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

- Welcome to the Huberman Lab Podcast,

where we discuss science and science-based tools

for everyday life.

I'm Andrew Huberman,

and I'm a professor of neurobiology and ophthalmology

at Stanford School of Medicine.

Today my guest is Dr. Peter Attia.

Dr. Attia is a physician who's focused on

nutritional, supplementation-based,

behavioral, prescription drug, and other interventions

that promote health span and lifespan.

His expertise spans from exercise physiology

to sleep physiology,

emotional and mental health and pharmacology.

Today we talk about all those areas of health,

starting with the very basics,

such as how to evaluate one's own health status

and how to define one's health trajectory.

We also talk about the various sorts of interventions

that one can take in order to optimize vitality,

while also extending longevity, that is lifespan.

Dr. Attia's uniquely qualified to focus on

the complete depth and breadth of topics that we cover.

And indeed, these are the same topics that he works with

his patients on in his clinic every day.

Dr. Attia earned his Bachelor of Science

in mechanical engineering and applied mathematics,

and his MD from Stanford University School of Medicine.

He then went on to train at Johns Hopkins Hospital

in general surgery,

one of the premier hospitals in the world,

where he was the recipient of several prestigious awards,

including Resident of the Year.

He's been an author on comprehensive reviews

of general surgery.

He spent two years at the National Institute of Health

as a surgical oncology fellow,

at the National Cancer Institute,

where his work focused on

immune-based therapies for melanoma.

In the fields of science and medicine,

it is well understood that we are much the product

of our mentors and the mentoring we receive.

Dr. Attia has trained with some of the best

and most innovative lipidologists, endocrinologists,

gynecologists, sleep physiologists and longevity scientists

in the United States and Canada.

So the expertise that funnels through him

and that he shares with us today

is really harnessed from the best of the best,

and his extensive training and expertise.

By the end of today's episode,

you will have answers to important basic questions such as

should you have blood work?

How often should you do blood work?

What specific things should you be looking for

on that blood work, that are either counterintuitive

or not often discussed,

and yet that immediately and in the long-term

influence your lifespan and health span?

We talk about hormone health and hormone therapies

for both men and women.

We talk about drug therapies that can influence the mind

as well as the body.

And of course, we talk about supplementation, nutrition,

exercise, and predictors of lifespan and health span.

It is an episode rich with information.

For some of you, you may want to get out a pen and paper

in order to take notes.

For others of you that learn better simply by listening,

I just want to remind you that we have timestamped

all this information

so that you can go back to the specific topics

most of interest to you.

I'm pleased to announce that the Huberman Lab Podcast

is now partnered with Momentous supplements.

We partnered with Momentous for several important reasons.

First of all, they ship internationally,

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Before we begin, I'd like to emphasize

that this podcast is separate

from my teaching and research roles at Stanford.

It is, however, part of my desire and effort

to bring zero cost to consumer information

about science and science-related tools

to the general public.

In keeping with that theme,

I'd like to thank the sponsors of today's podcast.

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And now for my discussion with Dr. Peter Attia.

Peter, thanks for joining me today.

- Thanks for having me, man.

- I've been looking forward to this for a very long time.

- [Peter] As have I.

- I'm a huge fan of your podcast.

I know that you went to Stanford

and worked with a number of people

that are colleagues of mine.

So for me, this is already a thrill, just to be doing this.

- Yeah, well, it's likewise.

- I have a ton of questions,

but I want to start off with something

that I wonder a lot about,

and that I know many other people wonder about, which is

how to assess their current health and their trajectory

in terms of health and wellbeing,

specifically as it relates to blood work.

So what are your thoughts on blood work?

Is it necessary for the typical person?

So this is somebody who's not dealing with

some acute syndrome or illness.

And at what age would you suggest

people start getting blood work?

How frequently should they get blood work?

How often do you get blood work done, et cetera?

- Yeah, there's a lot there.

I mean, the way I talk about this with patients is,

first, taking everything back to the objective.

So what's the thing we're trying to optimize?

So if a person says, look,

I'm trying to break 10 hours for an Ironman,

I don't know that blood work is going to be

a game-changing aspect of their trajectory

and their training.

You know, they're going to benefit much more

from sort of functional analyses of performance.

So I'm assuming, based on the question,

that you're really coming at this through the lens of

living longer and living better

through the lifespan health span

lens? - Mostly, yeah.

I think most people have some sense of their vitality

or lack of vitality, but I think everyone wonders

whether or not they could feel better,

and whether or not blood work will give them a window into

how they might go about feeling better.

- Yeah, I think it does to some extent,

but I also think that it has a lot of blind spots.

So I kind of break things down into

the two vectors that make up longevity,

which are lifespan and health span.

So lifespan is the easiest of those vectors to understand,

because it's pretty binary.

You're alive or you're not alive.

You're respiring or you're not.

You make ATP or you don't, end of story.

So what gets in the way of lifespan

is essentially the four horsemen of disease, right?

So atherosclerotic disease, cancer,

neurodegenerative disease, and metabolic disease,

which directly isn't the cause of many deaths,

but basically creates the foundation

to all of those other diseases.

So, you know, if you're a non-smoker,

what I just rattled off is about 80% of your death.

So how does blood work help address those?

It varies.

So on the atherosclerotic standpoint,

it's a very good predictor of risk,

if you know what to look for.

So primarily ApoB would be

the single most important lipoprotein that we care about.

I can explain what that means in a second.

And then also, other markers of inflammation,

endothelial health, and metabolic health.

When it comes to cancer, you know,

blood testing in the sense of biomarkers

is not particularly helpful,

outside of knowing that the second leading environmental

or modifiable cause of cancer

is metabolic ill health, after smoking.

So we don't actually know a lot about cancer

in the sense of what causes it.

It's really stochastic, and it's a lot of bad luck.

So we know that smoking drives it, and we know that,

even though epidemiologically we say obesity drives it,

what it really means is metabolic poor health.

It's probably the hyperinsulinemia

that comes with obesity that drives it.

So biomarkers help with that,

but there's still an enormous blind spot to cancer.

We could talk about liquid biopsies aside,

'cause those aren't really biomarker studies,

but put that away.

On the neurodegenerative side, you know,

I don't think we have a lot of insight

that comes to understanding Parkinson's disease,

but when it comes to dementia,

particularly Alzheimer's disease,

which is the most prevalent form of dementia,

I think the biomarkers can be quite helpful.

They overlap a lot with the atherosclerotic diseases.

So the same things that

drive the risk of heart disease

are driving the risk of dementia.

And then there's some novel stuff as well,

if you include genetic testing,

which you can get out of a blood test.

We get a whole suite of genes, not just APOE,

but far more nuanced stuff than that,

that can also play a role.

So you can stratify risk in that sense.

So in aggregate, I would say, you know,

blood testing of biomarkers

provides pretty good insight into lifespan.

When you get into health span, you have kind of

the cognitive, physical, emotional domains.

I think here the biomarkers are far less helpful,

and here we kind of rely more on functional testing.

So when it comes to sort of the cognitive piece, you know,

you can do cognitive testing.

In terms of long-term risk,

a lot of the things that imply

good cognitive health as you age,

are in line with the same things

that you would do to reduce the risk of dementia.

So all the biomarkers that you would look to improve

through dementia risk reduction,

you would be improving through cognitive health.

On the physical side,

I mean, outside of looking at hormone levels and things

which we look at extensively,

and understanding how those might aid in

or prevent some of the metrics that matter, it really is,

this is a biomarker aside thing.

I mean, I'd be much more interested in a person's DEXA,

CPET testing, VO2 max testing, you know,

zone two lactate testing, fat oxidation.

Those are what I would consider more functional tests

that give me far more insight into that.

And then of course the emotional piece,

which depending on who you are,

might be the single most important piece,

without which none of this other stuff matters, right?

If you're a totally miserable human being,

your relationships suck,

I don't think any of this other stuff matters.

And certainly there's nothing that I'm looking at

in biomarkers that's giving me great insight into that.

- Do you ask about emotional state,

or do you try and assess emotional state indirectly

when you do an intake with one of your patients?

- Probably not so much in the intake,

because I think it takes a while to form a relationship

with a patient before that starts to become

something that they're necessarily going to want to

talk with you about.

But I definitely think of it as an important part

of what we do.

And I think without it,

none of this other stuff really matters.

Again, the irony of thinking about

how many years I spent sort of in pursuit of

fully optimizing every detail of everything,

without any attention being paid to that dimension,

is not lost on me.

And look, there are some patients who,

that's just not something that,

that's something that's compartmentalized.

Maybe they're, you know,

they're doing well in that department, or maybe they aren't,

but they just aren't willing to engage on that yet.

- In terms of frequency of blood testing,

if somebody feels pretty good

and is taking a number of steps, exercise, nutrition,

et cetera, to try and extend lifespan

and improve health span,

is once a year frequent enough,

and should a 20-year-old start getting blood work done

just to get a window into what's going on?

Assuming that they can afford it

or their insurance can cover it.

- Yeah, I mean, look, I certainly think everybody

should be screened early in life because if you look at,

like, what's the single most prevalent genetic driver

of atherosclerosis, is Lp[a].

So unfortunately most physicians don't know

what Lp[a] is,

and yet somewhere between eight and 12% of the population

has a high enough, and depending on who you, you know,

I had a recent guest on my podcast

who suggested it could be as high as 20%,

have a high enough Lp[a],

that it is contributing to atherosclerosis.

So to not want to know that,

when it's genetically determined, right,

this is something that, you're born with this

and you only need to really check it once,

why we wouldn't want to know that in a 20-year-old,

when it can contribute to a lot of the early atherosclerosis

we see in people.

It's leaving money on the table, in my opinion.

The frequency with which you need to test

really comes down to the state of interventions.

I don't think it makes sense to just do blood tests

for the sake of doing blood tests.

There has to be kind of a reason.

Is something changing?

You know, a blood test is, for the most part,

a static intervention.

It's a look at a window in time.

And there's benefit in having

a few of those over the course of a year,

if you're unsure about a level.

So if something comes back and it doesn't look great, yeah,

it might make sense just to recheck it

without reacting to it.

But typically, you know, in patients,

we might check blood two to four times a year,

but we're also probably doing things in there to now check,

like hey, you know, we gave this drug,

did it have the desired outcome?

You put on three pounds of muscle

and lost three pounds of fat,

did it have the desired outcome?

- Speaking of tracking weight and fat,

lean mass percentages, is that something that you recommend

your patients do pretty often?

I know people that step on the scale every day,

I know people like myself that frankly,

I might step on the scale three times a year.

I don't really care.

I pay attention to other things

that are far more subjective.

Maybe I'm making a huge mistake.

What are your thoughts about

quantitative measurements of weight, BMI,

for the typical person?

