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 Atiyah.
Dr. Atiyah is a physician who’s focused
on nutritional, supplementation-based, behavioral,
prescription drug, and other interventions
that promote healthspan 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. Atiyah is 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. Atiyah 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 Institutes 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. Atiyah 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 healthspan?
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 healthspan.
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.
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.
Our first sponsor is Element.
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That means plenty of salt, magnesium, and potassium,
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in particular, to the function of your nerve cells,
also called neurons.
In fact, in order for your neurons to function properly,
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Today’s episode is also brought to us by Thesis.
Thesis makes what are called nootropics,
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We partnered with Momentus for several important reasons.
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And now for my discussion with Dr. Peter Atiyah.
Peter, thanks for joining me today.
Thanks for having me, man.
I’m looking forward to this for a very long time.
That’s fine.
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, 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?
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.
They’re gonna 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, healthspan lens?
Yeah, and just, 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 healthspan.
So lifespan is the easiest of those vectors to understand
because it’s pretty binary, right?
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 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,
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
because those aren’t really biomarker studies,
but put that away.
On the neurodegenerative side,
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,
blood testing with biomarkers
provides pretty good insight into lifespan.
When you get into healthspan,
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 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,
zone two lactate testing, fat oxidation.
Those, 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 gonna wanna 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 they,
that’s just not something that,
that’s something that’s compartmentalized.
Maybe 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 healthspan,
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 little a.
So unfortunately, most physicians
don’t know what LP little a is,
and yet somewhere between 8% and 12% of the population
has a high enough, and depending on who you,
I had a recent guest on my podcast
who suggested it could be as high as 20%,
have a high enough LP little 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 wanna 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?
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, 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, 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,
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?
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,
I can sort of tell my body fat by my abs, right?
So I can sort of tell by 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 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.
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
because 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.
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, it’s 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,
your 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 have 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, 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
because 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 a running must be the best,
some sort of impact must be the best thing you can do.
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 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,
because 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 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 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.
Yeah, they’re steroid-based.
Some of them, of course, are just beta agonists,
and they’re fine.
So anything corticosterone-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 corticosterone?
A lot of 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 if you’re talking about,
like I’ve got a little rash under my skin,
I’m gonna 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
and 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’ve missed that window.
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.
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,
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 gonna tell you, it’s gonna differentiate
power lifting from weight lifting.
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 dead lifting.
Now, I mean, I can count the number of days
left in my life when I’m gonna wanna do
sets over 400 pounds, but I’ll pick and choose
the days that I do, but 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 dead lift,
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.
It’s not as pure a movement as a dead lift,
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,
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, Everett.
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 wanna say she was 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 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.
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 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.
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 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,
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 fall, you break a wrist.
So this is a systemic issue,
but the majority of the response is a local response
because 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.
I’d like to take a quick break
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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,
even though 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 gonna help us live
to be, you know, whatever.
I mean, we’re all gonna 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 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 gonna 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 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 two and a half 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 gonna tell you what it is.
Just do it.
Could be playing basketball.
It could be swimming to Catalina Island.
It could be running a hundred 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 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 in 40 years,
you’re not gonna 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 wanna be able to do the things
we probably wanna 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 wanna 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 backcasting.
This backcasting 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, 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 backcasting 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 backcasting.
And I was like, I like the term backcasting better.
I think it’s more intuitive than reverse engineering.
Yeah, there’s a real genius to it.
And I think it,
because 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, but yeah, yeah, yeah.
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 let’s say we were on a short flight
from here to San Diego.
We’re in Los Angeles now.
And we’ve got takeoff and landing
and we don’t want to kink our neck too much
by doing this thing.
So if I just said, hey, give me 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 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 using smoking, smoking is approximately
a 40% increase in the risk of ACM.
What does that translate to?
And 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 gonna die
relative to a non-smoker and a never smoker.
Yeah, yeah.
So it’s important to distinguish.
It doesn’t mean your lifespan is gonna 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 end-stage kidney disease.
So these are patients that are on dialysis
waiting for an organ.
And again, there’s a confounder there
because what’s the underlying condition
that leads you to that?
It’s profound hypertension,
significant type two diabetes that’s been uncontrolled.
That’s enormous.
That’s about 175% increase in ACM.
So the hazard ratio is like 2.75.
Type two diabetes is probably about a 1.25 as well.
So 25% increase.
So now the 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 and 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 a 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 tease out strength,
you can realize that strength could be
probably three and a half X as a hazard ratio,
meaning about 250% greater risk
if you have low strength to high strength.
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, how much weight can you hold
for how long relative to body weight, things like that.
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.
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 cardiorespiratory 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 max.
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 for the-
But the point is like you don’t have to be
a world-class athlete to be elite here.
Got it.
So maybe we can 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.
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 your,
this nuance of your carnivore diet
versus this nuance of your paleo diet
versus this nuance of your 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 go 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.
No one will listen to it.
I don’t know about that.
We can make whatever rules we want.
We can call it Atiyah’s rule.
One thing I’ve done before in 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 Atiyah’s rule
until you can do the following things.
Don’t talk about-
Please refrain from talking about supplements and nutrition.
There it is.
Hereafter thought of, referred to,
and referenced as Atiyah’s rule.
I coined the phrase, not him.
So there’s no ego involved, but it is now Atiyah’s rule.
Watch out.
Hashtag Atiyah’s rule.
Oh God.
Wikipedia entry, Atiyah’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
or 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?
That’s a good question.
So there are really good VO2 max estimators online,
and you can plug in your activity du jour.
So it would be at a bike run or rowing machine,
and it can give you a sense of that.
And I don’t remember, I used to know all of those,
but now that I just actually do the testing,
I don’t recall them.
But it’s exactly that line of thinking.
Can you run a mile in this time?
If you can, your VO2 max is approximately this.
Great.
And I think somewhere in my podcast realm,
I’ve got all those charts posted of,
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 something.
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.
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 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.
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?
I think the test is going to get only more and more involved
as we get involved.
Because 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 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, 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 Pellichar,
and I said, Dan, I’m gonna 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 wanna know every single type of input.
And I wanna 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 gotta 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, this is hands down the best thing
because 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 ultimately it turned into a paper that we wrote
basically about this topic and a few others.
Because again, I thought, are you sure it’s not EPA and DHA?
Like that’s gotta 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 wanna 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.
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.
You know, 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, 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 healthspan side of this,
which is not necessarily captured in those data.
The healthspan gets back to the functional piece
that 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,
how can they take themselves to the bathroom?
They’re thinking, how can they sit up off the toilet?
I mean, yeah, really basic,
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 Anika data, 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 because 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.
Torrence and Wiesel for work on neuroplasticity.
And then Richard Axel, who’s also at Columbia,
Nobel Prize winning work for molecular biology
of smell 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.
Eric was, 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 some
of their intellectual vigor over time.
I want to just also use it 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, because nicotine is an acetylcholine receptor,
obviously, is known to create a state of focus
and neural enhancement.
What are your thoughts about not smoking?
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 a 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 get 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.
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.
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.
Because there was some reason we were doing this
potentially through an investment.
So I get up, literally ordered a lifetime supply
of this stuff.
And it’s pretty good.
It’s a really nice little patch.
Because 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.
I’m like, by the way,
I ordered all that nicotine stuff you told me about.
He’s like, what?
And he goes, oh, oh, the company’s name was something else.
It was totally unrelated.
I was 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 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.
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 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 wanna 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, 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 inappropriate 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 concentration
and cognitive performance
is not something we’re comfortable doing.
Yeah, it’s rampant on college campuses.
I can only imagine.
R-modafinil, modafinil,
which are slightly different, of course.
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 had one experience with R-modafinil
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 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 a 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 lasered in that I kind of forgot the context.
I’m a little bit of a kind of a tunnel vision OCD type.
Anyway, but 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.
I just-
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 was no email, there was no social media,
there was no internet.
I mean, I was in college when Mosaic launched
in the early nineties.
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 miss the text message
or something stupid.
That’s pretty infrequent.
I did a 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
that nothing focuses me like a deadline,
a little bit of a 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.
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 the 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, 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 done.
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.
Wow.
So phenotypically, right,
estrogen is the hormone that’s dominating.
So it’s the, you know,
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.
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 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 gonna 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 wanna 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 wanna 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 gonna 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 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 I think this is a legitimate thing, right?
I mean, it’s not like, oh, she’s crazy
because she’s having all these PMS symptoms.
We know that that’s the case
because if you put women on progesterone
for those seven days, those symptoms go away.
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 folks that don’t understand is looking at RNA
or 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 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 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?
Because 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 pre-cancerous
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 the 19,
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 cardiovascular disease,
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 gonna get it, right?
You couldn’t-
You gotta wait too long.
