.900 | that this matches up with the mechanistic data

00:56:12.900 | on acetylcholine and cognition

00:56:14.380 | that I'd love to get your thoughts on it.

00:56:16.220 | - So I can't speak to the AD prevention component of it.

00:56:19.300 | I'd have to run that by a couple of my colleagues

00:56:21.940 | who I collaborate with on that.

00:56:24.240 | But I can definitely speak to the cognitive enhancement

00:56:27.420 | piece of it, and I actually did an AMA on this

00:56:30.380 | probably a year ago, where I went into all of the gory

00:56:33.620 | details of it and talked about my own use of nicotine,

00:56:37.100 | which I'll cycle on and off.

00:56:38.680 | I've been doing it for the last 10 years.

00:56:40.380 | - What form do you take it in?

00:56:41.940 | - I used to use the gum.

00:56:43.300 | I don't like the gum anymore,

00:56:44.320 | so now I like these little lozenges that,

00:56:48.140 | and I'll tell you a funny story about this.

00:56:51.180 | So our mutual acquaintance, David Sinclair,

00:56:55.460 | mentioned a company to me a year ago.

00:56:59.700 | He's like, "Hey, have you heard of this company?"

00:57:02.120 | And I forget the name of the company,

00:57:03.440 | but he gave me some name.

00:57:04.920 | So I go online, and it's like this company

00:57:07.100 | selling nicotine, and I'm like,

00:57:09.020 | "I wonder why he's asking me to do this."

00:57:10.460 | Well, I'll just order a bunch, and then we'll figure out why

00:57:13.820 | because we were, you know, there was some reason

00:57:15.840 | we were doing this potentially through investment.

00:57:19.220 | So I get up, literally ordered a lifetime supply

00:57:21.780 | of this stuff, and it's pretty good.

00:57:23.600 | It's actually, it's a really nice little patch,

00:57:25.140 | 'cause the thing I didn't like about the gum

00:57:26.600 | was I hated just the taste of it.

00:57:29.100 | So then the next week, I'm talking to David,

00:57:32.820 | and I'm like, "By the way, I ordered all that

00:57:34.040 | "nicotine stuff you told me about."

00:57:35.400 | He's like, "What?"

00:57:36.880 | And he goes, "Oh, oh, the company's name was something else.

00:57:39.860 | "It was totally unrelated."

00:57:41.700 | I was like, "Oh, God."

00:57:43.380 | So the short answer is I think this stuff

00:57:47.480 | is absolutely a concentration-enhancing substance.

00:57:52.140 | It is addictive, and people need to be wary of that.

00:57:55.040 | Now, it's not addictive to everybody.

00:57:56.440 | I personally experience no addiction to it whatsoever.

00:58:00.600 | So I could do it every day for 30 days

00:58:04.280 | and stop and experience no withdrawal.

00:58:06.420 | I could forget about it.

00:58:07.420 | It doesn't really seem to matter.

00:58:09.020 | You have to be careful with the dose, truthfully.

00:58:12.460 | I mean, remember, one cigarette is about

00:58:14.620 | one milligram of nicotine, and a lot of these lozenges

00:58:18.900 | will plow four to eight milligrams into you in one shot.

00:58:23.420 | And for someone who is naive to that like I am,

00:58:28.420 | four milligrams is a lot of nicotine in one bolus.

00:58:31.420 | So you just have to be very mindful of it.

00:58:34.420 | I got a lot of flak when I did this AMA for obvious reasons,

00:58:39.900 | but people were like, how can you, as a doctor,

00:58:42.500 | encourage people to use nicotine?

00:58:43.860 | And I was like, first of all,

00:58:44.920 | I'm not encouraging anybody to use it.

00:58:46.160 | I just wanna be able to talk about the biochemistry of it.

00:58:49.740 | And if disclosing that I use it from time to time

00:58:52.300 | is an endorsement, then I apologize for that.

00:58:54.820 | But on the list of things that you can do

00:58:58.260 | to make your brain a little more focused,

00:59:01.100 | I would consider this infinitely safer

00:59:03.300 | than what a lot of people are doing,

00:59:04.540 | which is using stimulants.

00:59:06.340 | I mean, to me, I just tell patients outright,

00:59:10.420 | we are under no circumstance prescribing stimulants.

00:59:13.540 | I mean, we're not giving anybody Adderall.

00:59:16.420 | We're not giving anybody Vyvanse or any of these things.

00:59:20.020 | Not to say they don't have an appropriate clinical use,

00:59:22.020 | but they should be prescribed into the care

00:59:24.360 | of somebody who's really monitoring the use case for it.

00:59:27.380 | And using that as a tool to enhance concentration

00:59:31.500 | and cognitive performance

00:59:32.340 | is not something we're comfortable doing.

00:59:33.780 | - Yeah, it's rampant on college campuses.

00:59:36.460 | - I can only imagine.

00:59:37.780 | - R-modafinil, modafinil,

00:59:38.980 | which are slightly different, of course.

00:59:40.940 | So non-clinical use, not prescribed for ADHD,

00:59:44.580 | but just it's rampant.

00:59:46.020 | Recreational use, study-based use.

00:59:48.380 | - But the data I've seen on modafinil

00:59:50.460 | suggests that it only really provides a nootropic benefit

00:59:53.540 | in someone who is deprived of sleep.

00:59:55.440 | Is there data that in a totally well-rested person,

00:59:59.340 | there is a nootropic benefit of modafinil?

01:00:01.420 | - I don't know.

01:00:02.260 | I had one experience with R-modafinil

01:00:04.020 | where I took half a recommended dose.

01:00:06.220 | This was prescribed by a doctor.

01:00:08.400 | I went to give a talk, this is in Hawaii,

01:00:10.820 | and four hours into the talk,

01:00:13.140 | my co-speaker came up to me and just said,

01:00:15.940 | "Well, first of all,

01:00:16.780 | you got a little bit of a spit in the corner of your mouth,

01:00:18.760 | and second of all, you haven't blinked in three minutes."

01:00:20.820 | And third, there's only two people left in the audience.

01:00:23.900 | I was so lasered in that I kind of forgot the context.

01:00:27.820 | I'm a little bit of a kind of a tunnel vision OCD type.

01:00:31.340 | Anyway, but that was all it took.

01:00:33.580 | I never took any more of it.

01:00:35.120 | It was a powerful stimulant.

01:00:37.220 | I take 300 milligrams of alpha-GPC now and again

01:00:41.340 | before some cognitive work, sometimes before workouts.

01:00:43.860 | And I do subjectively feel that it narrows my focus

01:00:47.260 | in a nice way,

01:00:49.100 | but I don't take it more than once or twice a day

01:00:51.540 | and more than once or twice a week.

01:00:53.140 | - So this is an example of where,

01:00:54.880 | you know how we're talking about exercise

01:00:56.300 | versus sort of nutrition and supplements for longevity?

01:01:00.020 | - I think there may be a whole bunch of things

01:01:01.580 | that are kind of interesting around focus,

01:01:03.620 | but nothing would compare to changing our environment.

01:01:06.200 | Like I think that if I compare my focus today

01:01:09.540 | to my focus when I was in college, there's no comparison.

01:01:12.700 | Like in college, I was truly a robot,

01:01:16.120 | but I think a large part of it was there was no distraction.

01:01:19.400 | There was no email, there was no social media,

01:01:21.900 | there was no internet.

01:01:22.860 | I mean, I was in college when Mosaic launched

01:01:25.800 | in the early '90s, and you had to walk like a mile

01:01:29.880 | to get to the computer lab on a big sun workstation

01:01:32.580 | to do anything in some computer code language.

01:01:36.380 | So when you're sitting in your room studying,

01:01:39.940 | there was no distraction.

01:01:41.300 | And I think that's a far greater component

01:01:43.720 | of what it means to be focused

01:01:45.500 | than the challenges we have today.

01:01:46.600 | So my thoughts on this would be,

01:01:49.400 | if we really wanted to return to a state of focus,

01:01:52.140 | we're gonna have to individually do something

01:01:54.560 | about our environment.

01:01:56.200 | And I don't know what the answer is.

01:01:58.620 | I've tried every little trick I can think of,

01:02:00.960 | like closing my browsers when I'm writing and stuff,

01:02:03.600 | but I'm just not strong enough willed.

01:02:05.720 | Like I'll pick up my phone every 20 minutes

01:02:08.040 | to look and see if I miss the text message

01:02:09.800 | or something stupid.

01:02:10.880 | - That's pretty infrequent.

01:02:12.100 | I did a episode on habits and looking at the data.

01:02:15.600 | It seems that people are getting interrupted

01:02:19.040 | or interrupting themselves about once every three minutes

01:02:22.580 | in the typical workplace, now that typical has changed

01:02:25.240 | with a lot more people working at home.

01:02:27.100 | - I do put my phone away when I try and work,

01:02:29.040 | that nothing focuses me like a deadline,

01:02:31.680 | a little bit of a fear-based urgency.

01:02:34.160 | That's it, grant deadlines, drop deadlines, as I call them,

01:02:36.840 | or podcasts we're gonna record today,

01:02:38.720 | that nothing works quite like it, but such is life.

01:02:42.940 | Well, thanks for that offshoot about nicotine.

01:02:47.000 | Again, you're not recommending it.

01:02:49.440 | I'm not recommending it,

01:02:50.400 | but it's clear that augmenting the acetylcholine system,

01:02:54.320 | which is what nicotine does in its various forms

01:02:57.100 | and some related type pharmacology,

01:02:59.760 | does enhance focus and pretty potently.

01:03:01.800 | So I think it's gonna be an interesting area

01:03:03.260 | for real clinical trials and things of that sort.

01:03:06.320 | Love to chat about hormone therapies and hormones generally.

01:03:11.920 | When Robert Sapolsky came on the podcast,

01:03:13.980 | we talked a little bit about menopause

01:03:16.020 | and the data around menopause.

01:03:17.040 | He's very interested in these findings that,

01:03:20.600 | I think I'm gonna get this right,

01:03:22.140 | that whether or not women benefit from estrogen therapy

01:03:26.920 | to offset menopause really depends

01:03:28.620 | on when that therapy is initiated.

01:03:30.900 | I don't know if you're aware of those data,

01:03:32.240 | but he claimed that if they begin estrogen therapy

01:03:36.680 | in the middle to tail end of menopause,

01:03:40.040 | the outcomes can be quite bad,

01:03:43.040 | whereas if they initiate those estrogen therapies

01:03:45.740 | as they enter menopause or even before menopause,

01:03:48.600 | then the outcomes can be quite good.

01:03:50.600 | I don't know what percentage of the patients you treat

01:03:52.580 | are male versus female

01:03:53.780 | and what ages those patients are, of course,

01:03:55.860 | but what are your thoughts about estrogen therapy

01:03:58.560 | for women, menopause, and hormone therapies

01:04:01.600 | generally for women, maybe even testosterone therapy.

01:04:03.520 | You hear about that these days.

01:04:04.560 | And then we'll talk about men.

01:04:05.860 | - So our practice is probably 70, 30 male, female.

01:04:10.760 | So we have lots of women,

01:04:12.480 | and this is a very important topic.

01:04:15.160 | It's also probably, let me think.

01:04:19.280 | I just want to make sure I'm not being hyperbolic

01:04:20.920 | when I say this.

01:04:21.820 | Yeah, I don't think I am.

01:04:24.060 | It's hands down the biggest screw up

01:04:26.280 | of the entire medical field in the last 25 years.

01:04:29.380 | Now again, it's possible in the next hour,

01:04:32.200 | I'll think of, there's a bigger screw up.

01:04:34.840 | - Another giant screw up.

01:04:35.680 | - Yeah, but I don't think I will.

01:04:37.360 | I'm pretty confident that I won't be able to think

01:04:41.240 | of a bigger act of incompetence

01:04:48.000 | than what happened with the Women's Health Initiative

01:04:50.560 | in the late '90s and early 2000s,

01:04:52.880 | which is effectively the study

01:04:55.800 | that turned the entire medical field

01:04:58.240 | off hormone replacement therapy for women.

01:05:00.880 | So it's important, I think,

01:05:02.300 | to explain what the study looked at.

01:05:04.360 | So this was a study that was conducted in response

01:05:08.080 | to the widely held belief in the '70s and '80s

01:05:13.080 | that women should be placed on hormones

01:05:17.000 | as they're going through menopause, right?

01:05:19.560 | Menopause is, I guess maybe I'll even take a step back.

01:05:22.480 | I don't know how much your audience is familiar

01:05:23.840 | with how estrogen progesterone work.

01:05:25.360 | Is it worth going into that stuff?

01:05:26.840 | - Yeah, probably worth mentioning

01:05:27.680 | a bit of the top contour.

01:05:29.080 | Some of them might be familiar with it.

01:05:30.400 | We've done episodes on estrogen, testosterone,

01:05:32.120 | but frankly, as I think back to those,

01:05:34.080 | we didn't really go into the biology

01:05:35.360 | of estrogen, testosterone, you know.

01:05:37.180 | - Yeah, so, I mean, actually an interesting aside

01:05:40.360 | that I always tell my female patients

01:05:41.800 | who get a kick out of this.

01:05:43.200 | When you look at a woman's labs,

01:05:45.800 | you'll see her estrogen, her progesterone,

01:05:48.240 | her FSH, her LH, her testosterone,

01:05:50.900 | her sex hormone binding globulin, all these things.

01:05:52.840 | But based on the units they're reported in,

01:05:55.320 | it's a very distorting picture

01:05:57.440 | of what the most common androgen is in her body.

01:06:00.920 | If you actually convert them to the same units,

01:06:02.960 | she has much more testosterone in her body than estrogen.

01:06:05.760 | - Interesting. - Yeah.

01:06:08.840 | - I did not know that.

01:06:10.000 | Then again, I've never been a woman

01:06:11.480 | getting my hormone profile done.

01:06:13.080 | - Yeah, so even though a woman's testosterone

01:06:14.900 | is much less than a man's level,

01:06:18.680 | it's still more than she has estrogen in her body.

01:06:21.800 | So phenotypically, right,

01:06:23.280 | estrogen is the hormone that's dominating.

01:06:25.600 | She has much higher estrogen than a man

01:06:28.320 | and much lower testosterone than a man,

01:06:30.280 | but in absolute amounts,

01:06:31.800 | she has more testosterone than estrogen.

01:06:33.400 | Just worth pointing that out.

01:06:34.440 | - Incredible.

01:06:35.280 | - So, you know, what's happening to a woman

01:06:38.520 | from the age she starts menstruating

01:06:40.080 | until she goes through menopause,

01:06:41.840 | outside of pregnancy and birth control and stuff like that,

01:06:44.220 | is she has this cycle, you know,

01:06:45.760 | roughly every 28 days, but it can vary,

01:06:48.000 | where at the beginning of her period,

01:06:50.160 | we call that day zero,

01:06:51.600 | her estrogen and progesterone are very low.

01:06:55.040 | You can't measure them.

01:06:56.460 | And then what happens is the estrogen level starts to rise

01:07:00.960 | and it rises in response to a hormone

01:07:04.240 | called follicle stimulating hormone, FSH,

01:07:07.840 | that is getting her ready to ovulate.

01:07:09.560 | And she ovulates at about the midpoint of her cycle.

01:07:11.680 | So if we're just gonna make the math easy,

01:07:13.440 | on day 14, she's going to release a follicle

01:07:16.080 | from one of her ovaries.

01:07:17.880 | And the estrogen level is sort of rising, rising, rising.

01:07:20.960 | We love to measure hormones on day five,

01:07:24.180 | because I wanna have a standardized way

01:07:26.300 | in which I measure her hormones.

01:07:27.940 | So our women know if we're in the business

01:07:30.840 | of trying to understand her hormones,

01:07:32.120 | the day her period starts,

01:07:33.380 | even if it's just a day of spotting,

01:07:34.740 | that becomes our benchmark.

01:07:35.940 | And then day five, I wanna see every hormone on that day.

01:07:39.280 | And if everything is going well,

01:07:41.060 | they know what her FSH, LH, estradiol, and progesterone

01:07:43.860 | should be on that day.

01:07:45.380 | So the estrogen rises, starts to come down a little bit

01:07:48.220 | as she ovulates, and then the luteinizing hormone kicks on

01:07:51.580 | because it's now going to prepare her uterus

01:07:54.740 | for the lining to accommodate a pregnancy.

01:07:59.180 | So now you start to see estradiol go back,

01:08:01.460 | but now for the first time, progesterone goes up.

01:08:03.300 | So progesterone has been doing nothing for 14 days,

01:08:06.420 | and now it starts to rise.

01:08:07.700 | And actually progesterone is the hormone

01:08:09.300 | that's dominating the second half,

01:08:11.060 | which is called her luteal cycle.

01:08:13.300 | So the first 14 days is the follicular cycle,

01:08:15.600 | second is the luteal cycle.

01:08:17.540 | So once you get to about the halfway point of that,

01:08:20.060 | which is now, just to do the math, 21 days in,

01:08:23.060 | the body has figured out if she's pregnant or not.

01:08:25.380 | And again, most of the time she's not gonna be pregnant,

01:08:27.780 | so the body says, oh, I don't need this lining

01:08:29.980 | that I've been preparing, I'm going to shed it.

01:08:32.260 | So now progesterone and estrogen start crashing,

01:08:35.860 | and the lining is what is being shed,

01:08:37.580 | and that is the menses.

01:08:39.620 | By the way, it's that last seven days of that cycle

01:08:42.620 | that in a susceptible woman

01:08:44.260 | is what creates those PMS symptoms.

01:08:47.260 | So it's the, actually this is something

01:08:48.700 | that you would probably have

01:08:49.580 | a better understanding of than me.

01:08:51.340 | There is something about this in a susceptible woman

01:08:54.780 | where the enormous reduction of progesterone so quickly

01:08:59.080 | is probably impacting something in her brain.

01:09:01.860 | So I think this is a legitimate thing, right?

01:09:04.020 | I mean, it's not like, oh, she's crazy

01:09:05.960 | because she's having all these PMS symptoms, no.

01:09:09.320 | We know that that's the case

01:09:10.440 | because if you put women on progesterone

01:09:12.240 | for those seven days, those symptoms go away.

01:09:14.680 | So if you can stabilize their progesterone

01:09:16.640 | during the last half of their luteal phase,

01:09:19.640 | and sometimes we would just do it

01:09:20.680 | for the entire luteal phase,

01:09:21.840 | just put them on a low dose of progesterone,

01:09:24.100 | all PMS symptoms vanish.

01:09:25.460 | - Very interesting.

01:09:26.300 | I'll have to look up where the progesterone receptors

01:09:28.700 | are located in the brain.

01:09:29.540 | The Allen Brain Institute now has beautiful data

01:09:33.240 | of in situ hyperization,

01:09:34.520 | which for folks that don't understand is looking at RNA

01:09:37.600 | and sort of where genes and proteins ought to be expressed

01:09:40.680 | in the human brain by using actual human brain tissue

01:09:43.040 | sections as opposed to just mice.

01:09:44.320 | So I'll take a look.

01:09:45.140 | I think some insight into what that

01:09:48.160 | progesterone emotionality link might be

01:09:50.320 | and where it might exist neural circuit wise.

01:09:52.920 | - So then when the estrogen and progesterone

01:09:55.480 | reach their nadir again, that starts the cycle.