- I think they're pretty crude.

I think a DEXA, I'd rather take a DEXA annually,

and then maybe follow weight a little bit more closely

to get a sense of it.

And so with a DEXA you're getting,

at least the way we look at the data,

four pieces of information.

Now, most people when they do a DEXA,

should I explain what that is, I'm?

- Yeah, I think some people might not know what DEXA is.

In fact, I confess, I have a crude understanding

of what it is.

Tell me where I'm wrong,

and hopefully where I'm at least partially right.

My understanding is

that there are a number of different ways to measure

lean mass to non-lean mass ratio,

and there's one where they put you underwater.

There's one where they put you into some sort of

non-underwater chamber.

There's calipering.

And then there's the looking in the mirror and pinching

and changing the lighting.

- You know, it's funny,

if you've done it enough, you can,

I can sort of tell my body fat by my abs, right.

So I can sort of tell by, you know,

how good the six pack or how bad the six pack is,

what the leanness is.

And that's actually not a terrible way to do it.

A bodybuilder, for example, which I've never been,

can tell you the difference between being 6%, 7%, 8%, 10%,

just based on the degree of visibility within the abs.

But basically, a DEXA scan is an x-ray.

So it's the same principle as just getting a chest x-ray,

where ionizing radiation is passed through the body.

And there's a plate behind the body

that collects what comes through.

And the denser the medium

that the electrons are trying to go through,

the less of them that are collected.

So when you look at an x-ray,

as everybody's probably seen an x-ray,

that which is white is most dense.

So if you had, you know, a piece of metal in your pocket,

it would show up as a bright white thing.

That's why ribs and bones show up as white,

and the things that are the least dense, like the lungs,

where it's just air, are the blackest.

And everything is a shade of gray in between.

So a DEXA is just doing that effectively,

but it's a moving x-ray.

So you lay down on a bed and it takes maybe 10 minutes,

and this little, very low power x-ray

kind of goes over your body.

And the plate beneath it is collecting information

that is basically allowing it to differentiate

between three things, bone mineral content, fat, other.

And the other is quantified as lean body mass.

So that's organs, muscles, everything else.

So when most people do a DEXA, they get the report back,

and the reports are horrible.

I've yet to see one company that can do this in a way

that isn't abjectly horrible.

We've created our own templates,

so we have our own dashboard for how we do this,

'cause we've just given up on trying to use theirs.

But the first thing most people look at is

what's my body fat.

And this is the gold standard

outside of like MRI or something,

that's only used for research purposes.

So a DEXA is going to produce a far better estimate

of body fat, than calipers or buoyancy testing,

or things like that,

provided the machinery is well-calibrated,

and the operator knows how to use it.

I've heard some people argue that in the hands of like

the guy who's been doing calipers his whole life,

it could probably be comparable with calipers.

But nevertheless, for an off-the-shelf tech,

DEXA is amazing.

Of the four things that get spit out of the DEXA,

we think that the body fat is the least interesting.

And so I would rank that as fourth on the list of

what's germane to your health.

The other three things that you get spit out

are bone mineral density, visceral fat,

and then the metrics that allow you to compute,

like to basically compute what's called

appendicular lean mass index and fat-free mass index.

And so those three metrics are significantly more important

than body fat.

And the reason is as follows, right?

So, bone mineral density basically speaks to your risk

of osteoporosis and osteopenia.

And that doesn't sound very sexy

to people our age, you know.

50-year-old guys listening to this,

it's like, yeah, big deal.

But for a 50-year-old woman, this is a huge deal, right?

A woman who's just about to go through menopause,

or has just gone through menopause,

is at an enormous risk for osteopenia,

and then ultimately osteoporosis,

because estrogen is the single most important hormone

in regulating bone mineral density.

And we can come back and talk about why that's the case,

but it's very interesting

how the biomechanics of bones work,

and why estrogen specifically is so important.

And this is a huge cause of morbidity, right?

So, you know, if you're over the age of 65

and you fall and break your hip,

your one year morbidity is about 30 to 40%.

Which again, just to put that in English,

if you're 65 or older, you fall and break your hip,

there's a 30 to 40% chance you're dead in a year.

- [Andrew] Wow.

- Bones matter.

So we want to really get a sense of where you stack up

for your age, for your sex.

And if you're anywhere off the pace,

we have to ramp up our strategy and be super aggressive

about how to increase that, or at a minimum,

prevent any further decay.

- And are there age-related charts

for these sorts of things?

- Yeah, this all gets spit out into what's called a Z-score.

So when you're looking at your BMD,

it's going to give you a Z-score.

So a Z-score of zero means, and you understand this,

but it's like, a Z-score referring to

a probability distribution in a standard mode.

So Z-score of zero means you're at the 50th percentile

for your age and sex.

A Z-score of plus one, you're one standard deviation above,

minus one, below, et cetera.

There's also a T-score, which is doing the same thing,

but comparing you to a young person.

And so the T-score is technically used

to make the diagnosis of osteopenia or osteoporosis.

We tend to look more at the Z-score, and basically say,

look, if your Z-score right now is minus one,

in four years I want your Z-score to be zero.

Not necessarily because you've increased that entire way,

but maybe you've increased slightly

while it's expected that you would've declined.

- I see.

What are some things that we can do to improve

bone mineral density at any age?

- So it turns out there's a real critical window

in which we are malleable.

So depending on the age at which someone's listening to us

discuss this, you know, if you're under 20, 25,

you are still in that time of your life

when you are able to reach your potential.

So it turns out that strength training

is probably the single best thing you can do.

And this was a surprise to me, 'cause we, you know,

we did an AMA on this topic a little while ago,

and that's when I got really deep on this

with our analysts.

My assumption was running must be the best,

like some sort of impact must be the best thing you can do.

You know, I assumed running would be better

than swimming and cycling.

But it turned out that power lifting

was probably the best thing you could do.

And I think once you understand how bones work,

it became more clear, which is, you know,

power lifting is really putting more of a sheer force

from the muscle via the tendon onto the bone,

and that's what the bones are really sensing.

They're sensing that sheer force

that's being applied through the bone, in a compressive way,

depending on the bone of course.

And that's what's basically activating the osteoblasts,

which are the cells that are allowing bone to be built.

So this turns out to be probably more important for females,

because how high you can get

during that period of development, say till you're 20 or 25,

basically sets your trajectory for the rest of your life.

So where we get into real trouble is with patients who,

for example, used large amounts of inhaled steroids

during that period of their life,

'cause let's say they had really bad asthma.

Or patients who needed large amounts of corticosteroids

for some other immune-related condition.

So during their critical window of development,

they were taking a drug that was impairing this process.

So, you know, we have some patients like that

in our practice and that's just an enormous liability

that we're working really hard to overcome,

with nutrition, with hormones, with drugs, with training.

And, you know, it's just something you have to be aware of.

- I wasn't aware that inhalants for asthma

and things of that sort can impair bone mineral density.

- If they're steroid-based.

Some of them of course are just beta-agonists,

and they're fine.

- So anything corticosteroid like?

- Yep. - Interesting.

And then I always get asked this question,

and I always reflexively want to say no,

but I don't really know the answer so I don't reply.

What about topical corticosteroid?

You know, people will put cortisone cream.

To me, it seems almost inconceivable

that it would have a systemic effect, but then again,

what do I know?

- It's all dose and time-related.

So, you know, if you're talking about like I've got

a little rash under my skin,

I'm going to put corticosteroids on, probably not.

But certainly, with enough of it put on,

I mean it is absorbed, so it could be an issue.

But that's not typically what we're concerned with.

I mean, we're mostly concerned with people that are

taking even modest amounts of prednisone

for months, years at a time.

Or, like I said, kids that are using steroid inhalers

for years and years and years.

Again, I'm not suggesting

that if your kid's on a steroid inhaler they shouldn't be.

You have to solve the most important problem,

and if asthma is the most important problem, so be it.

I think you just want to turn that into, okay, well,

how much more imperative is it

that our kid is doing things that are putting

a high amount of stress on their bones, via their muscles,

to make sure that they're in that maximal capacity to build.

- Do you think that somebody in their 30s or 40s or 50s

could still benefit from strength training in terms of

bone mineral density and longevity,

as it relates to bone mineral density,

given that there's this key window earlier,

they might have missed that one.

- Oh yeah, no, no, this is essential for the rest of life

because you're now trying to prevent the fall off.

So basically the way it works is you're sort of,

from birth to say 20 you're in growth.

From 20 to 50, you plateau.

At 50, men start to decline, but it's really small.

Women start to decline and it's precipitous.

- And it's related to the drop in estrogen

associated with menopause or premenopause?

- [Peter] Correct.

- And can we get into any of the broad contours

of what that strength training looks like?

We had Dr. Andy Galpin on the show,

he talked a lot about ways to build strength

versus hypertrophy versus endurance, et cetera.

I think there's pretty good agreement across the fields of

physiotherapy, et cetera, of physiology and medicine,

in terms of how to do that.

But my understanding is fairly low repetition ranges,

so this is anywhere from one to six repetitions.

Typically not aiming for a pump hypertrophy,

that sort of thing.

But heavy loads that are hard to move,

80% of one repetition maximum or more,

done with long rest periods,

two to three times a week type thing, is that about right?

- Yeah, if you look at the literature on this,

it's going to tell you,

it's going to differentiate power lifting from weightlifting.

In other words, yeah,

you do need to be kind of moving against a very heavy load.

Now again, that can look very different

depending on your level of experience.

Like I really like deadlifting.

Now, I mean, I can count the number of days left in my life

when I'm going to want to do sets over 400 pounds.

But, you know, I'll pick and choose the days that I do.

But, you know, I grew up doing those things,

I'm comfortable with those movements.

If I had a 60-year-old woman

who's never lifted weights in her life,

who we now have to get lifting,

I mean, we could get her to deadlift, but I think,

I wouldn't make perfect the enemy of good.

I'd be happy to put her on a leg press machine

and just get her doing that.

You know, it's not as pure a movement as a deadlift,

but who cares, right?

We can still put her at a heavy load, for her,

and do so safely.

So, now that said, I mean,

there was a study that was done in Australia,

and I'm, you know, hopefully we can find a link to it.

There's a video on YouTube that actually kind of has the PI

sort of walking through the results.

I could send it to you.

- [Andrew] Okay, yeah we'll

track it down. - And it's just amazing.

They took a group of older women.

They looked like they were in their 60s or 70s,

who had never lifted weights in their life,

who had osteopenia,

and some probably already had osteoporosis,

and they basically just put them on

a strength training protocol.

And it is remarkable to watch these women.

They're doing good mornings.

They're doing dead lifts.

They're picking heavy things up off the ground.

I think one woman was picking up,

God, I want to say she was like picking like 50, 60 kilos up

off the ground.

