- Welcome to the Huberman Lab Podcast, where we discuss science
and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of
neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. Peter Attia. Dr. Attia is a physician who's focused on nutritional, supplementation-based, behavioral, prescription
drug, and other interventions that promote health span and lifespan. His expertise spans
from exercise physiology to sleep physiology, emotional and mental
health and pharmacology. Today we talk about all
those areas of health, starting with the very basics, such as how to evaluate
one's own health status and how to define one's health trajectory. We also talk about the
various sorts of interventions that one can take in order
to optimize vitality, while also extending
longevity, that is lifespan. Dr. Attia's uniquely qualified to focus on the complete depth and breadth
of topics that we cover. And indeed, these are the
same topics that he works with his patients on in his clinic every day. Dr. Attia earned his Bachelor of Science in mechanical engineering
and applied mathematics, and his MD from Stanford
University School of Medicine. He then went on to train
at Johns Hopkins Hospital in general surgery, one of the premier hospitals in the world, where he was the recipient of
several prestigious awards, including Resident of the Year. He's been an author on
comprehensive reviews of general surgery. He spent two years at the
National Institute of Health as a surgical oncology fellow, at the National Cancer Institute, where his work focused on immune-based therapies for melanoma. In the fields of science and medicine, it is well understood that
we are much the product of our mentors and the
mentoring we receive. Dr. Attia has trained
with some of the best and most innovative
lipidologists, endocrinologists, gynecologists, sleep physiologists
and longevity scientists in the United States and Canada. So the expertise that funnels through him and that he shares with us today is really harnessed from
the best of the best, and his extensive training and expertise. By the end of today's episode, you will have answers to
important basic questions such as should you have blood work? How often should you do blood work? What specific things
should you be looking for on that blood work, that
are either counterintuitive or not often discussed, and yet that immediately
and in the long-term influence your lifespan and health span? We talk about hormone
health and hormone therapies for both men and women. We talk about drug therapies
that can influence the mind as well as the body. And of course, we talk about
supplementation, nutrition, exercise, and predictors of
lifespan and health span. It is an episode rich with information. For some of you, you may want
to get out a pen and paper in order to take notes. For others of you that learn
better simply by listening, I just want to remind you
that we have timestamped all this information so that you can go back
to the specific topics most of interest to you. I'm pleased to announce that
the Huberman Lab Podcast is now partnered with
Momentous supplements. We partnered with Momentous
for several important reasons. First of all, they ship internationally, because we know that
many of you are located outside of the United States. Second of all, and perhaps most important, the quality of their
supplements is second to none, both in terms of purity and precision of the amounts of the ingredients. Third, we've really emphasized supplements that are single ingredient supplements, and that are supplied in dosages that allow you to build a
supplementation protocol that's optimized for cost, that's optimized for effectiveness, and that you can add
things and remove things from your protocol in a way that's really
systematic and scientific. If you'd like to see the supplements that we've partnered with Momentous on, you can go to livemomentous.com/huberman. There you'll see those supplements, and just keep in mind that
we are constantly expanding the library of supplements
available through Momentous, on a regular basis. Again, that's livemomentus.com/huberman. 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 Thesis. Thesis makes custom nootropics that are designed for your unique needs. Now, to be honest, I'm not a
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order and two free pillows. And now for my discussion
with Dr. Peter Attia. Peter, thanks for joining me today. - Thanks for having me, man. - I've been looking forward
to this for a very long time. - [Peter] As have I. - I'm a huge fan of your podcast. I know that you went to Stanford and worked with a number of people that are colleagues of mine. So for me, this is already a
thrill, just to be doing this. - Yeah, well, it's likewise. - I have a ton of questions, but I want to start off with something that I wonder a lot about, and that I know many other
people wonder about, which is how to assess their current
health and their trajectory in terms of health and wellbeing, specifically as it relates to blood work. So what are your thoughts on blood work? Is it necessary for the typical person? So this is somebody who's not dealing with some acute syndrome or illness. And at what age would you suggest people start getting blood work? How frequently should they get blood work? How often do you get blood
work done, et cetera? - Yeah, there's a lot there. I mean, the way I talk
about this with patients is, first, taking everything
back to the objective. So what's the thing
we're trying to optimize? So if a person says, look, I'm trying to break 10
hours for an Ironman, I don't know that blood
work is going to be a game-changing aspect of their trajectory and their training. You know, they're going
to benefit much more from sort of functional
analyses of performance. So I'm assuming, based on the question, that you're really coming
at this through the lens of living longer and living better through the lifespan health span lens?
- Mostly, yeah. I think most people have
some sense of their vitality or lack of vitality, but
I think everyone wonders whether or not they could feel better, and whether or not blood work
will give them a window into how they might go about feeling better. - Yeah, I think it does to some extent, but I also think that it
has a lot of blind spots. So I kind of break things down into the two vectors that make up longevity, which are lifespan and health span. So lifespan is the easiest of
those vectors to understand, because it's pretty binary. You're alive or you're not alive. You're respiring or you're not. You make ATP or you don't, end of story. So what gets in the way of lifespan is essentially the four
horsemen of disease, right? So atherosclerotic disease, cancer, neurodegenerative disease,
and metabolic disease, which directly isn't the
cause of many deaths, but basically creates the foundation to all of those other diseases. So, you know, if you're a non-smoker, what I just rattled off is
about 80% of your death. So how does blood work help address those? It varies. So on the atherosclerotic standpoint, it's a very good predictor of risk, if you know what to look for. So primarily ApoB would be the single most important
lipoprotein that we care about. I can explain what that means in a second. And then also, other
markers of inflammation, endothelial health, and metabolic health. When it comes to cancer, you know, blood testing in the sense of biomarkers is not particularly helpful, outside of knowing that the
second leading environmental or modifiable cause of cancer is metabolic ill health, after smoking. So we don't actually
know a lot about cancer in the sense of what causes it. It's really stochastic,
and it's a lot of bad luck. So we know that smoking
drives it, and we know that, even though epidemiologically
we say obesity drives it, what it really means is
metabolic poor health. It's probably the hyperinsulinemia that comes with obesity that drives it. So biomarkers help with that, but there's still an enormous
blind spot to cancer. We could talk about liquid biopsies aside, 'cause those aren't
really biomarker studies, but put that away. On the neurodegenerative side, you know, I don't think we have a lot of insight that comes to understanding
Parkinson's disease, but when it comes to dementia, particularly Alzheimer's disease, which is the most
prevalent form of dementia, I think the biomarkers
can be quite helpful. They overlap a lot with the
atherosclerotic diseases. So the same things that drive the risk of heart disease are driving the risk of dementia. And then there's some novel stuff as well, if you include genetic testing, which you can get out of a blood test. We get a whole suite of
genes, not just APOE, but far more nuanced stuff than that, that can also play a role. So you can stratify risk in that sense. So in aggregate, I would say, you know, blood testing of biomarkers provides pretty good
insight into lifespan. When you get into health
span, you have kind of the cognitive, physical,
emotional domains. I think here the biomarkers
are far less helpful, and here we kind of rely
more on functional testing. So when it comes to sort of
the cognitive piece, you know, you can do cognitive testing. In terms of long-term risk, a lot of the things that imply good cognitive health as you age, are in line with the same things that you would do to reduce
the risk of dementia. So all the biomarkers that
you would look to improve through dementia risk reduction, you would be improving
through cognitive health. On the physical side, I mean, outside of looking
at hormone levels and things which we look at extensively, and understanding how those might aid in or prevent some of the metrics
that matter, it really is, this is a biomarker aside thing. I mean, I'd be much more
interested in a person's DEXA, CPET testing, VO2 max testing, you know, zone two lactate testing, fat oxidation. Those are what I would
consider more functional tests that give me far more insight into that. And then of course the emotional piece, which depending on who you are, might be the single most important piece, without which none of this
other stuff matters, right? If you're a totally miserable human being, your relationships suck, I don't think any of
this other stuff matters. And certainly there's
nothing that I'm looking at in biomarkers that's giving
me great insight into that. - Do you ask about emotional state, or do you try and assess
emotional state indirectly when you do an intake
with one of your patients? - Probably not so much in the intake, because I think it takes a
while to form a relationship with a patient before
that starts to become something that they're
necessarily going to want to talk with you about. But I definitely think of
it as an important part of what we do. And I think without it, none of this other stuff really matters. Again, the irony of thinking about how many years I spent
sort of in pursuit of fully optimizing every
detail of everything, without any attention being
paid to that dimension, is not lost on me. And look, there are some patients who, that's just not something that, that's something that's compartmentalized. Maybe they're, you know, they're doing well in that
department, or maybe they aren't, but they just aren't willing
to engage on that yet. - In terms of frequency of blood testing, if somebody feels pretty good and is taking a number of
steps, exercise, nutrition, et cetera, to try and extend lifespan and improve health span, is once a year frequent enough, and should a 20-year-old
start getting blood work done just to get a window into what's going on? Assuming that they can afford it or their insurance can cover it. - Yeah, I mean, look, I
certainly think everybody should be screened early in
life because if you look at, like, what's the single most
prevalent genetic driver of atherosclerosis, is Lp[a]. So unfortunately most
physicians don't know what Lp[a] is, and yet somewhere between
eight and 12% of the population has a high enough, and
depending on who you, you know, I had a recent guest on my podcast who suggested it could be as high as 20%, have a high enough Lp[a], that it is contributing
to atherosclerosis. So to not want to know that, when it's genetically determined, right, this is something that,
you're born with this and you only need to really check it once, why we wouldn't want to
know that in a 20-year-old, when it can contribute to a lot
of the early atherosclerosis we see in people. It's leaving money on
the table, in my opinion. The frequency with which you need to test really comes down to the
state of interventions. I don't think it makes
sense to just do blood tests for the sake of doing blood tests. There has to be kind of a reason. Is something changing? You know, a blood test
is, for the most part, a static intervention. It's a look at a window in time. And there's benefit in having a few of those over the course of a year, if you're unsure about a level. So if something comes back and
it doesn't look great, yeah, it might make sense just to recheck it without reacting to it. But typically, you know, in patients, we might check blood two
to four times a year, but we're also probably doing
things in there to now check, like hey, you know, we gave this drug, did it have the desired outcome? You put on three pounds of muscle and lost three pounds of fat, did it have the desired outcome? - Speaking of tracking weight and fat, lean mass percentages, is that
something that you recommend your patients do pretty often? I know people that step
on the scale every day, I know people like myself that frankly, I might step on the
scale three times a year. I don't really care. I pay attention to other things that are far more subjective. Maybe I'm making a huge mistake. What are your thoughts about quantitative measurements of weight, BMI, for the typical person? - I think they're pretty crude. I think a DEXA, I'd rather
take a DEXA annually, and then maybe follow weight