01:09:58.500 | So that cycle is happening over and over and over again.

01:10:02.100 | - Okay, so it became well known in the '50s

01:10:06.620 | that okay, a woman's gonna stop menstruating at some point.

01:10:09.460 | Her estrogen goes down.

01:10:10.540 | Why don't we just give her estrogen?

01:10:12.540 | 'Cause that's clearly gonna help

01:10:13.940 | with some of the symptoms of menopause.

01:10:15.460 | So what do women experience when they go through menopause?

01:10:18.100 | The first symptoms are what are called vasomotor symptoms.

01:10:20.460 | So this is usually in the form of night sweats, hot flashes.

01:10:25.460 | So, and depending on the woman,

01:10:26.980 | this can be really significant, right?

01:10:28.680 | These are women who can have a hard time sleeping.

01:10:31.740 | They can be having hot flashes during the middle of the day.

01:10:33.540 | They can wake up soaked in a pool of sweat.

01:10:35.980 | Those tend to pass after a couple of years

01:10:40.660 | and then they get into sort of the more

01:10:43.120 | long-term complications of menopause.

01:10:45.300 | So what we call vaginal atrophy, vaginal dryness,

01:10:48.680 | and then the stuff that we talked about a while ago,

01:10:50.780 | which is the osteopenia, osteoporosis.

01:10:54.140 | A lot of women will complain of brain fog.

01:10:57.900 | So, I mean, clearly this was an issue

01:11:01.780 | and it was recognized 70 years ago.

01:11:04.720 | Why don't we give women estrogen back

01:11:06.780 | to replace that hormone?

01:11:08.840 | And so that went on for a couple of decades,

01:11:12.220 | maybe less, maybe a decade, and then it was realized,

01:11:14.380 | wait a minute, we were driving up the risk of uterine cancer.

01:11:17.920 | And the reason for that is if you just give estrogen

01:11:23.420 | with no progesterone to antagonize it,

01:11:26.700 | you will thicken the endometrium endlessly

01:11:29.980 | and you will increase the risk of hyperplasia.

01:11:33.220 | Well, you'll definitely undergo hyperplasia

01:11:35.140 | and then ultimately dysplasia.

01:11:36.580 | Dysplasia is precancerous and ultimately we were seeing that.

01:11:39.740 | So people figured out, well, actually,

01:11:42.120 | if you want to give estrogen to a woman

01:11:44.420 | who still has her uterus,

01:11:45.460 | you have to give her progesterone as well.

01:11:47.520 | You have to be able to have a hormone

01:11:49.340 | to oppose the estrogen.

01:11:50.900 | And then that became effectively in the 19,

01:11:53.580 | call it the 1970s-ish, the standard for HRT.

01:11:57.860 | So in the early 1990s, the NIH said,

01:12:04.540 | look, we haven't really studied this.

01:12:06.820 | We have a ton of epidemiology that says

01:12:10.400 | giving women hormones seems to be doing really good things.

01:12:14.100 | They feel better, so all their symptoms go away.

01:12:17.700 | They seem to have lower risk of heart disease,

01:12:20.140 | lower risk of cardiovascular disease,

01:12:24.720 | lower risk of bone fractures.

01:12:27.460 | Everything seems to get better, lower risk of diabetes.

01:12:30.360 | But we haven't tested this

01:12:31.560 | in a randomized prospective trial, so let's do this.

01:12:34.540 | So that became the WHI.

01:12:36.500 | And it randomized, it had two parallel arms.

01:12:39.180 | So it had a group for women who did not have a uterus.

01:12:44.180 | So these are women that had undergone hysterectomy

01:12:46.140 | for some other reason.

01:12:47.060 | And then it had a group for women

01:12:48.500 | that did have their uterus.

01:12:50.060 | In the first group, there was a placebo arm,

01:12:53.220 | and then an estrogen-only arm.

01:12:55.200 | And in the other group, there was a progesterone

01:12:57.220 | plus estrogen versus a placebo.

01:12:59.620 | Everything about the way this study was done

01:13:04.460 | is a bit wonky.

01:13:05.380 | Some of it is justifiable,

01:13:06.860 | but it's important to understand.

01:13:08.820 | First, the women were all way outside of menopause.

01:13:13.380 | So none of these women were started

01:13:16.460 | when you would normally start HRT.

01:13:19.500 | And there were probably several reasons for that,

01:13:23.040 | but one of them is, and I think this is a legitimate reason,

01:13:26.860 | they wanted hard outcomes.

01:13:28.900 | They wanted to know death rates.

01:13:31.160 | And if you're doing this on women in their 50s,

01:13:33.860 | you just weren't gonna get it, right?

01:13:35.500 | You couldn't-- - You gotta wait too long.

01:13:36.760 | - Yeah, you gotta wait too long.

01:13:37.600 | And this was only gonna be like a seven to 10-year study.

01:13:40.300 | So they had to do this on women who were much older.

01:13:43.200 | They also disproportionately took much sicker women.

01:13:47.100 | I believe the prevalence, and again,

01:13:49.140 | I'm gonna get some of these numbers wrong

01:13:50.280 | and people are gonna get all phosphorylated,

01:13:51.780 | but I'm in the ballpark, right?

01:13:54.420 | Something like 30, 40% of these women were smokers.

01:13:57.260 | The prevalence of obesity, diabetes was enormous.

01:14:00.520 | So they really disproportionately picked

01:14:02.780 | the most unhealthy population they could

01:14:04.620 | that was pretty advanced in age.

01:14:06.420 | And again, I think part of that was to say,

01:14:08.240 | look, we wanna make sure that after seven years,

01:14:10.460 | we really know if there's a difference

01:14:12.200 | in these causes of death.

01:14:13.580 | The other thing is, this is kinda weird,

01:14:18.920 | although again, I understand their rationale for it,

01:14:21.360 | but this is a great example of be very careful

01:14:25.100 | when you look at a clinical trial

01:14:27.340 | that it remotely represents the patients

01:14:29.420 | you're interested in treating.

01:14:30.940 | So they also treated no patients who were symptomatic.

01:14:33.820 | The rationale being, if we include in the study

01:14:38.260 | patients who are symptomatic,

01:14:39.780 | those who are randomized to placebo will drop out.

01:14:43.100 | - Okay, it makes sense in terms of study design,

01:14:47.460 | it makes no sense if the study design

01:14:49.300 | is intended to mimic the real world.

01:14:52.160 | - That's right.

01:14:53.000 | So now let's just keep track of the three issues.

01:14:54.520 | We have a disproportionately unhealthy patient population

01:14:58.200 | who are not symptomatic, and we're starting them

01:15:01.980 | more than 10 years after menopause.

01:15:03.860 | The next thing that they did,

01:15:06.960 | which again, I understand why they did it,

01:15:09.440 | but it's now the fourth strike against this study is,

01:15:13.640 | and I've spoken with the PI of the study

01:15:16.100 | and asked this question point blank,

01:15:17.740 | I'm actually going to have her on my podcast

01:15:19.540 | at some point soon to go over this in more detail,

01:15:22.620 | is why did you use conjugated equine estrogen and MPA,

01:15:26.940 | which is a synthetic form of progesterone?

01:15:29.300 | - Horse estrogen?

01:15:31.980 | - It's horse urine, they collect horse urine,

01:15:34.340 | so they're getting--

01:15:35.660 | - Horses do urinate a lot, or at least when they urinate,

01:15:39.000 | it seems like a large volume of urine

01:15:40.580 | from what I've observed.

01:15:42.100 | - You have a lot of experience with this?

01:15:43.380 | - No, but my sister rode horses for a little while.

01:15:46.460 | My high school girlfriend had a horse,

01:15:48.320 | and that thing, I mean, the peas were legendary.

01:15:52.520 | It's a male horse.

01:15:54.860 | - Yeah. - Yeah.

01:15:56.100 | - So yeah, so the conjugated equine estrogen

01:15:58.740 | is the estrogen that's collected from female horses,

01:16:02.280 | and then it's a synthetic progesterone.

01:16:04.240 | And I said to the person, I said,

01:16:07.900 | well, why didn't you use what we use today,

01:16:10.180 | which is bioidentical estrogen and progesterone?

01:16:12.500 | Like today, when we put women on estrogen,

01:16:15.060 | we use, it's an FDA product called the Vivel Dot,

01:16:18.020 | so it's a patch that you just put on,

01:16:19.900 | and it's estradiol, but it's bioidentical estradiol,

01:16:22.500 | and we use what's called micronized progesterone,

01:16:24.380 | so bioidentical progesterone.

01:16:26.580 | And she said, well, at the time,

01:16:29.440 | we just wanted to test what was currently being used.

01:16:31.580 | I said, totally makes sense.

01:16:32.960 | But again, now you have four considerations

01:16:35.700 | that you have to keep in mind.

01:16:37.620 | Okay, so despite those four considerations,

01:16:40.260 | and I'm gonna make a case for you

01:16:41.460 | why I think the MPA created a real problem in that study,

01:16:45.860 | the synthetic progesterone.

01:16:47.900 | When the preliminary results were first made available,

01:16:52.900 | but not yet peer reviewed and not yet published,

01:16:56.740 | there was a huge fiasco, huge press announcement about it,

01:17:00.740 | suggesting that the women receiving the CEE plus MPA

01:17:07.660 | in the group with the uterus had a higher incidence

01:17:11.700 | of breast cancer.

01:17:13.180 | And that basically became the headline that never went away,

01:17:16.500 | though it turned out not to be true.

01:17:19.060 | Let's talk about the numbers.

01:17:20.580 | What was the increase in the risk of breast cancer

01:17:23.780 | in that group, which gets to my, one of my,

01:17:25.620 | if you've ever listened to me on the podcast,

01:17:27.500 | rail on something.

01:17:28.600 | - Listen, I have about 3,800 pet peeves and counting.

01:17:32.020 | My laboratory staff know these, know a good number of them,

01:17:35.440 | so you do not have to apologize

01:17:37.460 | for having many pet peeves,

01:17:38.840 | because as long as they have experience and data

01:17:41.300 | to support them, it provides a better life.

01:17:42.980 | - So one of my biggest pet peeves is,

01:17:45.540 | and my team knows this,

01:17:47.020 | 'cause sometimes they'll occasionally, they'll do this

01:17:49.340 | and I'll have to remind them.

01:17:50.620 | You never talk about a relative risk change

01:17:52.860 | without an absolute risk accommodating it, right?

01:17:55.540 | So what does that look like?

01:17:56.780 | So the relative risk increase of breast cancer

01:18:00.320 | in the estrogen plus MPA group versus the placebo

01:18:04.380 | was 25, 27%, and that became the only headline.

01:18:09.380 | HRT increases risk of breast cancer by 27%.

01:18:15.400 | Now, I don't think that's true at all today,

01:18:19.860 | but let's even look at the data.

01:18:21.280 | What was the ARR?

01:18:22.960 | What was the absolute risk increase?

01:18:25.760 | It was a difference between five cases per thousand

01:18:29.500 | and four cases per thousand.

01:18:31.980 | So the ARR was 0.1%, one case in a thousand.

01:18:36.980 | And it's true, going from four in a thousand

01:18:41.540 | to five in a thousand is a 25% increase,

01:18:45.620 | but it's a completely inappropriate context.

01:18:48.340 | - I agree, and I feel like headlines of that sort,

01:18:51.900 | which have come up recently

01:18:52.900 | around various dietary interventions,

01:18:54.660 | we won't go there, at least not for the time being,

01:18:57.900 | are nothing short of criminal

01:18:59.380 | because they really distort people's thinking,

01:19:02.980 | but also they steer the course of science and medicine

01:19:06.180 | for, as you pointed out, for decades, if not longer,

01:19:09.740 | and they can really take us off our health track

01:19:12.140 | in serious ways.

01:19:13.700 | - So I'll bring this meandering to a close,

01:19:15.740 | which is to say, even though I could spend the next hour

01:19:18.460 | talking about all of the ways

01:19:19.940 | in which this study was flawed

01:19:21.800 | and all of the very unethical things

01:19:23.980 | that were done by a number of the investigators

01:19:26.100 | who went out of their way to mask the truth of this study

01:19:30.260 | from the world, I'll tell a woman today,

01:19:33.380 | we're gonna start you on this

01:19:35.980 | when you're going through menopause,

01:19:37.420 | we're using bioidentical hormones,

01:19:41.500 | and if your upper bound risk of breast cancer

01:19:45.900 | is one case in a thousand,

01:19:48.580 | you should at least weigh that

01:19:49.900 | against all of the other benefits, which I'll talk about.

01:19:51.960 | Now, there's something else I wanna say

01:19:53.420 | because a moment ago I alluded to the fact

01:19:54.720 | that I think the MPA might have been

01:19:56.340 | the biggest issue in that study.

01:19:57.940 | So there were two findings in that study that were negative.

01:20:01.420 | One was the small increase in the risk of heart disease

01:20:04.920 | and the small increase in the risk of breast cancer.

01:20:07.740 | But consider the other group.

01:20:09.860 | We forgot about the group that didn't have a uterus.

01:20:12.600 | 'Cause remember, those women got estrogen only

01:20:16.240 | versus placebo.

01:20:18.000 | What was the difference in breast cancer there?

01:20:20.780 | Well, this is interesting

01:20:21.620 | 'cause it didn't reach statistical significance,

01:20:24.100 | but its P value was 0.06 or 0.07.

01:20:27.040 | So it came very close, but it was in the opposite direction.

01:20:30.260 | It was a 24% risk reduction, about one in a thousand as well.

01:20:35.880 | So when you had estrogen plus MPA,

01:20:39.560 | you had a barely statistically significant,

01:20:42.360 | the P value was 0.05.

01:20:43.860 | So it just hit statistical significance,

01:20:45.860 | one in a thousand cases for breast cancer.

01:20:49.020 | And then you had one in a thousand cases,

01:20:51.720 | but P value of 0.07 for reduction of risk of breast cancer,

01:20:56.440 | which to me suggests that the MPA,

01:20:58.280 | the synthetic progesterone,

01:20:59.880 | was playing more of a role than anything else.

01:21:02.760 | The second thing I point out is oral estrogen,

01:21:06.120 | which we no longer use, does increase coagulability.

01:21:10.520 | It does increase the ability of the blood

01:21:12.840 | to clot a little bit.

01:21:14.120 | And when we look at the more recent data on HRT

01:21:17.800 | using topical estrogen or patches of estrogen,

01:21:21.960 | we don't see that at all.

01:21:22.880 | In fact, we see the opposite now.

01:21:24.020 | So now we see the risk of heart disease

01:21:25.320 | going down in women with estradiol.

01:21:27.720 | - And some women will be arriving to those treatments

01:21:30.040 | with mutations and things like Factor V Leiden

01:21:32.560 | and other clotting factors.

01:21:34.360 | Is it appropriate to say that everyone,

01:21:37.480 | both male and female, should know whether or not

01:21:39.360 | they have mutant forms of Factor V Leiden?

01:21:41.920 | - You know, we don't typically test people for Factor V.

01:21:44.360 | My wife actually has it, but we didn't learn it

01:21:46.060 | until she had Help Syndrome,

01:21:47.740 | giving birth to our first daughter.

01:21:50.320 | But we kind of look for more family history reason

01:21:54.260 | to be testing things like that.

01:21:56.040 | We take a pretty detailed family history,

01:21:57.400 | so we'll kind of look for clotting issues there.

01:21:59.880 | - What about, so your reflex nowadays is to put women

01:22:04.880 | on these topical estrogen therapies?

01:22:08.800 | - Well, it's to basically have the discussion, right?

01:22:10.720 | So here's where we still struggle, right?

01:22:12.720 | Is, you know, we, if it were up to me, I'd prefer

01:22:16.500 | for a woman's HRT to be provided by her GYN.

01:22:20.820 | Because we want to be able to work in partnership

01:22:22.660 | with the GYN, who we would like to see

01:22:24.580 | an endometrial ultrasound done every year.

01:22:27.500 | That's, you know, some would argue that's overkill,

01:22:29.380 | but you know, we think she'd be shoving a pap smear

01:22:31.300 | every year as well.

01:22:32.460 | So if we're looking at the cervix,

01:22:34.020 | we want to look at the endometrium,

01:22:35.100 | we want to make sure the lining isn't too thick.

01:22:37.100 | The other thing I should say, Andrew, is today,

01:22:39.360 | we now realize that not all women can tolerate,

01:22:43.060 | pardon me, progesterone.

01:22:44.780 | So you have to be careful.

01:22:45.800 | So assuming, again, a woman still has her uterus,

01:22:48.580 | the estrogen solves most of the problems,

01:22:51.160 | but then you have to decide,

01:22:52.320 | can she tolerate the progesterone?

01:22:54.340 | And it needs to be, if given systemically,

01:22:56.340 | like 100 to 200 milligrams.

01:22:58.500 | And for some women, that is a life-saving intervention.

01:23:01.180 | I mean, they start sleeping better,

01:23:02.540 | their hair gets thicker, they feel better.

01:23:04.700 | But for some women, it literally drives them crazy.

01:23:07.500 | It's probably the reciprocal of what we were seeing

01:23:09.980 | in the case of women with PMS.

01:23:12.060 | So in those situations, we say, great,

01:23:15.260 | we're done with oral progesterone.

01:23:16.760 | We just use a progesterone-coated IUD.

01:23:19.320 | So then you get the local progesterone in the uterus

01:23:22.760 | for protection in the systemic estrogen.

01:23:26.000 | - Fascinating.

01:23:26.880 | What about oral contraception in women?

01:23:30.700 | So the use of estrogen chronically through people's

01:23:36.380 | college years or 20s, 30s, maybe even teens, who knows?

01:23:39.720 | What's known about the long-term effects, if any?

01:23:44.380 | - I gotta be honest with you.

01:23:45.220 | I don't think I know enough to comment on it.

01:23:47.100 | It's not something that really impacts

01:23:48.820 | my patient population.

01:23:50.260 | At least in what I see, more women are using IUDs

01:23:55.300 | for contraception than OCs.

01:23:58.340 | I mean, we use OCs sometimes in women who are premenopausal

01:24:03.540 | for symptomatic control, but we'll typically use

01:24:07.160 | like a low, low estrogen, so a very low synthetic estrogen,

01:24:11.380 | which I don't like using these very much,

01:24:13.140 | but if it's the only thing that we can get

01:24:14.100 | to control certain symptoms,

01:24:15.440 | and we'll use it like half per cycle.

01:24:17.660 | But it's typically not something we're that experienced with.

01:24:23.300 | - What about testosterone?

01:24:24.660 | Because you mentioned that nanogram per mil,

01:24:28.660 | when you set everything to the same,

01:24:33.300 | I guess it's nanogram per deciliter,

01:24:34.860 | is it would be to kind of normalize everything?

01:24:37.060 | - First picogram per mole, yeah.

01:24:37.980 | - Right, yeah, and so what Peter was pointing out before

01:24:41.380 | is that you look at your charts,

01:24:42.640 | and they're all in these different measures,

01:24:43.980 | and so when you normalized,

01:24:45.180 | testosterone is actually higher than estrogen in women.

01:24:47.660 | That's a surprise to me.

01:24:48.860 | Do you prescribe testosterone therapy to women ever?

01:24:53.500 | - We do sometimes, but I do it with much more caution

01:24:56.700 | because I don't have the data, right?