I mean, just staggering sums of weight for these women

who have never done anything.

And their bone health is improving at this age.

So the goal, frankly, is to just, you know,

never get to the point where

you have to do this for the first time.

Strength training is such an essential part of our existence

that it's never too late to start,

but you should never stop.

- I love that advice.

Is it a systemic effect or a local effect?

So, for instance, let's say that, well,

my mother's in her late 70s.

She actually used to be really strong when we were kids.

She could move this fish tank that was in my room

long before I could move it, and I was always,

she's really strong.

Over the years, I wouldn't call her frail by any means,

but I certainly think she could benefit

from some strength training.

Let's say she were to start doing some leg presses

or start even with air squats

and maybe work up to some pushups,

are the effects all local,

meaning if she were to just train her legs

or just do pushups,

would it only be the loads applied to the limbs

and muscles and tissues

that were involved? - I think that's where

the bulk of it is, yeah.

- Okay. - Yeah.

- [Andrew] So you need to train

the whole body, essentially.

- Yeah, now keep in mind,

the diagnosis of osteopenia and osteoporosis

is based on only three locations, the left hip,

the right hip, and the lumbar spine.

So, you know, that's just the convention

by which we make the diagnosis.

And I think part of that has to do with

that's where the majority of the insults occur.

Now not all of the insults, I've seen people that have,

you know, because of horrible bone density,

they're fracturing ankles and tibia, fibula,

like they're having low tib fib fractures just walking.

So clearly bone density

outside of those regions does matter.

But much of it is really focused on, and, by the way,

you know, you fall, you break a wrist,

so this is a systemic issue.

But the majority of the response is a local response,

'cause it really comes down to putting a load

directly on that bone, and then having that bone, in kind,

respond by laying down more bone.

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You mentioned falling and the problems with falling

and breaking things, and mortality related to that.

I wonder whether or not there are also

health-related effects of just having weak bones

that are not just about falling and breaking a bone,

and dying a year later.

That's obviously very severe.

Because I think when people hear about that,

some people might think, well, I'll just be more careful.

I'll just move more slowly.

I'll sit in a wheelchair if I need to,

even though I might be able to walk,

if it keeps me from falling.

Some people I think adopt that mentality.

What are some of the benefits of having

high bone mineral density for men and women,

that are perhaps independent of risk of injury?

- Well, I think it's actually the inverse

of what you just said, right?

It's sort of like, you have to sort of be able to articulate

what it is you want in your marginal decade.

So we use this thing in our practice

called the marginal decade.

Marginal decade is the last decade of your life.

So everyone will have a marginal decade.

That's the only thing I can tell you

with absolute certainty, right?

- I believe you.

- There's no immortality.

There's no hidden elixir

that's going to help us live to be, you know, whatever.

I mean, we're all going to be in our last decade at some point.

And outside of people who die suddenly

or through an accident,

most of us know when we're in that marginal decade.

You might not know the day you enter it,

but most people, you know, who are old enough,

if you tell them, are you in the last decade of your life,

they probably have a sense that they are.

So I think the exercise that we like to go through

with our patients very early on is have them,

in exquisite detail,

more detail than they've ever considered,

so we have to prompt them with like 50 questions,

lay out what their marginal decade should look like.

- Wow, that's a serious exercise.

- It's a very serious exercise, right?

Like what, tell me everything that is going to happen

in your marginal decade.

I don't know when it's going to be, Andrew,

it could be 87 to 97 if we're doing well, right?

It might be 79 to 89, I don't know.

But, you know, it would really be a very nuanced exploration

of that topic.

And I think until you do that,

all of this other stuff is just abstract

and kind of nonsense.

Until a person can tell you

what it is that they want to be doing in that last decade,

you can't design a program to get them there.

I mean, think about it.

Someone wants to do an Ironman,

we take it for granted that we know what the objective is.

I have to be able to swim 2 1/2 miles.

I have to be able to get out, take my wetsuit off,

hop on my bike, ride 112 miles, get off my bike,

take the bike shoes off, put the run shoes on,

run 26.2 miles.

Like we get it, we know what the objective is.

And only by knowing that can you train.

Can you imagine if I said to you,

Andrew, I'm going to have you do

an athletic event in a year, start training.

I'm not going to tell you what it is, just do it.

Could be playing basketball.

You know, it could be swimming to Catalina Island.

It could be running 100 miles.

You wouldn't be able to do it.

So similarly, if we don't know

what our marginal decade is meant to be,

there's no way to train for it.

- Do you think this is a good exercise

for anyone and everyone to do on their own,

regardless of age here?

I'm hearing this - Absolutely.

- and I'm thinking,

I need to think about when my last decade might be

and what I want that to look like.

- Absolutely, I mean, when I say we do it with our patients,

that's only because that's the population I work with.

But there's simply no reason

everybody shouldn't be going through this exercise.

- And then you sort of back script from there,

figure out what people should be doing,

given their current health status.

- Exactly right, we call it back casting.

So the first step we do is, once we've really delineated

what the objective function looks like, we then say, okay,

how do you break down that into metrics that we can measure?

So, you know, you described doing a whole bunch of things.

Okay, just to let you know, to do that will require

a VO2 max of 30 milliliters of oxygen

per minute per kilogram.

And the person will say, okay, what does that mean?

We'll say, well, that's a measure of your maximal uptake

of oxygen, and that declines at about 8% to 10% per decade.

So if you have to be at 30,

and let's just assume you're going to be doing that at 90,

so what do you need to be at 80, 70, 60, 50.

Okay, here's what it would need to be at 50.

Okay, what are you now?

Ah, there's a big gap.

You're below where you need to be now.

So you're obviously higher than 30 now,

but if you're only at 42 now

and you need to be at 30 and 40 years,

you're not going to cut it.

You have to be a lot fitter.

Okay, now let's do the same exercise

around strength and stability.

And without exception, most people,

when they do this exercise,

will find out they're well below where they need to be.

So the gravity of aging is more vicious than people realize,

and therefore the height of your glider needs to be

much higher than you think it is when you're our age,

if you want to be able to do the things

we probably want to be able to do when we're 90.

- I absolutely love this approach.

I've never done it in terms of my health.

I've always thought about what I want to accomplish

in the next three to six months or next year or so.

- And by the way, that's a great approach.

That's forecasting.

Forecasting is fantastic.

Forecasting is really good at short-term things.

It doesn't work for long-term things.

Long-term, you have to do back casting.

- This back casting approach really appeals to me

because in my career, well, I never anticipate, excuse me.

I never anticipated I'd be podcasting.

But that's what I did at some point as an undergraduate,

I looked at professors,

I'm like, that looks like a pretty good life.

They seem pretty happy, I talked to a few of them,

and then I figured out what I need to do at each stage

in order to get to that next rung on the ladder,

and just kind of figured it out

in a back casting kind of way, as you refer to it.

I think this is incredibly useful

because it puts all the questions about blood work

and how often to get blood work and what to measure,

in a really nice context that's a highly individualized.

I've never heard of this before, so.

- And I should give a nod to Annie Duke.

I used to always refer to this as reverse engineering,

but in Annie Duke's book,

she wrote about this exact thing and called it back casting,

and I was like, I like the term back casting better.

I think it's more intuitive than reverse engineering.

- Yeah, there's a real genius to it and I think it,

'cause it sets so many things

into the appropriate bins and trajectories.

I've heard you talk before about some of the prime movers

for longevity and all-risk mortality.

And I'd love for you to review a little bit of that for us.

I think we all know that we shouldn't smoke

because it's very likely that we'll die earlier

if we smoke nicotine.

I'm neither a marijuana nor a nicotine smoker,

so I feel on stable ground there.

But anytime we see smoking nowadays,

people really want to distinguish

between cannabis and nicotine.

So I am curious about any differences there

in terms of impact on longevity.

But in that context,

what are the things that anyone and everyone can do,

should do, to live longer basically?

- How long you got?

- Well, you tell me.

You tell me.

I'd like to live, to be,

I'd like my final decade to be between 90 and 100.

- Oh no, I meant how long do you,

yeah yeah. - No no, I'm just kidding.

I'm just kidding. - And will we spend

from now until you're 90 talking about this?

- Well, there's a risk of that.

But top contour is fine,

I know you've done a lot of content on this,

and we will give people links

to some of that more in depth content.

But, you know, let's say we were on a short flight

from here to San Diego, we're in Los Angeles now,

and we got take off and landing,

and we don't want to kink our neck too much

by doing this thing.

So if I just said, hey, you know,

gimme the extended version of the three by five card.

What does that look like?

- So, let's start with a couple of the things

that you've already highlighted.

So smoking, how much does smoking increase your risk

of all-cause mortality?

And the reason we like to talk about what's called ACM,

or all-cause mortality,

is it's really agnostic to how you die.

And that doesn't always make sense.

I mean, if you're talking about, you know,

a very specific intervention,

like a anti-cancer therapeutic,

you really care about cancer-specific mortality

or heart-specific mortality.

But when we talk about these sort of broad things,

we like to talk about ACM.

So, you know, using smoking,

smoking is approximately a 40% increase in the risk of ACM.

- What does that translate to in,

that means I'm shortening my life by 40%?

- No, it means at any point in time,

there's a 40% greater risk that you're going to die

relative to a non-smoker

and a never smoker. - Got it.

- Yeah.

So it's important to distinguish.

It doesn't mean your lifespan is going to be 40% less.

It means at any point in time, standing there,

your risk of death is 40% higher.

And, by the way, that'll catch up with you, right?

At some point that catches up.

High blood pressure.

It's about a 20 to 25% increase in all-cause mortality.

You take something really extreme,

like endstage kidney disease.

So these are patients that are on dialysis,

waiting for an organ.

And again, there's a confounder there because

there's what's the underlying condition

that leads you to that.

It's, you know, profound hypertension, you know,

significant Type II diabetes that's been uncontrolled.

You know, that's enormous,

that's about 175% increase in ACM.

So the hazard ratio is like 2.75.

Type II diabetes is probably about a 1.25 as well.

So a 25% increase.

So another question is like, how do you improve?

So what are the things that improve those?

So now here we do this by comparing low to high achievers

on other metrics.

So if you look at low muscle mass versus high muscle mass,

what is the improvement?

And it's pretty significant.

It's about three X.

So if you compare low muscle mass people

to high muscle mass people as they age,

the low muscle mass people have about

a three X hazard ratio, or 200% increase

in all-cause mortality.

Now, if you look at the data more carefully,

you realize that it's probably less

the muscle mass fully doing that,

and it's more the high association with strength.

And when you start to just tease out strength,

you can realize that strength could be probably

3 1/2 X as a hazard ratio, meaning about 250% greater risk,

if you have low strength to high strength.

- And high strength is the ability to move loads

at 80 to 90% of one repetition?