a little bit more closely to get a sense of it. And so with a DEXA you're getting, at least the way we look at the data, four pieces of information. Now, most people when they do a DEXA, should I explain what that is, I'm? - Yeah, I think some people
might not know what DEXA is. In fact, I confess, I
have a crude understanding of what it is. Tell me where I'm wrong, and hopefully where I'm
at least partially right. My understanding is that there are a number of
different ways to measure lean mass to non-lean mass ratio, and there's one where
they put you underwater. There's one where they
put you into some sort of non-underwater chamber. There's calipering. And then there's the looking
in the mirror and pinching and changing the lighting. - You know, it's funny, if you've done it enough, you can, I can sort of tell my
body fat by my abs, right. So I can sort of tell by, you know, how good the six pack or
how bad the six pack is, what the leanness is. And that's actually not
a terrible way to do it. A bodybuilder, for example,
which I've never been, can tell you the difference
between being 6%, 7%, 8%, 10%, just based on the degree of
visibility within the abs. But basically, a DEXA scan is an x-ray. So it's the same principle as
just getting a chest x-ray, where ionizing radiation
is passed through the body. And there's a plate behind the body that collects what comes through. And the denser the medium that the electrons are
trying to go through, the less of them that are collected. So when you look at an x-ray, as everybody's probably seen an x-ray, that which is white is most dense. So if you had, you know, a
piece of metal in your pocket, it would show up as a bright white thing. That's why ribs and
bones show up as white, and the things that are the
least dense, like the lungs, where it's just air, are the blackest. And everything is a
shade of gray in between. So a DEXA is just doing that effectively, but it's a moving x-ray. So you lay down on a bed and
it takes maybe 10 minutes, and this little, very low power x-ray kind of goes over your body. And the plate beneath it
is collecting information that is basically allowing
it to differentiate between three things, bone
mineral content, fat, other. And the other is quantified
as lean body mass. So that's organs,
muscles, everything else. So when most people do a DEXA,
they get the report back, and the reports are horrible. I've yet to see one company
that can do this in a way that isn't abjectly horrible. We've created our own templates, so we have our own dashboard
for how we do this, 'cause we've just given up
on trying to use theirs. But the first thing most people look at is what's my body fat. And this is the gold standard outside of like MRI or something, that's only used for research purposes. So a DEXA is going to
produce a far better estimate of body fat, than calipers
or buoyancy testing, or things like that, provided the machinery is well-calibrated, and the operator knows how to use it. I've heard some people argue
that in the hands of like the guy who's been doing
calipers his whole life, it could probably be
comparable with calipers. But nevertheless, for
an off-the-shelf tech, DEXA is amazing. Of the four things that
get spit out of the DEXA, we think that the body fat
is the least interesting. And so I would rank that
as fourth on the list of what's germane to your health. The other three things
that you get spit out are bone mineral density, visceral fat, and then the metrics that
allow you to compute, like to basically compute what's called appendicular lean mass index
and fat-free mass index. And so those three metrics are
significantly more important than body fat. And the reason is as follows, right? So, bone mineral density
basically speaks to your risk of osteoporosis and osteopenia. And that doesn't sound very sexy to people our age, you know. 50-year-old guys listening to this, it's like, yeah, big deal. But for a 50-year-old woman,
this is a huge deal, right? A woman who's just about
to go through menopause, or has just gone through menopause, is at an enormous risk for osteopenia, and then ultimately osteoporosis, because estrogen is the
single most important hormone in regulating bone mineral density. And we can come back and talk
about why that's the case, but it's very interesting how the biomechanics of bones work, and why estrogen
specifically is so important. And this is a huge cause
of morbidity, right? So, you know, if you're over the age of 65 and you fall and break your hip, your one year morbidity
is about 30 to 40%. Which again, just to put that in English, if you're 65 or older, you
fall and break your hip, there's a 30 to 40% chance
you're dead in a year. - [Andrew] Wow. - Bones matter. So we want to really get a
sense of where you stack up for your age, for your sex. And if you're anywhere off the pace, we have to ramp up our strategy
and be super aggressive about how to increase
that, or at a minimum, prevent any further decay. - And are there age-related charts for these sorts of things? - Yeah, this all gets spit out
into what's called a Z-score. So when you're looking at your BMD, it's going to give you a Z-score. So a Z-score of zero means,
and you understand this, but it's like, a Z-score referring to a probability distribution
in a standard mode. So Z-score of zero means
you're at the 50th percentile for your age and sex. A Z-score of plus one, you're
one standard deviation above, minus one, below, et cetera. There's also a T-score, which
is doing the same thing, but comparing you to a young person. And so the T-score is technically used to make the diagnosis of
osteopenia or osteoporosis. We tend to look more at the
Z-score, and basically say, look, if your Z-score
right now is minus one, in four years I want
your Z-score to be zero. Not necessarily because you've
increased that entire way, but maybe you've increased slightly while it's expected that
you would've declined. - I see. What are some things
that we can do to improve bone mineral density at any age? - So it turns out there's
a real critical window in which we are malleable. So depending on the age at
which someone's listening to us discuss this, you know,
if you're under 20, 25, you are still in that time of your life when you are able to reach your potential. So it turns out that strength training is probably the single
best thing you can do. And this was a surprise to
me, 'cause we, you know, we did an AMA on this
topic a little while ago, and that's when I got really deep on this with our analysts. My assumption was
running must be the best, like some sort of impact must
be the best thing you can do. You know, I assumed
running would be better than swimming and cycling. But it turned out that power lifting was probably the best thing you could do. And I think once you
understand how bones work, it became more clear, which is, you know, power lifting is really
putting more of a sheer force from the muscle via the
tendon onto the bone, and that's what the
bones are really sensing. They're sensing that sheer force that's being applied through
the bone, in a compressive way, depending on the bone of course. And that's what's basically
activating the osteoblasts, which are the cells that are
allowing bone to be built. So this turns out to be probably
more important for females, because how high you can get during that period of development,
say till you're 20 or 25, basically sets your trajectory
for the rest of your life. So where we get into real
trouble is with patients who, for example, used large
amounts of inhaled steroids during that period of their life, 'cause let's say they
had really bad asthma. Or patients who needed large
amounts of corticosteroids for some other immune-related condition. So during their critical
window of development, they were taking a drug that
was impairing this process. So, you know, we have
some patients like that in our practice and that's
just an enormous liability that we're working
really hard to overcome, with nutrition, with hormones,
with drugs, with training. And, you know, it's just
something you have to be aware of. - I wasn't aware that inhalants for asthma and things of that sort can
impair bone mineral density. - If they're steroid-based. Some of them of course
are just beta-agonists, and they're fine. - So anything corticosteroid like? - Yep.
- Interesting. And then I always get asked this question, and I always reflexively want to say no, but I don't really know the
answer so I don't reply. What about topical corticosteroid? You know, people will put cortisone cream. To me, it seems almost inconceivable that it would have a systemic
effect, but then again, what do I know? - It's all dose and time-related. So, you know, if you're
talking about like I've got a little rash under my skin, I'm going to put corticosteroids
on, probably not. But certainly, with enough of it put on, I mean it is absorbed,
so it could be an issue. But that's not typically
what we're concerned with. I mean, we're mostly
concerned with people that are taking even modest amounts of prednisone for months, years at a time. Or, like I said, kids that
are using steroid inhalers for years and years and years. Again, I'm not suggesting that if your kid's on a steroid
inhaler they shouldn't be. You have to solve the
most important problem, and if asthma is the most
important problem, so be it. I think you just want to
turn that into, okay, well, how much more imperative is it that our kid is doing
things that are putting a high amount of stress on
their bones, via their muscles, to make sure that they're in
that maximal capacity to build. - Do you think that somebody
in their 30s or 40s or 50s could still benefit from
strength training in terms of bone mineral density and longevity, as it relates to bone mineral density, given that there's this
key window earlier, they might have missed that one. - Oh yeah, no, no, this is
essential for the rest of life because you're now trying
to prevent the fall off. So basically the way it
works is you're sort of, from birth to say 20 you're in growth. From 20 to 50, you plateau. At 50, men start to decline,
but it's really small. Women start to decline
and it's precipitous. - And it's related to the drop in estrogen associated with menopause or premenopause? - [Peter] Correct. - And can we get into
any of the broad contours of what that strength training looks like? We had Dr. Andy Galpin on the show, he talked a lot about
ways to build strength versus hypertrophy versus
endurance, et cetera. I think there's pretty good
agreement across the fields of physiotherapy, et cetera,
of physiology and medicine, in terms of how to do that. But my understanding is
fairly low repetition ranges, so this is anywhere from
one to six repetitions. Typically not aiming
for a pump hypertrophy, that sort of thing. But heavy loads that are hard to move, 80% of one repetition maximum or more, done with long rest periods, two to three times a week type
thing, is that about right? - Yeah, if you look at
the literature on this, it's going to tell you, it's going to differentiate
power lifting from weightlifting. In other words, yeah, you do need to be kind of moving
against a very heavy load. Now again, that can look very different depending on your level of experience. Like I really like deadlifting. Now, I mean, I can count the
number of days left in my life when I'm going to want to
do sets over 400 pounds. But, you know, I'll pick and
choose the days that I do. But, you know, I grew
up doing those things, I'm comfortable with those movements. If I had a 60-year-old woman who's never lifted weights in her life, who we now have to get lifting, I mean, we could get her
to deadlift, but I think, I wouldn't make perfect the enemy of good. I'd be happy to put her
on a leg press machine and just get her doing that. You know, it's not as pure
a movement as a deadlift, but who cares, right? We can still put her at
a heavy load, for her, and do so safely. So, now that said, I mean, there was a study that
was done in Australia, and I'm, you know, hopefully
we can find a link to it. There's a video on YouTube that
actually kind of has the PI sort of walking through the results. I could send it to you. - [Andrew] Okay, yeah we'll track it down.
- And it's just amazing. They took a group of older women. They looked like they
were in their 60s or 70s, who had never lifted
weights in their life, who had osteopenia, and some probably
already had osteoporosis, and they basically just put them on a strength training protocol. And it is remarkable to watch these women. They're doing good mornings. They're doing dead lifts. They're picking heavy
things up off the ground. I think one woman was picking up, God, I want to say she was like
picking like 50, 60 kilos up off the ground. I mean, just staggering sums
of weight for these women who have never done anything. And their bone health is
improving at this age. So the goal, frankly,
is to just, you know, never get to the point where you have to do this for the first time. Strength training is such an
essential part of our existence that it's never too late to start, but you should never stop. - I love that advice. Is it a systemic effect or a local effect? So, for instance, let's say that, well, my mother's in her late 70s. She actually used to be really
strong when we were kids. She could move this fish
tank that was in my room long before I could move
it, and I was always, she's really strong. Over the years, I wouldn't
call her frail by any means, but I certainly think she could benefit from some strength training. Let's say she were to start
doing some leg presses or start even with air squats and maybe work up to some pushups, are the effects all local, meaning if she were to just train her legs or just do pushups, would it only be the
loads applied to the limbs and muscles and tissues that were involved?
- I think that's where the bulk of it is, yeah. - Okay.