Yeah, you gotta wait too long.
And this was only gonna 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 gonna get some of these numbers wrong
and people are gonna get all phosphorylated,
but 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 wanna 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 and MPA,
which is a synthetic form of progesterone?
Horse?
Yes.
Estrogen?
It’s horse urine.
They collect horse urine.
So they’re getting the…
Horses do urinate a lot, or at least when they urinate,
it seems like a large volume of urine
from what I’ve observed.
You have a lot of experience with this?
No, but my sister rode horses for a little while.
My high school girlfriend had a horse and that thing,
I mean, the peas were legendary.
It’s a male horse.
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 and progesterone?
Like today, when we put women on estrogen,
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 bio-identical 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.
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 gonna 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 my, one of my,
if you’ve ever listened to me on the 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 to apologize for having many pet peeves,
because as long as they have experience
and data to support them, it provides a better life.
So one of my biggest pet peeves is,
and my team knows this,
because 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 1,000
and four cases per 1,000.
So the ARR was 0.1%,
one case in 1,000.
And it’s true, going from four in 1,000 to five in 1,000
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 gonna start you on this
when you’re going through menopause.
We’re using bioidentical hormones,
and if your upper bound risk of breast cancer
is one case in 1,000,
you should at least weigh that
against all of the other benefits, which I’ll talk about.
Now, there’s something else I wanna 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 a small increase in the risk of breast cancer.
But consider the other group.
We forgot about the group that didn’t have a uterus
because remember those women
got estrogen only versus placebo.
What was the difference in breast cancer there?
Well, this is interesting
because 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 1,000 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 1,000 cases for breast cancer.
And then you had one in 1,000 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 hoppical 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 HELP 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, we, 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, you know, we think she’d 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 estrogen, 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 100 to 200 milligrams.
And for some women, that is a life-saving 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 in the systemic estrogen.
Fascinating.
What about oral contraception in women?
So the use of estrogen chronically
through people’s college years or 20s, 30s,
maybe even teens, who knows?
What’s known about the long-term effects, if any?
I gotta 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.
You know, 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 estrogen,
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 nanogram per mil,
when you set everything to the same,
I guess it’s nanogram per deciliter,
as it would be to kind of normalize everything.
Versus picogram per mole.
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 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?
And then you prescribe them testosterone.
When it comes to estrogen,
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 is 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 replace her to a level
that is still physiologically normal.
Yeah, that’s key because when people hear HRT,
they think about super physiological.
It 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 acne, body hair, things like that.
Those are real symptoms that you have to be aware of,
but clitoral enlargement and things like that,
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 Anivar or 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 hypergonadal, et cetera,
but it seems to me, again, correct me if I’m wrong,
but it seems to me that similar to the Atiyah’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 per deciliter,
I think on the low end now in the US,
all the way up to 900 or 1,200.
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.
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 would use a microdose of Anivar
to lower SHBG in a person who had normal testosterone,
but low free testosterone.
What was a low dose of Anivar in that context?
10 milligrams subling, two to three times a week.
Anivar basically being DHT.
Oxandrolone.
Oxandrolone, yeah, exactly.
And again, we’re not recommending this.
It’s actually, if you’re playing a competitive sport,
it can get you banned from that sport.
No, no, yeah, yeah.
It can also get you banned from having children
if you do it incorrectly.
Yeah, so a microdose of this has to be small enough
that it doesn’t impair your body’s ability
to make testosterone.
But Anivar 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,
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 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.
Yeah.
Because I think the upper range is somewhere around 55, 56.
Exactly.
So we would first backstall 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 gonna 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
and attempt to drop some water and drop some weight
is going to increase their SHBG.
Yeah, if their insulin goes down.
Find up testosterone, less free testosterone.
I can tell the carnivore diet people
are gonna 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 gonna 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.
There is this idea.
Now there’s a much better review that 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 Tonga 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?
There are 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 nettle, well, just urine seems to be,
or 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.
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 hoveted and held onto
because you feel so much better when your DHT
is in the appropriate range.
And we’d love your thoughts on that.
Yeah, again, 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 that.
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 can be taken in supplement form
that can really profoundly drop SHBG.
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, 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.
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?
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 gonna get one to one and a half percent
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 1,500
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 antivirals,
oxandrol, sorry, to try and lower SHBG?
Because it’s too potent?
No, because it’s just too complicated for patients.
You know, 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 antivirals 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, it’s just, 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 it?
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 podcast?
I haven’t talked too much about it.
No, we’ve talked a little bit about the fact
that some people taking things like an astrazole
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’s 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.
Somebody signed up for this study.
Yeah, so you were with and without an astrazole
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 deciliter,
not 30 to 50% of one’s testosterone.
Okay, great.
Okay, so we haven’t talked, but clomid is,
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 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, 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 one 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 capacity,
he has the Leydig cells and the Sertulli 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 it for eight to 12 weeks
and then we reevaluate.
And estrogen and testosterone will increase in parallel.
Yes, and again, it depends.
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 an astrozole.
But it has to be real micro doses.
I mean, you cannot pound people with an astrozole.
To give you perspective,
the sort of on-label use,
like if you just go to a pharmacy and order an astrozole,
you’re gonna get one milligram tablets.
Like we can’t give anybody a milligram.
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 an astrozole.
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 an astrozole and they’re all over the place.
I’ve never really understood.
I mean, I guess I shouldn’t be surprised,
but it’s kind of blows my mind
that these TRT clinics are up all over the place
given how bad, I mean, I see the results
because 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 aromatizers that need it.
And so, yeah, when we’ll talk about testosterone,
we’ll talk about dosing there.
Because 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.
Yeah, yeah, the half-life of the drug is,
I think it’s about three and a half days
is the plasma half-life or something like that.
It could be off a little bit,
but twice a 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 gonna get acne with that.
You’re not gonna get gynecomastia.
You’re not gonna get anything.
The only real side effect you get from that
is you will get testicular atrophy.
That 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,
because 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 happened to measure called desmosterol.
I’m not familiar with that.
So in the way that cholesterol is made,
it’s made by, there’s two pathways that make cholesterol.
So it starts with two carbon subunits, like acetyl-CoA,
and it kind of marches down a pathway, bifurcates,
and cholesterol is the finished product of both.
But in one of those pathways,
the molecule right before cholesterol is called desmosterol.
In the other pathway, it’s called lethosterol.
So we constantly measure lethosterol and desmosterol
because we want to know how much cholesterol
is being synthesized in the body,
not just what your cholesterol is.
We wanna know how much cholesterol you reabsorb.
And those markers are really important to us
when we’re looking at cardiovascular disease risk.
So when we gave patients Clomid,
we were noticing a almost universal rise
in their desmosterol levels.
Now, the most obvious explanation for that,
though the last time I looked,
I couldn’t find clear explanation for this
in any of the clinical trials
that led to the approval of Clomid.
So I don’t know if it was described.
In fact, maybe it wasn’t known.
I suspect it is inhibiting the enzyme,
which I think is called delta-24 desaturase
that turns desmosterol into cholesterol.
Makes sense if you inhibit that enzyme,
you’re gonna see a rise in desmosterol.
This wouldn’t have been a concern to me
if not for the fact that Tom Dayspring,
who’s one of the physicians we work with,
who’s one of the world’s experts in lipids,
pointed out a very obscure story,
which was that the very first drug ever approved
to treat cardiovascular disease,
at least to treat hypercholesterolemia,
was a drug that attacked the same enzyme.
So this was in the early 1960s, I believe,
maybe the mid-60s.
This drug was approved and it lowered cholesterol.
And it was approved on the basis of lowering cholesterol.
Now, today, no drug for ASCVD is approved
on the basis of it lowering cholesterol.
That’s not a high enough bar.
You have to reduce events.
You actually have to show
that you’re preventing heart attacks and death.
But at the time, it was like, hey, it lowers cholesterol,
it’s gotta be good.
Well, in the late 60s, it was pulled from the market
because events were going up.
So cholesterol was coming down, events were going up.
How could that be?
We don’t know.
What we are suspecting is that desmosterol,
which is still a sterol, was potentially more damaging
and created more oxidative stress in the endothelium,
in the sub-endothelial space than cholesterol.
I see.
Which would at least suggest to us,
and again, we’re taking a lot of leaps here,
that maybe having high desmosterol,
very high desmosterol, is not a good thing.
And so, once we kind of pieced all that together
a few years ago, we were like,
yeah, we’re just not gonna prescribe clomid anymore.
And we then switched to HCG,
which we used to use sometimes instead of clomid,
but it’s more cumbersome to work with.
It needs to be refrigerated.
It’s a much more fragile molecule.
Yeah, I think we talked about this once.
It’s almost like if you accidentally
knock over the little bottle, it’s basically gone bad.