- It's all defined by given studies.

So, the most common things that are used are actually,

they're used for the purposes of experiments

that make it easy to do.

And I don't even think they're the best metrics.

So they're usually using like grip strength, leg extensions,

and like wall sits, squats, things like that.

So how long can you sit in a squatted position at 90 degrees

without support,

would be a great demonstration of quad strength.

A leg extension, you know, how much weight can you hold

for how long, relative to body weight, things like that.

You know, we have a whole strength program that we do

with our patients, we have something called the SMA.

So it's the strength metrics assessment.

And we put them through 11 tests that are really difficult,

you know, like a dead hang is one of them.

Like how long can you dead hang your body weight,

stuff like that.

So we're trying to be more granular in that insight,

but tie it back to these principles.

If you look at cardio respiratory fitness,

it's even more profound.

So if you look at people who are in the bottom 25%

for their age and sex, in terms of VO2 max,

and you compare them to the people that are just at

the 50th to 75th percentile,

you're talking about a two X difference roughly,

in the risk of ACM.

If you compare the bottom 25% to the top 2.5%,

so you're talking about

bottom quarter to the elite, for a given age,

you're talking about five X.

- Wow! - 400% difference

in all-cause mortality.

That's probably the single strongest association I've seen

for any modifiable behavior.

- Incredible.

So when you say elite,

these are people that are running marathons

at a pretty rapid clip.

- Not necessarily.

It's just like what the VO2 max is for that,

like my VO2 max would be in the elite for my age group.

My VO2, but again, I'm training very deliberately

to make sure that it's in that.

So I wouldn't consider myself elite at anything anymore,

but I still maintain a VO2 max that is elite for my age.

- I consider you an elite physician and podcaster.

And guy all around.

But true.

But in terms of, okay, so-

- But the point is like,

you don't have to be a world class athlete

to be elite here, yeah.

- Got it.

So maybe we could talk a little bit about

the specifics around the training to get into the

top two tiers there,

because it seems that those are enormous positive effects

of cardiovascular exercise,

far greater than the sorts of numbers that I see around,

let's just say supplement A or supplement B.

- Well, and that's, you know,

like this is my whole pet peeve in life, right?

It's like, I just can't get enough

of the machinating and arguing

about this supplement versus that supplement.

And I feel like you shouldn't be having those arguments

until you have your exercise house in order, you know.

You shouldn't be arguing about

this nuance if you're carnivore diet,

versus this nuance if you're paleo diet,

versus this nuance if you're vegan diet,

like, until you can deadlift your body weight for 10 reps.

Like then you can come and talk about those things,

or something like, let's just come up with some metrics.

Like until your VO2 max is at least to the 75th percentile

and you're able to dead hang for at least a minute,

and you're able to wall sit for at least two,

like we could rattle off a bunch of

relatively low hanging fruit.

I wish there was a rule that said like

you couldn't talk about anything else health-related.

- We can make that rule.

- [Peter] No one'll listen to it.

- I don't know about that.

We can make whatever rules we want.

We can call it Attia's rule.

One thing I've done before on this podcast,

and on social media is,

just borrowing from the tradition in science,

which is it's inappropriate to name something

after yourself, unless you were a scientist before 1950.

But it's totally appropriate to name things

after other people.

So I'm going to call it Attia's rule.

Until you can do the following things, don't talk about

supplements. - Please refrain

from talking about supplements and nutrition.

- There it is, hereafter, thought of, referred to,

and referenced as Attia's rule.

I coined the phrase, not him.

So there's no ego involved, but it is now Attia's rule.

Watch out.

Hashtag Attia's rule.

- Oh God!

- Wikipedia entry, Attia's rule.

In all seriousness, and I am serious about that.

Dead hang for about a minute seems like a really good goal

for a lot of people.

At least- - That's our goal.

I think we have a minute and a half is the goal

for a 40-year-old woman.

Two minutes is the goal for a 40-year-old man.

So we adjust them up and down, based on age and gender.

- Great.

And then the wall sit, what are some numbers?

- We don't use a wall sit,

we do just a straight squat, air squat at 90 degrees.

And I believe two minutes is the standard

for both men and women at 40.

- Great.

And then, because for some people thinking in terms

of VO2 max is a little more complicated,

they might not have access to the equipment to measure it,

et cetera, what can we talk about, think about,

in terms of cardiovascular.

So run a mile at seven minutes or less,

eight minutes or less?

- Oh, that's a good question.

So there are really good VO2 max estimators online,

and you can plug in your activity de jure,

so be it a bike, run, or rowing machine,

and it can give you a sense of that.

And I don't, I used to know all of those.

- Oh, that's okay. - But now that I just

actually do the testing, I don't recall them.

But it's exactly that line of thinking,

like, can you run a mile in this time.

If you can, your VO2 max is approximately this.

- [Andrew] Great.

- And I think, somewhere in my podcast realm,

I've got all those charts posted of like,

this is by age, by sex.

This is what the VO2 max is in each of those buckets.

- Terrific, we'll provide links to those.

We'll have our people find those links.

And then you mentioned deadlifting body weight 10 times.

- I just made that one up.

That's not one that we include, but-

- [Andrew] Something like that?

- We use farmer carries.

So we'll say for a male,

you should be able to farmer carry your body weight for,

I think we have two minutes.

- [Andrew] Great.

- So that's half your body weight in each hand.

You should be able to walk with that for two minutes.

For women, I think we're doing 75% of body weight

or something like that, yeah.

- Great.

I love it.

As indirect measures of how healthy and,

- Yeah. - we are.

And how long we're going to live.

- It's basically grip strength, it's mobility.

I mean, again, walking with that much weight,

for some people initially, is really hard.

You know, we use different things like vertical jump,

ground contact time if you're jumping off a box,

things like that.

So it's really trying to capture,

and it's an evolution, right?

Like I think the test is going to get

only more and more involved as we get involved,

'cause it took us about a year.

Beth Lewis did the majority of the work to develop this.

Beth runs our strength and stability program

in the practice.

And, you know, basically I just tasked her with like, hey,

go out to the literature and come up with

all of the best movements that we think are proxies

for what you need to be like the most kick-ass,

you know, what we call centenarian decathlete,

which is the person living in their marginal decade

at the best.

- Well, what I'm about to say is certainly

a mechanistic leap,

but if you look at the literature on

exercise-related neurogenesis in mice,

or brain atrophy or brain hypertrophy, et cetera,

in animal models,

it's very clear that the best way to get a nervous system

to atrophy, to lose neurons, shrink neurons,

and or lose connections between neurons,

is to stop that animal from moving.

Or to de-enrich its environment,

deprive it of some sensory input or multiple sensory inputs.

And the best way to enhance the size of neurons,

the number of connections between neurons,

and maybe even the number of neurons,

is to enrich its environment and get it moving

while enriching that environment.

- You know, Andrew, I think it's very difficult for me

to say that the same is not true in humans.

And so the first time this became clear to me was in 2014,

I had an analyst, Dan Pelletier, and I said, Dan,

I'm going to give you a project that is vexing me to no end,

which is, I want you to look at all of the literature

that we have, both mechanistic and clinical trial data,

that talks about Alzheimer's prevention.

And I want to know every single type of input.

And I want to have a clear sense of

via what mechanism does it offer what mode of protection?

And it took Dan, and this was obviously,

we iterated a lot on this together.

And he came back with kind of an amazing presentation

that took, I don't know, nine months to a year of work.

And what amazed me was when he came back to it, he said,

the single greatest efficacy we can point to is exercise.

And I was like Dan, that's got to be nonsense, dude.

There's no way exercise is the single best thing you can do

for the brain.

There has to be some drug you've missed.

There has to be some other thing that you've missed.

And he's like, no, like this is hands down the best thing

'cause you're, you know,

it's not just what it's doing to BDNF.

It's not just what it's doing to vascular endothelium.

It's not just what it's doing to glucose disposal

and insulin signaling and all these things.

It's just touching every aspect of the brain.

And I was very skeptical for about six months,

kind of really pushed on him and I was like,

I think you're missing something, Dan,

I think you're missing something.

And then finally in the end, looped in Richard Isaacson,

who's a neurologist that we work with really closely

on Alzheimer's prevention.

And you know, ultimately it turned into a paper

that we wrote basically, you know, about this topic,

and a few others.

'Cause again, I thought, oh,

are you sure it's not EPA and DHA?

Like that's got to have a bigger impact.

And again, there are a lot of things that I think do matter

and there's a whole host of things that we do

for Alzheimer's prevention.

But I think you're absolutely right.

There's not one thing that I'll tell patients

is more important than exercising.

And by the way,

it's not the sort of pathetic recommendations that are made.

Like it's, you have to exercise a lot more

if you want to get this maximum benefit.

You will get, you know, the maximum benefit comes

going from nothing to something.

So if you go from being completely sedentary

to doing 15 MET hours per week,

you'll get probably a 50% reduction in risk.

- Wow. - So a MET hour,

a MET, just for people who don't know,

is a metabolic equivalent.

So we're exerting about 1.3 METs sitting here talking.

If we were sitting here being quiet,

it would be about one MET.

Walking really briskly would be about five METs.

So 15 MET hours per week would be

three one hour really brisk walks.

That's not a lot of work.

But just going from doing nothing to doing that

would give you 50% of the benefit that you would get

from going all the way.

Now I, again, I think, I'm personally a little skeptical of

how much that's, I think it's probably a bit less than that.

I think there's more upside than people appreciate.

But the studies, I don't think, can truly capture that.

But look, you know, there's no reason to not be exercising

more than that, and capture more benefit,

even though the rate at which you accrue it is less.

And it also speaks to the health span side of this,

which is not necessarily captured in those data.

The health span gets back to

the functional piece we opened with, which is

what do you want to be doing in your marginal decade?

Do you want to be able to pick up a great-grandkid,

if they come running at you?

Do you want to be able to get up off the floor?

Do you want to be able to play on the floor with a kid

and then get up on your own?

- And I think most people are thinking final years of life,

they're trying to think, you know,

how can they take themselves to the bathroom?

They're thinking, how can they sit up off the toilet?

I mean you have like really base,

vegetative type functions, right, at some level.

I love this, again, this idea of marginal decade

and using that as a way to back cast,

to actual methods and behaviors and protocols

that one should be doing on a daily basis.

I'll use anecdata, as it's now called,

to cite just, I know three Nobel prize winners,

which doesn't mean anything

except that they did beautiful work.

But the point is that they're all in their 90s.

So I'll name them 'cause I'm complimenting them

for what they've done.

Not just their work, but what I'm about to describe.

So Eric Kandel at Columbia.

Nobel prize winner for work on memory.

Torsten Wiesel, work on neuroplasticity.