- Yeah. - [Andrew] So you need to train the whole body, essentially. - Yeah, now keep in mind, the diagnosis of
osteopenia and osteoporosis is based on only three
locations, the left hip, the right hip, and the lumbar spine. So, you know, that's just the convention by which we make the diagnosis. And I think part of that has to do with that's where the majority
of the insults occur. Now not all of the insults,
I've seen people that have, you know, because of
horrible bone density, they're fracturing
ankles and tibia, fibula, like they're having low tib
fib fractures just walking. So clearly bone density outside of those regions does matter. But much of it is really
focused on, and, by the way, you know, you fall, you break a wrist, so this is a systemic issue. But the majority of the
response is a local response, 'cause it really comes
down to putting a load directly on that bone, and
then having that bone, in kind, respond by laying down more bone. - Before we continue
with today's discussion, I'd like to just briefly acknowledge our sponsor Athletic
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health and calcium regulation. Again, you can go to
athleticgreens.com/huberman to claim that special offer. You mentioned falling and
the problems with falling and breaking things, and
mortality related to that. I wonder whether or not there are also health-related effects
of just having weak bones that are not just about
falling and breaking a bone, and dying a year later. That's obviously very severe. Because I think when
people hear about that, some people might think, well,
I'll just be more careful. I'll just move more slowly. I'll sit in a wheelchair if I need to, even though I might be able to walk, if it keeps me from falling. Some people I think adopt that mentality. What are some of the benefits of having high bone mineral density
for men and women, that are perhaps independent
of risk of injury? - Well, I think it's actually the inverse of what you just said, right? It's sort of like, you have to
sort of be able to articulate what it is you want in
your marginal decade. So we use this thing in our practice called the marginal decade. Marginal decade is the
last decade of your life. So everyone will have a marginal decade. That's the only thing I can tell you with absolute certainty, right? - I believe you. - There's no immortality. There's no hidden elixir that's going to help us live
to be, you know, whatever. I mean, we're all going to be in
our last decade at some point. And outside of people who die suddenly or through an accident, most of us know when we're
in that marginal decade. You might not know the day you enter it, but most people, you
know, who are old enough, if you tell them, are you in
the last decade of your life, they probably have a sense that they are. So I think the exercise
that we like to go through with our patients very
early on is have them, in exquisite detail, more detail than they've ever considered, so we have to prompt them
with like 50 questions, lay out what their marginal
decade should look like. - Wow, that's a serious exercise. - It's a very serious exercise, right? Like what, tell me everything
that is going to happen in your marginal decade. I don't know when it's
going to be, Andrew, it could be 87 to 97 if
we're doing well, right? It might be 79 to 89, I don't know. But, you know, it would really
be a very nuanced exploration of that topic. And I think until you do that, all of this other stuff is just abstract and kind of nonsense. Until a person can tell you what it is that they want to
be doing in that last decade, you can't design a
program to get them there. I mean, think about it. Someone wants to do an Ironman, we take it for granted that
we know what the objective is. I have to be able to swim 2 1/2 miles. I have to be able to get
out, take my wetsuit off, hop on my bike, ride 112
miles, get off my bike, take the bike shoes off,
put the run shoes on, run 26.2 miles. Like we get it, we know
what the objective is. And only by knowing that can you train. Can you imagine if I said to you, Andrew, I'm going to have you do an athletic event in a
year, start training. I'm not going to tell you
what it is, just do it. Could be playing basketball. You know, it could be
swimming to Catalina Island. It could be running 100 miles. You wouldn't be able to do it. So similarly, if we don't know what our marginal decade is meant to be, there's no way to train for it. - Do you think this is a good exercise for anyone and everyone
to do on their own, regardless of age here? I'm hearing this
- Absolutely. - and I'm thinking, I need to think about when
my last decade might be and what I want that to look like. - Absolutely, I mean, when I
say we do it with our patients, that's only because that's
the population I work with. But there's simply no reason everybody shouldn't be
going through this exercise. - And then you sort of
back script from there, figure out what people should be doing, given their current health status. - Exactly right, we call it back casting. So the first step we do is,
once we've really delineated what the objective function
looks like, we then say, okay, how do you break down that into
metrics that we can measure? So, you know, you described
doing a whole bunch of things. Okay, just to let you know,
to do that will require a VO2 max of 30 milliliters of oxygen per minute per kilogram. And the person will say,
okay, what does that mean? We'll say, well, that's a
measure of your maximal uptake of oxygen, and that declines
at about 8% to 10% per decade. So if you have to be at 30, and let's just assume you're
going to be doing that at 90, so what do you need to
be at 80, 70, 60, 50. Okay, here's what it
would need to be at 50. Okay, what are you now? Ah, there's a big gap. You're below where you need to be now. So you're obviously higher than 30 now, but if you're only at 42 now and you need to be at 30 and 40 years, you're not going to cut it. You have to be a lot fitter. Okay, now let's do the same exercise around strength and stability. And without exception, most people, when they do this exercise, will find out they're well
below where they need to be. So the gravity of aging is more
vicious than people realize, and therefore the height
of your glider needs to be much higher than you think
it is when you're our age, if you want to be able to do the things we probably want to be
able to do when we're 90. - I absolutely love this approach. I've never done it in terms of my health. I've always thought about
what I want to accomplish in the next three to six
months or next year or so. - And by the way, that's a great approach. That's forecasting. Forecasting is fantastic. Forecasting is really
good at short-term things. It doesn't work for long-term things. Long-term, you have to do back casting. - This back casting approach
really appeals to me because in my career, well, I
never anticipate, excuse me. I never anticipated I'd be podcasting. But that's what I did at some
point as an undergraduate, I looked at professors, I'm like, that looks
like a pretty good life. They seem pretty happy, I
talked to a few of them, and then I figured out what
I need to do at each stage in order to get to that
next rung on the ladder, and just kind of figured it out in a back casting kind of
way, as you refer to it. I think this is incredibly useful because it puts all the
questions about blood work and how often to get blood
work and what to measure, in a really nice context
that's a highly individualized. I've never heard of this before, so. - And I should give a nod to Annie Duke. I used to always refer to
this as reverse engineering, but in Annie Duke's book, she wrote about this exact thing
and called it back casting, and I was like, I like the
term back casting better. I think it's more intuitive
than reverse engineering. - Yeah, there's a real
genius to it and I think it, 'cause it sets so many things into the appropriate
bins and trajectories. I've heard you talk before
about some of the prime movers for longevity and all-risk mortality. And I'd love for you to review
a little bit of that for us. I think we all know
that we shouldn't smoke because it's very likely
that we'll die earlier if we smoke nicotine. I'm neither a marijuana
nor a nicotine smoker, so I feel on stable ground there. But anytime we see smoking nowadays, people really want to distinguish between cannabis and nicotine. So I am curious about
any differences there in terms of impact on longevity. But in that context, what are the things that
anyone and everyone can do, should do, to live longer basically? - How long you got? - Well, you tell me. You tell me. I'd like to live, to be, I'd like my final decade
to be between 90 and 100. - Oh no, I meant how long do you, yeah yeah.
- No no, I'm just kidding. I'm just kidding.
- And will we spend from now until you're
90 talking about this? - Well, there's a risk of that. But top contour is fine, I know you've done a
lot of content on this, and we will give people links to some of that more in depth content. But, you know, let's say
we were on a short flight from here to San Diego,
we're in Los Angeles now, and we got take off and landing, and we don't want to
kink our neck too much by doing this thing. So if I just said, hey, you know, gimme the extended version
of the three by five card. What does that look like? - So, let's start with
a couple of the things that you've already highlighted. So smoking, how much does
smoking increase your risk of all-cause mortality? And the reason we like to
talk about what's called ACM, or all-cause mortality, is it's really agnostic to how you die. And that doesn't always make sense. I mean, if you're talking about, you know, a very specific intervention, like a anti-cancer therapeutic, you really care about
cancer-specific mortality or heart-specific mortality. But when we talk about
these sort of broad things, we like to talk about ACM. So, you know, using smoking, smoking is approximately a 40%
increase in the risk of ACM. - What does that translate to in, that means I'm shortening my life by 40%? - No, it means at any point in time, there's a 40% greater risk
that you're going to die relative to a non-smoker and a never smoker.
- Got it. - Yeah. So it's important to distinguish. It doesn't mean your lifespan
is going to be 40% less. It means at any point
in time, standing there, your risk of death is 40% higher. And, by the way, that'll
catch up with you, right? At some point that catches up. High blood pressure. It's about a 20 to 25% increase
in all-cause mortality. You take something really extreme, like endstage kidney disease. So these are patients
that are on dialysis, waiting for an organ. And again, there's a
confounder there because there's what's the underlying condition that leads you to that. It's, you know, profound
hypertension, you know, significant Type II diabetes
that's been uncontrolled. You know, that's enormous, that's about 175% increase in ACM. So the hazard ratio is like 2.75. Type II diabetes is probably
about a 1.25 as well. So a 25% increase. So another question is
like, how do you improve? So what are the things that improve those? So now here we do this by
comparing low to high achievers on other metrics. So if you look at low muscle
mass versus high muscle mass, what is the improvement? And it's pretty significant. It's about three X. So if you compare low muscle mass people to high muscle mass people as they age, the low muscle mass people have about a three X hazard ratio, or 200% increase in all-cause mortality. Now, if you look at the
data more carefully, you realize that it's probably less the muscle mass fully doing that, and it's more the high
association with strength. And when you start to
just tease out strength, you can realize that
strength could be probably 3 1/2 X as a hazard ratio,
meaning about 250% greater risk, if you have low strength to high strength. - And high strength is
the ability to move loads at 80 to 90% of one repetition? - It's all defined by given studies. So, the most common things
that are used are actually, they're used for the
purposes of experiments that make it easy to do. And I don't even think
they're the best metrics. So they're usually using like
grip strength, leg extensions, and like wall sits,
squats, things like that. So how long can you sit in a
squatted position at 90 degrees without support, would be a great demonstration
of quad strength. A leg extension, you know,
how much weight can you hold for how long, relative to
body weight, things like that. You know, we have a whole
strength program that we do with our patients, we have
something called the SMA. So it's the strength metrics assessment. And we put them through 11
tests that are really difficult, you know, like a dead hang is one of them. Like how long can you dead
hang your body weight, stuff like that. So we're trying to be more
granular in that insight, but tie it back to these principles. If you look at cardio respiratory fitness, it's even more profound. So if you look at people
who are in the bottom 25% for their age and sex,
in terms of VO2 max, and you compare them to
the people that are just at the 50th to 75th percentile, you're talking about a
two X difference roughly, in the risk of ACM. If you compare the bottom
25% to the top 2.5%, so you're talking about bottom quarter to the
elite, for a given age, you're talking about five X. - Wow!
- 400% difference in all-cause mortality. That's probably the single
strongest association I've seen for any modifiable behavior. - Incredible. So when you say elite, these are people that
are running marathons at a pretty rapid clip. - Not necessarily. It's just like what the
VO2 max is for that, like my VO2 max would be in
the elite for my age group. My VO2, but again, I'm
training very deliberately to make sure that it's in that. So I wouldn't consider myself
elite at anything anymore, but I still maintain a VO2
max that is elite for my age. - I consider you an elite
physician and podcaster. And guy all around. But true. But in terms of, okay, so- - But the point is like, you don't have to be a world class athlete to be elite here, yeah. - Got it. So maybe we could talk a little bit about the specifics around the
training to get into the top two tiers there, because it seems that those
are enormous positive effects of cardiovascular exercise, far greater than the sorts
of numbers that I see around, let's just say supplement
A or supplement B. - Well, and that's, you know, like this is my whole
pet peeve in life, right? It's like, I just can't get enough of the machinating and arguing about this supplement
versus that supplement. And I feel like you shouldn't
be having those arguments until you have your exercise
house in order, you know. You shouldn't be arguing about this nuance if you're carnivore diet, versus this nuance if you're paleo diet, versus this nuance if you're vegan diet, like, until you can deadlift
your body weight for 10 reps. Like then you can come and
talk about those things, or something like, let's just
come up with some metrics. Like until your VO2 max is at
least to the 75th percentile and you're able to dead
hang for at least a minute, and you're able to wall
sit for at least two, like we could rattle off a bunch of relatively low hanging fruit. I wish there was a rule that said like you couldn't talk about
anything else health-related. - We can make that rule. - [Peter] No one'll listen to it. - I don't know about that. We can make whatever rules we want. We can call it Attia's rule. One thing I've done
before on this podcast, and on social media is, just borrowing from the
tradition in science, which is it's inappropriate
to name something after yourself, unless you
were a scientist before 1950. But it's totally
appropriate to name things after other people. So I'm going to call it Attia's rule. Until you can do the following
things, don't talk about supplements.