01:24:58.600 | So where I'll, what we'll say is,

01:25:02.300 | look, I mean, we're now really outside of an area

01:25:04.780 | where I can point to a lot of data.

01:25:06.620 | When it comes to estrogen and progesterone,

01:25:09.360 | I'll happily go toe-to-toe with anybody

01:25:11.860 | who wants to make the case that it's dangerous.

01:25:14.180 | Similarly, when it comes to using testosterone in men,

01:25:16.760 | I'll spend all day, and I can go through that literature

01:25:20.140 | until the other person cries

01:25:21.860 | and wants to just call uncle, right?

01:25:24.300 | - When it comes to--

01:25:25.140 | - And then you prescribe them testosterone.

01:25:26.020 | - When it comes to estrogen in,

01:25:27.660 | oh, testosterone in women, don't have that data.

01:25:30.500 | And I'd love to see that trial done.

01:25:32.820 | So what's the sweet spot?

01:25:35.600 | How do we reconcile that?

01:25:37.140 | So it's not something I consider standard.

01:25:39.860 | And basically, if a woman is,

01:25:41.740 | if her testosterone, first of all, is staggeringly low,

01:25:44.980 | and again, even though her testosterone's low

01:25:46.700 | compared to a male, we still have a range.

01:25:48.780 | So if it's really at the bottom of that range,

01:25:50.740 | she's really having difficulty putting on muscle mass

01:25:53.120 | and really complaining of low libido,

01:25:55.540 | I think in that situation,

01:25:56.940 | we'll go ahead and use topical testosterone.

01:26:00.240 | And replace her to a level

01:26:03.360 | that is still physiologically normal.

01:26:05.860 | - Yeah, that's key, because when people hear HRT,

01:26:08.100 | they think about super physiological,

01:26:10.360 | seems to be the term.

01:26:11.260 | - Yeah, like I've never seen a single symptom

01:26:14.120 | in a single woman that I've put testosterone on

01:26:16.200 | in terms of acne, body hair, things like that.

01:26:18.500 | Those are real symptoms that you have to be aware of.

01:26:20.940 | But clitoral enlargement and things like that,

01:26:24.740 | that doesn't happen under physiologic normal conditions.

01:26:29.460 | - I'd love to talk a little bit

01:26:30.360 | about hormone replacement therapy in men.

01:26:33.040 | When one looks on social media and the internet,

01:26:36.260 | there seems to be a younger and younger cohort of guys,

01:26:40.280 | people in their teens and 20s, showing up to the table,

01:26:43.140 | thinking that injecting testosterone,

01:26:45.860 | cipunate, or taking Anavar, or whatever it is,

01:26:48.100 | is going to be the right idea.

01:26:49.580 | They mainly seem to be focused on cosmetic effects.

01:26:52.720 | I'm not a physician, so I can't say whether or not

01:26:55.120 | they were actually hypogonadal, et cetera,

01:26:56.860 | but it seems to me, again, correct me if I'm wrong,

01:27:00.000 | but it seems to me that similar to the Atiyah's rule,

01:27:03.600 | as it relates to longevity,

01:27:05.300 | that we could come up with a broad contour rule

01:27:08.460 | in which if a male of any age is not trying

01:27:12.500 | to get decent sleep, exercise appropriately,

01:27:16.620 | appropriate nutrition, minding their social connections,

01:27:18.940 | et cetera, et cetera,

01:27:20.100 | the idea of going straight to testosterone

01:27:22.980 | seems like a bad idea.

01:27:24.420 | That said, just like with depression and antidepressants,

01:27:28.180 | there is a kind of a cliff

01:27:29.860 | after which low enough testosterone

01:27:34.020 | or low enough serotonin prevents people

01:27:35.960 | from sleeping, exercise, social connection, et cetera.

01:27:38.420 | So I do want to acknowledge that.

01:27:39.940 | But with that in mind,

01:27:41.700 | how do you think about and perhaps occasionally prescribe

01:27:45.620 | and direct your patients

01:27:47.740 | in terms of hormone replacement therapy in men,

01:27:50.420 | person in their 30s, person in their 40s,

01:27:52.060 | who's doing almost all the other things correctly?

01:27:55.680 | What sorts of levels do you think are meaningful?

01:27:58.980 | Because the range is tremendous in terms of blood tests,

01:28:01.420 | 300 nanograms per deciliter,

01:28:03.060 | I think on the low end now in the US,

01:28:04.420 | all the way up to 900 or 1200.

01:28:05.980 | That's an enormous range.

01:28:07.840 | What are some of the other hormones you like to look at?

01:28:09.740 | Estrogen, DHT, and so on.

01:28:11.580 | - So, a lot to unpack there.

01:28:15.740 | So let's start with the ranges, right?

01:28:18.420 | So the ranges you gave are for total testosterone, of course.

01:28:23.420 | And we don't spend a lot of time looking at that.

01:28:26.920 | I used to spend more time looking at total and free

01:28:31.840 | when I used more tricks to modulate it.

01:28:34.980 | So I'm actually far more simple

01:28:37.260 | in my manipulation of testosterone today

01:28:39.080 | than I was six or seven years ago.

01:28:41.180 | Six or seven years ago, I mean,

01:28:43.580 | we would use a micro dose of Anavar to lower SHBG

01:28:48.580 | in a person who had normal testosterone,

01:28:51.020 | but low free testosterone.

01:28:52.460 | - What was a low dose of Anavar in that context?

01:28:55.620 | - 10 milligrams, subling, two to three times a week.

01:29:00.100 | - Anavar basically being DHT.

01:29:02.100 | Oxandrolone, oxantrol, and again,

01:29:05.700 | we're not recommending this.

01:29:06.660 | It's actually, if you're playing a competitive sport,

01:29:08.380 | can get you banned from that sport.

01:29:09.940 | It can also get you banned from having children

01:29:13.100 | if you do it incorrectly.

01:29:14.060 | - Yeah, so a micro dose of this has to be small enough

01:29:18.180 | that it doesn't impair your body's ability

01:29:20.260 | to make testosterone, but Anavar has such a high affinity

01:29:24.380 | for SHBG that it basically distracts your SHBG

01:29:28.280 | from binding your testosterone.

01:29:30.100 | - Freeing up testosterone.

01:29:31.100 | - That's exactly right.

01:29:31.940 | So the goal was how do I just give you more free testosterone?

01:29:34.620 | So if a patient shows up and they've got

01:29:36.500 | a total testosterone of 900 nanograms per deciliter,

01:29:40.000 | which would place them at,

01:29:41.580 | depending on the scale you look at,

01:29:42.820 | that would place you at about the 70th percentile,

01:29:46.980 | but your free testosterone is, you know,

01:29:50.260 | eight nanograms per deciliter.

01:29:52.420 | So that's pretty bad.

01:29:53.260 | That means you're less than 1% free.

01:29:55.980 | A guy should be about 2% free T.

01:29:58.960 | So that dude should be closer

01:30:00.840 | to 16 to 18 nanograms per deciliter.

01:30:04.600 | So in that situation that I just gave you,

01:30:06.540 | his SHBG is really high.

01:30:08.340 | His SHBG is probably in the 80 to 90 range.

01:30:11.860 | - That's very high.

01:30:12.700 | 'Cause I think the upper range is somewhere around 55, 56.

01:30:15.220 | - Exactly.

01:30:16.540 | So we would first back stall for what's driving his SHBG.

01:30:21.020 | So there's basically three hormones.

01:30:22.700 | So genetics plays a huge role in this.

01:30:24.340 | There's no question that just out of the box,

01:30:27.340 | people have a different like set point for SHBG.

01:30:30.420 | Mine is incredibly low.

01:30:31.660 | My SHBG is like kind of in the 30s, 20s to 30s.

01:30:34.740 | But from a hormone perspective,

01:30:37.320 | there's basically three hormones that run it.

01:30:39.400 | So estradiol being probably the most important,

01:30:42.920 | insulin and thyroxine.

01:30:45.620 | So we're gonna look at all of those

01:30:47.400 | and decide if any of those are playing a role.

01:30:49.280 | So insulin suppresses it.

01:30:50.900 | So this is actually the great irony

01:30:53.360 | of helping a person get metabolically healthy

01:30:55.400 | is in the short run you can actually lower

01:30:57.880 | their free testosterone, all things equal.

01:31:00.300 | Because as insulin comes down, SHBG goes up.

01:31:03.440 | And if testosterone hasn't gone up with it,

01:31:05.160 | you're lowering free testosterone.

01:31:06.960 | So somebody who goes on a very low carbohydrate diet

01:31:10.020 | in an attempt to drop some water and drop some weight

01:31:12.700 | is going to increase their SHBG.

01:31:14.440 | - Yeah, if their insulin goes down-

01:31:15.280 | - Bind up testosterone, less free testosterone.

01:31:17.620 | I can tell the carnivore diet people

01:31:20.640 | are going to be coming after me with bone marrow in hand.

01:31:24.020 | But then again, after this discussion

01:31:25.920 | extends a little further,

01:31:26.760 | I'm sure the vegans will be coming after me

01:31:28.360 | with celery stalks.

01:31:29.320 | So it's-

01:31:30.160 | - So then the same as with estradiol.

01:31:32.320 | So except in the opposite direction.

01:31:33.560 | So higher estradiol is higher SHBG.

01:31:37.760 | So again, occasionally you'll see a guy

01:31:39.600 | with normal testosterone,

01:31:41.520 | but he's a very high aromatase activity person.

01:31:45.760 | So he has a lot of the enzyme

01:31:47.400 | that converts testosterone into estradiol.

01:31:50.920 | You can lower estradiol a bit with an aromatase inhibitor,

01:31:53.880 | and that can bring down SHBG.

01:31:55.260 | Now again, these things individually

01:31:57.140 | are rarely enough to move the needle.

01:31:59.840 | The last is thyroxine.

01:32:01.120 | So if you have a person whose thyroid is out of whack,

01:32:03.380 | you have to fix that before you,

01:32:05.360 | if their T4 is out of whack,

01:32:06.640 | you're going to interfere with SHBG.

01:32:09.160 | There are also some supplements,

01:32:10.220 | which I think you've probably talked about these

01:32:11.700 | on the podcast.

01:32:12.540 | I feel like I've heard you talk about these on the podcast.

01:32:14.060 | - Yeah, there are a few that will adjust.

01:32:15.680 | You know, there is this idea.

01:32:16.900 | Now there's a much better review that just came out.

01:32:19.640 | I'll send it to you.

01:32:20.480 | I'd love your thoughts on it.

01:32:21.300 | And I've been perusing it line by line,

01:32:24.020 | but I love input from experts like you

01:32:26.760 | on the use of Tonga Ali for reducing SHBG.

01:32:31.520 | In my experience, it does free up some testosterone

01:32:34.960 | by which mechanism it isn't exactly clear.

01:32:37.560 | And the effects aren't that dramatic, right?

01:32:39.760 | There are probably multiple effects.

01:32:41.460 | For all we know, it increases libido,

01:32:43.380 | and it does generally by way of increasing estrogen slightly

01:32:46.660 | which can also increase libido in some individuals.

01:32:48.700 | So we don't know the exact mode of action.

01:32:51.060 | So we've talked about a few.

01:32:51.920 | The one that a few years back people were claiming

01:32:54.120 | could reduce SHBG was stinging nettle.

01:32:58.700 | Stinging nettle, well, urinating seems to be coming up

01:33:02.480 | multiple times on this podcast for whatever reason.

01:33:05.560 | Stinging nettle extract,

01:33:06.580 | I took the most pronounced effect of that

01:33:09.360 | was you could basically urinate over a car

01:33:11.960 | when taking SHBG.

01:33:13.000 | What the underlying mechanism of that was, I do not know.

01:33:16.560 | I took it for a short while.

01:33:17.520 | It didn't drop my SHBG very much,

01:33:20.320 | but it did drop by DHT sufficiently

01:33:23.360 | so that I stopped taking it.

01:33:25.040 | I do not like anything that impedes DHT.

01:33:28.060 | I don't care if my hairline retreats.

01:33:30.260 | I don't care about any of that.

01:33:31.560 | DHT to me is something to be coveted and held onto

01:33:36.560 | because you feel so much better

01:33:38.460 | when your DHT is in the appropriate range.

01:33:40.720 | And I'd love your thoughts on that at some point too.

01:33:42.560 | - Yeah, again, it really depends on the guy

01:33:44.520 | and it depends on what risk you're trying to manage, right?

01:33:46.840 | So prostate size starts to become

01:33:49.000 | one of the issues with DHT.

01:33:50.600 | - Luckily, my prostate spastic antigen is low.

01:33:53.320 | And DHT, the things that I know can reduce it

01:33:56.920 | are things like finasteride, Propecia, things like that,

01:33:59.880 | right, things that people take to try and avoid hair loss

01:34:02.600 | can dramatically reduce DHT

01:34:04.560 | and leads to all sorts of terrible sexual side effects,

01:34:07.060 | mood-based side effects, et cetera.

01:34:08.840 | But yeah, so I'm not aware of anything

01:34:11.080 | that can be taken in supplement form

01:34:12.600 | that can really profoundly drop SHBG.

01:34:14.640 | - We don't spend much attention on it anymore.

01:34:16.920 | Basically, I used to have a much more complicated

01:34:19.840 | differential diagnosis eight years ago.

01:34:21.640 | Like, I mean, I would drive patients nuts

01:34:24.440 | with the whiteboard diagrams I would draw for them

01:34:26.460 | and in the end, I think they were just like,

01:34:27.640 | "Dude, just what do I need to take?"

01:34:29.900 | Today, we take a much more simple approach.

01:34:31.340 | So the first question is, should you or should you

01:34:33.760 | have your free testosterone being higher?

01:34:35.280 | That's the metric I care about,

01:34:36.780 | is free testosterone is the first most important,

01:34:38.880 | the second most important is estradiol.

01:34:40.440 | - And sorry to interrupt, but you said,

01:34:41.800 | if you look at your total testosterone,

01:34:43.280 | you want the free T to be about 2% of your total.

01:34:45.340 | - Well, it should be, right?

01:34:46.180 | Now, I might not change that anymore.

01:34:48.360 | So in other words, if a guy's at 1%,

01:34:50.720 | then I know I have to really boost his total testosterone.

01:34:53.440 | If he's only gonna get one to one and a half percent

01:34:55.440 | of it converted to free, I need to boost him.

01:34:57.840 | And that's why I don't care if he's outside the range.

01:34:59.800 | Like, I'll have a guy who's free T,

01:35:02.320 | I might have to get a guy's total T up to 1,500

01:35:04.780 | to get his free T to 18.

01:35:06.600 | - I see, so free T is the target.

01:35:08.000 | I like this approach. - Free T is what we treat.

01:35:09.360 | - And do you still use Anavarix?

01:35:12.000 | - I don't use Anavarix. - Los Angeles, sorry,

01:35:14.040 | to try and lower SHBG. - I don't, no.

01:35:16.360 | - Because it's too potent?

01:35:17.720 | - No, because it's just too complicated for patients.

01:35:20.240 | You know, it's a drug that can't be taken orally,

01:35:23.420 | so you have to take it under the tongue, right?

01:35:24.840 | - Like a troche or something.

01:35:25.860 | - Right, but I had one patient once who,

01:35:28.120 | even though we told him about 87 times that,

01:35:30.960 | he was like swallowing the anavars and his liver function,

01:35:33.360 | and he was like, we're talking 10 milligrams

01:35:35.020 | three times a week is a tiny dose.

01:35:37.520 | And three months of him, or whatever,

01:35:39.320 | two months of him swallowing that every time

01:35:41.640 | tripled his liver function test.

01:35:43.000 | So it's like, I was like, you know what,

01:35:44.680 | it's just not worth the hassle of doing this

01:35:47.200 | for perfection.

01:35:50.240 | In reality, we can fix this another way.

01:35:51.840 | So the first order question is,

01:35:54.320 | do we believe clinically you will benefit

01:35:57.240 | from normalizing your free testosterone,

01:36:00.760 | or taking it to a level that's call it

01:36:03.600 | 80th to 90th percentile?

01:36:05.340 | So upper normal limit of physiologic ranges.

01:36:09.240 | That's the first order question.

01:36:12.040 | And that's going to come down to symptoms,

01:36:13.640 | and that's going to come down to some biomarkers.

01:36:15.840 | I think there's two years ago, was it two years ago,

01:36:18.320 | or maybe a year ago, a very good study came out

01:36:20.620 | that looked at prediabetic men,

01:36:23.960 | you've probably talked about this study,

01:36:25.560 | and looking at insulin resistance and glucose disposal

01:36:29.520 | with and without testosterone.

01:36:30.720 | And the evidence was overwhelmingly clear.

01:36:33.140 | Testosterone improves glycemic control.

01:36:36.600 | Testosterone improves insulin signaling.

01:36:37.960 | This shouldn't be surprising, by the way,

01:36:39.740 | given the role muscles play as a glucose reservoir

01:36:42.440 | and a glucose sink.

01:36:43.720 | So now I include that as one of the things

01:36:45.700 | that we will consider as a factor for using testosterone.

01:36:49.300 | Now, again, it's not the only one,

01:36:50.800 | so you can accomplish that with exercise,

01:36:52.780 | you can accomplish that with these other things,

01:36:53.880 | but then you get into a little bit of the vicious cycle

01:36:55.760 | of will having a normalized testosterone

01:36:58.240 | facilitate you doing those things better?

01:37:00.800 | So let's just assume we come to the decision

01:37:03.700 | that this person is a good candidate

01:37:06.880 | for testosterone replacement therapy.

01:37:09.200 | The next question is what's the method

01:37:12.200 | we're going to do it?

01:37:13.020 | Are we going to do it indirectly or directly?

01:37:15.460 | Now, we used to use a lot of Clomid in our practice.

01:37:19.620 | And have you talked about Clomid on the podcast?

01:37:22.360 | - I haven't talked too much about it.

01:37:23.740 | - No, we've talked a little bit about the fact

01:37:26.140 | that some people taking things like anastrozole

01:37:28.400 | to reduce aromatase activity can potentially run

01:37:32.480 | into trouble because they think, oh, well,

01:37:35.100 | more testosterone good, lower estrogen bad,

01:37:37.700 | and then they end up with issues like joint pain,

01:37:40.060 | memory issues, and severe drops in libido,

01:37:42.840 | and I think a lot of the reason why.

01:37:43.680 | - And even fat accumulation.

01:37:45.400 | So if estrogen is too low, you can develop adiposity

01:37:49.120 | in a way that you wouldn't otherwise.

01:37:50.200 | There's a great New England Journal paper,

01:37:52.200 | it's probably 10 years old now,

01:37:53.320 | that looked at, I believe it was five different doses

01:37:56.900 | of testosterone siponate.

01:37:58.000 | So these men were chemically castrated

01:37:59.620 | and divided into 10 groups.

01:38:01.160 | It's pretty remarkable.

01:38:02.240 | - Somebody signed up for this study.

01:38:03.440 | - Yeah, so you were with and without anastrozole

01:38:07.040 | and five doses of testosterone.

01:38:09.040 | So now you basically had five testosterone levels,

01:38:12.420 | plus or minus high or low estradiol.

01:38:15.360 | And the results were really clear

01:38:17.100 | that the higher your testosterone

01:38:19.260 | and the more your estradiol was in kind of that 30 to 50

01:38:22.880 | range, the better you were.