And then Richard Axel, who's also at Columbia,

Nobel prize winning work for molecular biology

of smelling and molecular biology generally.

All three of them still alive,

Richard's younger compared to the other two.

All three of them either swim, jog, or play tennis,

or racquetball I think is Richard's thing,

multiple times per week.

They're all cognitively still extremely sharp,

still interested in the arts, doing science,

curious about science, running laboratories,

writing books, going on podcasts.

I mean, it's incredible.

Again, that's anecdata.

But I was kind of surprised to learn that

colleagues that were so intellectually strong

were also so obsessed with exercise.

I mean, they really are obsessed with their exercise routine

and early on linked that to their,

some of their intellectual vigor over time.

I want to just also use that as a jumping off point

to ask about one kind of niche thing, but it comes up.

I don't think I'm going to out which one of those told me this,

but one of those three individuals

chews an excessive amount of Nicorette.

Used to be a smoker and I asked him why and he said because,

in his estimation,

it's protective against Parkinson's and Alzheimer's,

or at least the

nicotinic acetylcholine augmentation of nicotine,

'cause nicotine is an acetylcholine receptor obviously,

is known to create a state of focus and neural enhancement.

What are your thoughts about not smoking, let's just,

I just want to be really clear, people, don't smoke nicotine,

vape nicotine, it's going to shorten your life.

Just terrible idea, addictive, et cetera, in my opinion.

But what are your thoughts about augmenting acetylcholine,

through the use of nicotine,

in order to keep the brain healthy and focused?

Again, this is one Nobel prize winner,

so it's truly N of one,

but he's so convinced that this matches up with

the mechanistic data on acetylcholine and cognition,

that I'd love to hear your thoughts on it.

- So I can't speak to the AD prevention component of it.

I'd have to run that by a couple of my colleagues

who I collaborate with on that.

But I can definitely speak to

the cognitive enhancement piece of it.

And I actually did an AMA on this, probably a year ago,

where I went into all of the gory details of it

and talked about my own use of nicotine,

which I'll cycle on and off,

I've been doing it for the last 10 years.

I haven't- - What form do you take it in?

- I used to use the gum.

I don't like the gum anymore,

so now I like these little lozenges that,

and I'll tell you a funny story about this.

So our mutual acquaintance, David Sinclair,

mentioned a company to me a year ago.

He's like, hey, have you heard of this company?

And I forget the name of the company,

but he gave me some name.

So I go online and it's like this company selling nicotine.

And I'm like, I wonder why he's asking me to do this.

Well, I'll just order a bunch

and then we'll figure out why, 'cause we were, you know,

there was some reason we were doing this

potentially through investment.

So I get a, like literally order like a lifetime supply

of this stuff.

And it's pretty good, it's actually,

it's a really nice little patch, 'cause I,

the thing I didn't like about the gum was

I hated just the taste of it.

So then the next week I'm talking to David and I'm like,

by the way, I ordered all that nicotine stuff

you told me about.

He's like what?

And he goes, oh, the company's name was something else.

It was totally unrelated.

It's like, oh God.

So the short answer is, I think this stuff is absolutely

a concentration-enhancing substance.

It is addictive and people need to be wary of that.

Now it's not addictive to everybody.

I personally experience no addiction to it whatsoever.

So I can, I could do it every day for 30 days

and stop and experience no withdrawal.

I could forget about it, it doesn't really seem to matter.

You have to be careful with the dose, truthfully.

I mean, remember one cigarette is about

one milligram of nicotine,

and a lot of these lozenges will plow

four to eight milligrams into you in one shot.

And for someone who is, you know, naive to that, like I am,

four milligrams is a lot of nicotine in one bolus.

So you just have to be very mindful of it.

I got a lot of flack when I did this AMA,

for obvious reasons, but people were like, how can you,

as a doctor, encourage people to use nicotine.

And I was like, first of all,

I'm not encouraging anybody to use it.

I just want to be able to talk about the biochemistry of it.

And if disclosing that I use it from time to time

is an endorsement then I apologize for that.

But on the list of things that you can do

to make your brain a little more focused,

I would consider this infinitely safer

than what a lot of people are doing,

which is using stimulants.

I mean, to me, you know, I just tell patients outright,

like we are under no circumstance prescribing stimulants.

I mean, yeah, we're not giving anybody Adderall.

We're not giving anybody Vyvanse, or any of these things.

Not to say they don't have an appropriate clinical use,

but they should be prescribed under the care of somebody

who's really monitoring the use case for it.

And using that as a tool to enhance, you know,

concentration in cognitive performance

is not something we're comfortable doing.

- Yeah, it's rampant on college campuses.

- [Peter] I can only imagine.

- Armodafinil, modafinil which are slightly different,

of course, but, so non-clinical use,

not prescribed for ADHD, but just, it's rampant.

Recreational use, study-based use.

- But the data I've seen on modafinil

suggests that it only really provides a nootropic benefit.

in someone who is deprived of sleep.

Is there data that in a totally well-rested person,

there is a nootropic benefit of modafinil?

- I don't know.

I have one experience with armodafinil,

where I took a half a recommended dose,

this was prescribed by a doctor.

I went to give a talk.

This was in Hawaii and I'm four hours into the talk.

My co-speaker came up to me and just said, well,

first of all, you got a little bit of spit

in the corner of your mouth.

And second of all, you haven't blinked in three minutes.

And third, there's only two people left in the audience.

I was so lazered in that I kind forgot the context.

Now I'm a little bit of a, kind of a tunnel vision,

OCD-type anyway, but one, that was all it took,

I never took any more of it.

It was a powerful stimulant.

I take 300 milligrams of Alpha-GPC now and again,

before some cognitive work, sometimes before workouts,

and I do subjectively feel that it narrows my focus

in a nice way.

But I don't take it more than once or twice a day,

and more than once or twice a week.

- See, this is an example of where,

you know how we're talking about exercise versus

sort of nutrition and supplements for longevity.

I think there may be a whole bunch of things

that are kind of interesting around focus,

but nothing would compare to changing our environment.

Like I think that if I compare my focus today

to my focus when I was in college, there's no comparison.

Like in college, I was truly a robot.

But I think a large part of it was,

there was no distraction.

There's no email.

There's no social media.

There's no internet.

I mean, I was in college when Mosaic launched

in the early '90s.

Like I, you know, and you had to walk like a mile

to get to the computer lab on a big Sun workstation

to do anything in, you know, some computer code language.

So when you're sitting in your room studying,

there was no distraction.

And I think that's a far greater component

of what it means to be focused,

than the challenges we have today.

So, you know, my thoughts on this would be,

if we really wanted to return to a state of focus,

we're going to have to individually do something about,

you know, our environment.

And I don't know what the answer is.

Like, I've tried every little trick I can think of,

like closing my browsers when I'm writing and stuff,

but, you know, I'm just not strong enough willed.

Like I'll pick up my phone every 20 minutes

to look and see if I missed a text message

or something stupid.

- That's pretty infrequent.

I did an episode on habits and looking at the data.

It seems that people are getting interrupted

or interrupting themselves about once every three minutes

in the typical workplace, now that typical has changed

with a lot more people working at home.

I do put my phone away when I try and work,

but nothing focuses me like a deadline.

A little bit of fear-based urgency.

That's it, grant deadlines, you know,

drop deadlines as I call them,

or podcasts we're going to record today,

that nothing works quite like it.

But such is life.

Well, thanks for that offshoot about nicotine.

Again, you're not recommending it, I'm not recommending it,

but it's clear that augmenting the acetylcholine system,

which is what nicotine does in its various forms,

and some related type pharmacology,

does enhance focus and pretty potently.

So I think it's going to be an interesting area

for real clinical trials and things of that sort.

Love to chat about hormone therapies,

and hormones generally.

When Robert Sapolsky came on the podcast,

we talked a little bit about menopause

and the data around menopause.

He's very interested in these findings that,

I think I'm going to get this right,

that whether or not women benefit from estrogen therapy

to offset menopause

really depends on when that therapy is initiated.

I don't know if you're aware of those data,

but he claimed that if they begin estrogen therapy

in the middle to tail end of menopause,

the outcomes can be quite bad.

Whereas if they initiate those estrogen therapies

as they enter menopause or even before menopause,

then the outcomes can be quite good.

I don't know what percentage of the patients you treat

are male versus female,

and what ages those patients are of course,

but what are your thoughts about estrogen therapy for women,

menopause, and hormone therapies generally for women,

maybe even testosterone therapy,

you hear about that these days,

and then we'll talk about men.

- So our practice is probably 70 30 male female.

So we have lots of women,

and this is a very important topic.

It's also probably, let me think.

I just want to make sure I'm not being hyperbolic

when I say this.

Yeah, I don't think I am.

It's hands down the biggest screw up

of the entire medical field in the last 25 years.

Now, again, it's possible in the next hour I'll think of,

nope, there's a bigger screw up.

- Another giant screw up.

- Yeah, but I don't think I will.

I'm pretty confident that I won't be able to think of

a bigger act of incompetence

than what happened with the women's health initiative

in the late '90s and early 2000s,

which is effectively the study

that turned the entire medical field

off hormone replacement therapy for women.

So it's important, I think,

to explain what this study looked at.

So this was a study that was conducted

in response to the widely held belief in the '70s and '80s

that women should be placed on hormones

as they're going through menopause, right?

Menopause is, I guess maybe I'll even take a step back.

I don't know how much your audience is familiar with

how estrogen progesterone work.

Is it worth going into that stuff?

- Yeah probably worth mentioning a bit of the top contour.

Some of them might be familiar with it,

we've done episodes on estrogen testosterone, but frankly,

as I think back to those,

we didn't really go into the biology

of estrogen testosterone enough.

- Yeah, so, I mean, actually an interesting aside

that I always tell my female patients

who get a kick out of this.

When you look at a woman's labs, you'll see her estrogen,

her progesterone, her FSH, her LH, her testosterone,

her sex hormone binding globulin, and all these things.

But based on the units they're reported in,

it's a very distorting picture

of what the most common androgen is in her body.

If you actually convert them to the same units,

she has much more testosterone in her body than estrogen.

- Interesting. - Yeah.

- I did not know that. - Yeah.

- Then again, I've never been a woman

getting my hormone profile.

- Yeah, yeah.

So even though a woman's testosterone

is much less than a man's level,

it's still more than she has estrogen in her body.

- [Andrew] Wow!

- So phenotypically, right,

estrogen is the hormone that's dominating and test,

so it's the, she has much higher estrogen than a man

and much lower testosterone than a man,

but in absolute amounts,

she has more testosterone than estrogen.

Just worth pointing that out.

- [Andrew] Incredible.