Yeah. Travel with it
is very challenging. Can’t travel with it.
It’s a needle.
You know, it’s an injection, sub-Q, so easy to administer.
It’s not IM or anything like that,
but it’s just more of a hassle factor.
But that said, it has the benefit that clomid does,
which is it preserves testicular function.
It preserves testicular volume.
So, you know, bodybuilders will often use this
in their post-cycle therapy
as a way to kind of recover function.
And we would just use it now as ongoing therapy
for a guy who still has testicular reserve.
So on its own, no testosterone,
no aromatase inhibitor, nothing,
just a way to crank out a bit more testosterone
from the testes, maybe some additional estrogen also.
HCG is a different model.
HCG is just an analog of luteinizing hormone.
So it’s basically like giving them luteinizing hormone.
So it’s gonna crush endogenous luteinizing hormone levels,
right, because it’s-
Yeah, and you don’t really see much of an impact on LH,
but you do see endogenous testosterone production go down.
Actually, no, I correct that.
Both FSH and LH will go down on a high enough dose.
Yep.
Just as a mention in here, I’m not making recommendations,
but one supplement I’ve talked a lot about publicly
is Phytogeoagrestis, which is this weird Nigerian shrub
that does-
You talked about this on Tim’s podcast.
On Tim’s podcast and Joe’s podcast.
And, you know, there was a bit of a backlash
because it does turn out that at high doses,
in rodent studies, it can cause some toxicity
to the testes.
But at lower doses,
it does seem to increase luteinizing hormone.
And after talking about this,
a number of people went out there,
did pre and post blood work,
and the consistent effect seems to be an increase
in luteinizing hormone.
There’s a noticeable effect on testicular size and volume.
So a lot of people take this and be like,
oh, you know, their balls are getting bigger.
And so they get all excited
that something good is happening.
But we don’t know the long-term safety and efficacy
of something like Fidogio,
whether or not it needs to be cycled.
Yeah, this is why I’m also very leery
of the supplements in this space,
because at least when we’re using HCG or testosterone,
like we have so many years of data.
You have to remember how many women are using this stuff
for reproductive medicine.
So, you know, I think the FDA has a lot of faults.
I think I have an entire podcast devoted
to the corruption of the FDA
and all of the mistakes that have been made
with respect to their oversight in especially generic drugs.
But it’s way more regulated than the wild, wild west
of nutty supplement land.
Absolutely.
I think that the reason for talking about things
like Tongad and Fidogio
was to provide some intermediate discussion
between doing all the correct things,
but no supplementation or hormone therapy,
and then going straight to hormone therapy.
It’s sort of like the leap from,
I can’t focus very well to Ritalin, right?
Without a real diagnosis of ADHD
to, oh, well, maybe some things like
alpha GPC low doses of nicotine, right?
But I agree entirely.
I mean, the sourcing is important.
The dosages are worked out empirically on an individual basis
and there aren’t randomized controlled trials.
There just aren’t.
Yeah.
And, you know, have kind of like a seven,
this is another Peter principle, right?
So I’ve got a lot of patients that come into the practice
and, you know, during our intake,
we go through what drugs and supplements
are you taking right now?
And a lot of people come in, I’m not taking anything, Peter.
I just, you’re in charge now.
Like, tell me what you think.
And then you get a lot of people that come in
and they’re like, we’re gonna need an extra few pages
for this part of the documentation.
People who travel with a suitcase that you can hear
as they walk through the airport from all the pills.
So I give these patients a little homework exercise,
which is you have to answer these seven questions
for every supplement you take.
And here’s the spreadsheet and let’s talk about it.
And it basically just runs through,
like, you know, it’s basically walking you through
the logic of why do you take this molecule?
And I think for many people,
when they do that, it’s very sobering, right?
They kind of, a lot of them will come back and be like,
you know what, I don’t think I can come up with any reason
along this really rigorous line of thinking
as to why I’m taking 80% of this stuff.
Well, I know people,
and actually we know some of the same people
who are fanatic about, like, red light on the testes,
sunning their testes, putting ice packs on their testes.
It’s kind of all over the place.
The number of things that people are trying and doing
in order to increase testosterone output
from their testes is pretty remarkable.
And that said, among some of the women I know,
the number of things that they’re doing
to try and promote longevity and fertility,
and in particular skin health, hair health,
and nail health is also kind of outrageous.
Everything from collagen to red light therapies,
which may actually have some efficacy in certain cases,
but there’s a hunger there, right?
Oh, for sure.
One of the things that I hope gets a lot more attention
is the use of rapamycin for preserving ovarian health.
So the animal literature on this is pretty impressive.
So in mouse models, rapamycin will preserve ovarian life.
And so it makes sense, right?
I mean, it totally makes sense
why the most potent geroprotective molecule we have
would also preserve and extend ovarian life,
at least in mice.
So I’d love to see the clinical trials done in women
to test this hypothesis.
I definitely want to come back to this
because it’s a key thing.
I know that a lot of people are interested
in female fertility out there,
including their male partners.
So going back to,
so now I understand why you don’t prescribe clomiphene
because of this potential dysmosterol link.
What about testosterone therapy?
So less frequent, lower doses,
less or no estrogen inhibition or aromatase inhibition.
We’re only using an aromatase blocker
and we use aromatics when we do.
It’s just to get that estradiol into the range we want.
I like to see it between 30 and 50.
That’s the sweet spot.
And I don’t know, I would say like a third,
maybe not even a third,
I’d say probably 20% of men require a microdose
of anastrozole to get into that range.
Most do not.
And I’d rather err on the side of being a little high
than a little low.
So I never really want to be below 25.
If, unless sometimes it’s just below 25 and it is,
it is what it is, that’s fine.
But if we’re suppressing it to below 25,
I never want to be in that zone.
And then yes, so TRT is ultimately,
giving testosterone cipionate is usually what we use.
Injectable, so as opposed to cream or pellet.
Correct.
I used to use pellets with women
for some who were really adamant
about the convenience of it.
But for a bunch of reasons, I just,
I’m mostly not doing that.
And I’ve never been a fan of pellets in men.
You can’t control the dosage once it’s in, right?
Well, even if you know the dose,
yeah, that’s obviously a problem.
But I don’t think, there’s a big difference
between putting a pellet into a man and a woman.
So when you’re putting a estrogen pellet into a woman,
it’s like, it’s that big.
When you’re putting enough pellets into a man
for six months of testosterone,
it’s two sums of pellets that are longer than my finger.
So you’re putting like a V-shape.
Where are you putting this?
You’re putting it into the gluteal fat.
So it’s just a more morbid procedure
and I don’t think it’s necessary.
I think if you know how to manage it,
you know, through sort of the injections.
Injections are no big deal.
Yeah, well, especially now if you’re doing,
you know, we’re having them do sub-Q injections anyway.
So it’s not IM.
They’re using a five eighths inch
to a one inch 25 gauge needle,
which is about the smallest needle
you can push the oil through once to twice a week,
depending on, and by the way, if they’re real needle fobs,
we use Ziosted, which is a preloaded pen.
And are you having all men take HCG
to maintain fertility and testicular size?
Only if they want to.
Got it.
Yeah, and by the way, we do not like to use TRT
in men who, we don’t like to use testosterone specifically
in men who still want to maintain fertility.
We just steer them away from that.
Because total sperm count goes down.
Yeah, we just say, why risk it?
Like we’d rather use HCG.
Just on its own.
Just wait, just wait till you’re done reproducing.
Bank sperm, wait till you’re done reproducing
before we go to testosterone.
What are some of the benefits
and what are some of the cautionary notes
with appropriate TRT,
meaning of the kind of contour
that we’re talking about here,
a lower dose with the yes or no low estrogen control?
People, what generally people report,
how do they feel?
What does it allow them to do
that they couldn’t do or feel before?
In terms of what are the markers to look for?
Is it LDL, blood pressure, water retention,
acne, those kinds of things?
Are there some other things as well?
Yeah, it depends on the doses, right?
I mean, again, we’re using these in really low doses.
So it’s pretty rare that we’d have a patient
on more than 100 milligrams a week of testosterone.
I think for comparison, like a bodybuilder
could easily take 500 to 1,000 during a high growth phase.
I know some of these guys, they go ballistic
or they’re doing moderate levels of testosterone,
so being eight, but they’re also taking
Dianabol, Oxandrolone,
SARMs and a bunch of other things.
I mean, their stacks are kind of ridiculous.
I mean, no disrespect to that sport,
but I mean, people are dying like crazy in that sport
right now.
It’s outside of physiology.
Yeah, and I think for 99% of people listening,
they just, they look, they hear bodybuilder
and they just get like, why would somebody do that anyway?
I think that’s the typical response.
