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, a Tia dr. T has 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
Sighs physiology to sleep, physiology, emotional, and mental health, and pharmacology. Today, we talked 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 talked about the various sorts of interventions that one can take in order to optimize Vitality. While also extending longevity, that is lifespan. Dr. Arati is uniquely qualified to focus on the complete depth and breadth of topics.
Topics that we cover. And indeed, these are the same topics that he works with his patients on in his Clinic every day dr. Tia 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 reuse of general surgery. He spent two years at the National Institutes of Health as a sir.
Call 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. Haataja has trained with some of the best and most Innovative lipid ologist endocrinologist, gynecologist sleep, physiologist 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.
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 life span 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.
Of course, we talked about supplementation nutrition exercise, and predictors of Life, Span 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. Just want to remind you that we have time-stamped 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 human Lab podcast is now partnered with Momentis supplements. We partnered with momentous for several important reasons. First of all, they ship internationally.
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For joining me today. Thanks for having me, man.
I'm looking forward to this for a very long time. That's right. 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 just to be doing
this. Yeah,
likewise I have a ton of questions but I want to start off with something that I wonder a lot about. And then I know many other people wonder about, which is how to assess their current health and their trajectory
In terms of health and well-being 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? Often, do you get blood work done,
Etc.
Yeah, that's left there. I mean the way I talk about this with patients is first, taking everything back to the objective. So what's the, what's the, 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 in their training, you know, they're going to benefit benefit much more from sort of functional analysis of performance. So I'm assuming based on the
Kitchen that you're really coming at this, through the lens of living longer and living better through the lifespan Health
span most lens. Yeah, and just, I think, most people have some sense of their Vitality or lack of Vitality, but I think everyone wonders whether or not they could feel better and whether or not blood work, will give them a window into how they might go about feeling
better. Yeah, I think it does to some extent, but I also think that it has a lot of blind spots so I kind of, you know, 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 aspiring or you're not, you make ATP or you don't end of story. So what gets in the way of life span is essentially The Four Horsemen of disease, right? So atherosclerosis disease, cancer neurodegenerative disease, and metabolic disease, which directly isn't the cause of many deaths, but, you know, because beep.
With creates the foundation to all of those other diseases. So, you know, if you're a nonsmoker, what I just rattled off is about 80% of your death. So how does blood work help address those it varies. So on the atherosclerosis standpoint it's a very good predictor of risk if you know what to look for. So primarily a poby would be the single most important lipoprotein that we care about. I got explain what that means in a second. And then also, you know,
No 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 because those aren't really biomarker studies, but put that away on the neurodegenerative decide. 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 atherosclerosis diseases. So the same things that, you know, Drive the risk of heart disease, or drawing drawing 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 a pony but far more, you know, new on stuff than that. They can also play a role so you can stratify risk in that sense. So in aggregate, I would say, you know, blood testing and biomarkers.
Provides pretty good insight into life. Span when you get into Health span, you have kind of the cognitive physical emotional domains. I think here the 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 too.
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. See Pat testing, VO2, max testing, you know, Zone to lactate testing.
Fat oxidation those, what I consider more functional tests that give me far more insight into that. And then, of course, the emotional piece, which depending on, you know, who you are, might be the single most important piece without, which none of this other stuff matters, or if you're 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, it's giving me great insight into
that. Do you ask about emotional state, where 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.
Me and look there are some patients who they, that's just not something that that's something that's compartmentalised. Maybe they're, you know, they're doing well in the 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, Etc, to try and extend lifespan and improve health span is once a year frequent enough and should a
Your old start getting blood work done, just to get a window into what's going on assuming that they can afford it or their insurance can cover
it. Yeah, I mean, look, I certainly think everybody should be screened early in life because if you look at like what's the single most prevalent genetic driver of atherosclerosis is LP little a. So unfortunately most Physicians don't know what LP little a is and yet you know somewhere between eight and twelve percent of the population has a high enough it depending on who you you know, I had a recent guest on my podcast who suggested it could be as high as 20 percent have a high NFL
LP little a that it is contributing to atherosclerosis. So to not want to know that when it's genetically determined, right? This is something that, you know, you're born with this and you only need to really check it once why we wouldn't want to know that in a twenty-year-old, when it can contribute to a lot of the early, a thorough sclerosis, we see in people, you know, it just it's, you know, 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, you know, 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, you know, 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
Are too now check like hey you know we gave this drug that it have the desired outcome you know you put on three pounds of muscle and lost 3 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. Kara, 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 add exit, I'd rather take a dexa annually and then maybe follow wait a little bit more closely to get a sense of it and so with a deck. So you're getting, at least the way we look at the data for pieces of information.
Now, most people, when they do a dexa at should I explain what that is?