- So, you know, what's happening to a woman

from the age she starts menstruating

until she goes through menopause,

outside of pregnancy and birth control and stuff like that,

is she has this cycle, you know, roughly every 28 days,

but it can vary, where at the beginning of her period,

we call that day zero, her basic,

her estrogen and progesterone are very low.

You can't measure them.

And then what happens is the estrogen level starts to rise,

and it rises in response to a hormone called

follicle stimulating hormone, FSH,

that is getting her ready to ovulate.

And she ovulates at about the midpoint of her cycle.

So if we're just going to make the math easy,

on day 14 she's going to release a follicle

from one of her ovaries.

And the estrogen level is sort of rising, rising, rising.

We love to measure hormones on day five,

because I want to have a standardized way

in which I measure her hormones.

So our women know if we're in the business

of trying to understand her hormones,

the day her period starts,

even if it's just a day of spotting,

that becomes our benchmark, and then day five,

I want to see every hormone on that day.

And if everything is going well,

I know what her FSH, LH, estradiol and progesterone

should be on that day.

So the estrogen rises, starts to come down a little bit

as she ovulates, and then the luteinizing hormone kicks on

because it's now going to prepare her uterus

for the lining to accommodate a pregnancy.

So now you start to see estradiol go back,

but now, for the first time, progesterone goes up.

So progesterone has been doing nothing for 14 days,

and now it starts to rise.

And actually progesterone is the hormone

that's dominating the second half,

which is called her luteal cycle.

So the first 14 days is the follicular cycle.

Second is the luteal cycle.

So once you get to about the halfway point of that,

which is now, just to do the math, 21 days in,

the body has figured out if she's pregnant or not.

And again, most of the time she's not going to be pregnant.

So the body says, oh,

I don't need this lining that I've been preparing,

I'm going to shed it.

So now progesterone and estrogen start crashing,

and the lining is what is being shed,

and that is the menses.

By the way, it's that last seven days of that cycle,

that in a susceptible woman is what creates

those PMS symptoms.

So it's the, actually, this is something

that you would probably have

a better understanding of than me.

There is something about this in a susceptible woman,

where the enormous reduction of progesterone so quickly

is probably impacting something in her brain.

So this is a legitimate thing, right?

I mean, you know, it's not like,

oh, she's crazy because she's having all these PMS symptoms.

No.

We know that that's the case

because if you put women on progesterone

for those seven days, those symptoms go away.

- [Andrew] Interesting.

- So if you can stabilize their progesterone

during the last half of their luteal phase,

and sometimes we would just do it

for the entire luteal phase,

just put them on a low dose of progesterone,

all PMS symptoms vanish.

- Very interesting.

I'll have to look up where the progesterone receptors

are located in the brain.

The Allen Brain Institute now has beautiful data of

in situ hybridization, which for,

'cause they don't understand is,

looking at RNA and sort of where genes and proteins

ought to be expressed in the human brain,

by using actual human brain tissue sections

as opposed to just mice.

So I'll take a look, I think-

- Yeah, I'm really

curious, yeah. - Some insight into what that

progesterone emotionality link might be,

and where it might exist, neural circuit wise.

- So then, when the estrogen and progesterone

reach their nadir again, that starts the cycle.

So that just, that cycle is happening

over and over and over again.

Okay, so it became well known in the '50s that, okay,

a woman's going to stop menstruating at some point,

her estrogen goes down.

Why don't we just give her estrogen?

'Cause that's clearly going to help

with some of the symptoms of menopause.

So what do women experience when they go through menopause?

The first symptoms are what are called vasomotor symptoms.

So this is usually in the form of night sweats, hot flashes.

So, and depending on the woman,

this can be really significant, right?

These are women who can have a hard time sleeping.

They can be having hot flashes during the middle of the day.

They can wake up soaked in a pool of sweat.

Those tend to pass after a couple of years,

and then they get into sort of the more

long-term complications of menopause.

So what we call vaginal atrophy, vaginal dryness,

and then the stuff that we talked about a while ago,

which is the osteopenia osteoporosis.

A lot of women will complain of brain fog.

So, I mean, clearly this was an issue

and it was recognized 70 years ago.

Why don't we give women estrogen back

to replace that hormone?

And so that went on for a couple of decades, maybe less,

maybe a decade, and then it was realized, wait a minute,

we were driving up the risk of uterine cancer.

And the reason for that is if you just give estrogen

with no progesterone to antagonize it,

you will thicken the endometrium endlessly

and you will increase the risk of hyperplasia.

Well, you'll definitely undergo hyperplasia,

and then ultimately dysplasia.

Dysplasia is precancerous,

and ultimately we were seeing that.

So people figured out, well, actually,

if you want to give estrogen to a woman

who still has her uterus,

you have to give her progesterone as well.

You have to be able to have a hormone

to oppose the estrogen.

And then that became effectively in, call it the 1970s-ish,

the standard for HRT.

So in the early 1990s the NIH said, look,

we haven't really studied this.

We have a ton of epidemiology that says

giving women hormones seems to be doing really good things.

They feel better, so all their symptoms go away.

They seem to have lower risk of heart disease,

lower risk of, you know, cardiovascular, pardon me,

lower risk of cardiovascular disease,

lower risk of bone fractures.

Everything seems to get better.

Lower risk of diabetes.

But we haven't tested this

in a randomized prospective trial, so let's do this.

So that became the WHI.

And it randomized, it had two parallel arms.

So it had a group for women who did not have a uterus.

So these are women that had undergone hysterectomy

for some other reason.

And then it had a group for women

that did have their uterus.

In the first group, there was a placebo arm

and then an estrogen only arm.

And in the other group,

there was a progesterone plus estrogen versus a placebo.

Everything about the way this study was done is a bit wonky.

Some of it is justifiable, but it's important to understand.

First, the women were all way outside of menopause.

So none of these women were started

when you would normally start HRT.

And there were probably several reasons for that,

but one of them is, and I think this is a legitimate reason,

they wanted hard outcomes.

They wanted to know death rates.

And if you're doing this on women in their 50s,

you just weren't going to get it, right.

You couldn't-

- Wait too long. - Yeah,

you got to wait too long.

And this was only going to be like a seven to 10-year study.

So they had to do this on women who were much older.

They also disproportionately took much sicker women.

I believe the prevalence, and again,

I'm going to get some of these numbers wrong

and people are going to get all phosphorylated, but, you know,

I mean, I'm in the ballpark, right?

Something like 30, 40% of these women were smokers.

The prevalence of obesity, diabetes was enormous.

So they really disproportionately picked

the most unhealthy population they could,

that was pretty advanced in age.

And again, I think part of that was to say, look,

we want to make sure that after seven years,

we really know if there's a difference

in these causes of death.

The other thing is, this is kind of weird,

although again, I understand their rationale for it,

but this is a great example of be very careful

when you look at a clinical trial,

that it remotely represents the patients

you're interested in treating.

So they also treated no patients who were symptomatic.

The rationale being, if we include in the study

patients who are symptomatic,

those who are randomized to placebo will drop out.

- Okay, it makes sense in terms of study design,

makes no sense if the study design is intended to mimic

the real world.

- That's right.

So now let's just keep track of the three issues.

We have a disproportionately unhealthy patient population

who are not symptomatic,

and we're starting them more than 10 years after menopause.

The next thing that they did, which again,

I understand why they did it,

but it's now the fourth strike against this study, is,

and I've spoken with the PI of the study

and asked this question point blank.

I'm actually going to have her on my podcast at some point soon

to go over this in more detail,

is why did you use conjugated equine estrogen, an MPA,

which is a synthetic form of progesterone.

- [Andrew] Horse-

- Yes. - estrogen?

- It's horse urine, is they collect horse urine,

so they're getting, it's-

- Horses do urinate a lot.

Or at least when they urinate,

it seems like a large volume of urine,

from what I've observed.

- [Peter] You have a lot of experience with this?

- No, but, you know,

my sister rode horses for a little while,

my high school girlfriend had a horse, and that thing,

I mean the pees were legendary.

It's a male horse.

- Yeah. - Yeah.

- So, yeah, so the conjugated equine estrogen

is the estrogen that's collected from female horses.

And then it's a synthetic progesterone.

And I said to the person, I said, well,

why didn't you use what we use today,

which is bio-identical estrogen in progesterone.

Like today, when we put women on estrogen, we use a,

it's an FDA product called the Vivelle-Dot.

So it's a patch that you just put on, and it's estradiol,

but it's bioidentical estradiol.

And we use what's called micronized progesterone.

So bio-identical progesterone.

And she said, well, at the time we just wanted to test

what was currently being used.

And I said, totally makes sense.

But again, now you have four considerations

that you have to keep in mind, okay.

So despite those four considerations,

and I'm going to make a case for you why I think the MPA

created a real problem in that study,

the synthetic progesterone,

when the preliminary results were first made available,

but not yet peer-reviewed and not yet published,

there was a huge fiasco, huge press announcement about it,

suggesting that the women receiving the CEE plus MPA,

in the group with the uterus,

had a higher incidence of breast cancer.

And that basically became the headline that never went away,

though it turned out not to be true.

Let's talk about the numbers.

What was the increase in the risk of breast cancer

in that group?

Which gets to one of my, you know,

if you ever listen to me on a podcast rail on something.

- Listen, I have about 3,800 pet peeves and counting.

My laboratory staff know these, know a good number of them.

So, you do not have - Here, I'll add to

one of them. - to apologize

for having many pet peeves.

Because as long as they have experience in data

to support them, it provides-

- So one of my biggest pet peeves is, and my team knows this

'cause sometimes they'll occasionally, you know,

they'll do this and I'll have to remind them,

you never talk about a relative risk change

without an absolute risk accommodating it, right.

So, what does that look like?

So the relative risk increase of breast cancer

in the estrogen plus MPA group versus the placebo

was 25, 27%.

And that became the only headline.

HRT increases risk of breast cancer by 27%.

Now, I don't think that's true at all today,

but let's even look at the data.

What was the ARR?

What was the absolute risk increase?

It was a difference between five cases per thousand

and four cases per thousand.

So the ARR was 0.1%, one case in a thousand.

And it's true, going from four in a thousand

to five in a thousand is a 25% increase,

but it's a completely inappropriate context.

- I agree, and I feel like headlines of that sort,

which have come up recently around

various dietary interventions, we won't go there,

at least not for the time being,

are nothing short of criminal

because they really distort people's thinking.

But also they steer the course of science and medicine for,

as you pointed out, for decades, if not longer.

And they can really take us off our health track

in serious ways.

- So I'll bring this meandering to a close, which is to say,

even though I could spend the next hour

talking about all of the ways

in which this study was flawed,

and all of the very unethical things that were done

by a number of the investigators

who went out of their way to mask the truth of this study

from the world, I'll tell a woman today,

we're going to start you on this

when you're going through menopause.

We're using bio-identical hormones.