01:38:24.240 | So if estrogen was too low,

01:38:26.040 | even in the presence of high testosterone,

01:38:28.120 | the outcomes were less significant.

01:38:30.760 | - And this is 30 to 50 nanograms per deciliter,

01:38:32.880 | not 30 to 50% of one's testosterone.

01:38:35.700 | Okay, great.

01:38:36.540 | - Okay, so- - But we haven't talked,

01:38:38.600 | but Clomid is, no, we have not talked a lot about Clomid.

01:38:41.000 | I'd love to get your thoughts on Clomid.

01:38:42.560 | - So Clomiphene is a fertility drug.

01:38:45.160 | It's a synthetic hormone.

01:38:46.720 | It's actually two drugs, M-Clomiphene

01:38:48.920 | and I forget the other one.

01:38:50.860 | And it tells the pituitary to secrete FSH and LH.

01:38:55.860 | And so the advantage of Clomid is it's oral

01:39:04.060 | and it's meant to be taken orally.

01:39:06.120 | So a typical starting dose would be like 50 milligrams

01:39:09.580 | three times a week.

01:39:10.540 | And if you do that, you'll notice in most men,

01:39:15.240 | especially young men, FSH, LH goes up.

01:39:17.720 | In any man, the FSH and LH go up.

01:39:19.540 | But if a man still has testicular reserve,

01:39:21.760 | he'll make lots of testosterone in response to that.

01:39:24.360 | 'Cause that's the first order question

01:39:27.580 | we're trying to answer is do you,

01:39:30.140 | is your failure to make testosterone central or peripheral?

01:39:34.080 | - Yeah, and I think just one point out,

01:39:36.160 | again, correct me if I'm wrong,

01:39:37.100 | but my understanding is that a lot of the drugs

01:39:39.560 | that we're talking about, the synthetic compounds,

01:39:42.480 | testosterone, estrogen,

01:39:43.760 | things related to growth hormone, et cetera,

01:39:46.400 | were discovered and designed in order to treat and,

01:39:50.180 | excuse me, in order to isolate

01:39:51.700 | and treat exactly these kinds of syndromes,

01:39:53.460 | whether or not it was the hypothalamus, the pituitary,

01:39:56.140 | or the target tissue, the ovaries, or the testes, correct?

01:39:59.700 | - Correct, yeah.

01:40:00.520 | I mean, I think the easiest way to go about doing this

01:40:02.400 | is just give the hormone that's missing

01:40:04.620 | without attention to where the deficiency is.

01:40:07.660 | Why this becomes relevant is if you have a 35-year-old guy

01:40:12.220 | whose testosterone is low,

01:40:14.540 | but you can demonstrate that it's low

01:40:16.600 | because he's not getting enough of a signal

01:40:18.500 | from the pituitary,

01:40:19.820 | why would you bother giving him more testosterone

01:40:22.040 | when he has the, he has the Leydig cells

01:40:24.100 | and the Sertuli cells to make testosterone.

01:40:25.780 | He just needs the signal.

01:40:27.020 | Sometimes, though not always,

01:40:29.780 | just a course of Clomid can wake him up,

01:40:32.820 | and he's back to making normal testosterone.

01:40:35.180 | - So he'll do this three times a week,

01:40:36.780 | 50 milligrams three times a week for a short course,

01:40:39.980 | and then-- - Yeah, we would do that

01:40:40.820 | for eight to 12 weeks, and then we reevaluate.

01:40:43.100 | And estrogen and testosterone will increase in parallel.

01:40:46.780 | - Yes, and again, it depends.

01:40:49.060 | Aromatase activity is dependent

01:40:50.740 | on how much body fat you have and genetics.

01:40:53.240 | And if estradiol gets too high,

01:40:56.100 | we think if it gets over about 55, 60,

01:40:58.660 | we will give microdoses of an astrozole.

01:41:01.420 | But it has to be real microdoses.

01:41:03.180 | I mean, you cannot pound people with an astrozole.

01:41:05.660 | To give you perspective, the sort of on-label use,

01:41:10.540 | like if you just go to a pharmacy and order an astrozole,

01:41:13.020 | you're going to get one milligram tablets.

01:41:15.180 | Like we can't give anybody a milligram.

01:41:16.860 | - They'll feel like garbage.

01:41:18.180 | - We have to have it compounded at 0.1 milligrams,

01:41:21.060 | and we might give a patient 0.1 two to three times a week.

01:41:24.100 | That would be a big dose of an astrozole.

01:41:26.720 | - Yeah, I think that the typical TRT clinic out there

01:41:30.140 | is giving 200 milligrams per mil, one mil,

01:41:34.160 | 200 milligrams of testosterone once every two weeks,

01:41:36.280 | and then hitting people with multiple milligrams

01:41:39.780 | of an astrozole, and they're all over the place.

01:41:42.300 | I've never really understood.

01:41:43.700 | I mean, I guess I shouldn't be surprised,

01:41:45.340 | but it kind of blows my mind that these TRT clinics

01:41:47.820 | are up all over the place, given how bad.

01:41:49.580 | I mean, I see the results,

01:41:50.820 | 'cause I have patients that come from them,

01:41:53.440 | and I don't understand like why they're so incompetent.

01:41:56.300 | - I actually think it's worse than that.

01:41:57.800 | I think that they simply don't understand and don't care,

01:42:01.220 | because it's a pill mill and it's a money mill.

01:42:04.860 | I think that nowadays it seems almost everybody

01:42:07.180 | who's doing TRT is taking lower doses more frequently

01:42:09.820 | every other day or twice a week, dividing the dose,

01:42:12.260 | and being very, very careful

01:42:13.620 | with these estrogen or aromatase blockers.

01:42:16.100 | - Most of our patients do not take aromatase inhibitors.

01:42:20.180 | It's not needed.

01:42:21.020 | It's really only the high aromatizers that need it.

01:42:23.740 | And so, yeah, when we'll talk about testosterone,

01:42:27.260 | we'll talk about dosing there, 'cause I agree,

01:42:28.860 | the more frequently you can take it, the better.

01:42:30.580 | And frankly, you don't need to go more frequently

01:42:32.860 | than twice a week.

01:42:34.380 | - Because it's so slow-acting.

01:42:35.660 | - Yeah, the half-life of the drug is,

01:42:37.260 | I think it's about three and a half days,

01:42:38.540 | is the plasma half-life or something like that.

01:42:39.900 | It could be off a little bit,

01:42:41.260 | but twice-week dosing is really nice.

01:42:44.980 | So if you go to a testosterone clinic

01:42:49.340 | that's giving you 200 every two weeks,

01:42:51.460 | 50 twice a week is the same total dose,

01:42:54.480 | which, by the way, is a physiologic dose.

01:42:56.200 | That's not going to give somebody

01:42:58.620 | any of the side effects you would see.

01:42:59.940 | You're not gonna get acne with that.

01:43:01.520 | You're not gonna get gynecomastia.

01:43:03.540 | You're not gonna get any things.

01:43:04.460 | The only real side effect you get from that

01:43:06.180 | is you will get testicular atrophy.

01:43:08.300 | That is enough to suppress.

01:43:09.740 | - Yeah, to maintain fertility,

01:43:12.080 | what do you typically do for--

01:43:13.580 | - Well, so this is where,

01:43:14.740 | so I'll finish the story on Clomid,

01:43:16.300 | 'cause we currently do not use Clomid,

01:43:18.140 | and that's due to a really interesting observation

01:43:22.420 | that we made that I don't think has been reported

01:43:25.820 | in the literature yet,

01:43:27.260 | which is that Clomid was increasing levels of a sterol

01:43:31.420 | that we also happen to measure called desmosterol.

01:43:34.500 | - I'm not familiar with that.

01:43:36.000 | - So in the way that cholesterol is made,

01:43:39.540 | it's made by, there's two pathways that make cholesterol.

01:43:43.340 | So it starts with two carbon subunits, like acetyl-CoA,

01:43:46.420 | and it kind of marches down a pathway, bifurcates,

01:43:49.120 | and cholesterol is the finished product of both,

01:43:52.540 | but in one of those pathways,

01:43:54.700 | the molecule right before cholesterol is called desmosterol,

01:43:58.420 | and the other pathway, it's called lathosterol.

01:44:00.660 | So we constantly measure lathosterol and desmosterol

01:44:04.740 | because we want to know how much cholesterol

01:44:06.740 | is being synthesized in the body,

01:44:08.540 | not just what your cholesterol is.

01:44:10.780 | We want to know how much cholesterol you reabsorb,

01:44:13.760 | and those markers are really important to us

01:44:15.600 | when we're looking at cardiovascular disease risk.

01:44:18.140 | So when we gave patients Clomid,

01:44:22.300 | we were noticing a almost universal rise

01:44:26.840 | in their desmosterol levels.

01:44:28.760 | Now, the most obvious explanation for that,

01:44:31.840 | though the last time I looked,

01:44:33.740 | I couldn't find clear explanation for this

01:44:35.980 | in any of the clinical trials

01:44:38.580 | that led to the approval of Clomid,

01:44:40.240 | so I don't know if it was described.

01:44:41.700 | In fact, maybe it wasn't known.

01:44:43.340 | I suspect it is inhibiting the enzyme,

01:44:46.100 | which I think is called Delta-24 desaturase

01:44:48.520 | that turns desmosterol into cholesterol.

01:44:51.500 | Makes sense if you inhibit that enzyme,

01:44:53.180 | you're gonna see a rise in desmosterol.

01:44:55.560 | This wouldn't have been a concern to me

01:44:58.420 | if not for the fact that Tom Dayspring,

01:45:00.160 | who's one of the physicians we work with,

01:45:01.420 | who's one of the world's experts in lipids,

01:45:02.880 | pointed out a very obscure story,

01:45:06.240 | which was that the very first drug ever approved

01:45:09.760 | to treat cardiovascular disease,

01:45:12.560 | at least to treat hypercholesterolemia,

01:45:14.840 | was a drug that attacked the same enzyme.

01:45:17.460 | So this was in the early 1960s, I believe,

01:45:21.740 | maybe the mid-60s.

01:45:22.580 | This drug was approved and it lowered cholesterol,

01:45:26.520 | and it was approved on the basis of lowering cholesterol.

01:45:28.800 | Now, today, no drug for ASCVD is approved

01:45:32.140 | on the basis of it lowering cholesterol.

01:45:34.140 | That's not a high enough bar.

01:45:35.420 | You have to reduce events.

01:45:36.980 | They actually have to show

01:45:37.820 | that you're preventing heart attacks and death.

01:45:40.740 | But at the time, it was like,

01:45:41.660 | "Hey, it lowers cholesterol, it's gotta be good."

01:45:43.700 | Well, in the late 60s, it was pulled from the market

01:45:45.860 | because events were going up.

01:45:47.860 | So cholesterol was coming down, events were going up.

01:45:50.780 | How could that be?

01:45:52.460 | We don't know.

01:45:53.600 | What we are suspecting is that desmosterol,

01:45:58.180 | which is still a sterol,

01:46:00.280 | was potentially more damaging

01:46:02.900 | and created more oxidative stress in the endothelium,

01:46:05.940 | in the sub-endothelial space, than cholesterol,

01:46:08.580 | which would at least suggest to us,

01:46:10.840 | and again, we're taking a lot of leaps here,

01:46:13.020 | that maybe having high desmosterol,

01:46:15.140 | very high desmosterol, is not a good thing.

01:46:17.440 | And so once we kind of pieced all that together

01:46:20.980 | a few years ago, we were like,

01:46:22.360 | "Yeah, we're just not gonna prescribe Clomid anymore."

01:46:26.380 | And we then switched to HCG,

01:46:30.720 | which we used to use sometimes instead of Clomid,

01:46:33.320 | but it's more cumbersome to work with.

01:46:35.100 | It needs to be refrigerated.

01:46:36.280 | It's a much more fragile molecule.

01:46:38.120 | - Yeah, I think we talked about this once.

01:46:39.320 | It's almost like if you accidentally knock over

01:46:42.240 | the little bottle, it's basically gone bad.

01:46:45.800 | Travel with it is very challenging.

01:46:47.280 | - Can't travel with it.

01:46:48.840 | It's a needle, it's an injection, sub-Q,

01:46:51.320 | so easy to administer.

01:46:52.540 | It's not IM or anything like that,

01:46:53.960 | but it's just more of a hassle factor.

01:46:56.800 | But that said, it has the benefit that Clomid does,

01:47:00.120 | which is it preserves testicular function,

01:47:02.520 | it preserves testicular volume.

01:47:05.160 | So bodybuilders will often use this

01:47:07.640 | in their post-cycle therapy

01:47:09.500 | as a way to kind of recover function.

01:47:11.780 | And we would just use it now as ongoing therapy

01:47:15.160 | for a guy who still has testicular reserve.

01:47:17.920 | - So on its own, no testosterone,

01:47:19.680 | no aromatase inhibitor, nothing,

01:47:21.520 | just a way to crank out a bit more testosterone

01:47:23.880 | from the testes, maybe some additional estrogen also.

01:47:26.300 | - And HCG is a different model.

01:47:28.140 | HCG is just an analog of luteinizing hormone.

01:47:30.880 | So it's basically like giving them luteinizing hormone.

01:47:33.280 | - So it's going to crush endogenous

01:47:35.000 | luteinizing hormone levels, right?

01:47:36.360 | Because it's-

01:47:37.200 | - Actually, yeah, and you don't really see

01:47:40.520 | much of an impact on LH,

01:47:41.960 | but you do see endogenous testosterone production go down.

01:47:45.400 | Actually, no, I correct that.

01:47:46.360 | Both FSH and LH will go down on a high enough dose, yep.

01:47:49.940 | - Just as a mention, and here I'm not making recommendations,

01:47:52.480 | but one supplement I've talked a lot about publicly

01:47:55.560 | is Fidogia agrestis, which is this weird Nigerian shrub

01:47:58.680 | that does- - You talked about this

01:48:00.380 | on Tim's podcast.

01:48:01.220 | - On Tim's podcast and Joe's podcast.

01:48:03.120 | And, you know, there was a bit of a backlash

01:48:05.600 | because it does turn out that at high doses

01:48:07.960 | in rodent studies, it can cause some toxicity to the testes.

01:48:12.340 | But at lower doses,

01:48:14.520 | it does seem to increase luteinizing hormone.

01:48:16.600 | And after talking about this,

01:48:17.520 | a number of people went out there,

01:48:18.400 | did pre and post blood work.

01:48:19.640 | And the consistent effect seems to be an increase

01:48:21.960 | in luteinizing hormone.

01:48:23.060 | There's a noticeable effect on testicular size and volume.

01:48:26.680 | So a lot of people will take this and be like,

01:48:27.840 | oh, you know, their balls are getting bigger.

01:48:29.740 | And so they get all excited that something good is happening.

01:48:32.720 | But we don't know the long-term safety and efficacy

01:48:35.520 | of something like Fidogia,

01:48:36.680 | whether or not it needs to be cycled.

01:48:37.880 | - Yeah, this is why I'm also very leery

01:48:40.040 | of the supplements in this space,

01:48:41.560 | because at least when we're using HCG or testosterone,

01:48:46.080 | like we have so many years of data.

01:48:48.560 | You have to remember how many women are using this stuff

01:48:51.080 | for reproductive medicine.

01:48:53.040 | So, you know, I think the FDA has a lot of faults.

01:48:57.240 | I think I have an entire podcast devoted

01:49:00.480 | to the corruption of the FDA and all of the mistakes

01:49:03.280 | that have been made with respect to their oversight

01:49:05.720 | in especially generic drugs.

01:49:07.740 | But it's way more regulated than the wild, wild west

01:49:11.640 | of nutty supplement land.

01:49:13.280 | - Absolutely.

01:49:14.120 | I think that the reason for talking about things

01:49:16.240 | like Tonga and Fidogia was to provide

01:49:18.140 | some intermediate discussion between doing

01:49:21.280 | all the correct things, but no supplementation

01:49:23.420 | or hormone therapy, and then going straight

01:49:24.940 | to hormone therapy.

01:49:25.780 | It's sort of like the leap from I can't focus very well

01:49:28.700 | to Ritalin, right, without a real diagnosis of ADHD,

01:49:33.320 | to, oh, well, maybe some things like alpha-GPC low doses

01:49:36.820 | of nicotine, right?

01:49:38.020 | But I agree entirely.

01:49:39.740 | I mean, the sourcing is important.

01:49:41.440 | The dosages are worked out empirically on an individual basis

01:49:45.680 | and there aren't randomized control trials.

01:49:47.820 | There just aren't.

01:49:49.260 | - Yeah, and have kind of like a seven,

01:49:54.260 | this is another Peter principle, right?

01:49:56.360 | So I've got a lot of patients that come into the practice

01:49:58.560 | and during our intake, we go through what drugs

01:50:01.920 | and supplements are you taking right now?

01:50:03.360 | And a lot of people come in, I'm not taking anything,

01:50:05.360 | Peter, I just, you're in charge now,

01:50:07.320 | like, tell me what you think.

01:50:08.800 | And then you get a lot of people that come in

01:50:09.980 | and they're like, we're gonna need an extra few pages

01:50:12.640 | for this part of the documentation.

01:50:13.480 | - Right, the people who travel with a suitcase

01:50:15.120 | that you can hear as they walk through the airport

01:50:16.680 | from all the pills battling.

01:50:18.380 | - So I give these patients a little homework exercise,

01:50:20.520 | which is you have to answer these seven questions

01:50:22.680 | for every supplement you take.

01:50:23.940 | And here's the spreadsheet and let's talk about it.

01:50:26.100 | And it basically just runs through,

01:50:28.140 | like, you know, it's basically walking you through

01:50:31.260 | the logic of why do you take this molecule?

01:50:34.340 | And I think for many people, when they do that,

01:50:38.740 | it's very sobering, right?

01:50:40.340 | They kind of, a lot of them will come back and be like,

01:50:42.220 | you know what, I don't think I can come up with any reason

01:50:45.800 | along this really rigorous line of thinking

01:50:47.940 | as to why I'm taking 80% of this stuff.

01:50:50.440 | - Well, I know people,

01:50:51.280 | and actually we know some of the same people,

01:50:52.320 | were fanatic about like red light on the testes,

01:50:55.860 | sunning their testes, putting ice packs on their testes.

01:50:59.680 | It's kind of all over the place.

01:51:00.960 | The number of things that people are trying and doing

01:51:03.480 | in order to increase testosterone output

01:51:05.800 | from their testes is pretty remarkable.

01:51:07.340 | And that said, among some of the women I know,

01:51:10.280 | the number of things that they're doing

01:51:11.320 | to try and promote longevity and fertility,

01:51:13.600 | and in particular skin health, hair health, and nail health,

01:51:17.800 | is also kind of outrageous.

01:51:19.640 | Everything from collagen to red light therapies,

01:51:21.800 | which may actually have some efficacy in certain cases,

01:51:24.000 | but there's a hunger there, right?

01:51:26.960 | - Oh, for sure.

01:51:27.880 | One of the things that I hope gets a lot more attention

01:51:29.780 | is the use of rapamycin for preserving ovarian health.

01:51:33.160 | So the animal literature on this is pretty impressive, right?

01:51:36.600 | So in mouse models, rapamycin will preserve ovarian life.

01:51:41.600 | And so it makes sense, right?