I'm, yeah, I think some people might not know what Dex is, iin fact, I confess, I have a crude understanding of what it is. My tell me where I'm wrong and hopefully, where I'm parked least partially, right? My understanding, is that there a number of different ways to measure lean mass to not only Mass ratio and there's one where they put you under water, there's one where they put you into some sort of non underwater chamber, there's caliper and yep. And then there's the looking in the mirror and
King and changing the lighting
here. It's funny when you, 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, that's actually not a terrible way to do it. There are, you know, a body builder, for example, which I've never been can can tell you the difference between being 6% 7%, 8% 10%, just based on the degree of visibility within within the apps. But
Basically a dexa scan is an x-ray. So it's the same Principle as, you know, 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 they're the denser. The medium that the electrons are trying to go through the less of them that are collected. So when you look at an x-ray, as everybody's probably seen an x-ray that which is white is most dense. So, if you had a piece of metal in your pocket, it would show up as a bright white thing. That's why
And Bones show up as white and the things that are the least dense like the lungs where it's just are, 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 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 decks of the, you know, 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 abject lie, horrible, we've created our own template. So we have our own dashboard for how we do this because we've just given up on trying to use theirs. But the first thing most people look at is what's my body fat? And this is the gold standard outside of
MRI or something that's only used for research purposes. So, so a dexa is going to produce a far better estimate of body fat and calipers or buoyancy testing or things like that. Provided the Machinery as well calibrated in 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 Decks is amazing.
You know, of the four things that get spit out of the deck. So 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, our bone mineral density, visceral fat, and then the metrics that allow you to compute. Like, to see 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, 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 a big deal, but for a 50 year old woman is a huge deal, right? A woman who's just about to go through menopause or has just gone through menopause. Is it 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 it's very interesting how the, 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 percent which again just to put that in English. If you're 65 or older you fall and break your hip, there's a
40% chance. You're dead in a year.
Wow, bones matter. So we want to really get a sense of where you stack up for your age for your sex and if you're anywhere off the pace, we have to ramp up our strategy and be super aggressive about how to increase that or at a minimum prevent any further
Decay and are there age-related charts for the all sorts of
things? Yeah, this is 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
Z score. So a z-score of zero means and you understand this, but it's like it's really Square referring to a probability distribution in a standard mode. So the Z score of zero, it means you're at the 50th percentile for your age and sex is he score of +1. Your one, standard deviation above minus one below 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
- one in four years, I want your Z score to be 0, not necessarily, because you've increased that entire way. But maybe you've increased slightly while it's expected that you would have declined. I see
what are some things that we can do to improve bone mineral density at any age?
So it turns out, there's a real critical window in which we are malleable. So, depending on the age at which someone is listening to us, discuss this, you know, if you're if you're under 20 25,
You are still in that time of your life when you are able to reach your potential. So it turns out that strength training is probably the single best thing you can do. And this was a surprise to me because we, you know, we did an AMA on this topic a little while ago. And that's when I got, you know, really deep on this with our analysts, my assumption was a running, must be the best, like some sort of impact must be. The best thing you can do it was, you know, I assumed running would be better than swimming and cycling, but it turned out that powerlifting.
It 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, powerlifting is really putting more of a Shear force, from the muscle, via the tendon on to the Bone. And that's what the bones are really sensing. They're sensing that Shear Force that's being applied through the bone and a compressive way, depending on the bone, of course. And that's what's basically activating the osteoblasts which are the cells that are, you know, allowing bone to be built.
It's this is this turns out to be probably more important for females because how high you can get during that period of development say till you're 20 or 25 basically sets your trajectory for the rest of your life. So where we get into real trouble is with patients. Who, for example, used large amounts of inhaled steroids during that period of their life because let's say they had really bad asthma. We're patients, who needed large amounts of corticosteroids for some other immune related condition. So, during their critical,
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, you know, with nutrition, with hormones, with drugs, with training. And, you know, it's, 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. Yeah.
They're steroid based. Some of them, of course, are just beta agonists and they're
fine. So anything corticosteroids and like shooting 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 I would have a systemic effect. But then again, what do I
know? It's all. It's all dose, and 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, you know, corticosteroids on, probably not. But but certainly with enough of it, put on a mean, it is absorbed. So it could be an issue, but that's not typically what we're concerned with them. And we're mostly concerned with people that are, you know, 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 kids on a steroid inhaler, they shouldn't be. You have to solve the most important problem and if asthma is the most important problem. So be it, I think you just want to turn that into. Okay, well, how much more imperative is it that our kid is doing things that are putting a high amount of stress on their bones and the other 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 a
It's a bone mineral density given that there's this key window earlier. They might have missed
that. 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-year run during 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 perimenopause. Correct. And, and can we get into any of the
Broad Contours of what that straight training looks like we had and dr. Any Galpin on the show? We talked a lot about ways to build strength versus hypertrophy versus endurance etcetera. Think there's pretty good agreement across the fields of, you know, physiotherapy Etc, physiology and Medicine 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, you know, a pomp, hypertrophy that sort of thing, but heavy load.
That are hard to move 80% of one repetition maximum or more done with long rest periods. Through to do that, three times a week type thing. Is that about?