And if your upper bound risk of breast cancer

is one case in a thousand,

you should at least weigh that against

all of the other benefits, which I'll talk about.

Now, there's something else I want to say,

because a moment ago I alluded to the fact that

I think the MPA might have been the biggest issue

in that study.

So there were two findings in that study that were negative.

One was the small increase in the risk of heart disease,

and the small increase in the risk of breast cancer.

But consider the other group,

we forgot about the group that didn't have a uterus.

'Cause remember, those women got estrogen only

versus placebo.

What was the difference in breast cancer there?

Well, this is interesting 'cause it didn't reach

statistical significance, but its P value was 0.06 or 0.07.

So it came very close, but it was in the opposite direction.

It was a 24% risk reduction,

about one in a thousand as well.

So when you had estrogen plus MPA,

you had a barely statistically significant,

the P value was 0.05,

so it just hit statistical significance,

one in a thousand cases for breast cancer.

And then you had one in a thousand cases,

but P value of 0.07, for reduction of risk of breast cancer.

Which to me suggests that the MPA,

the synthetic progesterone,

was playing more of a role than anything else.

The second thing I point out is oral estrogen,

which we no longer use, does increase coagulability.

It does increase the ability of the blood

to clot a little bit.

And when we look at the more recent data on HRT,

using topical estrogen or patches of estrogen,

we don't see that at all.

In fact, we see the opposite now.

So now we see the risk of heart disease

going down in women with estradiol.

- And some women will be arriving to those treatments

with mutations and things like Factor V Leiden

and other clotting factors.

Is it appropriate to say that everyone,

both male and female, should know whether or not they have

mutant forms of Factor V Leiden?

- You know, we don't typically test people for Factor V.

My wife actually has it,

but we didn't learn it until she had HELLP syndrome

giving birth to our first daughter.

But, you know, we kind of look for

more family history reason to be testing things like that.

We take a pretty detailed family history,

so we'll kind of look for clotting issues there.

- What about, so your reflex nowadays

is to put women on these topical

estrogen therapies? - Well it's to basically

have the discussion, right?

So here's where we still struggle, right, is, you know,

if it were up to me, I'd prefer for a woman's HRT

to be provided by her GYN,

because we want to be able to work in partnership with the GYN

who we would like to see

an endometrial ultrasound done every year.

That's, you know, some would argue that's overkill,

but we think she should be having a pap smear

every year as well.

So if we're looking at the cervix,

we want to look at the endometrium,

we want to make sure the lining isn't too thick.

The other thing I should say, Andrew, is today,

we now realize that not all women can tolerate estro,

pardon me, progesterone.

So you have to be careful.

So assuming, again, a woman still has her uterus,

the estrogen solves most of the problems,

but then you have to decide,

can she tolerate the progesterone?

And it needs to be, if given systemically

like a hundred to 200 milligrams.

And for some women, that is a lifesaving intervention.

I mean, they start sleeping better, their hair gets thicker,

they feel better.

But for some women, it literally drives them crazy.

It's probably the reciprocal of what we were seeing

in the case of women with PMS.

So in those situations we say, great,

we're done with oral progesterone.

We just use a progesterone coated IUD.

So then you get the local progesterone in the uterus

for protection, and the systemic estrogen.

- Fascinating.

What about oral contraception in women?

So the use of estrogen chronically through people's,

you know, college years or 20s, 30s,

maybe even teens, who knows.

What's known about the long-term effects, if any?

- I got to be honest with you,

I don't think I know enough to comment on it.

It's not something that really impacts

my patient population.

At least in what I see, more women are using IUDs

for contraception than OCs.

I mean, we use OCs sometimes in women who are premenopausal,

for symptomatic control, but we'll typically use like

a low low estrin, so a very low synthetic estrogen,

which I don't like using these very much.

But if it's the only thing that we can get

to control certain symptoms,

and we'll use it like half her cycle.

But it's typically not something

we're that experienced with.

- What about testosterone, because you mentioned that,

you know, nanogram per mill,

when you said everything to the same, you know,

I guess it's nanogram per deciliter,

- Yeah yeah. - as it would be

to kind of normalize

everything. - Versus picogram per ML.

- Right, yeah.

And so, what Peter was pointing out before is that

you look at your charts

and they're all in these different measures,

and so when you normalize,

testosterone is actually higher than estrogen in women.

That's a surprise to me.

Do you prescribe testosterone therapy to women ever?

- We do sometimes, but I do it with much more caution

because I don't have the data, right.

So where I'll, you know, what we'll say is, look,

I mean, we're now really outside of an area

where I can point to a lot of data.

Like when it comes to estrogen and progesterone,

I'll happily go toe to toe with anybody

who wants to make the case that it's dangerous.

Similarly, when it comes to using testosterone in men,

I'll spend all day, and I can go through that literature

until the other person cries

and wants to just call uncle, right.

When it comes to- - And then you

prescribe them testosterone.

- When it comes to estrogen in,

testosterone in women, don't have that data.

And I'd love to see that trial done.

So what's the sweet spot, how do we reconcile that?

So it's not something I consider standard.

And basically, if a woman is, if her testosterone,

first of all, is staggeringly low, and again,

even though her testosterone's low compared to a male,

we still have a range.

So if it's really at the bottom of that range,

she's really having difficulty putting on muscle mass

and really complaining of low libido,

I think in that situation,

we'll go ahead and use topical testosterone, and, you know,

replace her to a level that is still physiologically normal.

- Yeah, that's key because when people hear HRT,

they think about, super physiological seems to be the term.

- Yeah, like I've never seen a single symptom

in a single woman that I've put testosterone on,

in terms of like acne, body hair, things like that.

Like those are real symptoms that you have to be aware of,

but, you know, like clitoral enlargement

and things like that, like that doesn't happen

under physiologic normal conditions.

- I'd love to talk a little bit about

hormone replacement therapy in men.

When one looks on social media and the internet,

there seems to be a younger and younger cohort of guys

and people in their teens and 20s,

showing up to the table

thinking that injecting testosterone cypionate

or taking Anavar, whatever it is,

is going to be the right idea.

They mainly seem to be focused on cosmetic effects.

I'm not a physician, so I can't say whether or not

they were actually hypogonadal et cetera,

but it seems to me, again, correct me if I'm wrong,

but it seems to me that similar to the Attia's rule

as it relates to longevity,

that we could come up with a broad contour rule

in which if a male of any age

is not trying to get decent sleep, exercise appropriately,

appropriate nutrition, minding their social connections,

et cetera, et cetera,

the idea of going straight to testosterone

seems like a bad idea.

That said, just like with depression and antidepressants,

there is a kind of a cliff after which

low enough testosterone, or low enough serotonin,

prevents people from sleeping, exercise,

social connection, et cetera.

So I do want to acknowledge that.

But with that in mind, how do you think about,

and perhaps occasionally prescribe and direct your patients

in terms of hormone replacement therapy in men,

person in their 30s, person in their 40s,

who's doing almost all the other things correctly.

What sorts of levels do you think are meaningful?

Because the range is tremendous in terms of blood tests.

300 nanograms for deciliter,

I think on the low end now in the U.S.,

all the way up to 900 or 1200, that's an enormous range.

What are some of the other hormones you like to look at,

estrogen, DHT and so on?

- So, a lot to unpack there.

So, let's start with the ranges, right?

So the ranges you gave

are for total testosterone, of course,

and we don't spend a lot of time looking at that

the way we, you know,

I used to spend more time looking at total and free

when I used more tricks to modulate it.

So I'm actually far more simple

in my manipulation of testosterone today

than I was six or seven years ago.

Six or seven years ago, I mean, we were, you know,

we would use a micro dose of Anavar to lower SHBG

in a person who had normal testosterone,

but low free testosterone.

- What was a low dose of Anavar in that context?

- 10 milligrams subling two to three times a week.

- Anavar basically being DHT.

Oxandrolone- - Yeah, oxandrolone,

yeah exactly.

- And again, we're not recommending this.

This actually, if you're playing a competitive sport,

can get you banned from that sport.

- No no, yeah yeah.

This is- - It can also get you banned

from having children if you do it incorrectly.

- Yeah, so a micro dose of this has to be small enough

that it doesn't impair your body's ability

to make testosterone.

But Anavar has such a high affinity for SHBG,

that it basically distracts your SHBG

from binding your testosterone.

- Freeing up testosterone.

- That's exactly right.

So the goal was, how do I just give you

more free testosterone?

So if a patient shows up and they've got

a total testosterone of 900 nanograms per deciliter,

which would place them at, you know,

depending on the scale you look at,

the scale we look at, that would place you at about

the 70th percentile.

But your free testosterone is, you know,

eight nanograms per deciliter.

So that's pretty bad.

That means you're less than 1% free.

A guy should be about 2% free T.

So that dude should be closer to

16 to 18 nanograms per deciliter.

So in that situation that I just gave you,

his SHBG is really high.

His SHBG is probably in the 80 to 90 range.

- That's very high.

'Cause I think the upper range is somewhere around 55, 56.

- Exactly. - Yeah.

- So we would first back stall for what's driving his SHBG.

So there's basically three hormones,

so genetics plays a huge role in this.

There's no question that just out of the box,

people have a different like set point for SHBG.

Mine is incredibly low.

My SHBG is like kind of in the 30s, 20s to 30s.

But from a hormone perspective,

there's basically three hormones that run it.

So estradiol being probably the most important,

insulin and thyroxine.

So we're going to look at all of those

and decide if any of those are playing a role.

So insulin suppresses it.

So this is actually the great irony

of helping a person get metabolically healthy,

is in the short run,

you can actually lower their free testosterone,

all things equal.

Because as insulin comes down, SHBG goes up,

and if testosterone hasn't gone up with it,

you're lowering free testosterone.

- So somebody who goes on a very low carbohydrate diet

in an attempt to drop some water and drop some weight,

is going to increase their SHBG?

- Yeah, if their insulin

goes down enough. - Bind up testosterone,

less free testosterone.

I can tell the carnivore diet people

are going to be coming after me with bone marrow in hand.

But then again,

after this discussion extends a little further,

I'm sure the vegans will be coming after me

with celery stalks, so it's a.

- So then the same as with estradiol.

So except in the opposite direction.

So higher estradiol is higher SHBG.

So again, occasionally you'll see a guy with

normal testosterone, but he's a very high

aromatase activity person.

So he has a lot of the enzyme

that converts testosterone into estradiol.

You can lower estradiol a bit with an aromatase inhibitor,

and that can bring down SHBG.

Now, again, these things individually are rarely enough

to move the needle.

The last is thyroxine.

So if you have a person whose thyroid is out of whack,

you have to fix that before you, if their T4 is out of whack,

you're going to interfere with SHBG.

There are also some supplements

which I think you've probably talked about these

on the podcast.