01:51:43.200 | I mean, it totally makes sense why the most potent

01:51:46.480 | giroprotective molecule we have would also preserve

01:51:50.180 | and extend ovarian life, at least in mice.

01:51:52.720 | So I'd love to see the clinical trials done in women

01:51:57.660 | to test this hypothesis.

01:51:59.280 | - I definitely want to come back to this

01:52:00.500 | 'cause it's a key thing.

01:52:01.640 | I know that a lot of people are interested

01:52:02.720 | in female fertility out there,

01:52:05.240 | including their male partners.

01:52:06.320 | So going back to, so now I understand

01:52:10.000 | why you don't prescribe clomiphene

01:52:11.180 | because of this potential dysmosterol link.

01:52:16.180 | What about testosterone therapy?

01:52:19.100 | So less frequent, lower doses,

01:52:21.560 | less or no estrogen inhibition or aromatase inhibition?

01:52:25.840 | - Again, we're only using an aromatase blocker,

01:52:29.600 | and we use Aromatex when we do.

01:52:31.560 | It's just to get that estradiol into the range we want.

01:52:34.560 | I like to see it between 30 and 50.

01:52:36.800 | That's the sweet spot.

01:52:37.940 | And I don't know, I would say like a third,

01:52:41.360 | maybe a, not even a third,

01:52:43.360 | I'd say probably 20% of men require a microdose

01:52:47.200 | of an estrozole to get into that range.

01:52:49.800 | Most do not.

01:52:50.620 | And I'd rather err on the side

01:52:53.080 | of being a little high than a little low.

01:52:54.920 | So I never really want to be below 25.

01:52:57.880 | If, unless, sometimes it's just below 25 and it is.

01:53:00.960 | It is what it is, that's fine.

01:53:01.960 | But if we're suppressing it to below 25,

01:53:04.460 | I never want to be in that zone.

01:53:06.860 | And then yes, so TRT is ultimately,

01:53:09.520 | giving testosterone, cipunate is usually what we use.

01:53:12.640 | - Injectable, so as opposed to cream or pellet.

01:53:15.040 | - Correct.

01:53:16.480 | I used to use pellets with women

01:53:19.600 | for some who were really adamant

01:53:23.880 | about the convenience of it.

01:53:26.720 | But for a bunch of reasons, I just,

01:53:29.120 | I'm mostly not doing that.

01:53:31.240 | And I've never been a fan of pellets in men.

01:53:34.680 | - You can't control the dosage once it's in, right?

01:53:37.100 | - Well, even if you know the dose,

01:53:37.940 | yeah, that's obviously a problem.

01:53:38.780 | But I don't think, there's a big difference

01:53:40.700 | between putting a pellet into a man and a woman.

01:53:42.100 | So when you're putting a estrogen pellet into a woman,

01:53:44.220 | it's like, it's that big.

01:53:47.400 | When you're putting enough pellets into a man

01:53:49.820 | for six months of testosterone,

01:53:51.540 | it's two sums of pellets that are longer than my finger.

01:53:54.780 | So you're putting like a V-shape,

01:53:56.660 | you're putting it into the gluteal fat.

01:53:59.780 | So it's just a more morbid procedure.

01:54:01.660 | And I don't think it's necessary.

01:54:02.820 | I think if you know how to manage it

01:54:05.140 | through sort of the injections and now--

01:54:06.980 | - Injections are no big deal.

01:54:07.820 | - Yeah, well, especially now if you're doing,

01:54:09.560 | we're having them do sub-Q injections anyway.

01:54:11.620 | So it's not IM, they're using a 5/8 inch

01:54:14.780 | to a one inch, 25 gauge needle,

01:54:16.820 | which is about the smallest needle

01:54:17.740 | you can push the oil through once to twice a week,

01:54:21.420 | depending on, and by the way, if they're real needlephobes,

01:54:23.500 | we use Xyosted, which is a preloaded pen.

01:54:26.300 | - And are you having all men take HCG

01:54:29.820 | to maintain fertility and testicular size?

01:54:31.260 | - Only if they want to.

01:54:32.300 | - Got it.

01:54:33.140 | - And by the way, we do not like to use TRT in men who,

01:54:36.260 | we don't like to use testosterone specifically

01:54:37.860 | in men who still want to maintain fertility.

01:54:39.900 | We just steer them away from that.

01:54:41.060 | - Because total sperm count goes down.

01:54:42.580 | - Yeah, we just say, why risk it?

01:54:43.500 | Like we'd rather use HCG.

01:54:45.080 | - Just on its own.

01:54:46.760 | - Yeah, just wait, just wait until you're done reproducing.

01:54:48.580 | Bank sperm, wait till you're done reproducing

01:54:50.600 | before we go to testosterone.

01:54:52.100 | - What are some of the benefits

01:54:54.920 | and what are some of the cautionary notes

01:54:57.700 | with appropriate TRT, meaning of the kind of contour

01:55:01.820 | that we're talking about here?

01:55:03.260 | A lower dose with the yes or no low estrogen control.

01:55:08.180 | People, what generally people report, how do they feel?

01:55:13.180 | What does it allow them to do

01:55:14.460 | that they couldn't do or feel before?

01:55:16.700 | And then in terms of what are the markers to look for?

01:55:19.860 | Is it LDL, blood pressure, water retention, acne,

01:55:24.020 | those kinds of things?

01:55:24.840 | Are there some other things as well?

01:55:25.680 | - Yeah, it depends on the doses, right?

01:55:26.660 | I mean, again, we're using these in really low doses.

01:55:29.060 | So it's pretty rare that we'd have a patient

01:55:31.140 | on more than a hundred milligrams a week of testosterone.

01:55:34.320 | I think for comparison, like a bodybuilder

01:55:37.980 | could easily take 500 to 1,000 during a high growth phase.

01:55:41.900 | - I know some of these guys, they go ballistic

01:55:43.980 | or they're doing moderate levels of testosterone sibonate,

01:55:47.420 | but they're also taking dianabolix, andralone,

01:55:50.700 | SARMs and a bunch of other things.

01:55:54.500 | I mean, their stacks are kind of ridiculous.

01:55:56.180 | I mean, no disrespect to that sport,

01:55:58.340 | but I mean, people are dying like crazy in that sport

01:56:01.460 | right now. - It's outside

01:56:02.300 | of physiology. - Yeah, and I think

01:56:03.380 | for 99% of people listening, they hear bodybuilder

01:56:06.660 | and they just go, "Why would somebody do that anyway?"

01:56:09.660 | I think that's the typical response.

01:56:10.980 | - So the point is, but we owe those guys

01:56:14.160 | a great deal of gratitude

01:56:15.420 | 'cause they've shown us the boundaries.

01:56:17.100 | - Including the women.

01:56:18.140 | - That's right, yeah.

01:56:19.780 | And so those bodybuilders have taught us a lot

01:56:23.740 | about what happens.

01:56:26.140 | And so, yeah, the bloating, the water retention, acne,

01:56:31.140 | hair loss, hair growth, all of those things,

01:56:34.020 | we understand the truth of it is,

01:56:36.020 | we just don't see those things in our patients.

01:56:39.100 | - But 100 milligrams per week is a very low output.

01:56:41.900 | My understanding is-- - But it's a physiologic dose.

01:56:43.240 | I mean, the reality of it is it's enough for most people.

01:56:44.940 | I mean, probably the highest we've ever had to go

01:56:47.060 | is maybe 70 twice a week.

01:56:49.500 | - What's the youngest patient you've ever had to put on TRT?

01:56:52.780 | - Actual testosterone.

01:56:55.060 | Probably, that's a good question, I'm thinking about maybe 40.

01:57:00.060 | - I think that's great for people to hear

01:57:03.300 | 'cause I know that a lot of guys in their 20s

01:57:04.960 | are thinking TRT is the way to go, and I would argue,

01:57:07.180 | unless you're doing everything else right

01:57:08.580 | and you're still hypogonadal and you're really struggling,

01:57:11.060 | put that time off because also the fertility issue,

01:57:14.020 | you want to delay the delay.

01:57:14.940 | - Well, again, it depends if when we say TRT,

01:57:17.100 | if you're in your 20s and there's no other way,

01:57:19.720 | I would hope you would be steered toward HCG

01:57:22.560 | to at least preserve testicular function.

01:57:24.360 | Now, again, we don't actually know if after being on HCG

01:57:27.840 | for 10 years, your pituitary will still work.

01:57:31.540 | - Right, you won't be able to make your own luteinizing.

01:57:33.240 | - Exactly, so it might be the case

01:57:35.260 | that you're gonna need something upstream of that,

01:57:37.640 | like Clomid to kickstart it.

01:57:39.620 | But again, I don't want anybody who's listening to this

01:57:42.500 | who's using Clomid for fertility

01:57:44.360 | to think that there's anything wrong with it.

01:57:46.240 | My concern over this became like,

01:57:47.940 | if you're gonna be on this for 10 years, is it problematic?

01:57:50.680 | Not if you're using this for a course of IVF

01:57:52.860 | or something like that.

01:57:54.120 | So again, if we felt that someone's pituitary

01:57:57.400 | was not working, I would be happy to put three months

01:57:59.800 | of Clomid on them to kind of try to see

01:58:01.480 | if we could blast it back.

01:58:02.840 | - Do you have men cycle on and off testosterone

01:58:05.640 | at these low dosages?

01:58:06.680 | Are they taking a month vacation from it every once in a while?

01:58:08.720 | - Yeah, it totally depends.

01:58:09.560 | You know, I was talking to a patient yesterday

01:58:10.880 | where we're gonna do, we just decided to change the cycle,

01:58:13.680 | eight weeks on, then eight weeks on HCG,

01:58:15.720 | eight weeks on, then eight weeks on HCG.

01:58:17.400 | So that's gonna be a cycle

01:58:18.520 | that maintains his testosterone level,

01:58:20.520 | but fluctuates between endogenous, exogenous,

01:58:22.800 | endogenous, exogenous.

01:58:23.940 | Sometimes we'll just do testosterone on, off, on, off.

01:58:27.600 | And there it's like, how much can he replenish naturally,

01:58:30.680 | but understanding his T will dip during those off cycles.

01:58:34.320 | - Seems to me there's a tremendous incentive

01:58:37.200 | for somebody to develop a molecule

01:58:40.760 | that can directly target SHBG,

01:58:43.440 | besides oxyandrel and Anivar, right?

01:58:46.360 | If one could just drop SHBG just the tiniest bit,

01:58:49.960 | it seems like one could adjust the free T

01:58:52.000 | in a way that would be great.

01:58:54.680 | I don't know why that molecule is so hard to target,

01:58:56.640 | but somebody ought to do it.

01:58:57.760 | The chemistry can't be that hard.

01:58:58.920 | - I talked with Patrick Arnold about this

01:59:01.100 | many, many years ago.

01:59:02.800 | I wish I could remember what his ID,

01:59:06.840 | he had a comment about this that at the time made sense.

01:59:09.560 | And I don't remember what it was.

01:59:10.560 | 'Cause I had that thought too, like, man,

01:59:13.160 | especially for that subset of guys

01:59:15.800 | who have normal testosterone,

01:59:17.600 | but they're just overbinding it.

01:59:19.640 | I'm really glad that you brought up this issue

01:59:21.360 | of total testosterone versus free T.

01:59:23.080 | And the reason is ever since going on podcasts

01:59:25.500 | and talking about this stuff

01:59:26.560 | and talking about it on this podcast,

01:59:28.540 | people will send me their numbers,

01:59:30.080 | they'll send me their charts,

01:59:31.400 | and then they'll send photos of themselves.

01:59:33.020 | And I can tell you, while I'm not a clinician

01:59:34.840 | and I haven't done fancy statistics on it,

01:59:37.220 | there's very little correlation

01:59:38.600 | between someone's absolute testosterone

01:59:40.680 | and how they appear.

01:59:42.000 | I mean, some of these guys look really lean, really strong,

01:59:46.040 | and they'll say, oh, total testosterone is 550.

01:59:49.360 | 480, right?

01:59:50.640 | And then other people, you know, testosterone is 860,

01:59:53.920 | but they, you look at them and you think,

01:59:55.540 | oh, they kind of have a kind of a doughy look to them.

01:59:57.800 | And so it's gotta be this free testosterone thing

02:00:00.320 | plus estrogen, et cetera.

02:00:01.540 | - Well, but also training and nutrition too, right?

02:00:04.080 | I mean, I just think, I think for all this talk

02:00:08.240 | about testosterone, which I enjoy talking about,

02:00:10.400 | and I enjoy talking about the data

02:00:12.240 | on long-term health consequences of testosterone,

02:00:15.040 | 'cause it's another controversial topic,

02:00:17.460 | I also think people kind of overstate its importance.

02:00:20.020 | - I agree.

02:00:20.860 | - And I think there's a group of people who think,

02:00:23.580 | if I could just fix my testosterone,

02:00:24.940 | everything will be better.

02:00:25.880 | And it's sort of like, no, actually that's not true at all.

02:00:29.660 | Really, the only purpose in my mind of fixing testosterone

02:00:32.620 | is to give you the capacity to work harder.

02:00:36.260 | It's really going to help you recover more

02:00:38.640 | from your workouts.

02:00:39.580 | This should just give you a greater ability

02:00:41.980 | to experience muscle protein synthesis.

02:00:45.020 | So, you know, if I just give you a bunch of testosterone

02:00:47.340 | and you sit on the couch and your nutrition doesn't change

02:00:49.500 | and you're not exercising anymore,

02:00:50.580 | you're not gonna experience any benefits of this thing.

02:00:53.580 | I mean, my testosterone level has fluctuated quite a bit

02:00:55.880 | throughout my life.

02:00:57.060 | And when I think about as an adult,

02:00:59.460 | not sort of including when I was sort of

02:01:01.420 | a fanatical teenager, but as an adult,

02:01:03.980 | when was I at my absolute most insane physique,

02:01:08.100 | like my best performance on a DEXA scan?

02:01:11.300 | Would have been 30, I was 38 years old.

02:01:16.060 | By DEXA, I was 7% body fat.

02:01:18.260 | My fat-free mass index was like 23.2,

02:01:21.500 | 23.3 kilograms per meter squared.

02:01:24.780 | I mean, I was huge, strong, and totally ripped.

02:01:29.780 | My testosterone was in the toilet.

02:01:32.160 | I was over-training like crazy.

02:01:34.740 | I was exercising probably 26 hours a week,

02:01:38.860 | killing it in the gym, swimming like a banshee,

02:01:41.420 | cycling like my life depended on it,

02:01:43.660 | grossly over-trained, low T,

02:01:46.580 | but I mean, physically looked like twice the guy I am today.

02:01:51.500 | Today, my T is probably twice as high as it was then.

02:01:54.340 | So now, you could say, well, Peter,

02:01:57.140 | what if you took T back then?

02:01:58.700 | How much better could you have been?

02:01:59.820 | Sure.

02:02:01.100 | But again, I think the take-home is

02:02:03.820 | just giving somebody T doesn't do much of anything.

02:02:06.740 | It probably helps on the insulin resistance front

02:02:08.980 | without any other thing, but to me, that's a waste.

02:02:12.580 | That's squandering the gift that it is giving you,

02:02:15.260 | which is the ability to do more work

02:02:17.900 | and capture the benefit of it via muscle protein synthesis.

02:02:22.200 | - I agree.

02:02:23.040 | And I think that the psychological effect of testosterone,

02:02:25.780 | whether or not it's exogenous or endogenous,

02:02:27.820 | is it makes effort feel good.

02:02:30.600 | - Yeah.

02:02:31.440 | - At some level, it really seems to do that.

02:02:32.760 | And Sapolsky tells me the main reason,

02:02:34.900 | or mechanistically, the main reason that it can do that

02:02:37.520 | is by adjusting levels of activity in the amygdala.

02:02:41.060 | - Interesting.

02:02:41.900 | There's some interesting imaging there.

02:02:43.980 | I'd love to chat more about the cholesterol pathway.

02:02:47.480 | And I know this is a huge landscape as well,

02:02:49.480 | but I think we're doing a good job of diving in deep,

02:02:53.000 | but not getting stuck in the underlying currents at all.

02:02:56.980 | There's tremendous debate about whether or not

02:03:02.060 | dietary cholesterol directly relates to,

02:03:05.380 | or does not relate to serum cholesterol, LDL and HDL.

02:03:09.860 | Here's my- - Is there?

02:03:11.260 | - I think, well, let me put it this way.

02:03:13.340 | There are people that argue,

02:03:16.320 | I'm certainly not arguing that,

02:03:17.500 | there are people that argue that

02:03:20.560 | if one eats a ton of saturated fat,

02:03:24.620 | that LDL goes up and HDL goes down.

02:03:27.580 | - Okay, but that's not dietary cholesterol per se.

02:03:29.660 | - No, not dietary cholesterol per se.

02:03:31.160 | But, and then there are people that argue that, you know,

02:03:35.500 | any increase in saturated fat intake is going to be bad,

02:03:38.960 | that you already synthesize enough cholesterol

02:03:40.780 | for hormone production, et cetera.

02:03:42.620 | I'd like to talk about this in terms of

02:03:44.220 | how one should read their charts.

02:03:45.860 | My LDL is in what I'm told is healthy range.

02:03:49.700 | My HDL is in what I'm told is healthy range.

02:03:52.340 | I do try and not overeat things like butter, cheese,

02:03:55.700 | and red meat, but I do eat some of those things

02:03:58.020 | and I feel pretty good.

02:03:59.420 | But most people are operating under the assumption

02:04:04.420 | that eating saturated fat is bad and you only do it

02:04:08.300 | insofar as you want to taste it.

02:04:10.940 | And then, of course, there's a small group of people

02:04:13.120 | that love to eat organs and meats

02:04:15.580 | and really pack cholesterol and would argue

02:04:19.060 | that it doesn't matter if your LDL is 870,

02:04:21.940 | it's not going to impact your health.

02:04:24.420 | What's the reality around LDL, HDL, dietary cholesterol,

02:04:29.080 | saturated fat, at least in your view?

02:04:31.800 | - So first, let's differentiate between cholesterol and fat,

02:04:35.700 | just for the listener, 'cause we use them,

02:04:38.940 | I don't want to make sure people understand.

02:04:40.080 | So cholesterol is a really complicated molecule.

02:04:43.620 | So it's a ringed molecule.

02:04:45.600 | God, I used to know exactly what its structure was,

02:04:49.180 | but it could have 36 carbons for all I remember.

02:04:53.020 | It is a lipid, so it is a hydrophobic molecule

02:04:56.700 | that is synthesized by every cell in the human body.

02:05:00.980 | It is so important that without it,

02:05:04.020 | if you look at sort of genetic conditions

02:05:07.740 | that impair cholesterol synthesis,

02:05:10.580 | depending on their severity, they can be fatal in utero.

02:05:14.300 | So in other words, anything that really interferes

02:05:16.780 | with our ability to produce cholesterol

02:05:19.380 | is a threat to us as a species.

02:05:23.020 | And the reason for that is cholesterol makes up

02:05:26.440 | the cell membrane of every cell in our body.

02:05:29.460 | So as you know, but maybe the listeners don't,

02:05:33.020 | even though a cell is a spherical thing,

02:05:35.180 | it has to be fluid, right?

02:05:36.900 | It's not just a rigid sphere, like a blow up ball, right?