- Please refrain from talking about
supplements and nutrition. - There it is, hereafter,
thought of, referred to, and referenced as Attia's rule. I coined the phrase, not him. So there's no ego involved,
but it is now Attia's rule. Watch out. Hashtag Attia's rule. - Oh God! - Wikipedia entry, Attia's rule. In all seriousness, and
I am serious about that. Dead hang for about a minute
seems like a really good goal for a lot of people. At least-
- That's our goal. I think we have a minute
and a half is the goal for a 40-year-old woman. Two minutes is the goal
for a 40-year-old man. So we adjust them up and
down, based on age and gender. - Great. And then the wall sit,
what are some numbers? - We don't use a wall sit, we do just a straight squat,
air squat at 90 degrees. And I believe two minutes is the standard for both men and women at 40. - Great. And then, because for some
people thinking in terms of VO2 max is a little more complicated, they might not have access to
the equipment to measure it, et cetera, what can we
talk about, think about, in terms of cardiovascular. So run a mile at seven minutes or less, eight minutes or less? - Oh, that's a good question. So there are really good
VO2 max estimators online, and you can plug in your activity de jure, so be it a bike, run, or rowing machine, and it can give you a sense of that. And I don't, I used to know all of those. - Oh, that's okay.
- But now that I just actually do the testing,
I don't recall them. But it's exactly that line of thinking, like, can you run a mile in this time. If you can, your VO2 max
is approximately this. - [Andrew] Great. - And I think, somewhere
in my podcast realm, I've got all those charts posted of like, this is by age, by sex. This is what the VO2 max is
in each of those buckets. - Terrific, we'll provide links to those. We'll have our people find those links. And then you mentioned
deadlifting body weight 10 times. - I just made that one up. That's not one that we include, but- - [Andrew] Something like that? - We use farmer carries. So we'll say for a male, you should be able to farmer
carry your body weight for, I think we have two minutes. - [Andrew] Great. - So that's half your
body weight in each hand. You should be able to walk
with that for two minutes. For women, I think we're
doing 75% of body weight or something like that, yeah. - Great. I love it. As indirect measures of how healthy and, - Yeah.
- we are. And how long we're going to live. - It's basically grip
strength, it's mobility. I mean, again, walking
with that much weight, for some people initially, is really hard. You know, we use different
things like vertical jump, ground contact time if
you're jumping off a box, things like that. So it's really trying to capture, and it's an evolution, right? Like I think the test is going to get only more and more involved
as we get involved, 'cause it took us about a year. Beth Lewis did the majority
of the work to develop this. Beth runs our strength
and stability program in the practice. And, you know, basically I
just tasked her with like, hey, go out to the literature and come up with all of the best movements
that we think are proxies for what you need to be
like the most kick-ass, you know, what we call
centenarian decathlete, which is the person living
in their marginal decade at the best. - Well, what I'm about to say is certainly a mechanistic leap, but if you look at the literature on exercise-related neurogenesis in mice, or brain atrophy or brain
hypertrophy, et cetera, in animal models, it's very clear that the best
way to get a nervous system to atrophy, to lose
neurons, shrink neurons, and or lose connections between neurons, is to stop that animal from moving. Or to de-enrich its environment, deprive it of some sensory input
or multiple sensory inputs. And the best way to enhance
the size of neurons, the number of connections between neurons, and maybe even the number of neurons, is to enrich its environment
and get it moving while enriching that environment. - You know, Andrew, I think
it's very difficult for me to say that the same
is not true in humans. And so the first time this
became clear to me was in 2014, I had an analyst, Dan
Pelletier, and I said, Dan, I'm going to give you a project
that is vexing me to no end, which is, I want you to look
at all of the literature that we have, both mechanistic
and clinical trial data, that talks about Alzheimer's prevention. And I want to know every
single type of input. And I want to have a clear sense of via what mechanism does it
offer what mode of protection? And it took Dan, and this was obviously, we iterated a lot on this together. And he came back with kind
of an amazing presentation that took, I don't know, nine
months to a year of work. And what amazed me was when
he came back to it, he said, the single greatest efficacy
we can point to is exercise. And I was like Dan, that's
got to be nonsense, dude. There's no way exercise is the
single best thing you can do for the brain. There has to be some drug you've missed. There has to be some other
thing that you've missed. And he's like, no, like this
is hands down the best thing 'cause you're, you know, it's not just what it's doing to BDNF. It's not just what it's doing
to vascular endothelium. It's not just what it's
doing to glucose disposal and insulin signaling
and all these things. It's just touching every
aspect of the brain. And I was very skeptical
for about six months, kind of really pushed
on him and I was like, I think you're missing something, Dan, I think you're missing something. And then finally in the end,
looped in Richard Isaacson, who's a neurologist that
we work with really closely on Alzheimer's prevention. And you know, ultimately
it turned into a paper that we wrote basically,
you know, about this topic, and a few others. 'Cause again, I thought, oh, are you sure it's not EPA and DHA? Like that's got to have a bigger impact. And again, there are a lot of
things that I think do matter and there's a whole host
of things that we do for Alzheimer's prevention. But I think you're absolutely right. There's not one thing
that I'll tell patients is more important than exercising. And by the way, it's not the sort of pathetic
recommendations that are made. Like it's, you have to exercise a lot more if you want to get this maximum benefit. You will get, you know,
the maximum benefit comes going from nothing to something. So if you go from being
completely sedentary to doing 15 MET hours per week, you'll get probably a
50% reduction in risk. - Wow.
- So a MET hour, a MET, just for people who don't know, is a metabolic equivalent. So we're exerting about 1.3
METs sitting here talking. If we were sitting here being quiet, it would be about one MET. Walking really briskly
would be about five METs. So 15 MET hours per week would be three one hour really brisk walks. That's not a lot of work. But just going from doing
nothing to doing that would give you 50% of the
benefit that you would get from going all the way. Now I, again, I think, I'm
personally a little skeptical of how much that's, I think it's
probably a bit less than that. I think there's more upside
than people appreciate. But the studies, I don't
think, can truly capture that. But look, you know, there's
no reason to not be exercising more than that, and capture more benefit, even though the rate at
which you accrue it is less. And it also speaks to the
health span side of this, which is not necessarily
captured in those data. The health span gets back to the functional piece we
opened with, which is what do you want to be doing
in your marginal decade? Do you want to be able to
pick up a great-grandkid, if they come running at you? Do you want to be able
to get up off the floor? Do you want to be able to
play on the floor with a kid and then get up on your own? - And I think most people are
thinking final years of life, they're trying to think, you know, how can they take
themselves to the bathroom? They're thinking, how can
they sit up off the toilet? I mean you have like really base, vegetative type functions,
right, at some level. I love this, again, this
idea of marginal decade and using that as a way to back cast, to actual methods and
behaviors and protocols that one should be doing on a daily basis. I'll use anecdata, as it's now called, to cite just, I know
three Nobel prize winners, which doesn't mean anything except that they did beautiful work. But the point is that
they're all in their 90s. So I'll name them 'cause
I'm complimenting them for what they've done. Not just their work, but
what I'm about to describe. So Eric Kandel at Columbia. Nobel prize winner for work on memory. Torsten Wiesel, work on neuroplasticity. And then Richard Axel,
who's also at Columbia, Nobel prize winning work
for molecular biology of smelling and molecular
biology generally. All three of them still alive, Richard's younger
compared to the other two. All three of them either
swim, jog, or play tennis, or racquetball I think is Richard's thing, multiple times per week. They're all cognitively
still extremely sharp, still interested in the
arts, doing science, curious about science,
running laboratories, writing books, going on podcasts. I mean, it's incredible. Again, that's anecdata. But I was kind of surprised to learn that colleagues that were so
intellectually strong were also so obsessed with exercise. I mean, they really are obsessed
with their exercise routine and early on linked that to their, some of their intellectual
vigor over time. I want to just also use
that as a jumping off point to ask about one kind of
niche thing, but it comes up. I don't think I'm going to out
which one of those told me this, but one of those three individuals chews an excessive amount of Nicorette. Used to be a smoker and I asked
him why and he said because, in his estimation, it's protective against
Parkinson's and Alzheimer's, or at least the nicotinic acetylcholine
augmentation of nicotine, 'cause nicotine is an
acetylcholine receptor obviously, is known to create a state of
focus and neural enhancement. What are your thoughts about
not smoking, let's just, I just want to be really clear,
people, don't smoke nicotine, vape nicotine, it's going
to shorten your life. Just terrible idea, addictive,
et cetera, in my opinion. But what are your thoughts
about augmenting acetylcholine, through the use of nicotine, in order to keep the
brain healthy and focused? Again, this is one Nobel prize winner, so it's truly N of one, but he's so convinced
that this matches up with the mechanistic data on
acetylcholine and cognition, that I'd love to hear your thoughts on it. - So I can't speak to the AD
prevention component of it. I'd have to run that by
a couple of my colleagues who I collaborate with on that. But I can definitely speak to the cognitive enhancement piece of it. And I actually did an AMA on
this, probably a year ago, where I went into all of
the gory details of it and talked about my own use of nicotine, which I'll cycle on and off, I've been doing it for the last 10 years. I haven't-
- What form do you take it in? - I used to use the gum. I don't like the gum anymore, so now I like these little lozenges that, and I'll tell you a
funny story about this. So our mutual acquaintance,
David Sinclair, mentioned a company to me a year ago. He's like, hey, have you
heard of this company? And I forget the name of the company, but he gave me some name. So I go online and it's like
this company selling nicotine. And I'm like, I wonder why
he's asking me to do this. Well, I'll just order a bunch and then we'll figure out
why, 'cause we were, you know, there was some reason we were doing this potentially through investment. So I get a, like literally
order like a lifetime supply of this stuff. And it's pretty good, it's actually, it's a really nice little patch, 'cause I, the thing I didn't like about the gum was I hated just the taste of it. So then the next week I'm
talking to David and I'm like, by the way, I ordered
all that nicotine stuff you told me about. He's like what? And he goes, oh, the company's
name was something else. It was totally unrelated. It's like, oh God. So the short answer is, I
think this stuff is absolutely a concentration-enhancing substance. It is addictive and people
need to be wary of that. Now it's not addictive to everybody. I personally experience no
addiction to it whatsoever. So I can, I could do it
every day for 30 days and stop and experience no withdrawal. I could forget about it, it
doesn't really seem to matter. You have to be careful
with the dose, truthfully. I mean, remember one cigarette is about one milligram of nicotine, and a lot of these lozenges will plow four to eight milligrams
into you in one shot. And for someone who is, you
know, naive to that, like I am, four milligrams is a lot
of nicotine in one bolus. So you just have to be very mindful of it. I got a lot of flack when I did this AMA, for obvious reasons, but
people were like, how can you, as a doctor, encourage
people to use nicotine. And I was like, first of all, I'm not encouraging anybody to use it. I just want to be able to talk
about the biochemistry of it. And if disclosing that I
use it from time to time is an endorsement then
I apologize for that. But on the list of things that you can do to make your brain a little more focused, I would consider this infinitely safer than what a lot of people are doing, which is using stimulants. I mean, to me, you know, I
just tell patients outright, like we are under no circumstance
prescribing stimulants. I mean, yeah, we're not
giving anybody Adderall. We're not giving anybody
Vyvanse, or any of these things. Not to say they don't have
an appropriate clinical use, but they should be prescribed
under the care of somebody who's really monitoring
the use case for it. And using that as a tool
to enhance, you know, concentration in cognitive performance is not something we're comfortable doing. - Yeah, it's rampant on college campuses. - [Peter] I can only imagine. - Armodafinil, modafinil
which are slightly different, of course, but, so non-clinical use, not prescribed for ADHD,
but just, it's rampant. Recreational use, study-based use. - But the data I've seen on modafinil suggests that it only really
provides a nootropic benefit. in someone who is deprived of sleep. Is there data that in a
totally well-rested person, there is a nootropic benefit of modafinil? - I don't know. I have one experience with armodafinil, where I took a half a recommended dose, this was prescribed by a doctor. I went to give a talk. This was in Hawaii and I'm
four hours into the talk. My co-speaker came up to
me and just said, well, first of all, you got a little bit of spit in the corner of your mouth. And second of all, you haven't
blinked in three minutes. And third, there's only two
people left in the audience. I was so lazered in that
I kind forgot the context. Now I'm a little bit of a,
kind of a tunnel vision, OCD-type anyway, but one,
that was all it took, I never took any more of it. It was a powerful stimulant. I take 300 milligrams of