So the point is a lot of,
but we owe those guys a great deal of gratitude
because they’ve shown us the boundaries.
Including the women.
That’s right, yeah, yeah.
And so those bodybuilders have taught us a lot
about like what happens.
And so, yeah, the bloating, the water retention,
acne, hair loss, hair growth, all of those things,
we understand the truth of it is,
we just don’t see those things in our patients.
But a hundred milligrams per week is a very low output.
My understanding is-
But it’s a physiologic dose.
I mean, the reality of it is it’s enough for most people.
I mean, there’s probably the highest we’ve ever had to go
is maybe 70 twice a week.
What’s the youngest patient you’ve ever had to put on TRT?
Actual testosterone?
Mm-hmm.
Probably, that’s a good question.
I’m thinking about maybe 40.
I think that’s great for people to hear
because I know that a lot of guys in their 20s
are thinking TRT is the way to go.
And I would argue, unless you’re doing everything else right
and you’re still hypogonadal and you’re really struggling,
put that time off because also the fertility issue,
you want to delay, delay, delay.
Well, again, it depends if when we say TRT,
if you’re in your 20s and there’s no other way,
I would hope you would be steered toward HCG
to at least preserve testicular function.
Now, again, we don’t actually know
if after being on HCG for 10 years,
your pituitary will still work.
Right, you won’t be able to make your own luteinizing.
Exactly, so it might be the case
that you’re going to need something upstream of that,
like Clomid to kickstart it.
But again, I don’t want anybody who’s listening to this
who’s using Clomid for fertility
to think that there’s anything wrong with it.
My concern over this became like,
if you’re going to be on this for 10 years,
is it problematic?
Not if you’re using this for a course of IVF
or something like that.
So again, if we felt that someone’s pituitary
was not working, I would be happy to put three months
of Clomid on them to kind of try to see
if we could blast it back.
Do you have men cycle on and off testosterone
at these low dosages?
Are they taking a month vacation from it every once in a while?
Yeah, it totally depends.
You know, I was talking to a patient yesterday
where we’re going to do,
we just decided to change his cycle,
eight weeks on, then eight weeks on HCG,
eight weeks on, then eight weeks on HCG.
So that’s going to be a cycle
that maintains his testosterone level,
but fluctuates between endogenous, exogenous,
endogenous, exogenous.
Sometimes we’ll just do testosterone on, off, on, off.
And there it’s like, how much can he replenish naturally,
but understanding his T will dip during those off cycles.
Seems to me there’s a tremendous incentive
for somebody to develop a molecule
that can directly target SHBG,
besides oxandrolone anamore, right?
If one could just drop SHBG, just the tiniest bit,
it seems like one could adjust the free T
in a way that would be great.
I don’t know why that molecule is so hard to target,
but somebody ought to do it.
The chemistry can’t be that hard.
I talked with Patrick Arnold about this
many, many years ago.
I wish I could remember what his idea,
he had a comment about this that at the time made sense,
and I don’t remember what it was,
because I had that thought too, like, man,
especially for that subset of guys
who have normal testosterone,
but they’re just overbinding it.
I’m really glad that you brought up this issue
of total testosterone versus free T.
And the reason is, ever since going on podcasts
and talking about this stuff,
and talking about it on this podcast,
people will send me their numbers,
they’ll send me their charts,
and then they’ll send photos of themselves.
And I can tell you, while I’m not a clinician
and I haven’t done fancy statistics on it,
there’s very little correlation
between someone’s absolute testosterone and how they appear.
I mean, some of these guys look really lean, really strong,
and they’ll say, oh, total testosterone is 550, 480, right?
And then other people, you know, testosterone is 860,
but you look at them and you think,
oh, they kind of have a kind of a doughy look to them.
And so it’s got to be this free testosterone thing,
plus estrogen, et cetera.
Well, but also training and nutrition too, right?
I mean, I just think, I think for all this talk
about testosterone, which I enjoy talking about,
and I enjoy talking about the data
on long-term health consequences of testosterone,
because it’s another controversial topic,
I also think people kind of overstate its importance.
I agree.
And I think there’s a group of people who think,
if I could just fix my testosterone,
everything will be better.
And it’s sort of like, no, actually that’s not true at all.
Really, the only purpose in my mind of fixing testosterone
is to give you the capacity to work harder.
It’s really going to help you recover
more from your workouts.
This should just give you a greater ability
to experience muscle protein synthesis.
So, you know, if I just give you a bunch of testosterone
and you sit on the couch and your nutrition doesn’t change
and you’re not exercising anymore,
you’re not gonna experience any benefits of this thing.
I mean, my testosterone level has fluctuated
quite a bit throughout my life.
And when I think about, as an adult,
not sort of including when I was sort of
a fanatical teenager, but as an adult,
when was I at my absolute most insane physique?
Like my best performance on a DEXA scan
would have been 30, I was 38 years old.
By DEXA, I was 7% body fat.
My fat-free mass index was like 23.2,
23.3 kilograms per meter squared.
I mean, I was huge, strong, and totally ripped.
My testosterone was in the toilet.
I was overtraining like crazy.
I was, you know, exercising probably 26 hours a week,
killing it in the gym, swimming like a banshee,
cycling like my life depended on it,
grossly overtrained, low T, but, you know,
I mean, physically looked like twice the guy I am today.
You know, today my T’s probably twice as high
as it was then.
So, you know, now you could say,
well, Peter, what if you took T back then?
How much better could you have been?
Sure, but again, I think the take home
is just giving somebody T doesn’t do much of anything.
It probably helps on the insulin resistance front
without any other thing, but to me, that’s a waste.
Like that’s squandering the gift that it is giving you,
which is the ability to do more work
and, you know, capture the benefit of it
via muscle protein synthesis.
I agree, and I think that the psychological effect
of testosterone, whether or not it’s exogenous
or endogenous, is it makes effort feel good.
Yeah.
At some level, it really seems to do that.
And Sapolsky tells me the main reason,
or mechanistically, the main reason that it can do that
is by adjusting levels of activity in the amygdala.
Interesting.
And so there’s some interesting imaging there.
I’d love to chat more about the cholesterol pathway.
And I know this is a huge landscape as well,
but I think we’re doing a good job of diving in deep,
but not getting stuck in the underlying currents at all.
There’s tremendous debate about whether or not
dietary cholesterol directly relates to,
or does not relate to serum cholesterol, LDL and HDL.
Here’s my-
Is there?
I think, well, let me put it this way.
There are people that argue, I’m certainly not arguing,
there are people that argue that
if one eats a ton of saturated fat,
that LDL goes up and HDL goes down.
Okay, but that’s not dietary cholesterol per se.
No, not dietary cholesterol per se.
And then there are people that argue that
any increase in saturated fat intake is going to be bad,
that you already synthesize enough cholesterol
for hormone production, et cetera.
I’d like to talk about this in terms of
how one should read their charts.
My LDL is in what I’m told is healthy range.
My HDL is in what I’m told is healthy range.
I do try and not overeat things like
butter, cheese and red meat,
but I do eat some of those things and I feel pretty good.
But most people are operating under the assumption
that eating saturated fat is bad
and you only do it insofar as you want to taste it.
And then of course, there’s a small group of people
that love to eat organs and meats
and really pack cholesterol and would argue that
it doesn’t matter if your LDL is 870,
it’s not going to impact your health.
What’s the reality around LDL, HDL, dietary cholesterol,
saturated fat, at least in your view?
So first let’s differentiate between cholesterol and fat
just for the listener, because we use them,
I don’t want to make sure people understand.
So cholesterol is a really complicated molecule.
So it’s a ringed molecule.
God, I used to know exactly what its structure was,
but like it could have 36 carbons for all I remember.
It is a lipid, so it is a hydrophobic molecule
that is synthesized by every cell in the human body.
It is so important that without it,
if you look at sort of genetic conditions
that impair cholesterol synthesis,
depending on their severity, they can be fatal in utero.
So in other words, anything that really interferes
with our ability to produce cholesterol
is a threat to us as a species.
And the reason for that is cholesterol makes up
the cell membrane of every cell in our body.
So as you know, but maybe the listeners don’t,
even though a cell is a spherical thing,
it has to be fluid, right?
It’s not just a rigid sphere, like a blow up ball, right?
It’s gotta be able to kind of move in this way
to mesh with other cells.
It also has to accommodate having porous structures
that traverse its membrane to allow ions
and things like that to go across.
And it’s cholesterol that gives the fluidity
to that membrane.
It’s also, as you’re alluding to,
the backbone of some of the most important hormones
in our body, estrogen, progesterone, testosterone,
cortisol, so we have this thing, super important, okay.
Then let’s talk about does cholesterol,
can you get cholesterol in your diet?
Yes, you can eat foods that are rich in cholesterol.