02:05:41.340 | It's gotta be able to kind of move in this way

02:05:44.940 | to mesh with other cells.

02:05:47.380 | It also has to accommodate having porous structures

02:05:50.620 | that traverse its membrane to allow ions

02:05:54.340 | and things like that to go across.

02:05:56.700 | And it's cholesterol that gives the fluidity

02:05:59.420 | to that membrane.

02:06:01.140 | It's also, as you're alluding to,

02:06:02.900 | the backbone of some of the most important hormones

02:06:06.220 | in our body, estrogen, progesterone,

02:06:09.260 | testosterone, cortisol.

02:06:11.460 | So we have this thing, super important.

02:06:14.580 | Okay, then let's talk about, does cholesterol,

02:06:17.940 | can you get cholesterol in your diet?

02:06:20.220 | Yes, you can eat foods that are rich in cholesterol.

02:06:23.380 | What was known in 1960, but somehow escaped

02:06:29.820 | everybody's imagination until finally,

02:06:32.640 | the American Heart Association acknowledged this

02:06:34.540 | a few years ago, is that the cholesterol you eat

02:06:37.980 | does not really make it into your body.

02:06:40.260 | And the reason for that is it's hysterified.

02:06:42.700 | So we have, and not to get too nerdy,

02:06:45.080 | but I think people, I really think it's important

02:06:47.500 | people understand how this thing works.

02:06:48.740 | So we have cells in our gut, enterocytes,

02:06:51.820 | they're the endothelial cells of our gut.

02:06:54.420 | They have, each one of them has basically

02:06:57.540 | two transporters on them.

02:06:58.740 | So the first is called the Niemann-Pick C1-Like1 transporter.

02:07:03.040 | The second is called the ATP-Binding cassette G5-G8.

02:07:07.040 | Okay, the Niemann-Pick C1-Like1 transporter

02:07:11.460 | will bring in any sterile, cholesterol,

02:07:14.840 | zosterol, phytosterol, any sterile

02:07:17.520 | that fits through the door will come in.

02:07:19.520 | Virtually all of that is the cholesterol we produce

02:07:25.240 | that gets taken back to the liver,

02:07:27.480 | that the liver packages in bile and secretes.

02:07:30.960 | So that's what aids in our digestion,

02:07:32.800 | which is another thing I should have mentioned earlier.

02:07:34.420 | In addition to using cholesterol

02:07:36.780 | for cell membranes and hormones,

02:07:38.780 | we wouldn't be able to digest our food without cholesterol

02:07:41.200 | because it's what makes up the bile salts.

02:07:44.080 | So our own cholesterol is basically recirculated

02:07:47.200 | in a pool throughout our body,

02:07:48.880 | and this is the way it gets back into the body.

02:07:51.580 | It's through this Niemann-Pick C1-Like1 transporter.

02:07:54.720 | When it gets in there, the body,

02:07:56.640 | this is the checkpoint of regulation.

02:07:58.560 | This is where the body says,

02:07:59.460 | "Do you have enough cholesterol in the body, yes or no?"

02:08:02.340 | If yes, I will let that cholesterol

02:08:05.160 | make its way into the circulation.

02:08:07.360 | So it'll go off the basolateral side of the cell,

02:08:10.060 | not the luminal side, into the body.

02:08:12.080 | Alternatively, the body says,

02:08:13.600 | "You know what, we have enough cholesterol.

02:08:16.100 | I'm gonna let you poop this out."

02:08:17.440 | And now the ATP binding cassette will shoot it out.

02:08:20.040 | It'll go back into the luminal side, and away it goes.

02:08:25.040 | So all of the cholesterol in our body is not esterified,

02:08:27.900 | meaning it doesn't have that big,

02:08:29.140 | bulky side chain attached to it.

02:08:31.840 | The cholesterol you eat is esterified,

02:08:34.460 | and an esterified cholesterol molecule

02:08:37.180 | simply can't physically pass

02:08:38.940 | through that Niemann-Pick C1-Like1 transporter.

02:08:41.200 | Now, we probably manage to deesterify

02:08:46.200 | 10 to 15% of our dietary cholesterol.

02:08:50.260 | So in other words, there are small amounts

02:08:52.340 | of dietary cholesterol that do make their way

02:08:54.880 | into our circulation, but it represents a small fraction

02:08:59.780 | of our total body's pool of cholesterol.

02:09:02.160 | Again, this was known even by Ancel Keys,

02:09:05.420 | the guy who turned fat into the biggest boogeyman

02:09:08.560 | of all time.

02:09:09.580 | Ancel Keys acknowledged this in the 1960s.

02:09:12.760 | Dietary cholesterol plays no role in serum cholesterol.

02:09:16.040 | Again, it took the American Heart Association

02:09:19.120 | another 60 years to figure that out,

02:09:21.380 | but even now they acknowledge that.

02:09:23.560 | Dietary cholesterol has no bearing.

02:09:25.500 | - So why is it that it's pretty easy to find studies,

02:09:29.980 | or at least people who are highly credentialed

02:09:32.960 | from good institutions, claiming that eating

02:09:35.620 | saturated fat, cheese, and-- - Saturated fat's different.

02:09:38.380 | - Saturated fat, red meat, things that are rich

02:09:40.560 | in cholesterol, to be more specific,

02:09:44.760 | is bad for us in terms of our eventual LDL.

02:09:47.940 | - So this is two different things.

02:09:49.140 | So saturated fat consumption in many people

02:09:52.660 | will raise LDL cholesterol.

02:09:54.900 | So it's important to differentiate between the,

02:09:57.740 | what is saturated fat?

02:09:58.940 | So saturated fat, of course, is a fatty acid,

02:10:00.880 | just so people understand, totally different molecule

02:10:03.060 | from cholesterol.

02:10:03.900 | Cholesterol is this very complicated ring structure,

02:10:06.000 | multiple rings stuck together.

02:10:08.140 | SFA, saturated fat, is just a long chain fatty acid

02:10:11.360 | that is fully saturated, meaning it has no double bonds,

02:10:14.200 | and it can exist in isolation, it can exist

02:10:16.920 | in a triglyceride, triacylglyceride,

02:10:19.560 | or a phospholipid, or all sorts of things like that.

02:10:23.180 | So when we eat foods that contain fat,

02:10:27.780 | basically there are three distinctions for that fat.

02:10:30.380 | Is it saturated?

02:10:31.480 | Is it monounsaturated, one double bond?

02:10:33.260 | Or is it polyunsaturated, two or more double bonds?

02:10:35.860 | The observation that eating saturated fat

02:10:40.680 | raises cholesterol is generally correct.

02:10:43.980 | But again, now it makes, because if we're gonna start

02:10:46.920 | talking about LDL, we have to explain what LDL is.

02:10:49.160 | This is another one of those things

02:10:50.180 | that's just so grossly misunderstood

02:10:52.420 | that it makes having discussions about this very complicated.

02:10:57.420 | Let's go back to the cholesterol problem, right?

02:11:00.380 | So every cell in our body makes cholesterol,

02:11:04.460 | and almost without exception, they make enough.

02:11:08.500 | There are a handful of times, however,

02:11:11.340 | when a cell needs to borrow cholesterol from another cell.

02:11:14.980 | Okay, so how would you do this, right?

02:11:18.000 | So if you're playing God for a minute

02:11:20.900 | and you wanna design a system,

02:11:22.760 | you have to be able to transport cholesterol

02:11:24.980 | from one cell to another.

02:11:27.000 | The most logical place you would transport this

02:11:30.140 | is through the circulation.

02:11:31.580 | And the problem with circulation is it's water.

02:11:35.220 | Plasma is water.

02:11:36.900 | So now you have this problem,

02:11:38.220 | which is I want to transport cargo that is hydrophobic

02:11:43.220 | in a hydrophilic medium, can't do it.

02:11:46.780 | So if you think about all the things

02:11:48.340 | that we transport in our blood, sodium, electrolytes,

02:11:52.920 | glucose, things like that, they're water soluble.

02:11:56.540 | It's easy.

02:11:57.380 | They just move back and forth in our blood with no chaperone.

02:11:59.860 | But when you wanna move cholesterol,

02:12:01.980 | you have to package it in something that's hydrophilic.

02:12:04.980 | That something is called a lipoprotein.

02:12:07.940 | So we have these spherical molecules

02:12:10.500 | that are lipid on the inside,

02:12:11.980 | protein on the outside, lipoprotein,

02:12:14.800 | and inside they contain cholesterol and triglycerides.

02:12:18.200 | So now you've got the spherical thing,

02:12:20.560 | triglyceride, cholesterol on the inside,

02:12:23.140 | and it's chaperoned by a hydrophilic molecule

02:12:26.520 | that allows it to move through our circulation.

02:12:30.360 | And those lipoproteins exist in different densities.

02:12:34.320 | So if you run these out on a gel electrophoresis plate,

02:12:37.360 | you'll identify different densities.

02:12:39.160 | The density is a function of how much protein

02:12:40.980 | and how much lipid is in it.

02:12:42.740 | So the highest density of this is called

02:12:44.940 | a high density lipoprotein.

02:12:47.000 | And the lowest density of this is called

02:12:49.020 | a very low density lipoprotein, a VLDL.

02:12:52.600 | And then next to that, you have an LDL,

02:12:54.740 | a low density lipoprotein.

02:12:56.200 | And then next to that, you have an IDL,

02:12:57.800 | an intermediate density lipoprotein.

02:12:59.940 | So, you know, it actually goes VLDL, IDL, LDL.

02:13:06.260 | But anyway, so when people say my LDL is high

02:13:12.260 | or my LDL is 100, what are they saying?

02:13:15.400 | They're saying the cholesterol concentration

02:13:17.800 | of my LDL particles is 100 milligrams per deciliter.

02:13:21.500 | So the total cholesterol concentration you have

02:13:24.580 | in your circulation is that number

02:13:27.120 | that says total cholesterol.

02:13:28.000 | So if someone's blood panel says my total cholesterol is 200,

02:13:30.560 | it means that if you take all the lipoproteins

02:13:33.000 | in their circulation, bust them open,

02:13:34.880 | and measure the cholesterol content,

02:13:36.400 | it's 200 milligrams per deciliter.

02:13:38.440 | And for all intents and purposes,

02:13:40.560 | because the IDLs are so short-lived,

02:13:42.940 | that's basically the sum of your LDL cholesterol,

02:13:45.360 | your VLDL cholesterol, and your HDL cholesterol.

02:13:47.900 | Those three things sum to your total cholesterol.

02:13:51.580 | - What about LDL little a that you mentioned earlier?

02:13:53.700 | - LP little a is another, yeah, yeah.

02:13:55.460 | He's another actor.

02:13:56.460 | He is a special type of LDL that, again,

02:14:00.380 | in sort of 10 to 20% of the population

02:14:02.900 | is a really bad actor.

02:14:04.540 | So that's an LDL that has another apolipoprotein on it

02:14:09.140 | called apolipoprotein little a.

02:14:11.540 | The other thing I'll just say on this,

02:14:14.540 | because earlier I mentioned apoB,

02:14:16.960 | there are two broad families of lipoproteins.

02:14:19.880 | There are those that are wrapped in apoBs

02:14:22.120 | and those that are wrapped in apoAs.

02:14:24.400 | The apoA family is the HDL family.

02:14:27.300 | The apoB family is the VLDL, IDL, LDL family.

02:14:31.860 | - I see.

02:14:32.700 | So for somebody who, let's say their total cholesterol is,

02:14:35.220 | let's just stay with 200 for simplicity,

02:14:37.860 | what do you like to see in terms of the HDL/LDL ratio?

02:14:41.660 | - Couldn't care less.

02:14:43.100 | I only care about apoB.

02:14:45.380 | I only care about apoB.

02:14:47.700 | I care about the causative agent of atherosclerosis.

02:14:51.180 | ApoB is the thing that drives atherosclerosis.

02:14:54.580 | - And what levels are attractive or repulsive for you

02:14:58.140 | when you see levels of apoB that are blank,

02:15:02.120 | you get really concerned, what rate-

02:15:04.780 | - It depends on the person's objectives.

02:15:06.940 | So again, we take a very different view.

02:15:10.540 | I mean, we have-

02:15:12.260 | - Vitality now, and I want to live to be 100.

02:15:15.380 | I'm assuming some taper-

02:15:16.860 | - If you tell me you want to live to be 100,

02:15:18.620 | you're going to need to keep your apoB

02:15:20.180 | below 30 milligrams per deciliter.

02:15:22.380 | - Let's say I want to live to be 100,

02:15:25.140 | but I also, well, how about I don't care how long I live,

02:15:29.660 | but I want to feel great while I live.

02:15:32.560 | - Again, it depends, right?

02:15:33.840 | Like anybody who's had a heart attack

02:15:35.340 | is going to be compromised in their ability

02:15:37.180 | to feel well after, right?

02:15:40.100 | - I guess I say it that way,

02:15:42.220 | because if you're going to tell me

02:15:43.340 | that in order to achieve that live to 100 level,

02:15:46.940 | I'm going to have to give up my personal life

02:15:50.100 | and my brain functioning,

02:15:53.040 | then I'm not really interested in that.

02:15:54.300 | - Sure, but to get LDL levels,

02:15:57.060 | and really, again, people think of it as LDL,

02:15:58.900 | it's really apoB, right?

02:16:00.180 | ApoB is this total concentration of LDL and VLDL,

02:16:04.300 | and that's what matters.

02:16:05.140 | Those are the big atherogenic particles.

02:16:06.940 | LDL also includes the Lp(a),

02:16:10.180 | although the concentration of Lp(a)

02:16:11.660 | is relatively speaking so small

02:16:13.740 | that it doesn't generally show up as much in the apoB.

02:16:16.860 | So we treat apoB, and basically what it comes down to

02:16:20.300 | is you want apoB to be as close to the level

02:16:23.420 | as it was when you were born.

02:16:24.980 | So we start developing heart disease when we're born.

02:16:27.900 | That's just the way it is.

02:16:29.940 | The autopsy studies make this abundantly clear.

02:16:32.940 | When you look at autopsies of young people

02:16:36.260 | who are dying in their 20s,

02:16:37.560 | and this was first done in the 1970s,

02:16:39.400 | it was again repeated.

02:16:40.740 | Again, it's always done after we have a war, right?

02:16:42.540 | So in the 1970s, it was done on people who died in Vietnam.

02:16:46.160 | In the early 2000s, it was done on mostly young men

02:16:49.020 | but some young women who were dying in Iraq and Afghanistan.

02:16:52.460 | And we saw without any ambiguity

02:16:54.580 | that cardiovascular disease is already taking hold

02:16:56.900 | in people who are 18, 19, 20 years old.

02:17:00.140 | And to be clear, they aren't gonna die of atherosclerosis

02:17:03.220 | at that age.

02:17:04.060 | They're still 40, 50 years away from it,

02:17:06.100 | but this is a lifelong disease.

02:17:09.260 | And we also know that the disease can't really develop

02:17:12.940 | until apoB reaches a certain threshold.

02:17:16.060 | And that's the threshold that most of us get to

02:17:17.580 | by the time we're sort of in our teens.

02:17:20.000 | So it's this really young apoB level

02:17:23.300 | of kind of 20 to 30 milligrams per deciliter

02:17:26.460 | that makes it impossible to get atherosclerosis.

02:17:28.940 | So apoB is necessary, but not sufficient to develop ASCVD.

02:17:33.940 | Now that, go ahead.

02:17:35.380 | - Oh, I'm sorry, I was just gonna ask,

02:17:36.520 | what are some of the top behavioral,

02:17:38.480 | nutritional supplementation, if any,

02:17:41.380 | based and prescription drug based ways to target apoB?

02:17:45.820 | - Well, nutritionally, you basically have two big tools,

02:17:50.180 | right, and it depends on what's driving up apoB.

02:17:52.660 | So apoB, remember, is the concentration

02:17:56.080 | of LDL and VLDL particles.

02:17:58.260 | And what do they carry?

02:18:00.500 | Cholesterol and triglycerides.

02:18:02.180 | So anything that reduces cholesterol

02:18:05.340 | and reduces triglycerides is going to reduce apoB.

02:18:09.840 | Triglycerides are generally driven by carbohydrate intake.

02:18:13.700 | So more insulin resistance, more carbohydrate intake,

02:18:17.300 | more triglycerides.

02:18:19.020 | So we, I mean, clinically, this is readily apparent

02:18:22.460 | to anyone who treats patients.

02:18:23.860 | If you restrict carbohydrates,

02:18:25.360 | you will reduce triglycerides.

02:18:27.100 | That just happens all day long.

02:18:29.020 | But if you reduce triglycerides

02:18:30.540 | by raising fat intake so much, it can still raise apoB.

02:18:35.220 | So you have to be able to think about it.

02:18:37.020 | So in an ideal world, it's can you lower saturated fat,

02:18:41.700 | which tends to be the one that is most driving apoB,

02:18:44.900 | while lowering carbohydrate, and then see what you can get.

02:18:48.060 | But here's the reality of it is,

02:18:49.580 | there's nobody with dietary intervention

02:18:51.860 | that's going to get to a level

02:18:52.940 | of 30 milligrams per deciliter.

02:18:54.620 | I mean, I've never seen anybody--

02:18:55.740 | - Under dietary intervention.

02:18:57.040 | - Yeah.

02:18:57.880 | - So what are the other things--

02:18:58.700 | - It's got to be pharmacologic at this point.

02:18:59.900 | - Statin type interventions.

02:19:01.220 | - Well, now you have multiple classes of drugs.

02:19:03.040 | So the tried and true is the statin.

02:19:05.140 | So statins work by inhibiting cholesterol synthesis.

02:19:08.280 | And the net effect of that is that the,

02:19:10.980 | so the liver is really sensitive to cholesterol levels.

02:19:13.620 | It doesn't want too much, it doesn't want too little.

02:19:15.860 | When you inhibit cholesterol synthesis,

02:19:18.100 | the liver says, I want more cholesterol.

02:19:20.780 | So it puts more LDL receptors on its surface

02:19:23.660 | and it pulls the LDL out of circulation.

02:19:26.620 | That's what lowers the LDL in the circulation.

02:19:30.780 | So again, nine statins in use today.

02:19:35.840 | We typically use four of them.

02:19:38.760 | The side effect profile,

02:19:40.060 | contrary to kind of all the sort of statin-hating

02:19:43.420 | propaganda out there, very benign, right?

02:19:46.100 | 5% of people experience muscle soreness,

02:19:48.280 | which reverses upon cessation.

02:19:52.660 | - Cognitive effects.

02:19:54.580 | - Again, I think it's,

02:19:56.820 | in terms of actual comparing it at a placebo,

02:19:59.100 | no effect whatsoever, right?

02:20:00.380 | So does that mean that you put a patient on it,

02:20:02.320 | they won't complain of something?

02:20:03.700 | No, but if you look at clinical trials,

02:20:05.700 | there's no evidence whatsoever

02:20:07.380 | that statins impair cognition.

02:20:09.340 | There's also no evidence in clinical trials

02:20:11.220 | that they accelerate the risk of neurodegenerative disease.

02:20:13.200 | In fact, it's the opposite.

02:20:14.540 | Now we will, there's a very nuanced case we make, Andrew,

02:20:18.500 | which is we'll look at patients

02:20:19.860 | with highly suppressed desmosterol levels.

02:20:23.300 | We will back off.