Alpha-GPC now and again, before some cognitive work,
sometimes before workouts, and I do subjectively feel
that it narrows my focus in a nice way. But I don't take it more
than once or twice a day, and more than once or twice a week. - See, this is an example of where, you know how we're talking
about exercise versus sort of nutrition and
supplements for longevity. I think there may be a
whole bunch of things that are kind of interesting around focus, but nothing would compare
to changing our environment. Like I think that if I
compare my focus today to my focus when I was in
college, there's no comparison. Like in college, I was truly a robot. But I think a large part of it was, there was no distraction. There's no email. There's no social media. There's no internet. I mean, I was in college
when Mosaic launched in the early '90s. Like I, you know, and you
had to walk like a mile to get to the computer lab
on a big Sun workstation to do anything in, you know,
some computer code language. So when you're sitting
in your room studying, there was no distraction. And I think that's a far greater component of what it means to be focused, than the challenges we have today. So, you know, my thoughts
on this would be, if we really wanted to
return to a state of focus, we're going to have to
individually do something about, you know, our environment. And I don't know what the answer is. Like, I've tried every
little trick I can think of, like closing my browsers
when I'm writing and stuff, but, you know, I'm just
not strong enough willed. Like I'll pick up my
phone every 20 minutes to look and see if I missed a text message or something stupid. - That's pretty infrequent. I did an episode on habits
and looking at the data. It seems that people
are getting interrupted or interrupting themselves
about once every three minutes in the typical workplace,
now that typical has changed with a lot more people working at home. I do put my phone away
when I try and work, but nothing focuses me like a deadline. A little bit of fear-based urgency. That's it, grant deadlines, you know, drop deadlines as I call them, or podcasts we're going to record today, that nothing works quite like it. But such is life. Well, thanks for that
offshoot about nicotine. Again, you're not recommending
it, I'm not recommending it, but it's clear that augmenting
the acetylcholine system, which is what nicotine
does in its various forms, and some related type pharmacology, does enhance focus and pretty potently. So I think it's going to
be an interesting area for real clinical trials
and things of that sort. Love to chat about hormone therapies, and hormones generally. When Robert Sapolsky came on the podcast, we talked a little bit about menopause and the data around menopause. He's very interested
in these findings that, I think I'm going to get this right, that whether or not women
benefit from estrogen therapy to offset menopause really depends on when
that therapy is initiated. I don't know if you're
aware of those data, but he claimed that if
they begin estrogen therapy in the middle to tail end of menopause, the outcomes can be quite bad. Whereas if they initiate
those estrogen therapies as they enter menopause
or even before menopause, then the outcomes can be quite good. I don't know what percentage
of the patients you treat are male versus female, and what ages those
patients are of course, but what are your thoughts about
estrogen therapy for women, menopause, and hormone
therapies generally for women, maybe even testosterone therapy, you hear about that these days, and then we'll talk about men. - So our practice is
probably 70 30 male female. So we have lots of women, and this is a very important topic. It's also probably, let me think. I just want to make sure
I'm not being hyperbolic when I say this. Yeah, I don't think I am. It's hands down the biggest screw up of the entire medical
field in the last 25 years. Now, again, it's possible in
the next hour I'll think of, nope, there's a bigger screw up. - Another giant screw up. - Yeah, but I don't think I will. I'm pretty confident that
I won't be able to think of a bigger act of incompetence than what happened with the
women's health initiative in the late '90s and early 2000s, which is effectively the study that turned the entire medical field off hormone replacement therapy for women. So it's important, I think, to explain what this study looked at. So this was a study that was conducted in response to the widely held
belief in the '70s and '80s that women should be placed on hormones as they're going through menopause, right? Menopause is, I guess maybe
I'll even take a step back. I don't know how much your
audience is familiar with how estrogen progesterone work. Is it worth going into that stuff? - Yeah probably worth mentioning
a bit of the top contour. Some of them might be familiar with it, we've done episodes on estrogen
testosterone, but frankly, as I think back to those, we didn't really go into the biology of estrogen testosterone enough. - Yeah, so, I mean, actually
an interesting aside that I always tell my female patients who get a kick out of this. When you look at a woman's
labs, you'll see her estrogen, her progesterone, her FSH,
her LH, her testosterone, her sex hormone binding
globulin, and all these things. But based on the units
they're reported in, it's a very distorting picture of what the most common
androgen is in her body. If you actually convert
them to the same units, she has much more testosterone
in her body than estrogen. - Interesting.
- Yeah. - I did not know that.
- Yeah. - Then again, I've never been a woman getting my hormone profile. - Yeah, yeah. So even though a woman's testosterone is much less than a man's level, it's still more than she
has estrogen in her body. - [Andrew] Wow! - So phenotypically, right, estrogen is the hormone
that's dominating and test, so it's the, she has much
higher estrogen than a man and much lower testosterone than a man, but in absolute amounts, she has more testosterone than estrogen. Just worth pointing that out. - [Andrew] Incredible. - So, you know, what's
happening to a woman from the age she starts menstruating until she goes through menopause, outside of pregnancy and birth
control and stuff like that, is she has this cycle, you
know, roughly every 28 days, but it can vary, where at
the beginning of her period, we call that day zero, her basic, her estrogen and
progesterone are very low. You can't measure them. And then what happens is the
estrogen level starts to rise, and it rises in response
to a hormone called follicle stimulating hormone, FSH, that is getting her ready to ovulate. And she ovulates at about
the midpoint of her cycle. So if we're just going
to make the math easy, on day 14 she's going
to release a follicle from one of her ovaries. And the estrogen level is sort
of rising, rising, rising. We love to measure hormones on day five, because I want to have a standardized way in which I measure her hormones. So our women know if we're in the business of trying to understand her hormones, the day her period starts, even if it's just a day of spotting, that becomes our benchmark,
and then day five, I want to see every hormone on that day. And if everything is going well, I know what her FSH, LH,
estradiol and progesterone should be on that day. So the estrogen rises, starts
to come down a little bit as she ovulates, and then the
luteinizing hormone kicks on because it's now going
to prepare her uterus for the lining to accommodate a pregnancy. So now you start to see estradiol go back, but now, for the first
time, progesterone goes up. So progesterone has been
doing nothing for 14 days, and now it starts to rise. And actually progesterone is the hormone that's dominating the second half, which is called her luteal cycle. So the first 14 days is
the follicular cycle. Second is the luteal cycle. So once you get to about
the halfway point of that, which is now, just to
do the math, 21 days in, the body has figured out
if she's pregnant or not. And again, most of the time
she's not going to be pregnant. So the body says, oh, I don't need this lining
that I've been preparing, I'm going to shed it. So now progesterone and
estrogen start crashing, and the lining is what is being shed, and that is the menses. By the way, it's that last
seven days of that cycle, that in a susceptible
woman is what creates those PMS symptoms. So it's the, actually, this is something that you would probably have a better understanding of than me. There is something about
this in a susceptible woman, where the enormous reduction
of progesterone so quickly is probably impacting
something in her brain. So this is a legitimate thing, right? I mean, you know, it's not like, oh, she's crazy because she's
having all these PMS symptoms. No. We know that that's the case because if you put women on progesterone for those seven days,
those symptoms go away. - [Andrew] Interesting. - So if you can stabilize
their progesterone during the last half
of their luteal phase, and sometimes we would just do it for the entire luteal phase, just put them on a low
dose of progesterone, all PMS symptoms vanish. - Very interesting. I'll have to look up where
the progesterone receptors are located in the brain. The Allen Brain Institute
now has beautiful data of in situ hybridization, which for, 'cause they don't understand is, looking at RNA and sort of
where genes and proteins ought to be expressed in the human brain, by using actual human
brain tissue sections as opposed to just mice. So I'll take a look, I think- - Yeah, I'm really curious, yeah.
- Some insight into what that progesterone emotionality link might be, and where it might exist,
neural circuit wise. - So then, when the
estrogen and progesterone reach their nadir again,
that starts the cycle. So that just, that cycle is happening over and over and over again. Okay, so it became well
known in the '50s that, okay, a woman's going to stop
menstruating at some point, her estrogen goes down. Why don't we just give her estrogen? 'Cause that's clearly going to help with some of the symptoms of menopause. So what do women experience
when they go through menopause? The first symptoms are what
are called vasomotor symptoms. So this is usually in the form
of night sweats, hot flashes. So, and depending on the woman, this can be really significant, right? These are women who can
have a hard time sleeping. They can be having hot flashes
during the middle of the day. They can wake up soaked
in a pool of sweat. Those tend to pass
after a couple of years, and then they get into sort of the more long-term complications of menopause. So what we call vaginal
atrophy, vaginal dryness, and then the stuff that we
talked about a while ago, which is the osteopenia osteoporosis. A lot of women will complain of brain fog. So, I mean, clearly this was an issue and it was recognized 70 years ago. Why don't we give women estrogen back to replace that hormone? And so that went on for a
couple of decades, maybe less, maybe a decade, and then it
was realized, wait a minute, we were driving up the
risk of uterine cancer. And the reason for that is
if you just give estrogen with no progesterone to antagonize it, you will thicken the endometrium endlessly and you will increase
the risk of hyperplasia. Well, you'll definitely
undergo hyperplasia, and then ultimately dysplasia. Dysplasia is precancerous, and ultimately we were seeing that. So people figured out, well, actually, if you want to give estrogen to a woman who still has her uterus, you have to give her progesterone as well. You have to be able to have a hormone to oppose the estrogen. And then that became effectively
in, call it the 1970s-ish, the standard for HRT. So in the early 1990s the NIH said, look, we haven't really studied this. We have a ton of epidemiology that says giving women hormones seems to
be doing really good things. They feel better, so all
their symptoms go away. They seem to have lower
risk of heart disease, lower risk of, you know,
cardiovascular, pardon me, lower risk of cardiovascular disease, lower risk of bone fractures. Everything seems to get better. Lower risk of diabetes. But we haven't tested this in a randomized prospective
trial, so let's do this. So that became the WHI. And it randomized, it
had two parallel arms. So it had a group for women
who did not have a uterus. So these are women that
had undergone hysterectomy for some other reason. And then it had a group for women that did have their uterus. In the first group,
there was a placebo arm and then an estrogen only arm. And in the other group, there was a progesterone plus
estrogen versus a placebo. Everything about the way this
study was done is a bit wonky. Some of it is justifiable, but
it's important to understand. First, the women were all
way outside of menopause. So none of these women were started when you would normally start HRT. And there were probably
several reasons for that, but one of them is, and I think
this is a legitimate reason, they wanted hard outcomes. They wanted to know death rates. And if you're doing this
on women in their 50s, you just weren't going to get it, right. You couldn't- - Wait too long.
- Yeah, you got to wait too long. And this was only going to be
like a seven to 10-year study. So they had to do this on
women who were much older. They also disproportionately
took much sicker women. I believe the prevalence, and again, I'm going to get some
of these numbers wrong and people are going to get all
phosphorylated, but, you know, I mean, I'm in the ballpark, right? Something like 30, 40% of
these women were smokers. The prevalence of obesity,
diabetes was enormous. So they really disproportionately picked the most unhealthy population they could, that was pretty advanced in age. And again, I think part
of that was to say, look, we want to make sure
that after seven years, we really know if there's a difference in these causes of death. The other thing is, this is kind of weird, although again, I understand
their rationale for it, but this is a great
example of be very careful when you look at a clinical trial, that it remotely represents the patients you're interested in treating. So they also treated no
patients who were symptomatic. The rationale being, if
we include in the study patients who are symptomatic, those who are randomized
to placebo will drop out. - Okay, it makes sense
in terms of study design, makes no sense if the study
design is intended to mimic the real world. - That's right. So now let's just keep
track of the three issues. We have a disproportionately
unhealthy patient population who are not symptomatic, and we're starting them more
than 10 years after menopause. The next thing that they did, which again, I understand why they did it, but it's now the fourth
strike against this study, is, and I've spoken with the PI of the study and asked this question point blank. I'm actually going to have her
on my podcast at some point soon to go over this in more detail, is why did you use conjugated
equine estrogen, an MPA, which is a synthetic form of progesterone. - [Andrew] Horse- - Yes.