What was known in 1960,
but somehow escaped everybody’s imagination
until finally the American Heart Association
acknowledged this a few years ago,
is that the cholesterol you eat
does not really make it into your body.
And the reason for that is it’s esterified.
So we have, and not to get too nerdy,
but I think people, I think if,
I really think it’s important people understand
how this thing works.
So we have cells in our gut and enterocytes,
they’re the endothelial cells of our gut.
They have, each one of them has basically
two transporters on them.
So the first is called the Niemann-Pick
C1-Like-1 transporter.
The second is called the ATP binding cassette G5-G8.
Okay, the Niemann-Pick C1-Like-1 transporter
will bring in any sterol,
cholesterol, zoosterol, phytosterol,
any sterol that fits through the door will come in.
Virtually all of that is the cholesterol we produce
that gets taken back to the liver
that the liver packages in bile and secretes.
So that’s what aids in our digestion,
which is another thing I should have mentioned earlier.
In addition to using cholesterol
for cell membranes and hormones,
we wouldn’t be able to digest our food without cholesterol
because it’s what makes up the bile salts.
So our own cholesterol is basically recirculated
in a pool throughout our body,
and this is the way it gets back into the body.
It’s through this Niemann-Pick C1-Like-1 transporter.
When it gets in there, the body,
this is the checkpoint of regulation.
This is where the body says,
do you have enough cholesterol in the body, yes or no?
If yes, I will let that cholesterol
make its way into the circulation.
So it’ll go off the basolateral side of the cell,
not the luminal side, into the body.
Alternatively, the body says,
you know what, we have enough cholesterol.
I’m gonna let you poop this out,
and now the ATP binding cassette will shoot it out.
It’ll go back into the luminal side, and away it goes.
So all of the cholesterol in our body is not esterified,
meaning it doesn’t have that big,
bulky side chain attached to it.
The cholesterol you eat is esterified,
and an esterified cholesterol molecule
simply can’t physically pass
through that Niemann-Pick C1-Like-1 transporter.
Now, we probably manage to de-esterify
10 to 15% of our dietary cholesterol.
So in other words, there are small amounts
of dietary cholesterol that do make their way
into our circulation,
but it represents a small fraction
of our total body’s pool of cholesterol.
Again, this was known even by Ancel Keys,
the guy who turned fat
into the biggest boogeyman of all time.
Ancel Keys acknowledged this in the 1960s.
Dietary cholesterol plays no role in serum cholesterol.
Again, it took the American Heart Association
another 60 years to figure that out,
but even now they acknowledge that.
Dietary cholesterol has no bearing.
So why is it that it’s pretty easy to find studies,
or at least people who are highly credentialed
from good institutions,
claiming that eating saturated fat,
cheese and- Saturated fat’s different.
Saturated fat, red meat,
things that are rich in cholesterol,
to be more specific,
is bad for us in terms of our eventual LDL.
So this is two different things.
So saturated fat consumption in many people
will raise LDL cholesterol.
So it’s important to differentiate between the-
What is saturated fat?
So saturated fat, of course, is a fatty acid,
just so people understand.
Totally different molecule from cholesterol.
Cholesterol is this very complicated ring structure,
multiple rings stuck together.
SFA, saturated fat, is just a long-chain fatty acid
that is fully saturated, meaning it has no double bonds,
and it can exist in isolation,
it can exist in a triglyceride, triacylglyceride,
or a phospholipid, or all sorts of things like that.
So when we eat foods that contain fat,
basically there are three distinctions for that fat.
Is it saturated?
Is it monounsaturated, one double bond?
Or is it polyunsaturated, two or more double bonds?
The observation that eating saturated fat
raises cholesterol is generally correct.
But again, now it makes-
Because if we’re gonna start talking about LDL,
we have to explain what LDL is.
This is another one of those things
that’s just so grossly misunderstood
that it makes having discussions about this
very complicated.
Let’s go back to the cholesterol problem.
So every cell in our body makes cholesterol,
and almost without exception, they make enough.
There are a handful of times, however,
when a cell needs to borrow cholesterol from another cell.
Okay, so how would you do this?
So if you’re playing God for a minute
and you wanna design a system,
you have to be able to transport cholesterol
from one cell to another.
The most logical place you would transport this
is through the circulation.
And the problem with circulation is it’s water.
Plasma is water.
So now you have this problem,
which is I want to transport cargo
that is hydrophobic in a hydrophilic medium.
Can’t do it.
So if you think about all the things
that we transport in our blood,
sodium, electrolytes, glucose, things like that,
they’re water-soluble.
It’s easy.
They just move back and forth in our blood with no chaperone.
But when you wanna move cholesterol,
you have to package it in something that’s hydrophilic.
That something is called a lipoprotein.
So we have these spherical molecules
that are lipid on the inside,
protein on the outside, lipoprotein.
And inside they contain cholesterol and triglycerides.
So now you’ve got the spherical thing,
triglyceride, cholesterol on the inside,
and it’s chaperoned by a hydrophilic molecule
that allows it to move through our circulation.
And those lipoproteins exist in different densities.
So if you run these out on a gel electrophoresis plate,
you’ll identify different densities.
The density is a function of how much protein
and how much lipid is in it.
So the highest density of this
is called a high-density lipoprotein.
And the lowest density of this
is called a very low-density lipoprotein, a VLDL.
And then next to that, you have an LDL,
a low-density lipoprotein.
And then next to that, you have an IDL,
an intermediate-density lipoprotein.
So it actually goes VLDL, IDL, LDL.
But anyway, so when people say my LDL is high,
or my LDL is 100, what are they saying?
They’re saying the cholesterol concentration
of my LDL particles is 100 milligrams per deciliter.
So the total cholesterol concentration
you have in your circulation
is that number that says total cholesterol.
So if someone’s blood panel says my total cholesterol’s 200,
it means that if you take all the lipoproteins
in their circulation, bust them open,
and measure the cholesterol content,
it’s 200 milligrams per deciliter.
And for all intents and purposes,
because the IDLs are so short-lived,
that’s basically the sum of your LDL cholesterol,
your VLDL cholesterol, and your HDL cholesterol.
Those three things sum to your total cholesterol.
What about LDL-a that you mentioned earlier?
LP-a is another, yeah, yeah.
He’s another actor.
He is a special type of LDL that, again,
in sort of 10 to 20% of the population
is a really bad actor.
So that’s an LDL that has another apolipoprotein on it
called apolipoprotein little a.
Got it.
The other thing I’ll just say on this,
because earlier I mentioned APO-B,
there are two broad families of lipoproteins.
There are those that are wrapped in APO-Bs
and those that are wrapped in APO-As.
The APO-A family is the HDL family.
The APO-B family is the VLDL, IDL, LDL family.
I see.
So for somebody who, let’s say their total cholesterol is,
let’s just stay with 200 for simplicity,
what do you like to see in terms of the HDL, LDL ratio?
Couldn’t care less.
I only care about APO-B.
I only care about APO-B.
I care about the causative agent of atherosclerosis.
APO-B is the thing that drives atherosclerosis.
And what levels are attractive or repulsive for you
when you see levels of APO-B that are blank,
you get really concerned?
It depends on the person’s objectives.
So again, we take a very different view.
I mean, we have-
Vitality now, and I want to live to be 100.
Yeah, so if you-
I’m becoming some taper.
If you tell me you want to live to be 100,
you’re going to need to keep your APO-B
below 30 milligrams per deciliter.
Let’s say I want to live to be 100, but I also,
well, how about I don’t care how long I live,
but I want to feel great while I live.
Again, it depends, right?
Like anybody who’s had a heart attack
is going to be compromised in their ability
to feel well after, right?
So-
I guess I make, say it that way,
because if you’re going to tell me
that I’m in order to achieve that live to 100 level,
I’m going to have to give up my personal life
and my brain functioning,
then I’m not really interested in it.
Sure, but to get LDL levels,
and really, again, people think of it as LDL.
It’s really APO-B, right?
APO-B is this total concentration of LDL and VLDL.
And that’s what matters.
Those are the big atherogenic particles.
LDL also includes the LP little a,
although the concentration of LP little a
is relatively speaking so small
that it doesn’t generally show up as much in the APO-B.
So we treat APO-B,
and basically what it comes down to is
you want APO-B to be as close to the level
as it was when you were born.
So we start developing heart disease when we’re born.
That’s just the way it is.
The autopsy studies make this abundantly clear.
When you look at autopsies of young people
who are dying in their 20s,
and this was first done in the 1970s,
it was again repeated.
Again, it’s always done after we have a war, right?
So in the 1970s, it was done on people who died in Vietnam.
In the early 2000s, it was done on mostly young men,
but some young women who were dying in Iraq and Afghanistan.