02:20:24.700 | We do want to maintain desmosterol above a certain level

02:20:28.380 | because of some evidence that is still,

02:20:31.700 | I think, very preliminary,

02:20:32.860 | but enough for us that we say, why take the chance?

02:20:35.140 | We have so many other tools to lower cholesterol.

02:20:37.180 | Why would we over suppress synthesis

02:20:39.340 | in a susceptible individual?

02:20:40.840 | So the next tool you look at is a drug

02:20:45.500 | that blocks the absorption or the reabsorption of cholesterol.

02:20:49.080 | Remember that Niemann-Pixie-1-like-1 transporter?

02:20:51.580 | So that guy has a drug called ezetimibe

02:20:55.520 | that just mechanically blocks it.

02:20:57.280 | So in people, and that's why I mentioned earlier,

02:21:01.340 | we measure all those sterols in people,

02:21:03.580 | so we also measure things called phytosterols,

02:21:05.700 | and the phytosterols give us an indication

02:21:07.460 | of how active that transporter is.

02:21:09.320 | So the higher your phytosterols,

02:21:10.640 | the more likely you are to respond to ezetimibe.

02:21:13.600 | Next class of drugs is a drug

02:21:15.960 | that blocks cholesterol synthesis, but only in the liver.

02:21:18.300 | So the statin does it globally.

02:21:19.920 | This other drug called benbedoic acid

02:21:23.420 | does it only in the liver.

02:21:24.600 | So it has a very similar mechanism to statins,

02:21:26.720 | different enzyme, not quite as potent,

02:21:29.860 | but way fewer side effects.

02:21:31.220 | So any patient that's having a response

02:21:32.620 | to statins that's adverse, we'll try this other thing.

02:21:35.940 | - What's it called one more time?

02:21:37.060 | - Benbedoic acid.

02:21:37.900 | - Benbedoic acid.

02:21:39.180 | - The most potent drug of the lot is the PCSK9 inhibitor.

02:21:42.980 | So PCSK9, it's a protein that was discovered

02:21:46.100 | in the late '90s, I believe,

02:21:48.980 | is responsible for the degradation of LDL receptors.

02:21:53.440 | This was first discovered in people

02:21:55.820 | who had a condition called familial hypercholesterolemia,

02:21:58.460 | or FH.

02:21:59.420 | So these are people that have incredibly high cholesterol.

02:22:01.700 | Typically, their total cholesterol level is 300.

02:22:05.580 | Their LDL cholesterol is typically

02:22:08.220 | north of 200 milligrams per deciliter.

02:22:10.180 | This is a disease that is defined by the phenotype,

02:22:14.320 | not the genotype.

02:22:15.160 | So the phenotype has a very clear definition,

02:22:17.120 | which I basically just gave you.

02:22:18.700 | The genotype is there's a million paths to get there.

02:22:21.680 | There's over 3,000 mutations that are known

02:22:23.700 | to produce that phenotype.

02:22:25.080 | This was discovered to be one of them.

02:22:26.880 | In people who had hyperfunctioning PCSK9,

02:22:29.880 | this protein was just constantly hammering

02:22:35.500 | and destroying the LDL receptors,

02:22:37.620 | and so their LDL would be huge.

02:22:40.020 | And by extension, their total cholesterol would be.

02:22:41.840 | So in 2006, Helen Hobbs and colleagues

02:22:46.840 | discovered an opposite group of population,

02:22:49.820 | people who had LDL cholesterol naturally

02:22:52.420 | of 10 to 20 milligrams per deciliter,

02:22:55.020 | which would be an ApoB of about 20 milligrams

02:22:57.180 | per deciliter, and who never got heart disease.

02:23:00.820 | They were immune to heart disease,

02:23:01.860 | no matter how long they lived.

02:23:03.180 | And they had the opposite.

02:23:04.240 | They had hypofunctioning PCSK9.

02:23:07.060 | And so that was 2006 in the New England Journal of Medicine.

02:23:09.160 | That basically got a whole bunch of drug companies

02:23:11.160 | hot on the trail of producing a drug to mimic it.

02:23:13.980 | So now we have these antibodies,

02:23:15.740 | and they're wildly effective.

02:23:17.780 | - What percentage of your patients over 45

02:23:21.260 | do you have on either a statin

02:23:24.100 | or on one of these other classic compounds?

02:23:25.380 | - Well, often it's in combinations,

02:23:27.100 | and I would say 80%.

02:23:29.260 | - Eight zero.

02:23:30.100 | - We have to remember what our objective is.

02:23:31.700 | Like, we're in the business of trying

02:23:34.180 | to make sure people live as long as possible.

02:23:36.760 | And you have to take a sort of worldview of this, right?

02:23:39.620 | If you, like, what's the most prevalent

02:23:41.360 | cause of death globally?

02:23:42.760 | - It's the cardiovascular disease.

02:23:43.580 | - Yeah, and like, how close is it?

02:23:45.640 | So the last year before COVID,

02:23:48.340 | COVID kind of messes up these numbers a little bit.

02:23:49.800 | But if you go to 2019, 18.6 million people

02:23:54.800 | died of heart disease.

02:23:56.740 | Number two, cancer, 10 million.

02:23:59.260 | Like, nothing's in the zip code of atherosclerosis.

02:24:05.040 | And if you remember what I just said,

02:24:06.640 | if you took everybody in their 20s

02:24:09.700 | and reduced them to a level of that of a child,

02:24:14.060 | you'd make ASCVD an orphan disease.

02:24:16.460 | So the question is, can you do that?

02:24:20.080 | - Why don't we hear more about this?

02:24:21.260 | I realize there's some nuance.

02:24:22.460 | It's not straightforward.

02:24:24.000 | It's not as simple as saying eat less cheese, red meat,

02:24:26.480 | and watch your LDL get on a statin.

02:24:29.520 | But why do we hear so little about ApoB

02:24:33.600 | in the general discussion?

02:24:35.060 | Social media is such a skewed landscape, as we know.

02:24:38.600 | People shouting into tunnels of varying clarity.

02:24:44.600 | Some are beautiful bronze tunnels

02:24:48.600 | with clean walls and others are sewer lines, right?

02:24:51.060 | [laughing]

02:24:52.300 | And they all converge in the same place, right, as we know.

02:24:55.740 | But why do we hear so little about this?

02:24:57.400 | I mean, I'm not on a statin,

02:24:59.460 | but now I'm beginning to think that

02:25:00.620 | maybe that might be a good idea to consider

02:25:02.320 | one of these other compounds.

02:25:04.000 | I don't know the last time I looked

02:25:05.280 | at my ApoBs specifically.

02:25:06.560 | I'm guessing my physician did.

02:25:07.780 | But why don't we hear more about this?

02:25:10.520 | This sounds so important.

02:25:12.920 | It sounds like the most important conversation

02:25:14.720 | 'cause all the hormone stuff and all the stuff

02:25:16.820 | about smoking and head injuries and ADHD and all the rest,

02:25:21.820 | I mean, is irrelevant if you're dead, right?

02:25:24.400 | - Yeah, it's a good question.

02:25:26.160 | I don't think I have a great insight

02:25:27.500 | as to why this isn't more front and center.

02:25:32.180 | I think the bigger problem is

02:25:34.360 | why don't we even understand how to think about it?

02:25:36.460 | I mean, and there's a whole chapter in my book

02:25:39.260 | I'm working on that really gets to this problem

02:25:42.020 | of why aren't we looking at atherosclerosis

02:25:46.820 | in terms of treating the causative agent?

02:25:49.380 | Instead, we look at modifying 10-year risk.

02:25:53.020 | So that's the fundamental difference

02:25:54.180 | between what I call medicine 2.0 and medicine 3.0.

02:25:56.940 | Medicine 2.0, which is what we're generally practicing today,

02:26:00.080 | when it comes to ASCVD, says,

02:26:01.520 | look, we will treat you.

02:26:03.460 | We will lower that LDL cholesterol.

02:26:05.280 | They still don't talk about ApoB,

02:26:06.560 | but that's a very American thing.

02:26:08.320 | If you go outside of the United States,

02:26:09.740 | everybody's talking about ApoB.

02:26:11.020 | It's in the guidelines in Europe and Canada, everywhere else.

02:26:13.240 | The United States is very stubborn on this,

02:26:15.660 | and it's due to a couple of really weird personalities

02:26:18.020 | in the lipid world.

02:26:19.080 | But the paradigm is when your 10-year risk reaches 5%,

02:26:28.340 | and there's a 5% chance

02:26:30.700 | that you're gonna have a heart attack, stroke, or die

02:26:32.540 | in the next 10 years, now it's time to treat you.

02:26:35.060 | Medicine 3.0 says that's not the way to think about it.

02:26:39.400 | You treat the causative agent.

02:26:41.700 | If there's a causative agent, you treat it.

02:26:44.500 | If blood pressure raises the risk of heart disease,

02:26:46.940 | you lower blood pressure.

02:26:48.380 | If smoking raises the risk of something, you treat smoking.

02:26:51.340 | And the reason that the risk model is so bad

02:26:57.140 | when you're looking at 10-year risk

02:26:58.520 | is age is the biggest driver of risk.

02:27:01.400 | I mean, bar none, right?

02:27:02.480 | So if you take a 70-year-old with perfect lipids

02:27:07.080 | and perfect blood pressure and perfect everything,

02:27:10.040 | their 10-year risk of ASCVD is probably

02:27:14.040 | four to five times higher

02:27:16.480 | than the most unhealthy 30-year-old.

02:27:19.080 | It's not even close.

02:27:20.040 | - It's a lot like eye disease.

02:27:21.960 | There are exceptions, of course,

02:27:23.100 | but you always say that the biggest risk factor

02:27:24.640 | for going blind from glaucoma is being an older person,

02:27:28.200 | frankly.

02:27:30.200 | - Right, so if you could identify

02:27:31.480 | what the risk factors are for glaucoma,

02:27:33.720 | imagine if the paradigm was we're only gonna treat it

02:27:37.720 | when your risk of blindness reaches 5%,

02:27:40.320 | which isn't triggered until you're old enough.

02:27:42.400 | Anyway, wouldn't you rather know that when you're 30

02:27:45.120 | and say, wait, if maybe being in the sun without sunglasses

02:27:48.320 | or using this type of eye drop or something like that

02:27:51.520 | has a negative impact, I would rather know that sooner.

02:27:53.960 | So that's the fundamental difference.

02:27:56.600 | It's a philosophical difference with respect to prevention.

02:28:01.600 | And I will acknowledge that in one element of prevention,

02:28:06.160 | I make no consideration.

02:28:08.160 | I am only coming at this through the lens of the individual.

02:28:11.040 | I am never coming at this through the lens of society.

02:28:13.960 | That makes my life easier

02:28:16.200 | and it makes the problem I'm solving easier.

02:28:17.660 | I don't have to answer

02:28:19.040 | the quality-adjusted life of your problem.

02:28:21.240 | I don't have to ask the question, is it economical

02:28:24.520 | to treat people at 30?

02:28:26.700 | I don't know the answer to that question.

02:28:27.900 | But I also know that when you're trying to solve

02:28:29.520 | really complicated problems,

02:28:30.520 | the more you can simplify, the better.

02:28:31.960 | So I've just acknowledged openly, not solving that.

02:28:34.840 | If you wanna criticize me for it, that's fine.

02:28:36.760 | Let's be transparent.

02:28:38.240 | But all I care about is the person I'm sitting across from.

02:28:41.000 | And in that situation, it's really their decision

02:28:43.800 | if they can justify the cost of treatment.

02:28:46.640 | - An esoteric question and then a less esoteric question.

02:28:50.320 | The esoteric question relates to something

02:28:52.480 | that I think is a little bit niche, but not necessarily so,

02:28:56.580 | which is peptides and stem cells and PRP.

02:29:00.280 | I don't wanna go off on too much of a tangent on rehab,

02:29:02.760 | but I know you've done a number of posts

02:29:04.240 | on social media recently that were,

02:29:06.040 | I have to just tell you, are really thoughtful

02:29:07.720 | and I really appreciate that you're willing to share

02:29:09.240 | your own tissue rehabilitation experience

02:29:12.280 | and point people to that because this is a landscape

02:29:14.680 | that a lot of people are in

02:29:16.000 | and they don't know how to navigate it.

02:29:17.720 | And a mutual friend of ours, not to be named,

02:29:20.240 | sent me a text and said, I'm gonna be talking to Atiyah

02:29:23.600 | and what do you know about studies on things like BPC-157,

02:29:27.320 | this gastric peptide, that anecdotally,

02:29:30.480 | again, anecdotally, people report getting injections of this

02:29:34.440 | in the shoulder, knee, et cetera,

02:29:35.920 | and feeling so much better, so much faster,

02:29:38.080 | but there really aren't good studies, controlled studies.

02:29:42.380 | And you hear all the same sorts of things

02:29:44.880 | about platelet-rich plasma, PRP,

02:29:47.760 | which if someone tells you there are a lot of stem cells in

02:29:50.120 | them, they're lying,

02:29:51.280 | there are not a lot of stem cells in them.

02:29:52.720 | And you also hear about stem cells,

02:29:54.080 | which are not FDA approved, at least in this, you know,

02:29:56.440 | for most uses in this country,

02:29:57.720 | but are certainly people are flying down to Columbia

02:29:59.900 | and getting injections.

02:30:00.920 | And what is your understanding or experience

02:30:04.120 | with things like BPC-157 specifically,

02:30:06.920 | 'cause peptides is a huge landscape,

02:30:08.380 | we should probably do a whole episode on peptides,

02:30:10.580 | things like PRP, PRP is now approved for,

02:30:14.280 | I mean, women are getting injections of this

02:30:15.760 | into their ovaries to improve follicle count.

02:30:19.360 | We know this, people are getting injections of PRP

02:30:21.520 | into every tissue and organ,

02:30:23.200 | and hell, men are getting injected into their penis,

02:30:25.880 | so I hear, for all sorts of reasons that are unclear to me.

02:30:30.420 | What's the deal with PRP, BPC-157, and stem cells?

02:30:35.800 | Do you ever see interesting effects?

02:30:38.040 | Are you curious about these compounds?

02:30:40.840 | Do you prescribe or direct people towards these?

02:30:43.440 | The FDA approved ones, of course.

02:30:44.560 | - Yeah, so short answer is I'm definitely curious about them

02:30:47.560 | and I'd love to see the work done,

02:30:48.900 | but I also think this is about as wild, wild west

02:30:51.920 | as it gets.

02:30:53.040 | PRP less so, but certainly stem cells and peptides.

02:30:57.920 | And, you know, I just think,

02:31:00.060 | if you're gonna do something without a clinical trial,

02:31:04.840 | you gotta show up with a lot more data, right?

02:31:06.520 | So let's use rapamycin as an example, right?

02:31:08.600 | I'm a huge proponent of rapamycin,

02:31:10.240 | and you can say, well, Peter, how can you take

02:31:12.560 | or prescribe rapamycin for zero protective effects

02:31:15.840 | when we do not have a human clinical trial

02:31:17.560 | demonstrating that it lengthens life?

02:31:19.880 | And the answer is because I have 84 other pieces of data

02:31:24.740 | that all point in the same direction

02:31:27.760 | across every model organism going back

02:31:30.440 | more than a billion years.

02:31:31.960 | And that's really different from Joey, Sammy,

02:31:37.200 | and Sally did this thing, and I think it works.

02:31:40.680 | And they just can't be compared.

02:31:43.080 | Now, I have no idea if stem cells work.

02:31:46.220 | I have no idea if BPC157 works.

02:31:49.480 | I have no idea, frankly, if PRP even works,

02:31:52.620 | though it might seem to have some efficacy

02:31:54.680 | and some indications.

02:31:55.900 | For example, maybe when it comes to early hair loss,

02:31:59.360 | maybe when it comes to, you know, certain joint issues.

02:32:03.640 | But the reality of it is like,

02:32:06.360 | I think we just have to accept the fact

02:32:08.240 | that everything we do has an opportunity cost,

02:32:11.440 | and that opportunity cost is sometimes financial,

02:32:15.020 | but I actually find a lot of times it's in time

02:32:18.480 | and effort and energy that goes into something.

02:32:20.880 | Now, when I was, you know,

02:32:23.560 | waiting to get my shoulder surgery,

02:32:24.980 | this is an injury that I've had forever, right?

02:32:27.000 | This is an injury, you know,

02:32:28.640 | this injury was actually probably the greatest source

02:32:33.080 | of discomfort I had swimming the Catalina Channel

02:32:35.640 | the last time in 2009.

02:32:37.000 | So that tells you how long I've had this injury.

02:32:39.400 | But, you know, I sort of knew at some point,

02:32:41.980 | like I'm gonna have to have it fixed.

02:32:44.100 | And I sort of went down this rabbit hole like,

02:32:46.160 | hey, is there anything I can do to avoid having surgery?

02:32:48.560 | You know, would infusing a million stem cells into it work?

02:32:52.080 | And in speaking with as many orthopedic surgeons as I could,

02:32:56.400 | the answer was kind of unambiguously no.

02:33:00.040 | And by the way, it doesn't mean you wouldn't feel better

02:33:01.740 | if I injected a bunch of stem cells into your shoulder.

02:33:03.920 | There are a lot of reasons that might make you feel better,

02:33:05.840 | just like there are a bunch of reasons you can feel better

02:33:07.940 | if somebody injects saline directly into your joint.

02:33:10.800 | So the question is, is it going to fix the underlying

02:33:14.800 | problem and if so, will it do so by what mechanism?

02:33:17.480 | So I'm pretty sure that if you took 1,000 people

02:33:21.200 | with my particular injury and injected them with stem cells,

02:33:25.040 | it wouldn't do a thing because of the nature of my injury.

02:33:27.760 | I had a complete labral tear.

02:33:29.600 | Are there some injuries that might benefit from it?

02:33:33.400 | Yeah, possible.

02:33:34.800 | So the question is, how would you design the trial

02:33:37.400 | to narrow down your patient population correctly

02:33:41.000 | so that you might see a signal?

02:33:42.680 | 'Cause the other risk of doing a trial is you have too much

02:33:46.240 | of a heterogeneous patient population.

02:33:48.840 | You don't know what the heck you're really doing

02:33:51.040 | and you get meaningless results.

02:33:53.120 | You get a null result when in fact there's a small signal,

02:33:55.660 | but you were underpowered to pick it up

02:33:57.600 | because you only had 10% of your patient population

02:34:00.720 | that was the right patient population to get that.

02:34:03.220 | So will we ever get there?

02:34:05.660 | I don't know because I don't see what the incentive is.

02:34:08.500 | You have people who are making money hand over fist

02:34:11.300 | doing procedures on the basis of I'm not sure what,

02:34:16.240 | what would their motivation or incentive be

02:34:18.500 | to sort of see this legitimized.

02:34:21.160 | You'd really have to be able to say,

02:34:22.560 | well, there really needs to be sort of a pharma angle

02:34:25.100 | to this.

02:34:25.940 | It's sort of one of the wishes I had.

02:34:29.180 | Like if I was a billionaire, I feel like the way

02:34:33.160 | I would probably waste all of my money

02:34:34.980 | would be running clinical trials

02:34:36.760 | on stuff nobody cared about.

02:34:38.620 | It would just be-- - Likewise.