- estrogen? - It's horse urine, is
they collect horse urine, so they're getting, it's- - Horses do urinate a lot. Or at least when they urinate, it seems like a large volume of urine, from what I've observed. - [Peter] You have a lot
of experience with this? - No, but, you know, my sister rode horses for a little while, my high school girlfriend
had a horse, and that thing, I mean the pees were legendary. It's a male horse. - Yeah.
- Yeah. - So, yeah, so the
conjugated equine estrogen is the estrogen that's
collected from female horses. And then it's a synthetic progesterone. And I said to the person, I said, well, why didn't you use what we use today, which is bio-identical
estrogen in progesterone. Like today, when we put
women on estrogen, we use a, it's an FDA product
called the Vivelle-Dot. So it's a patch that you just
put on, and it's estradiol, but it's bioidentical estradiol. And we use what's called
micronized progesterone. So bio-identical progesterone. And she said, well, at the
time we just wanted to test what was currently being used. And I said, totally makes sense. But again, now you have
four considerations that you have to keep in mind, okay. So despite those four considerations, and I'm going to make a case
for you why I think the MPA created a real problem in that study, the synthetic progesterone, when the preliminary results
were first made available, but not yet peer-reviewed
and not yet published, there was a huge fiasco, huge
press announcement about it, suggesting that the women
receiving the CEE plus MPA, in the group with the uterus, had a higher incidence of breast cancer. And that basically became the
headline that never went away, though it turned out not to be true. Let's talk about the numbers. What was the increase in
the risk of breast cancer in that group? Which gets to one of my, you know, if you ever listen to me on
a podcast rail on something. - Listen, I have about 3,800
pet peeves and counting. My laboratory staff know these,
know a good number of them. So, you do not have
- Here, I'll add to one of them.
- to apologize for having many pet peeves. Because as long as they
have experience in data to support them, it provides- - So one of my biggest pet
peeves is, and my team knows this 'cause sometimes they'll
occasionally, you know, they'll do this and I'll
have to remind them, you never talk about
a relative risk change without an absolute risk
accommodating it, right. So, what does that look like? So the relative risk
increase of breast cancer in the estrogen plus MPA
group versus the placebo was 25, 27%. And that became the only headline. HRT increases risk of
breast cancer by 27%. Now, I don't think
that's true at all today, but let's even look at the data. What was the ARR? What was the absolute risk increase? It was a difference between
five cases per thousand and four cases per thousand. So the ARR was 0.1%,
one case in a thousand. And it's true, going
from four in a thousand to five in a thousand is a 25% increase, but it's a completely
inappropriate context. - I agree, and I feel like
headlines of that sort, which have come up recently around various dietary interventions,
we won't go there, at least not for the time being, are nothing short of criminal because they really
distort people's thinking. But also they steer the course
of science and medicine for, as you pointed out, for
decades, if not longer. And they can really take
us off our health track in serious ways. - So I'll bring this meandering
to a close, which is to say, even though I could spend the next hour talking about all of the ways in which this study was flawed, and all of the very unethical
things that were done by a number of the investigators who went out of their way to
mask the truth of this study from the world, I'll tell a woman today, we're going to start you on this when you're going through menopause. We're using bio-identical hormones. And if your upper bound
risk of breast cancer is one case in a thousand, you should at least weigh that against all of the other benefits,
which I'll talk about. Now, there's something else I want to say, because a moment ago I
alluded to the fact that I think the MPA might have
been the biggest issue in that study. So there were two findings in
that study that were negative. One was the small increase
in the risk of heart disease, and the small increase in
the risk of breast cancer. But consider the other group, we forgot about the group
that didn't have a uterus. 'Cause remember, those
women got estrogen only versus placebo. What was the difference
in breast cancer there? Well, this is interesting
'cause it didn't reach statistical significance, but
its P value was 0.06 or 0.07. So it came very close, but it
was in the opposite direction. It was a 24% risk reduction, about one in a thousand as well. So when you had estrogen plus MPA, you had a barely
statistically significant, the P value was 0.05, so it just hit statistical significance, one in a thousand cases for breast cancer. And then you had one in a thousand cases, but P value of 0.07, for reduction
of risk of breast cancer. Which to me suggests that the MPA, the synthetic progesterone, was playing more of a
role than anything else. The second thing I point
out is oral estrogen, which we no longer use,
does increase coagulability. It does increase the ability of the blood to clot a little bit. And when we look at the
more recent data on HRT, using topical estrogen
or patches of estrogen, we don't see that at all. In fact, we see the opposite now. So now we see the risk of heart disease going down in women with estradiol. - And some women will be
arriving to those treatments with mutations and things
like Factor V Leiden and other clotting factors. Is it appropriate to say that everyone, both male and female, should
know whether or not they have mutant forms of Factor V Leiden? - You know, we don't typically
test people for Factor V. My wife actually has it, but we didn't learn it
until she had HELLP syndrome giving birth to our first daughter. But, you know, we kind of look for more family history reason to
be testing things like that. We take a pretty detailed family history, so we'll kind of look for
clotting issues there. - What about, so your reflex nowadays is to put women on these topical estrogen therapies?
- Well it's to basically have the discussion, right? So here's where we still
struggle, right, is, you know, if it were up to me, I'd
prefer for a woman's HRT to be provided by her GYN, because we want to be able to
work in partnership with the GYN who we would like to see an endometrial ultrasound done every year. That's, you know, some
would argue that's overkill, but we think she should
be having a pap smear every year as well. So if we're looking at the cervix, we want to look at the endometrium, we want to make sure the
lining isn't too thick. The other thing I should
say, Andrew, is today, we now realize that not all
women can tolerate estro, pardon me, progesterone. So you have to be careful. So assuming, again, a
woman still has her uterus, the estrogen solves most of the problems, but then you have to decide, can she tolerate the progesterone? And it needs to be, if given systemically like a hundred to 200 milligrams. And for some women, that is
a lifesaving intervention. I mean, they start sleeping
better, their hair gets thicker, they feel better. But for some women, it
literally drives them crazy. It's probably the reciprocal
of what we were seeing in the case of women with PMS. So in those situations we say, great, we're done with oral progesterone. We just use a progesterone coated IUD. So then you get the local
progesterone in the uterus for protection, and the systemic estrogen. - Fascinating. What about oral contraception in women? So the use of estrogen
chronically through people's, you know, college years or 20s, 30s, maybe even teens, who knows. What's known about the
long-term effects, if any? - I got to be honest with you, I don't think I know
enough to comment on it. It's not something that really impacts my patient population. At least in what I see,
more women are using IUDs for contraception than OCs. I mean, we use OCs sometimes
in women who are premenopausal, for symptomatic control,
but we'll typically use like a low low estrin, so a very
low synthetic estrogen, which I don't like using these very much. But if it's the only thing that we can get to control certain symptoms, and we'll use it like half her cycle. But it's typically not something we're that experienced with. - What about testosterone,
because you mentioned that, you know, nanogram per mill, when you said everything
to the same, you know, I guess it's nanogram per deciliter, - Yeah yeah.
- as it would be to kind of normalize everything.
- Versus picogram per ML. - Right, yeah. And so, what Peter was
pointing out before is that you look at your charts and they're all in these
different measures, and so when you normalize, testosterone is actually
higher than estrogen in women. That's a surprise to me. Do you prescribe testosterone
therapy to women ever? - We do sometimes, but I do
it with much more caution because I don't have the data, right. So where I'll, you know,
what we'll say is, look, I mean, we're now really
outside of an area where I can point to a lot of data. Like when it comes to
estrogen and progesterone, I'll happily go toe to toe with anybody who wants to make the
case that it's dangerous. Similarly, when it comes to
using testosterone in men, I'll spend all day, and I can
go through that literature until the other person cries and wants to just call uncle, right. When it comes to-
- And then you prescribe them testosterone. - When it comes to estrogen in, testosterone in women,
don't have that data. And I'd love to see that trial done. So what's the sweet spot,
how do we reconcile that? So it's not something I consider standard. And basically, if a woman
is, if her testosterone, first of all, is
staggeringly low, and again, even though her testosterone's
low compared to a male, we still have a range. So if it's really at the
bottom of that range, she's really having difficulty
putting on muscle mass and really complaining of low libido, I think in that situation, we'll go ahead and use topical
testosterone, and, you know, replace her to a level that is
still physiologically normal. - Yeah, that's key because
when people hear HRT, they think about, super
physiological seems to be the term. - Yeah, like I've never
seen a single symptom in a single woman that
I've put testosterone on, in terms of like acne, body
hair, things like that. Like those are real symptoms
that you have to be aware of, but, you know, like clitoral enlargement and things like that,
like that doesn't happen under physiologic normal conditions. - I'd love to talk a little bit about hormone replacement therapy in men. When one looks on social
media and the internet, there seems to be a younger
and younger cohort of guys and people in their teens and 20s, showing up to the table thinking that injecting
testosterone cypionate or taking Anavar, whatever it is, is going to be the right idea. They mainly seem to be
focused on cosmetic effects. I'm not a physician, so I
can't say whether or not they were actually hypogonadal et cetera, but it seems to me, again,
correct me if I'm wrong, but it seems to me that
similar to the Attia's rule as it relates to longevity, that we could come up
with a broad contour rule in which if a male of any age is not trying to get decent
sleep, exercise appropriately, appropriate nutrition, minding
their social connections, et cetera, et cetera, the idea of going straight to testosterone seems like a bad idea. That said, just like with
depression and antidepressants, there is a kind of a cliff after which low enough testosterone,
or low enough serotonin, prevents people from sleeping, exercise, social connection, et cetera. So I do want to acknowledge that. But with that in mind,
how do you think about, and perhaps occasionally
prescribe and direct your patients in terms of hormone
replacement therapy in men, person in their 30s, person in their 40s, who's doing almost all the
other things correctly. What sorts of levels do
you think are meaningful? Because the range is tremendous
in terms of blood tests. 300 nanograms for deciliter, I think on the low end now in the U.S., all the way up to 900 or 1200,
that's an enormous range. What are some of the other
hormones you like to look at, estrogen, DHT and so on? - So, a lot to unpack there. So, let's start with the ranges, right? So the ranges you gave are for total testosterone, of course, and we don't spend a lot
of time looking at that the way we, you know, I used to spend more time
looking at total and free when I used more tricks to modulate it. So I'm actually far more simple in my manipulation of testosterone today than I was six or seven years ago. Six or seven years ago, I
mean, we were, you know, we would use a micro dose
of Anavar to lower SHBG in a person who had normal testosterone, but low free testosterone. - What was a low dose of
Anavar in that context? - 10 milligrams subling
two to three times a week. - Anavar basically being DHT. Oxandrolone-
- Yeah, oxandrolone, yeah exactly. - And again, we're not recommending this. This actually, if you're
playing a competitive sport, can get you banned from that sport. - No no, yeah yeah. This is-
- It can also get you banned from having children if
you do it incorrectly. - Yeah, so a micro dose of
this has to be small enough that it doesn't impair your body's ability to make testosterone. But Anavar has such a
high affinity for SHBG, that it basically distracts your SHBG from binding your testosterone. - Freeing up testosterone. - That's exactly right. So the goal was, how do I just give you more free testosterone? So if a patient shows up and they've got a total testosterone of 900
nanograms per deciliter, which would place them at, you know, depending on the scale you look at, the scale we look at, that
would place you at about the 70th percentile. But your free testosterone is, you know, eight nanograms per deciliter. So that's pretty bad. That means you're less than 1% free. A guy should be about 2% free T. So that dude should be closer to 16 to 18 nanograms per deciliter. So in that situation that I just gave you, his SHBG is really high. His SHBG is probably
in the 80 to 90 range. - That's very high. 'Cause I think the upper range
is somewhere around 55, 56. - Exactly.