And we saw without any ambiguity
that cardiovascular disease is already taking hold
in people who are 18, 19, 20 years old.
Wow.
And to be clear,
they aren’t gonna die of atherosclerosis at that age.
They’re still 40, 50 years away from it,
but this is a lifelong disease.
And we also know that the disease can’t really develop
until APO-B reaches a certain threshold.
And that’s the threshold that most of us get to
by the time we’re sort of in our teens.
So it’s this really young APO-B level
of kind of 20 to 30 milligrams per deciliter
that makes it impossible to get atherosclerosis.
So APO-B is necessary,
but not sufficient to develop ASCVD.
Now that, go ahead.
Oh, I’m sorry.
I was just gonna ask,
what are some of the top behavioral,
nutritional, supplementation, if any,
based and prescription drug based ways to target APO-B?
Well, nutritionally,
you basically have two big tools, right?
And it depends on what’s driving up APO-B.
So APO-B, remember,
is the concentration of LDL and VLDL particles.
And what do they carry?
Cholesterol and triglycerides.
So anything that reduces cholesterol
and reduces triglycerides is going to reduce APO-B.
Triglycerides are generally driven by carbohydrate intake.
So more insulin resistance,
more carbohydrate intake, more triglycerides.
So we, I mean, clinically,
this is readily apparent to anyone who treats patients.
If you restrict carbohydrates,
you will reduce triglycerides.
That just happens all day long.
But if you reduce triglycerides
by raising fat intake so much,
it can still raise APO-B.
So you have to be able to think about it.
So in an ideal world, it’s,
can you lower saturated fat,
which tends to be the one that is most driving APO-B,
while lowering carbohydrate,
and then see what you can get.
But here’s the reality of it is,
there’s nobody with dietary intervention
that’s going to get to a level
of 30 milligrams per deciliter.
I mean, I’ve never seen any.
Pure dietary intervention.
Yeah.
So what are the other things?
It’s got to be pharmacologic at this point.
Statin type interventions?
Well, now you have multiple classes of drugs.
So the tried and true is the statin.
So statins work by inhibiting cholesterol synthesis.
And the net effect of that is that the,
so the liver is really sensitive to cholesterol levels.
It doesn’t want too much.
It doesn’t want too little.
When you inhibit cholesterol synthesis,
the liver says, I want more cholesterol.
So it puts more LDL receptors on its surface,
and it pulls the LDL out of circulation.
That’s what lowers the LDL in the circulation.
So again, nine statins in use today.
We typically use four of them.
The side effect profile,
contrary to kind of all the sort of statin hating propaganda
out there, very benign, right?
5% of people experience muscle soreness,
which reverses upon cessation.
You know.
Cognitive effects?
Again, I think it’s,
in terms of actual comparing it at a placebo,
no effect whatsoever, right?
So does that mean that you put a patient on it,
they won’t complain of something?
No, but if you look at clinical trials,
there’s no evidence whatsoever
that statins impair cognition.
There’s also no evidence in clinical trials
that they accelerate the risk of neurodegenerative disease.
In fact, it’s the opposite.
Now we will, there’s a very nuanced case we make,
Andrew, which is we’ll look at patients
with highly suppressed desmosterol levels,
we will back off.
We do want to maintain desmosterol above a certain level
because of some evidence that is still,
I think, very preliminary,
but enough for us that we say, why take the chance?
We have so many other tools to lower cholesterol.
Why would we over suppress synthesis
in a susceptible individual?
So the next tool you look at is a drug
that blocks the absorption or the reabsorption
of cholesterol.
Remember that Neiman-Pixie one-like-one transporter?
So that guy has a drug called ezetimibe
that just mechanically blocks it.
So in people, and that’s why I mentioned earlier,
we measure all those sterols in people.
So we also measure things called phytosterols,
and the phytosterols give us an indication
of how active that transporter is.
So the higher your phytosterols,
the more likely you are to respond to ezetimibe.
Next class of drugs is a drug
that blocks cholesterol synthesis, but only in the liver.
So the statin does it globally.
This other drug called benpedoic acid
does it only in the liver.
So it has a very similar mechanism to statins,
different enzyme, not quite as potent,
but way fewer side effects.
So any patient that’s having a response to statins
that’s adverse will try this other thing.
What’s it called one more time?
Benpedoic acid.
Benpedoic acid.
The most potent drug of the lot is the PCSK9 inhibitor.
So PCSK9 is a protein that was discovered
in the late 90s, I believe,
is responsible for the degradation of LDL receptors.
This was first discovered in people
who had a condition called familial hypercholesterolemia,
or FH.
So these are people that have incredibly high cholesterol.
Typically, their total cholesterol level is 300.
Their LDL cholesterol is typically, you know,
north of 200 milligrams per deciliter.
This is a disease that is defined by the phenotype,
not the genotype.
So the phenotype has a very clear definition,
which I basically just gave you.
The genotype is there’s a million paths to get there.
There’s over 3,000 mutations
that are known to produce that phenotype.
This was discovered to be one of them.
In people who had hyperfunctioning PCSK9,
this protein was just constantly hammering
and destroying the LDL receptors.
And so their LDL would be huge.
And by extension, their total cholesterol would be.
So in 2006, Helen Hobbs and colleagues
discovered an opposite group of population,
people who had LDL cholesterol naturally
of 10 to 20 milligrams per deciliter,
which would be an ApoB of about 20 milligrams per deciliter,
and who never got heart disease.
They were immune to heart disease,
no matter how long they live.
And they had the opposite.
They had hypofunctioning PCSK9.
And so that was 2006, the New England Journal of Medicine.
That basically got a whole bunch of drug companies
hot on the trail of producing a drug to mimic it.
So now we have these antibodies,
and they’re wildly effective.
What percentage of your patients over 45
do you have on either a statin
or on one of these other classifiers?
Well, often it’s in combinations, and I would say 80%.
Eight zero?
Well, you have to remember what our objective is.
We’re in the business of trying to make sure
people live as long as possible.
And you have to take a sort of worldview of this, right?
What’s the most prevalent cause of death globally?
Is it cardiovascular disease?
Yeah, and how close is it?
So the last year before COVID,
COVID kind of messes up these numbers a little bit,
but if you go to 2019,
18.6 million people died of heart disease.
Number two, cancer, 10 million.
Nothing’s in the zip code of atherosclerosis.
And if you remember what I just said,
if you took everybody in their 20s
and reduced them to a level of that of a child,
you’d make ASCVD an orphan disease.
So the question is, can you do that?
Why don’t we hear more about this?
I realize there’s some nuance.
It’s not straightforward.
It’s not as simple as saying,
eat less cheese, red meat, and watch your LDL.
Get on a statin.
But why do we hear so little about ApoB
in the general discussion?
Social media is such a skewed landscape, as we know.
People shouting into tunnels of varying clarity.
Some are beautiful bronze tunnels with clean walls,
and others are sewer lines.
And they all converge in the same place, as we know.
But why do we hear so little about this?
I mean, I’m not on a statin,
but now I’m beginning to think
that maybe that might be a good idea to consider,
one of these other compounds.
I don’t know the last time I looked at my ApoB specifically.
I’m guessing my physician did.
But why don’t we hear more about this?
This sounds so important.
It sounds like the most important conversation,
because all the hormone stuff,
and all the stuff about smoking,
and head injuries, and ADHD, and all the rest,
I mean, is irrelevant if you’re dead, right?
Yeah, it’s a good question.
I don’t think I have a great insight
as to why this isn’t more front and center.
I think the bigger problem is,
why don’t we even understand how to think about it?
I mean, and there’s a whole chapter in my book
I’m working on that really gets to this problem,
of why aren’t we looking at atherosclerosis
in terms of treating the causative agent?
Instead, we look at modifying 10-year risk.
So that’s the fundamental difference
between what I call medicine 2.0 and medicine 3.0.
Medicine 2.0, which is what we’re generally practicing today,
when it comes to ASCBD, says, look, we will treat you.
We will lower that LDL cholesterol.
They still don’t talk about ApoB,
but that’s a very American thing.
If you go outside of the United States,
everybody’s talking about ApoB.
It’s in the guidelines in Europe and Canada,
and everywhere else.
The United States is very stubborn on this,
and it’s due to a couple of really weird personalities
in the lipid world.
But the paradigm is,
when your 10-year risk reaches 5%,
and there’s a 5% chance
that you’re gonna have a heart attack, stroke, or die
in the next 10 years, now it’s time to treat you.
Medicine 3.0 says, that’s not the way to think about it.
You treat the causative agent.
If there’s a causative agent, you treat it.
If blood pressure raises the risk of heart disease,
you lower blood pressure.
If smoking raises the risk of something, you treat smoking.