I feel like I've heard you talk about these on the podcast.

- Yeah, there are a few that will adjust, you know,

there's this idea now there's a much better review,

it just came out, I'll send it to you,

I'd love your thoughts on it,

and I've been perusing it line by line.

But I love input from experts like you

on the use of Tongkat Ali for reducing SHBG.

In my experience, it does free up some testosterone.

By which mechanism it isn't exactly clear.

And the effects aren't that dramatic.

Right, they're probably multiple effects.

For all we know, it increases libido, and it does,

generally, by way of increasing estrogen slightly,

which can also increase libido in some individuals.

So we don't know the exact mode of action.

So we've talked about a few.

The one that a few years back people were claiming

could reduce SHBG was

stinging nettles. - Stinging nettles, yeah.

- Stinging nettle, well I'll just,

urinating seems to be coming up multiple times

on this podcast, for whatever reason.

Stinging nettle extract, I took,

the most pronounced effect of that was

you could basically urinate over a car when taking SHBG.

What the underlying mechanism of that was, I do not know.

I took it for a short while,

it didn't drop my SHBG very much,

but it did drop my DHT sufficiently so that I

stopped taking it. - You felt that, yeah.

- I do not like anything that impedes DHT.

I don't care if my hairline retreats,

I don't care about any of that.

DHT to me is something to be coveted and held onto

because you feel so much better

when your DHT is in the appropriate range,

and I'd love your thoughts on that.

- Yeah, again- - At some point too.

- It really depends on the guy,

and it depends on what risk you're trying to manage, right.

So prostate size starts to become

one of the issues with DHT.

- Luckily my prostate-specific antigen is low, and DHT,

the things that I know can reduce it

are things like finasteride, Propecia,

things like, yeah, right.

Things that people take to try and avoid hair loss

can dramatically reduce DHT

and lead to all sorts of terrible sexual side effects,

mood-based side effects, et cetera.

But yeah, so I'm not aware of anything

that could be taken in supplement form

that can really profoundly drop

SHBG. - Yeah, we don't spend

much attention on it anymore.

Basically, I used to have a much more complicated

differential diagnosis eight years ago.

Like, I mean it was, I would drive patients nuts

with the whiteboard diagrams I would draw for them,

when in the end, I think they were just like, dude, just,

what do I need to take?

Today we take a much more simple approach.

So the first question is, should you or should you

have your free testosterone being higher?

That's the metric I care about,

is free testosterone is the first, most important,

the second most important is estradiol.

- And sorry to interrupt, you said,

if you look at your total testosterone,

you want the free T to be about 2% of your total.

- Well, it should be, right.

Now I can't, I might not change that anymore.

So in other words, if a guy's at 1%,

then I know I have to really boost his total testosterone.

If he's only going to get one to 1 1/2% of it

converted to free, I need to boost him.

And that's why I don't care if he's outside the range.

Like, I'll have a guy who's free T,

I might have to get a guy's total T up to 1500

to get his free T to 18.

- I see, so free T is the target.

I like this approach. - Free T is what we treat.

- And do you still use Anavarax,

- I don't use- - oxandrolone, sorry,

to try and lower SHBG.

- I don't, no. - Because it's too potent?

- No, because it's just too complicated for patients.

It's a drug that can't be taken orally,

so you have to take it under the tongue.

- Like a troche or something.

- Right, but then, you know, I had one patient once who,

even though we told him about 87 times that,

he was like swallowing the Anavars and his liver function,

and he was like, we're talking 10 milligrams

three times a week is a tiny dose, and three months of him,

or whatever, two months of him swallowing that every time

tripled his liver function test.

So it's like, I was like, you know,

it's just not worth the hassle of doing this

for, you know, perfection.

In reality, we can fix this another way.

So the first order question is,

do we believe clinically you will benefit

from normalizing your free testosterone,

or taking it to a level,

let's call it 80th to 90th percentile.

So upper normal limit of physiologic ranges.

That's the first order question.

And that's going to come down to symptoms,

and that's going to come down to some biomarkers.

I think there's, two years ago,

was it two years ago or maybe a year ago,

very good study came out that looked at pre-diabetic men,

you've probably talked about this study,

and looking at insulin resistance and glucose disposal

with and without testosterone.

And the evidence was overwhelmingly clear.

Testosterone improves glycemic control.

Testosterone improves insulin signaling.

This shouldn't be surprising by the way,

given the role muscles play as a glucose reservoir

and a glucose sink.

So now I include that as one of the things

that we will consider as a factor for using testosterone.

Now, again, it's not the only one.

So you can accomplish that with exercise,

you can accomplish that with these other things,

but then you get into a little bit of the vicious cycle of

will having a normalized testosterone

facilitate you doing those things better.

So let's just assume we come to the decision

that this person is a good candidate

for testosterone replacement therapy.

The next question is,

what's the method we're going to do.

Are we going to do it indirectly or directly?

Now we used to use a lot of Clomid in our practice.

And have you talked about Clomid on the pod?

- Haven't talked too much about it.

No, we've talked a little bit about the fact that

some people taking things like anastrozole

to reduce aromatase activity,

can potentially run into trouble because they think,

oh well, more testosterone, good, lower estrogen, bad,

and then they end up with issues like joint pain,

memory issues, and severe drops in libido.

And I think a lot of the reason why-

- And even fat accumulation.

So if estrogen is too low,

you can develop adiposity in a way

that you wouldn't otherwise.

There was a great New England Journal paper,

it's probably 10 years old now, that looked at,

I believe it was five different doses

of testosterone cypionate.

So these men were chemically castrated

and divided into 10 groups.

It's pretty remarkable-

- [Andrew] That somebody signed up for this study.

- Yeah, so you were with and without anastrozole

and five doses of testosterone.

So now you basically had five testosterone levels,

plus or minus high or low estradiol.

And the results were really clear

that the higher your testosterone

and the more your estradiol was in kind of that

30 to 50 range, the better you were.

So if estrogen was too low,

even in the presence of high testosterone,

the outcomes were less significant.

- And this is 30 to 50 nanograms per decile,

not 30 to 50% of one's testosterone.

Okay, great.

No, we haven't talked, but Clomid is,

you know, we have not talked a lot about Clomid.

I'd love to get your thoughts on Clomid.

- So Clomiphene is a fertility drug.

It's a synthetic hormone.

It's actually two drugs, M Clomiphene

and I forget the other one.

And it tells the pituitary to secrete FSH and LH.

So you, and so the advantage of Clomid is it's oral,

and it's meant to be taken orally.

So, you know, a typical starting dose would be like

50 milligrams three times a week.

And if you do that, you'll notice, in most men,

especially young men, FSH and LH goes up.

In any man, the FSH and LH go up,

but if a man still has testicular reserve,

he'll make lots of testosterone in response to that.

'Cause that's the first order question

we're trying to answer is do you,

is your failure to make testosterone central or peripheral?

- Yeah, and I think, just want to point out,

again, correct me if I'm wrong,

but my understanding is that a lot of the drugs

that we're talking about, the synthetic compounds,

testosterone, estrogen, things related to growth hormone,

et cetera, were discovered and designed

in order to treat, and excuse me,

in order to isolate and treat

exactly these kinds of syndromes,

whether or not it was the hypothalamus, the pituitary,

or the target tissue, the ovaries or the testes.

Correct?

- Correct, yeah.

I mean, I think, the easiest way to go about doing this

is just give the hormone that's missing,

without attention to where the deficiency is.

Why this becomes relevant is if you have a 35-year-old guy

whose testosterone is low,

but you can demonstrate that it's low

because he's not getting enough of a signal

from the pituitary,

why would you bother giving him more testosterone

when he has the Leydig cells and the Sertoli cells

to make testosterone.

He just needs the signal.

Sometimes, though not always,

just a course of Clomid can wake him up,

and he's back to making normal testosterone.

- So he'll do this three times a week, 50 milligrams,

three times a week, for a short course, and then?

- Yeah, we would do that for eight to 12 weeks

and then we reevaluate.

- And estrogen and testosterone will increase in parallel.

- Yes.

And again, it depends, you know,

aromatase activity is dependent

on how much body fat you have and genetics.

And if estradiol gets too high,

we think if it gets over about 55, 60,

we will give micro doses of anastrozole.

But it has to be real micro doses.

I mean, you cannot pound people with anastrozole.

To give you perspective, the sort of on-label use,

like if you just go to a pharmacy and order anastrozole,

you're going to get one milligram tablets.

Like we can't give anybody a milligram.

- [Andrew] They'll feel like garbage.

- We have to have it compounded at 0.1 milligrams,

and we might give a patient 0.1, two to three times a week.

That would be a big dose of anastrozole.

- Yeah, I think that the typical TRT clinic out there

is giving 200 milligrams per mil, one mil,

200 milligrams of testosterone once every two weeks,

and then hitting people with multiple milligrams

of anastrozole, and they're all over the place.

- I've never really understood,

I mean, I guess I shouldn't be surprised,

but it kind of blows my mind that these TRT clinics

are up all over the place, given how bad.

I mean, I see the results,

'cause I have patients that come from them,

and I don't understand like why they're so incompetent.

- I actually think it's worse than that.

I think that they simply don't understand and don't care,

because it's a pill mill and it's a money mill.

I think that nowadays it seems

almost everybody who's doing TRT

is taking lower doses more frequently every other day,

or twice a week, dividing the dose,

and being very, very careful with these estrogen

or aromatase blockers.

- Most of our patients do not take aromatase inhibitors.

It's not needed.

It's really only the high aromatasers that need it.

And so yeah, when we'll talk about testosterone,

we'll talk about dosing there, 'cause I agree.

The more frequently you can take it the better,

and frankly, you don't need to go more frequently

than twice a week.

- Because it's so slow-acting. - The half-life, yeah,

the half life of the drug is,

I think it's about 3 1/2 days,

is the plasma half-life or something like that.

I could be off a little bit, but twice week dosing

is really nice.

So if you go to like a testosterone clinic

that's giving you 200 every two weeks,

50 twice a week is the same total dose, which, by the way,

is a physiologic dose.

That's not going to give somebody any of the side effects

you would see.

You're not going to get acne with that.

You're not going to get gynecomastia.

You're not going to get anything.

The only real side effect you get from that

is you will get testicular atrophy.

It is enough to suppress.

- Yeah, to maintain fertility,

what do you typically do for?

- Well, so this is where,

so I'll finish the story on Clomid,

'cause we currently do not use Clomid,

and that's due to a really interesting observation

that we made, that I don't think has been reported

in the literature yet,

which is that Clomid was increasing levels of a sterol

that we also happen to measure called desmosterol.

- [Andrew] I'm not familiar with that.

- So, and the way that cholesterol is made, it's made by,

there's two pathways that make cholesterol.