- Yeah. - So we would first back stall
for what's driving his SHBG. So there's basically three hormones, so genetics plays a huge role in this. There's no question that
just out of the box, people have a different
like set point for SHBG. Mine is incredibly low. My SHBG is like kind of
in the 30s, 20s to 30s. But from a hormone perspective, there's basically three
hormones that run it. So estradiol being probably
the most important, insulin and thyroxine. So we're going to look at all of those and decide if any of
those are playing a role. So insulin suppresses it. So this is actually the great irony of helping a person get
metabolically healthy, is in the short run, you can actually lower
their free testosterone, all things equal. Because as insulin comes
down, SHBG goes up, and if testosterone
hasn't gone up with it, you're lowering free testosterone. - So somebody who goes on a
very low carbohydrate diet in an attempt to drop some
water and drop some weight, is going to increase their SHBG? - Yeah, if their insulin goes down enough.
- Bind up testosterone, less free testosterone. I can tell the carnivore diet people are going to be coming after
me with bone marrow in hand. But then again, after this discussion
extends a little further, I'm sure the vegans
will be coming after me with celery stalks, so it's a. - So then the same as with estradiol. So except in the opposite direction. So higher estradiol is higher SHBG. So again, occasionally
you'll see a guy with normal testosterone, but he's a very high aromatase activity person. So he has a lot of the enzyme that converts testosterone into estradiol. You can lower estradiol a bit
with an aromatase inhibitor, and that can bring down SHBG. Now, again, these things
individually are rarely enough to move the needle. The last is thyroxine. So if you have a person whose
thyroid is out of whack, you have to fix that before you,
if their T4 is out of whack, you're going to interfere with SHBG. There are also some supplements which I think you've
probably talked about these on the podcast. I feel like I've heard you talk
about these on the podcast. - Yeah, there are a few
that will adjust, you know, there's this idea now
there's a much better review, it just came out, I'll send it to you, I'd love your thoughts on it, and I've been perusing it line by line. But I love input from experts like you on the use of Tongkat
Ali for reducing SHBG. In my experience, it does
free up some testosterone. By which mechanism it isn't exactly clear. And the effects aren't that dramatic. Right, they're probably multiple effects. For all we know, it increases
libido, and it does, generally, by way of
increasing estrogen slightly, which can also increase
libido in some individuals. So we don't know the exact mode of action. So we've talked about a few. The one that a few years
back people were claiming could reduce SHBG was stinging nettles.
- Stinging nettles, yeah. - Stinging nettle, well I'll just, urinating seems to be
coming up multiple times on this podcast, for whatever reason. Stinging nettle extract, I took, the most pronounced effect of that was you could basically urinate
over a car when taking SHBG. What the underlying mechanism
of that was, I do not know. I took it for a short while, it didn't drop my SHBG very much, but it did drop my DHT
sufficiently so that I stopped taking it.
- You felt that, yeah. - I do not like anything that impedes DHT. I don't care if my hairline retreats, I don't care about any of that. DHT to me is something to
be coveted and held onto because you feel so much better when your DHT is in the appropriate range, and I'd love your thoughts on that. - Yeah, again-
- At some point too. - It really depends on the guy, and it depends on what risk
you're trying to manage, right. So prostate size starts to become one of the issues with DHT. - Luckily my prostate-specific
antigen is low, and DHT, the things that I know can reduce it are things like finasteride, Propecia, things like, yeah, right. Things that people take
to try and avoid hair loss can dramatically reduce DHT and lead to all sorts of
terrible sexual side effects, mood-based side effects, et cetera. But yeah, so I'm not aware of anything that could be taken in supplement form that can really profoundly drop SHBG.
- Yeah, we don't spend much attention on it anymore. Basically, I used to have
a much more complicated differential diagnosis eight years ago. Like, I mean it was, I
would drive patients nuts with the whiteboard diagrams
I would draw for them, when in the end, I think they
were just like, dude, just, what do I need to take? Today we take a much more simple approach. So the first question is,
should you or should you have your free testosterone being higher? That's the metric I care about, is free testosterone is
the first, most important, the second most important is estradiol. - And sorry to interrupt, you said, if you look at your total testosterone, you want the free T to be
about 2% of your total. - Well, it should be, right. Now I can't, I might
not change that anymore. So in other words, if a guy's at 1%, then I know I have to really
boost his total testosterone. If he's only going to
get one to 1 1/2% of it converted to free, I need to boost him. And that's why I don't care
if he's outside the range. Like, I'll have a guy who's free T, I might have to get a
guy's total T up to 1500 to get his free T to 18. - I see, so free T is the target. I like this approach.
- Free T is what we treat. - And do you still use Anavarax, - I don't use-
- oxandrolone, sorry, to try and lower SHBG. - I don't, no.
- Because it's too potent? - No, because it's just too
complicated for patients. It's a drug that can't be taken orally, so you have to take it under the tongue. - Like a troche or something. - Right, but then, you know,
I had one patient once who, even though we told him
about 87 times that, he was like swallowing the
Anavars and his liver function, and he was like, we're
talking 10 milligrams three times a week is a tiny
dose, and three months of him, or whatever, two months of
him swallowing that every time tripled his liver function test. So it's like, I was like, you know, it's just not worth the
hassle of doing this for, you know, perfection. In reality, we can fix this another way. So the first order question is, do we believe clinically you will benefit from normalizing your free testosterone, or taking it to a level, let's call it 80th to 90th percentile. So upper normal limit
of physiologic ranges. That's the first order question. And that's going to come down to symptoms, and that's going to come
down to some biomarkers. I think there's, two years ago, was it two years ago or maybe a year ago, very good study came out that
looked at pre-diabetic men, you've probably talked about this study, and looking at insulin
resistance and glucose disposal with and without testosterone. And the evidence was overwhelmingly clear. Testosterone improves glycemic control. Testosterone improves insulin signaling. This shouldn't be surprising by the way, given the role muscles
play as a glucose reservoir and a glucose sink. So now I include that as one of the things that we will consider as a
factor for using testosterone. Now, again, it's not the only one. So you can accomplish that with exercise, you can accomplish that
with these other things, but then you get into a little
bit of the vicious cycle of will having a normalized testosterone facilitate you doing those things better. So let's just assume
we come to the decision that this person is a good candidate for testosterone replacement therapy. The next question is, what's the method we're going to do. Are we going to do it
indirectly or directly? Now we used to use a lot
of Clomid in our practice. And have you talked
about Clomid on the pod? - Haven't talked too much about it. No, we've talked a little
bit about the fact that some people taking things like anastrozole to reduce aromatase activity, can potentially run into
trouble because they think, oh well, more testosterone,
good, lower estrogen, bad, and then they end up with
issues like joint pain, memory issues, and severe drops in libido. And I think a lot of the reason why- - And even fat accumulation. So if estrogen is too low, you can develop adiposity in a way that you wouldn't otherwise. There was a great New
England Journal paper, it's probably 10 years
old now, that looked at, I believe it was five different doses of testosterone cypionate. So these men were chemically castrated and divided into 10 groups. It's pretty remarkable- - [Andrew] That somebody
signed up for this study. - Yeah, so you were with
and without anastrozole and five doses of testosterone. So now you basically had
five testosterone levels, plus or minus high or low estradiol. And the results were really clear that the higher your testosterone and the more your estradiol
was in kind of that 30 to 50 range, the better you were. So if estrogen was too low, even in the presence of high testosterone, the outcomes were less significant. - And this is 30 to 50
nanograms per decile, not 30 to 50% of one's testosterone. Okay, great. No, we haven't talked, but Clomid is, you know, we have not
talked a lot about Clomid. I'd love to get your thoughts on Clomid. - So Clomiphene is a fertility drug. It's a synthetic hormone. It's actually two drugs, M Clomiphene and I forget the other one. And it tells the pituitary
to secrete FSH and LH. So you, and so the advantage
of Clomid is it's oral, and it's meant to be taken orally. So, you know, a typical
starting dose would be like 50 milligrams three times a week. And if you do that, you'll
notice, in most men, especially young men, FSH and LH goes up. In any man, the FSH and LH go up, but if a man still has testicular reserve, he'll make lots of testosterone
in response to that. 'Cause that's the first order question we're trying to answer is do you, is your failure to make
testosterone central or peripheral? - Yeah, and I think,
just want to point out, again, correct me if I'm wrong, but my understanding is
that a lot of the drugs that we're talking about,
the synthetic compounds, testosterone, estrogen, things
related to growth hormone, et cetera, were discovered and designed in order to treat, and excuse me, in order to isolate and treat exactly these kinds of syndromes, whether or not it was the
hypothalamus, the pituitary, or the target tissue, the
ovaries or the testes. Correct? - Correct, yeah. I mean, I think, the easiest
way to go about doing this is just give the hormone that's missing, without attention to
where the deficiency is. Why this becomes relevant is
if you have a 35-year-old guy whose testosterone is low, but you can demonstrate that it's low because he's not getting
enough of a signal from the pituitary, why would you bother giving
him more testosterone when he has the Leydig
cells and the Sertoli cells to make testosterone. He just needs the signal. Sometimes, though not always, just a course of Clomid can wake him up, and he's back to making
normal testosterone. - So he'll do this three
times a week, 50 milligrams, three times a week, for
a short course, and then? - Yeah, we would do that
for eight to 12 weeks and then we reevaluate. - And estrogen and testosterone
will increase in parallel. - Yes. And again, it depends, you know, aromatase activity is dependent on how much body fat
you have and genetics. And if estradiol gets too high, we think if it gets over about 55, 60, we will give micro doses of anastrozole. But it has to be real micro doses. I mean, you cannot pound
people with anastrozole. To give you perspective,
the sort of on-label use, like if you just go to a
pharmacy and order anastrozole, you're going to get one milligram tablets. Like we can't give anybody a milligram. - [Andrew] They'll feel like garbage. - We have to have it
compounded at 0.1 milligrams, and we might give a patient
0.1, two to three times a week. That would be a big dose of anastrozole. - Yeah, I think that the
typical TRT clinic out there is giving 200 milligrams per mil, one mil, 200 milligrams of testosterone
once every two weeks, and then hitting people
with multiple milligrams of anastrozole, and
they're all over the place. - I've never really understood, I mean, I guess I shouldn't be surprised, but it kind of blows my
mind that these TRT clinics are up all over the place, given how bad. I mean, I see the results, 'cause I have patients
that come from them, and I don't understand like
why they're so incompetent. - I actually think it's worse than that. I think that they simply don't
understand and don't care, because it's a pill mill
and it's a money mill. I think that nowadays it seems almost everybody who's doing TRT is taking lower doses more
frequently every other day, or twice a week, dividing the dose, and being very, very
careful with these estrogen or aromatase blockers. - Most of our patients do not
take aromatase inhibitors. It's not needed. It's really only the high
aromatasers that need it. And so yeah, when we'll
talk about testosterone, we'll talk about dosing
there, 'cause I agree. The more frequently you
can take it the better, and frankly, you don't
need to go more frequently than twice a week. - Because it's so slow-acting.