And the reason that the risk model is so bad
when you’re looking at 10-year risk
is age is the biggest driver of risk.
I mean, bar none, right?
So if you take a 70-year-old with perfect lipids
and perfect blood pressure and perfect everything,
their 10-year risk of ASCVD
is probably four to five times higher
than the most unhealthy 30-year-old.
It’s not even close.
Yeah, there’s a lot like eye disease.
There are exceptions, of course,
but you always say that the biggest risk factor
for going blind from glaucoma is being an older person,
frankly.
Right, so if you could identify
what the risk factors are for glaucoma,
imagine if the paradigm was,
we’re only gonna treat it
when your risk of blindness reaches 5%,
which isn’t triggered until you’re old enough anyway.
Wouldn’t you rather know that when you’re 30
and say, wait, if maybe being in the sun without sunglasses
or using this type of eyedrop or something like that
has a negative impact, I would rather know that sooner.
So that’s the fundamental difference.
It’s a philosophical difference with respect to prevention.
And I will acknowledge that in one element of prevention,
I make no consideration.
I am only coming at this
through the lens of the individual.
I am never coming at this through the lens of society.
That makes my life easier
and it makes the problem I’m solving easier.
I don’t have to answer
the quality-adjusted-life-year problem.
I don’t have to ask the question,
is it economical to treat people at 30?
I don’t know the answer to that question.
But I also know that when you’re trying to solve
really complicated problems,
the more you can simplify, the better.
So I’ve just acknowledged openly, not solving that.
If you wanna criticize me for it, that’s fine.
Let’s be transparent.
But all I care about is the person I’m sitting across from.
And in that situation, it’s really their decision
if they can justify the cost of treatment.
An esoteric question and then a less esoteric question.
The esoteric question relates to something
that I think is a little bit niche, but not necessarily so,
which is peptides and stem cells and PRP.
I don’t wanna go off on too much of a tangent on rehab,
but I know you’ve done a number of posts
on social media recently that were,
I have to just tell you, are really thoughtful
and I really appreciate that you’re willing
to share your own tissue rehabilitation experience
and point people that because this is a landscape
that a lot of people are in
and they don’t know how to navigate it.
And a mutual friend of ours, not to be named,
sent me a text and said, I’m gonna be talking to Atiya
and what do you know about studies
on things like BPC-157, this gastric peptide,
that anecdotally, again, anecdotally,
people report getting injections of this
in the shoulder, knee, et cetera,
and feeling so much better, so much faster,
but there really aren’t good studies, controlled studies.
And you hear all the same sorts of things
about platelet-rich plasma, PRP,
which if someone tells you there are a lot of stem cells
in them, they’re lying.
There are not a lot of stem cells in them.
And you also hear about stem cells,
which are not FDA approved, at least for most uses
in this country, but are certainly,
people are flying down to Columbia and getting injections.
And what is your understanding or experience
with things like BPC-157, specifically,
because peptides is a huge landscape,
we should probably do a whole episode on peptides.
Things like PRP, PRP is now approved for,
I mean, women are getting injections of this
into their ovaries to improve follicle count.
People are getting injections of PRP
into every tissue and organ.
Hell, men are getting injected into their penis,
so I hear, for all sorts of reasons that are unclear to me.
What’s the deal with PRP, BPC-157, and stem cells?
Do you ever see interesting effects?
Are you curious about these compounds?
Do you prescribe or direct people towards these?
The FDA approved ones, of course.
Yeah, so short answer is I’m definitely curious about them,
and I’d love to see the work done,
but I also think this is about
as wild, wild west as it gets.
PRP, less so, but certainly stem cells and peptides.
And I just think,
if you’re gonna do something without a clinical trial,
you gotta show up with a lot more data, right?
So let’s use rapamycin as an example, right?
I’m a huge proponent of rapamycin,
and you can say, well, Peter,
how can you take or prescribe rapamycin
for geroprotective effects
when we do not have a human clinical trial
demonstrating that it lengthens life?
And the answer is, because I have 84 other pieces of data
that all point in the same direction
across every model organism
going back more than a billion years.
And that’s really different from,
Joey, Sammy, and Sally did this thing,
and I think it works.
And they just can’t be compared.
Now, I have no idea if stem cells work.
I have no idea if BPC-157 works.
I have no idea, frankly, if PRP even works,
though it might seem to have some efficacy
and some indications.
For example, maybe when it comes to early hair loss,
maybe when it comes to certain joint issues.
But the reality of it is,
I think we just have to accept the fact
that everything we do has an opportunity cost,
and that opportunity cost is sometimes financial,
but I actually find a lot of times
it’s in time and effort and energy
that goes into something.
Now, when I was waiting to get my shoulder surgery,
this is an injury that I’ve had forever, right?
This is an injury, this injury was actually
probably the greatest source of discomfort
I had swimming the Catalina Channel the last time in 2009.
So that tells you how long I’ve had this injury.
But I sort of knew at some point,
I’m gonna have to have it fixed.
And I sort of went down this rabbit hole,
like, hey, is there anything I can do
to avoid having surgery?
Would infusing a million stem cells into it work?
And in speaking with as many orthopedic surgeons as I could,
the answer was kind of unambiguously, no.
And by the way, it doesn’t mean you wouldn’t feel better
if I injected a bunch of stem cells into your shoulder.
There are a lot of reasons that might make you feel better,
just like there are a bunch of reasons you can feel better
if somebody injects saline directly into your joint.
So the question is,
is it going to fix the underlying problem?
And if so, will it do so by what mechanism?
So I’m pretty sure that if you took 1,000 people
with my particular injury and injected them with stem cells,
it wouldn’t do a thing because of the nature of my injury.
I had a complete labral tear.
Are there some injuries that might benefit from it?
Yeah, possible.
So the question is, how would you design the trial
to narrow down your patient population correctly
so that you might see a signal?
Because the other risk of doing a trial
is you have too much of a heterogeneous patient population.
You don’t know what the heck you’re really doing
and you get meaningless results.
You get a null result when in fact there’s a small signal,
but you were underpowered to pick it up
because you only had 10% of your patient population
that was the right patient population to get that.
So will we ever get there?
I don’t know because I don’t see what the incentive is.
You have people who are making money hand over fist
doing procedures on the basis of I’m not sure what,
what would their motivation or incentive be
to sort of see this legitimized?
You’d really have to be able to say,
well, there really needs to be
sort of a pharma angle to this.
It’s sort of one of the wishes I had, right?
Like if I was a billionaire,
I feel like the way I would probably waste all of my money
would be running clinical trials
on stuff nobody cared about.
It would just be-
Likewise, I would join you because that would be,
yesterday we recorded a sit down with somebody from Caltech
who works on aggression and rage
and other things related to that.
And has identified peptides that are approved,
the FDA for other reasons that seem to adjust anxiety,
might even adjust aggression and pathologic aggression
and went off on to a long description
of why none of these drugs exist on the market
for the treatment of psychiatric illness
and yet probably would work.
And what’s missing is a billionaire
or a billion dollar company
that is willing to invest in something
that very likely will work,
but the market value isn’t quite there
or it failed in a previous trial.
And so no one wants to touch it with a 10 foot pole.
Hopefully someone listening to this will be incentivized
to provide this sort of a venue for that,
the kind of work that we’re talking about.
I have to ask-
But I want to make one other point, Andrew,
which is to me, the problem with a lot of these things
is it gets, it’s a crutch.
You know, it’s sort of like what we talked about with like,
hey, just fix my T-man and everything’s going to be fine.
And it’s like, no, that’s just the beginning.
You know, what I worry about when I see people
who are clamoring for this stuff
is a lot of times they don’t realize that
whether it’s psychologically or otherwise,
they sort of say, well, now that I’ve had this thing done,
I don’t have to do the hard work of the real rehab.
I mean, if I’ve learned anything
through my shoulder surgery,
and I’m now three and a half months out.
How does it feel?
Amazing.
I mean, look, I still can’t do a lot of stuff.
It’s going to be, you know, a while.
I haven’t even been able to shoot a bow yet.
And it’ll probably be a year before I’ll go back to,
you know, long dead hangs and heavy deadlifts.
I mean, I don’t know, maybe nine months,
but it’s, you know, I’m not there yet.
But what I learned through a really amazing prehab
and rehab process is like, you just got to do the work.
And it’s freaking hard.
Shoulders are the most tedious, boring thing in the world.
I mean, three days a week, I am doing, four days a week,
I am doing one hour of just dedicated stuff
for this shoulder that is super uncomfortable,
super boring, super frustrating.
But I mean, I have faith in the methodology, right?
And I think a lot of people are saying,
just shoot the stem cells into me,
but I don’t have to do any of that stuff.
And the reality of it is,
I think that’s a very dangerous place to be.