02:34:39.820 | I would join you because that would be,

02:34:41.680 | yesterday we recorded a sit down with somebody from Caltech

02:34:45.980 | who works on aggression and rage

02:34:49.340 | and other things related to that

02:34:50.940 | and has identified peptides that are approved the FDA

02:34:54.580 | for other reasons that seem to adjust anxiety,

02:34:57.260 | might even adjust aggression and pathologic aggression

02:35:00.260 | and went off on to a long description

02:35:02.060 | of why none of these drugs exist on the market

02:35:04.220 | for the treatment of psychiatric illness

02:35:05.640 | and yet probably would work.

02:35:07.960 | And what's missing is a billionaire

02:35:12.400 | or a billion dollar company that is willing to invest

02:35:15.560 | in something that very likely will work,

02:35:17.720 | but the market value isn't quite there

02:35:20.360 | or it failed in a previous trial

02:35:22.520 | and so no one wants to touch it with a 10 foot pole.

02:35:25.180 | Hopefully someone listening to this will be incentivized

02:35:27.560 | to provide this sort of a venue for that,

02:35:30.400 | the kind of work that we're talking about.

02:35:32.540 | I have to ask--

02:35:34.480 | - But I want to make one other point, Andrew,

02:35:35.860 | which is to me the problem with a lot of these things

02:35:40.680 | is it gets, it's a crutch.

02:35:43.340 | You know, it's sort of like what we talked about with like,

02:35:45.400 | hey, just fix my T-man and everything's gonna be fine

02:35:47.800 | and it's like, no, that's just the beginning.

02:35:50.360 | You know, what I worry about when I see people

02:35:52.380 | who are clamoring for this stuff

02:35:54.480 | is a lot of times they don't realize

02:35:56.900 | that whether it's psychologically or otherwise,

02:35:59.100 | they sort of say, well, now that I've had this thing done,

02:36:00.940 | I don't have to do the hard work of the real rehab.

02:36:03.120 | I mean, if I've learned anything through my shoulder surgery

02:36:05.140 | and I'm now three and a half months out.

02:36:06.980 | - How does it feel?

02:36:07.820 | - Amazing.

02:36:08.640 | I mean, look, I still can't do a lot of stuff.

02:36:10.580 | It's gonna be, you know, a while.

02:36:12.060 | I haven't even been able to shoot a bow yet

02:36:13.860 | and it'll probably be a year before I'll go back to,

02:36:17.820 | you know, long dead hangs and heavy dead lifts.

02:36:19.980 | I mean, I don't know, maybe nine months,

02:36:21.240 | but it's, you know, I'm not there yet.

02:36:23.300 | But what I learned through a really amazing

02:36:26.700 | rehab and rehab process is like,

02:36:30.960 | you just gotta do the work and it's freaking hard.

02:36:35.100 | Shoulders are the most tedious, boring thing in the world.

02:36:38.560 | I mean, three days a week, I am doing,

02:36:41.540 | four days a week, I am doing one hour

02:36:43.980 | of just dedicated stuff for this shoulder

02:36:47.740 | that is super uncomfortable, super boring,

02:36:53.500 | super frustrating, but I mean,

02:36:57.140 | I have faith in the methodology, right?

02:36:59.540 | And I think a lot of people are saying,

02:37:01.080 | just shoot the stem cells into me

02:37:02.480 | and I don't have to do any of that stuff.

02:37:03.740 | And the reality of it is,

02:37:05.100 | I think that's a very dangerous place to be.

02:37:08.060 | - Have you ever tried BPC-157?

02:37:10.740 | - Yeah, we tried it.

02:37:14.180 | We had, you know, again, maybe seven, eight years ago,

02:37:16.940 | we had a bunch of patients ask about it.

02:37:18.660 | So, you know, my view is, okay,

02:37:21.220 | I was pretty convinced that there was no safety downside

02:37:23.600 | to it, so I was like, well, I wouldn't prescribe it

02:37:25.140 | to a patient unless I tried it myself.

02:37:26.900 | So me and another doc in the practice, Ralph,

02:37:29.900 | we did it for, I don't know, a couple of months.

02:37:32.300 | I didn't notice a single thing.

02:37:34.340 | - Interesting.

02:37:35.500 | Well, thank you for that.

02:37:36.980 | Shifting to a less esoteric,

02:37:38.900 | and I think probably more important topic overall,

02:37:43.500 | metabolomics, we're talking about this

02:37:45.520 | before we set down to record.

02:37:47.380 | What is, what are metabolomics?

02:37:50.940 | Why should we be thinking about them?

02:37:52.940 | I have some idea of what it might be about,

02:37:55.980 | but most people, I think, are not thinking

02:37:58.340 | about metabolomics at all.

02:38:01.100 | And for those that are, I'm sure they could learn more.

02:38:03.660 | So tell us about metabolomics and what you'd like

02:38:05.700 | to see more of in the world of metabolomics.

02:38:08.540 | - Yeah, so omics is just the term that we use

02:38:10.460 | to describe the study of something.

02:38:12.520 | So genomics, right, is like the broad study of genes,

02:38:15.260 | and, you know, proteomics, the broad study of proteins,

02:38:18.360 | and things like that.

02:38:19.520 | So metabolomics is the study of metabolites.

02:38:22.380 | And metabolites, unlike a lot of these other things,

02:38:25.680 | they're a relatively finite number of these things,

02:38:28.520 | many of which are known, but some of which are not known.

02:38:30.760 | So glucose is a metabolite.

02:38:32.600 | Acetyl-CoA is a metabolite.

02:38:34.100 | Lactate is a metabolite.

02:38:35.840 | And so the question is, what do we know

02:38:39.560 | about these things and how they work?

02:38:42.360 | And more importantly, what do we know

02:38:44.560 | about certain physiologic states

02:38:46.460 | and the metabolomic profile that results from them?

02:38:49.400 | So let's use two extreme examples, like exercise.

02:38:54.400 | Everybody understands, the data are unambiguously clear,

02:38:58.000 | exercise produces about the most

02:39:00.400 | favorable phenotype imaginable.

02:39:03.720 | So if you wanted to take a genomics approach

02:39:06.480 | to understanding that, you might look at,

02:39:08.900 | is there a change in the genome when you exercise?

02:39:11.640 | And the answer is, you know, probably not.

02:39:13.400 | But maybe if you looked at the, you know,

02:39:15.800 | methylation patterns and epigenome,

02:39:18.200 | you could look at epigenomic studies.

02:39:20.040 | But you might instead look at kind of

02:39:22.700 | the proteomic side of that.

02:39:24.000 | Like, what is gene expression doing?

02:39:26.640 | And there you would see a lot of changes.

02:39:28.620 | Well, what I don't think people are really understanding,

02:39:30.320 | although there was a very interesting paper

02:39:31.880 | that just came out two weeks ago

02:39:35.120 | that looks for novel metabolites that are changing.

02:39:39.960 | Is there a huge signal in a metabolomic profile

02:39:44.500 | that looks different in the state

02:39:46.400 | of exercise versus non-exercise?

02:39:48.520 | And could that represent part of how exercise

02:39:52.400 | is transmitting its benefit through the body?

02:39:54.640 | You know, people always talk about the holy grail

02:39:57.960 | of metabolomics would be, can you find a pill

02:40:00.300 | to mimic exercise?

02:40:02.080 | And I think the answer to that question

02:40:03.120 | is going to be undoubtedly no, for a couple reasons.

02:40:07.080 | One, even if you could mimic the longevity,

02:40:10.400 | sort of lifespan parts of it,

02:40:12.100 | you could never mimic the healthspan parts of it.

02:40:14.960 | But what if you could do both, right?

02:40:16.520 | What if there were small molecules

02:40:18.680 | that can replicate some of the protective benefits

02:40:21.440 | of exercise and you could combine those with exercise?

02:40:23.980 | What if those could be treatments

02:40:25.500 | for other disease states like diabetes, things like that?

02:40:28.640 | So that's why I think this field of metabolomics

02:40:30.400 | is relatively untapped and I think,

02:40:35.400 | potentially the next sort of frontier.

02:40:38.260 | - Speaking of frontiers, I hear a lot nowadays

02:40:40.240 | about GLP-1 and pharmacology, prescription drugs

02:40:45.240 | that mimic or increase GLP-1 directly.

02:40:48.960 | Glucagon-like peptide, people are talking about this

02:40:53.480 | as the blockbuster obesity drug.

02:40:55.720 | I haven't heard this much talk about a drug

02:40:57.540 | to adjust human body weight favorably

02:41:01.200 | since the discussions of Fen-Phen when I was in college.

02:41:04.000 | And then of course, Fen-Phen was pulled from the market

02:41:06.400 | because people were dying, not left and right,

02:41:09.160 | but enough people died that they pulled it from the market.

02:41:11.280 | - Which by the way, is an interesting story.

02:41:14.140 | It was the enantiomer that they chose to use

02:41:17.040 | that was the wrong enantiomer.

02:41:18.700 | And what it resulted in was, God, I think it was like--

02:41:23.080 | - So mitral valve, prolapse.

02:41:24.960 | - It was an MVP, yeah, it was something in the mitral valve.

02:41:28.600 | Yeah, I think the chordae tendineae were rupturing

02:41:30.640 | in the mitral valve and it was mostly young women

02:41:34.120 | I think were getting horrible pulmonary disease

02:41:36.600 | as a result of it, probably pulmonary hypertension

02:41:38.880 | or something like that.

02:41:40.040 | But there were two enantiomers of the drug

02:41:43.900 | and had they just used the other one,

02:41:45.820 | this issue wouldn't have happened

02:41:47.220 | and there was a stupid reason why they made the choice

02:41:49.600 | to use the one they did.

02:41:51.200 | And it's one of those things where once you make the mistake

02:41:52.920 | you're never going back.

02:41:53.760 | It's not like that company could say,

02:41:54.920 | okay, we wanna do over,

02:41:56.320 | but we're gonna do it with the right version.

02:41:57.920 | So it's a tragic outcome.

02:42:00.720 | But you're absolutely right.

02:42:01.960 | I think the GLP-1 agonists have more efficacy

02:42:06.680 | and for all intensity and for everything we can see

02:42:10.400 | certainly seem safer.

02:42:11.760 | - Are you excited about them?

02:42:13.000 | - Yeah, I am, yeah.

02:42:13.840 | I mean, I think we're just seeing

02:42:15.160 | the kind of tip of the iceberg.

02:42:16.880 | They're not miracle drugs, right?

02:42:18.500 | They come with problems, right?

02:42:19.820 | Which is, they're catabolic across the board.

02:42:23.620 | So patients are losing fat,

02:42:25.680 | but they're losing muscle as well.

02:42:27.560 | So--

02:42:28.400 | - You just sent all the Jim jockeys running

02:42:31.560 | from semaglutinol, that's all you have to say.

02:42:34.800 | All you have to say nowadays about something

02:42:36.640 | is that it's gonna drop testosterone, lower fertility,

02:42:40.020 | change someone's skin, hair, or nails.

02:42:41.840 | And it's like people,

02:42:43.680 | it could extend life to being 250 years old

02:42:46.120 | and people are gone.

02:42:47.800 | Humans are humans.

02:42:49.080 | That's a neuroscience and psychology issue,

02:42:51.080 | not a biology medicine issue.

02:42:54.000 | But I'm pleased to hear that you're excited by them

02:42:56.160 | 'cause I hear a lot of excitement.

02:42:58.040 | I haven't heard anything disastrous about them.

02:43:01.320 | - It takes a while to get people up to dose.

02:43:03.400 | So if you're looking at semaglutide,

02:43:05.240 | the dose that was studied,

02:43:07.220 | so they did a one year trial,

02:43:09.600 | or maybe it was a little over that, maybe 60 weeks.

02:43:11.760 | But it took about 16 weeks to get the patients comfortably

02:43:15.700 | up to 2.4 milligrams weekly,

02:43:17.460 | which was the dose that they ultimately stayed on.

02:43:20.120 | In our experience, when we use it,

02:43:21.840 | we don't even usually go up to 2.4 milligrams.

02:43:24.160 | We can usually get enough benefit

02:43:25.240 | between one and two milligrams.

02:43:26.840 | And we usually move people along a little bit quicker,

02:43:28.960 | but we've definitely had our share of patients

02:43:30.940 | who can't tolerate it due to the nausea.

02:43:32.800 | - Interesting.

02:43:33.640 | - Which might be part of how it's working, right?

02:43:35.760 | Is sort of suppression of appetite,

02:43:37.980 | which if taken to an extreme can produce nausea.

02:43:41.220 | - Interesting.

02:43:42.060 | - Yeah, I think most of the effect of semaglutide

02:43:44.100 | is central, not peripheral.

02:43:45.760 | - Huh, so I don't know.

02:43:47.560 | I saw one paper that GLP-1 is acting both on cells

02:43:52.560 | in the periphery to cause gut distension in some ways,

02:43:57.700 | or sort of make people feel full

02:43:59.640 | through promotion of literally mechanoreceptors

02:44:03.320 | that make people feel as if their stomach is distended,

02:44:05.520 | even though their stomach is empty,

02:44:06.760 | and then perhaps some central hypothalamic effects.

02:44:09.080 | Is that what you think?

02:44:09.920 | - Yeah, I think it's doing,

02:44:11.360 | I would bet 80% of it's in the hypothalamus.

02:44:14.080 | It is also improving insulin sensitivity in the periphery,

02:44:18.140 | but I don't think that that's accounting

02:44:20.040 | for much of its benefit.

02:44:22.040 | - Super interesting.

02:44:22.880 | - And there's next gen versions of these

02:44:25.960 | that seem to be more long lasting.

02:44:27.480 | So right now, if you look at coming off semaglutide,

02:44:31.060 | you're going to see a weight regain.

02:44:32.880 | So there's newer versions

02:44:34.560 | that seem to preserve the weight loss, even off the drug.

02:44:38.240 | So it begs the ultimate question, which is like,

02:44:39.880 | what's the total use case for this going to be?

02:44:42.200 | Is this going to be a drug you cycle on and off?

02:44:44.540 | Or is it going to be a drug

02:44:45.440 | that a person has to stay on indefinitely?

02:44:47.080 | And if so, will they become tachyphylactic?

02:44:48.860 | Will they gain a resistance to it?

02:44:51.680 | So it's still super early days on these things.

02:44:54.200 | - My hope is that it would be a little bit like

02:44:55.920 | the way that you described testosterone

02:44:57.400 | and estrogen therapies,

02:44:58.260 | that it would allow people to do more of the behavioral work

02:45:00.960 | that's absolutely required for healthspan and lifespan.

02:45:04.360 | - Yep, and we've also seen on the flip side of that,

02:45:07.240 | you can cheat through semaglutide, right?

02:45:11.240 | People who, you know, you can drink a lot of calories

02:45:13.920 | and sort of get around the drug.

02:45:17.280 | So, you know, for example, like, you know,

02:45:19.680 | we always encourage patients who want to lose weight

02:45:21.740 | to really just eliminate alcohol.

02:45:23.160 | Like that's like, that's the cheapest,

02:45:24.760 | easiest trick to lose weight.

02:45:27.800 | And so if you're still drinking a lot of alcohol,

02:45:30.200 | which is incredibly caloric,

02:45:32.000 | and just drinking a lot of caloric stuff,

02:45:34.480 | we've seen that that's less,

02:45:37.560 | this is just anecdotal with our patients,

02:45:39.640 | but we've seen that that's,

02:45:41.360 | it's easier to get around the benefits of the drug that way.

02:45:45.720 | - Interesting.

02:45:47.240 | I so appreciate your answers today.

02:45:49.260 | First of all, they were incredibly thorough

02:45:51.880 | and pointed towards real world application.

02:45:54.920 | I also just want to thank you more broadly

02:45:58.080 | for the work that you do,

02:45:59.640 | because obviously you have this incredible

02:46:02.240 | clinical experience and patient population

02:46:04.560 | that you work very closely with.

02:46:06.020 | But I see you really as one of the few,

02:46:08.480 | both clinicians, and I realize you're an MD.

02:46:13.040 | Did you do a PhD as well?

02:46:14.160 | No, but I consider you a scientist clinician.

02:46:17.480 | Clinician scientist is the appropriate wording

02:46:19.400 | of that, of course, in the way that you really

02:46:22.160 | still drill into studies in detail.

02:46:24.140 | I know a lot of clinicians,

02:46:25.160 | not all of them do that for sure.

02:46:28.320 | And the fact that you're so hungry

02:46:29.600 | for the new incoming knowledge,

02:46:31.280 | as well as the old literature.

02:46:33.000 | So it's an incredibly rich data set in that brain of yours.

02:46:37.020 | And I really appreciate you sharing it with us,

02:46:39.360 | both in your podcast, in the upcoming book,

02:46:41.960 | which I think that we'll certainly have you on here again

02:46:45.680 | in anticipation of that.

02:46:46.640 | But I know I and a ton of other people

02:46:48.640 | are really excited for the book

02:46:50.320 | and in the way that you approach social media

02:46:52.200 | and podcasts and going on podcasts.

02:46:54.580 | Thank you so much.

02:46:55.560 | I learned a ton.

02:46:56.400 | I know everyone learned a ton.

02:46:58.360 | - Thanks, Andrew.

02:46:59.200 | Great to be here, man.

02:47:00.240 | - Thank you.

02:47:01.080 | - Thank you for joining me today for my discussion

02:47:02.460 | with Dr. Peter Attia,

02:47:04.000 | all about the things that we can do

02:47:05.800 | in order to maximize our lifespan and health span.

02:47:09.280 | I highly recommend people check out Dr. Attia's podcast,

02:47:11.960 | "The Drive."

02:47:12.800 | It is excellent, as you can imagine,

02:47:15.420 | based on today's conversation.

02:47:16.800 | And it's easily available on Apple Podcasts,

02:47:19.160 | Spotify, Overcast, and Google.

02:47:21.320 | Please also check out Dr. Attia's website.

02:47:23.480 | It's PeterAttiaMD.com.

02:47:26.040 | There you can find links to his podcast episodes,

02:47:28.340 | as well as a sign up for his excellent weekly newsletter.

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02:49:19.300 | interviews with various guests.

02:49:20.560 | We talk about things like caffeine,

02:49:21.960 | when to drink caffeine relative to sleep,

02:49:24.400 | alcohol, when and how,

02:49:25.660 | and if anyone should ingest it relative to sleep,

02:49:28.780 | dopamine, serotonin, mental health, physical health,

02:49:31.380 | and on and on, all the things that relate

02:49:33.360 | to the topics most of interest to you.

02:49:35.600 | You can find that easily by going to YouTube,

02:49:38.260 | look for Huberman Lab Clips in the search area,

02:49:41.160 | and it will take you there.

02:49:42.000 | Subscribe, and we are constantly updating those

02:49:44.380 | with new clips.

02:49:45.220 | This is especially useful, I believe,

02:49:46.640 | for people that have missed some of the earlier episodes

02:49:48.640 | or you're still working through the back catalog

02:49:50.260 | of Huberman Lab Podcasts,

02:49:51.340 | which admittedly can be rather long.

02:49:53.460 | And last, but certainly not least,

02:49:55.760 | thank you for your interest in science.

02:49:57.620 | [upbeat music]

02:50:00.200 | (upbeat music)

Dr. Peter Attia: Exercise, Nutrition, Hormones for Vitality & Longevity | Huberman Lab Podcast #85

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