- The half-life, yeah, the half life of the drug is, I think it's about 3 1/2 days, is the plasma half-life
or something like that. I could be off a little
bit, but twice week dosing is really nice. So if you go to like a testosterone clinic that's giving you 200 every two weeks, 50 twice a week is the same
total dose, which, by the way, is a physiologic dose. That's not going to give
somebody any of the side effects you would see. You're not going to get acne with that. You're not going to get gynecomastia. You're not going to get anything. The only real side
effect you get from that is you will get testicular atrophy. It is enough to suppress. - Yeah, to maintain fertility, what do you typically do for? - Well, so this is where, so I'll finish the story on Clomid, 'cause we currently do not use Clomid, and that's due to a really
interesting observation that we made, that I don't
think has been reported in the literature yet, which is that Clomid was
increasing levels of a sterol that we also happen to
measure called desmosterol. - [Andrew] I'm not familiar with that. - So, and the way that
cholesterol is made, it's made by, there's two pathways
that make cholesterol. So it starts like with
two carbon sub units, 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 lathosterol. So we constantly measure
lathosterol and desmosterol, because we want to know how much cholesterol is being
synthesized in the body. Not just what your cholesterol is. We want to 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, like 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 desaturates, that turns desmosterol into cholesterol. Makes sense if you inhibit that enzyme, you're going to 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 is 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. 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 got to 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. - [Andrew] 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 going to
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 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, body builders
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? - Yeah, and 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 going to crush endogenous
luteinizing hormone levels, right, because it's- - Actually, yeah. 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, and here I'm not making recommendations, but one supplement I've
talked a lot about publicly is Fadogia agrestis, which is this weird Nigerian shrub that- - 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 of 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 Fadogia, 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 we're
talking about things like Tongkat and Fadogia 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. - Yeah, I-
- 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 control trials. There just aren't. - Yeah, and, you know,
have kind of like a seven, this is another Peter Principle, right. So I 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, you know, 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, are going
to need an extra few pages for this part of the documentation. - Right, the people who
travel with a suitcase that you can hear as they
walk through the airport from all the pills rattling. - 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,
it's 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. - As an interesting aside.
- 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, right? So in mouse models, rapamycin
will preserve ovarian life. And so- - Interesting.
- It makes sense, right. I mean, it totally makes sense why the most potent GRo
protective 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, 'cause that'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 desmosterol,
potential desmosterol link. What about testosterone therapy? So less, - Yeah.
- less frequent, lower doses, less or no estrogen inhibition or aromatase inhibition.
- Yeah, only, we're only using an aromatase blocker, and we use Arimidex 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 a, not even a third, I'd
say probably 20% of men require a micro dose 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, 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, you know, giving testosterone cypionate
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
dosages, 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 fingers. So you're putting like a V-shape. - [Andrew] 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, and now- - [Andrew] Injections are no big deal. - Yeah, well especially
now if you're doing, we're having them do
Sub-Q injections anyway. So it's not IM, they're using
five-eights 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-phobes we use Xyosted, 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. - 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. - [Andrew] Yeah, just on its own. - Yeah, 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 the kind of contour
that we're talking about here. A lower dose with the yes
or no low estrogen control. People, what did generally
people report, how do they feel? What does it allow them to do that they couldn't do or feel before? And then 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 a hundred milligrams
a week of testosterone. I think for comparison, like a bodybuilder could
easily take 500 to a thousand during a high growth phase. - I know some of these
guys, they go ballistic, or they're doing moderate levels
of testosterone cypionate, but they're also taking
Dianabols, Nandrolone, you know, 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. - [Peter] It's outside of physiology. - Yeah, and I think for
99% of people listening, they look, they hear bodybuilder
and they just go, like, why would somebody do that anyway? - [Peter] Right. - I think that's the typical response. - So the point is, a lot of, but we owe those guys a
great deal of gratitude 'cause 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-
- 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, 'cause 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 hormone.
- Exactly. So, it might be the case that you're going to need something
upstream of that, like Clomid, to kick start it, and
then we're, 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. I was, 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, 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 and Anavar, 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's so hard to target, but somebody ought to do it. The chemistry can't be
- Yeah, it's funny. - that hard.
- I talked with Patrick Arnold about this many, many years ago. I wish I could remember what his ID, he had a comment about this
that at the time made sense, and I don't remember what it was, 'cause I had that thought too, like man. Especially for that subset of guys who have normal testosterone, but they're just over binding 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, you know, 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 kind of
a dough-y look to them. And so it's got to be this
free testosterone thing, plus estrogen, et cetera. And so cosmetically-
- Well, but also training and nutrition too, right.
- Yeah, absolutely. - I mean, I just think, I think for all this
talk about testosterone, which I enjoy talking about and, you know, I enjoy talking about
the data on, you know, long-term health
consequences of testosterone, 'cause it's another controversial topic, I also think people kind of
overstate its importance. - [Andrew] 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 going to 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've been, 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 over-training 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 over-trained,
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. - Yeah, yeah, yeah.
- There are people that argue that if one eats a ton of saturated fat, that LDL goes up and HDL goes down. - Oh, okay, but that's not
dietary cholesterol per se. - No, not dietary cholesterol per se, but, and then there are people
that argue that, you know, 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,
'cause we use them, you know, I 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, you know, 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 like
sphere, like a, you know, a blow up ball, right? It's got to 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, 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 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've 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 going to 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. And 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- - [Peter] Saturated fat's different. - Saturated fat and 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 erase 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, triglycerides, or, you know, a phospho lipid, 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 going to
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's, it makes having discussions
about this very complicated. Let's go back to the
cholesterol problem, right? 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, right? So if you're sort of, if
you're playing God for a minute and you want to 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 want to 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 this 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, you know, 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 a hundred
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 little a
that you mentioned earlier? - [Peter] LP little a is another- - LP, excuse me.
- 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. - [Andrew] Got it. - The other thing I'll just say on this, because earlier I mentioned ApoB. There are two broad
families of lipoproteins. There are those that are wrapped in ApoBs, and those that are wrapped in ApoAs. The ApoA family is the HDL family. The ApoB 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 ApoB. I only care about ApoB. I care about the causative
agent of atherosclerosis. ApoB is the thing that
drives atherosclerosis. - And what levels are
attractive or repulsive for you when you see levels of
ApoB 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 a hundred. - Yeah, so if you see-
- And I'm assuming some taper. - If you tell me you want
to live to be a hundred, you're going to need to keep your ApoB below 30 milligrams per deciliter. - Let's say I want to live to
be a hundred, 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 say it that way, because if you're going to tell me that in order to achieve that
live to a hundred level, I'm going to have to
give up my personal life and my- - No no, to get-
- and my brain functioning, then I'm not really interested. - Sure, but to get LDL
levels, and really, again, people think of it as LDL,
it's really ApoB, right? ApoB is this total
concentration of LDL and VLDL. And that's what matters. Those are the big atherogenic particles. LDL also includes the Lp[a], although the concentration of Lp[a] is relatively speaking so small that it doesn't generally
show up as much in the ApoB. So we treat ApoB, and basically
what it comes down to is you want ApoB 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, you know, who died in Vietnam. In the early 2000s it was
done on mostly young men, but some young women, who were, you know, 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. - [Andrew] Wow! - And to be clear, they aren't
going to 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 ApoB 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 ApoB level of kind of 20 to 30
milligrams per deciliter, that makes it impossible
to get atherosclerosis. So ApoB is necessary, but not
sufficient to develop ASCVD. Now that, go ahead. - Oh, I'm sorry, I was just going to ask, what are some of the top behavioral nutritional
supplementation, if any, based, and prescription drug-based
ways to target ApoB? - Well, nutritionally, you basically have two big tools, right? And it depends on what's driving up ApoB. So ApoB, 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 ApoB. 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 ApoB. 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 ApoB, 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 anything. - Pure dietary intervention.
- Yeah. - So what are the other things that- - [Peter] 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, you know, 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. - Cognitive effects? - Again, I think it's, in
terms of actual comparing it in 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 Niemann-pick
C1-like 1 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 bempedoic 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, we'll
try this other thing. - What's it called, one more time? - [Peter] Bempedoic acid. - Bempedoic acid. - The most potent drug of the
lot is the PCSK9 inhibitor. So PCSK9, it's 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 3000 mutations that are known to produce that phenotype. This was discovered to be one of them. In people who had hyper functioning 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 19, no sorry, 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 in 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 classic compounds? - Well, often it's in
combinations, and I would say 80%. - [Andrew] Eight zero? - Well you have to remember
what our objective is. Like, we're in the business
of trying to make sure people live as long as possible. And you have to take a sort
of world view of this, right? If you, like what's the most prevalent cause of death globally? - [Andrew] Say cardiovascular disease. - Yeah, and like, 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. Like 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.
- So the question is can you do that?
- Why don't we hear more, 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, right. And they all converge in the same place. - Yeah.
- Right, 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, 'cause 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 great 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 the, 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 ASCVD 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%, when there's a 5% chance
that you're going to 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. - It's a lot like eye disease. You know, there are exceptions, of course, but we always say that
the biggest risk factor for going blind from glaucoma is being an older person, frankly. - So if you could identify
what the risk factors are for glaucoma, imagine if the paradigm was, we're only going to 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? - Absolutely.
- And say, wait, if maybe being in the sun
without sunglasses, or, you know, using this type of eye drop
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 want to 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 want to 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
were really thoughtful, and I really appreciate
that you're willing to share your own tissue rehabilitation experience, and point people to 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
going to be talking to Attia, 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 into 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 in this, for most uses in this
country, but are certainly, people are flying down to
Colombia and getting injections. And what is your
understanding or experience with things like BPC-157, specifically, 'cause 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. We know this. People are getting injections of PRP into every tissue and organ and, 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, you know, I just think, if you're going to do something
without a clinical trial, you got to 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 GRo protective 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, you
know, certain joint issues. But the reality of it is like, 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, you know, waiting to get my shoulder surgery, this is an injury that
I've had forever, right? This is an injury, you know, 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, you know, I sort
of knew at some point, like, I'm going to 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? You know, 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 a thousand 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? 'Cause 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 know, you only had 10% of
your patient population that was the right patient
population to get that. So, you know, will we ever get there? I don't know, because I don't see what
the incentive is, right. 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. - Yeah.
- It would just be- - Likewise, I will 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 3 1/2 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 dunno, 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 and 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. We're 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, they're a relatively finite
number of these things, many of which are known, but
some of which are not known. 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 probably not, but maybe if you looked at
the methylation patterns and 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 they're 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
health span 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, that 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. You know, 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. - Was it 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, you know, horrible pulmonary
disease as a result of it. Probably pulmonary hypertension
or something like that. But there were, you know, 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, wait, 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, you know, 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 [indistinct], 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 or
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, 'cause 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 semaglutide, the dose that was studied,
so 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 semaglutide is central, not peripheral. - Huh. 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 mechanical receptors 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- - 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 semaglutide, you're going to 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 going to be? Is this going to be a
drug you cycle on and off? Or is it going to be a drug that a person has to stay
on indefinitely, and if so, will they become tachyphylactic? Will they gain 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 describe testosterone and estrogen therapies, that it would allow people to
do more of the behavioral work that's absolutely required
for health span and lifespan. - Yep, and we've also seen,
on the flip side of that, you can cheat through semaglutide, right? You can drink a lot of calories, and sort of get around the drug. So, you know, for example, like, you know, we always encourage patients
who want to lose weight to really just eliminate alcohol. That's like, 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 that's, 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 want to 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, a 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,
in the upcoming book, which I think that 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 your podcast and going on podcasts. So 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
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