Have you ever tried BPC 157?
Yeah, we tried it.
We had, you know, again, maybe seven, eight years ago,
we had a bunch of patients ask about it.
So, you know, my view is, okay,
I was pretty convinced that there was no safety downside
to it, so I was like, well,
I wouldn’t prescribe it to a patient
unless I tried it myself.
So me and another doc in the practice, Ralph,
we did it for, I don’t know, a couple months.
I didn’t notice a single thing.
Interesting.
Well, thank you for that.
Shifting to a less esoteric,
but, and I think probably more important topic overall,
metabolomics.
Talking about this before we sat down to record.
What is, what are metabolomics?
Why should we be thinking about them?
I have some idea of what it might be about,
but most people, I think,
are not thinking about metabolomics at all.
And for those that are, I’m sure they could learn more.
So tell us about metabolomics
and what you’d like to see more of
in the world of metabolomics.
Yeah, so omics is just the term
that we use to describe the study of something.
So genomics, right, is like the broad study of genes
and, you know, proteomics,
the broad study of proteins and things like that.
So metabolomics is just study of metabolites.
And metabolites, unlike a lot of these other things,
there are a relatively finite number of these things,
many of which are known, but some of which are not known.
And so glucose is a metabolite.
Acetyl-CoA is a metabolite.
Lactate is a metabolite.
And so the question is,
what do we know about these things and how they work?
And more importantly,
what do we know about certain physiologic states
and the metabolomic profile that results from them?
So let’s use two extreme examples, like exercise.
Everybody understands the data are unambiguously clear.
Exercise produces about the most favorable phenotype
imaginable.
So if you wanted to take a genomics approach
to understanding that, you might look at,
is there a change in the genome when you exercise?
And the answer is, you know, probably not,
but maybe if you looked at the, you know,
methylation patterns in epigenome,
you could look at epigenomic studies.
But you might instead look at
kind of the proteomic side of that.
Like, what is gene expression doing?
And there you would see a lot of changes.
Well, what I don’t think people are really understanding,
although there was a very interesting paper
that just came out two weeks ago
that looks for novel metabolites that are changing.
Is there a huge signal in a metabolomic profile
that looks different in the state of exercise
versus non-exercise?
And could that represent part of how exercise
is transmitting its benefit through the body?
You know, people always talk about
the holy grail of metabolomics would be,
can you find a pill to mimic exercise?
And I think the answer to that question
is going to be undoubtedly no, for a couple of reasons.
One, even if you could mimic the longevity,
sort of lifespan parts of it,
you could never mimic the healthspan parts of it.
But what if you could do both, right?
What if there were small molecules
that can replicate some of the protective benefits
of exercise and you could combine those with exercise?
What if those could be treatments for other disease states
like diabetes, things like that?
So that’s why I think this field of metabolomics
is relatively untapped,
and I think potentially the next sort of frontier.
Speaking of frontiers, I hear a lot nowadays
about GLP-1 and pharmacology, prescription drugs
that mimic or increase GLP-1 directly.
Glucagon-like peptide, people are talking about this
as the blockbuster obesity drug.
I haven’t heard this much talk about a drug
to adjust human body weight favorably
since the discussions of Fen-Phen when I was in college.
And then of course, Fen-Phen was pulled from the market
because people were dying, not left and right,
but enough people died that they pulled it from the market.
Which by the way, is an interesting story.
It was the enantiomer that they chose to use
that was the wrong enantiomer.
And what it resulted in was, God, I think it was like-
It’s a mitral valve, prolapse.
It was an MVP, yeah, it was something in the mitral valve.
Yeah, I think the chordae tendineae were rupturing
in the mitral valve, and it was mostly young women,
I think, were getting horrible pulmonary disease
as a result of it, probably pulmonary hypertension
or something like that.
But there were two enantiomers of the drug,
and had they just used the other one,
this issue wouldn’t have happened,
and there was a stupid reason why they made the choice
to use the one they did.
And it’s one of those things where once you make the mistake
you’re never going back.
It’s not like that company could say,
okay, we want to do over,
but we’re going to do it with the right version.
So it’s a tragic outcome.
But you’re absolutely right.
I think the GLP-1 agonists have more efficacy,
and for all intensity and for everything we can see,
certainly seem safer.
Are you excited about them?
Yeah, I am, yeah.
I mean, I think we’re just seeing
the kind of tip of the iceberg.
They’re not miracle drugs, right?
They come with problems, right?
Which is, you know, they’re catabolic across the board.
So patients are losing fat,
but they’re losing muscle as well.
So, you know-
You just sent all the gym jockeys
running from semi-glutathione.
That’s all you have to say.
All you have to say nowadays about something
is that it’s going to drop testosterone,
lower fertility, change someone’s skin, hair, and nails,
and it’s like people,
it could extend life to being 250 years old
and people are gone.
Humans are humans.
That’s a neuroscience and psychology issue,
not a biology medicine issue.
But I’m pleased to hear that you’re excited by them
because I hear a lot of excitement.
I haven’t heard anything disastrous about them.
It takes a while to get people up to dose.
So if you’re looking at semi-glutide,
the dose that was studied,
so they did a one-year trial,
or maybe it was a little over that, maybe 60 weeks,
but it took about 16 weeks to get the patients
comfortably up to 2.4 milligrams weekly,
which was the dose that they ultimately stayed on.
In our experience, when we use it,
we don’t even usually go up to 2.4 milligrams.
We can usually get enough benefit
between one and two milligrams,
and we usually move people along a little bit quicker,
but we’ve definitely had our share of patients
who can’t tolerate it due to the nausea.
Interesting.
Which might be part of how it’s working, right,
is the sort of suppression of appetite,
which if taken to an extreme, can produce nausea.
Interesting.
Yeah, I think most of the effect of semi-glutide
is central, not peripheral.
So I don’t know.
I saw one paper that GLP-1 is acting
both on cells in the periphery to cause gut distention
in some ways, or sort of make people feel full
through promotion of literally mechanoreceptors
that make people feel as if their stomach is distended,
even though their stomach is empty,
and then perhaps some central hypothalamic effects.
Is that what you’re saying?
Yeah, I think it’s doing,
I would bet 80% of it’s in the hypothalamus.
It is also improving insulin sensitivity in the periphery,
but I don’t think that that’s accounting
for much of its benefit.
Super interesting.
And there’s next-gen versions of these
that seem to be more long-lasting.
So right now, if you look at coming off semi-glutide,
you’re gonna see a weight regain.
So there’s newer versions that seem to preserve
the weight loss, even off the drug.
So it begs the ultimate question, which is like,
what’s the total use case for this gonna be?
Is this gonna be a drug you cycle on and off,
or is it gonna be a drug that a person
has to stay on indefinitely?
And if so, will they become tachyphylactic?
Will they gain a resistance to it?
So it’s still super early days on these things.
My hope is that it would be a little bit like
the way that you described testosterone
and estrogen therapies,
that it would allow people to do more of the behavioral work
that’s absolutely required for healthspan and lifespan.
Yep, and we’ve also seen on the flip side of that,
you can cheat through semi-glutide, right?
You can drink a lot of calories
and sort of get around the drug.
So for example, we always encourage patients
who wanna lose weight to really just eliminate alcohol.
That’s the cheapest, easiest trick to lose weight.
And so if you’re still drinking a lot of alcohol,
which is incredibly caloric,
and just drinking a lot of caloric stuff,
we’ve seen that that’s less,
this is just anecdotal with our patients,
but we’ve seen that it’s easier to get around
the benefits of the drug that way.
Interesting.
I so appreciate your answers today.
First of all, they were incredibly thorough
and pointed towards real-world application.
I also just wanna thank you more broadly
for the work that you do,
because obviously you have this incredible
clinical experience and patient population
that you work very closely with,
but I see you really as one of the few,
both clinicians, and I realize you’re an MD.
Did you do a PhD as well?
No, but I consider you a scientist-clinician,
clinician-scientist is the appropriate wording of that,
of course, in the way that you really
still drill into studies in detail.
I know a lot of clinicians,
not all of them do that, for sure.
And the fact that you’re so hungry
for the new incoming knowledge,
as well as the old literature.
So it’s an incredibly rich data set
in that brain of yours,
and I really appreciate you sharing it with us,
both in your podcast and the upcoming book,
which I think we’ll certainly have you on here again
in anticipation of that,
but I know I and a ton of other people
are really excited for the book
and in the way that you approach social media
and podcasts and going on podcasts.
Thank you so much.
I learned a ton.
I know everyone learned a ton.
Thanks, Andrew.
Great to be here, man.
Thank you.
Thank you for joining me today
for my discussion with Dr. Peter Attia,
all about the things that we can do
in order to maximize our lifespan and healthspan.
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