Right, if you if you look at the literature on this it's going to tell you it's going to differentiate powerlifting 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 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, you know, 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
Pure movement is 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. It's there's a video on YouTube that actually kind of has the pi sort of walking through the result. I can send it to you have. Okay. Yeah. And it's just amazing. You they took a group of, you know, older women. They look like they're in their 60s or 70s, who had never lifted weights in their life who, you know, had osteopenia and some probably already had osteoporosis and they basically,
We just put them on a strength training protocol and it is remarkable to watch these women. They're doing good mornings, they're doing deadlifts, 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 way 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 know you have to do this for the first time you know. Strength training is such an essential part of our existence that you know, there's never it's never too late to start but you should never stop.
Love that advice. Is it a systemic effect or a local effect? So for instance, let's say that. Well my mother is in her late 70s. She actually should be really strong when we were kids. She could move this fish tank, that was in my room long before I could move it and she's really strong over the years. I would 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 push-ups.
The effects. All local meaning if she were to just train her legs or just do push-ups. Would it only be the loads applied to the limbs and muscles and
tissues? They were involved. That's where the bulk of it is. Yeah. Okay, yeah.
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 in the lumbar spine. So, you know, that's just the convention by which we make the diagnosis and I
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 you know 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 because it really
He comes down to putting a load directly on that bone and then having that bone in kind respond by laying down more bone.
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Letta greens.com huberman and claim, a special offer, they're giving away 5 free travel packs. Plus a year supply of vitamin D3 K to with every order and of course, vitamin D3 k 2 is vital for all sorts of things, like Hormone Health, and metabolic health and K2 for cardiovascular health and calcium regulation. Again, you can go to athletic greens.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
Late effects of just having weak bones that are not just about falling and breaking a bone and dying a year later. Even that 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 just move more slowly. I'll sit in a wheelchair if I need to. If even though I might be able to walk, the 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 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 under. It could be 87 to 97 if we're doing well, right? It might be 79 to 89, I don't know. But I, you know, we would really be in 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, you know, until a person can tell you what?
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, you know, someone wants to do an Ironman, we take it for granted that we know what the objective is. I have to be able to swim two and a half miles. I could be able to get out. Take my wet suit 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,
Enter, 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, right? Could be playing basketball. If you know it could be swimming to Catalina Island, it could be running a hundred miles. You wouldn't be able to do it. So similarly if we don't know what our marginal decade is meant to be, there's no way to train for it.
Do you think this is a good exercise for anyone and everyone to do on their own regardless of age here? I'm hearing this and I was thinking I need to think about when my last decade
And what I want that to look like,
absolutely. I mean when I say we do with our patients that's only because that's the population at work with but there's simply no reason, everybody shouldn't be going through this
exercise and then you use sort of back script from there. Figure out what we should be doing, giving their current health status,
exactly what we call it back casting. So the first step we do is once we've really delineate it. 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 describe doing a whole bunch of things, okay? Just to let you know to do that will require a vo2max of 30 ml of oxygen per minute per kilogram. And the person will say, okay, what does that mean? Will 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 a 30 and let's just assume you're going to be doing that at 90, so what do you need to be 87?
D 60 50. Okay, here's what it would need to be at 50. Okay, what are you now? Ah, there's a big gap. Your 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
vide 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 won't be able to do when we're 90.
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 for casting is really good at short-term things, it doesn't
For long-term things, long-term you have to do
backcasting. This backcasting approach really appeals to me because in my career, I never anticipated, excuse me, I never anticipated. I'd be podcasting. But that's why I did at some point as an undergraduate, I look professors and 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 and in a backcasting, kind of way as you refer to it. I think is
Doubly useful, because it puts all the questions about blood work and how often to get blood work and what to measure into, you know, a really nice context. It's a highly individualized. I've never heard of this before. So,
and I should give a nod to any Duke. I used to always refer to, this is reverse engineering, but in any Dukes book, she wrote about this exact thing and called it back casting. And I was like, I like the term backcasting better. I think it's more intuitive and reverse
engineering. Yeah, there's a Real Genius to it and I think it because it sets so many things into the appropriate bins and
I've heard you talk before about some of the Prime movers for longevity and all risk of 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 Nora, nicotine smoker. So I feel unstable ground there. But until we see smoking nowadays, people want really want to distinguish between cannabis and nicotine. So I am curious about
out 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 had. No, no, no. But, yeah, well, we spend from now until you're 90.
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
In-depth content. But, you know, let's say we sought A short flight from here to San Diego. We're in Los Angeles now and we got takeoff and landing and we don't want to kick our neck too much by doing this thing. So if I just said, hey, you know, give me the extended version of the three by five card. Yeah. 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 a cm
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 as a very specific intervention like an 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 a CM so you know, using smoking smoking is approximately a 40% increase in the risk of a CM.
What does that translate to in? That means I'm, I'm shortening my life.
By 40%. So it means at any point in time there's a 40% great greater risk that you're going to die relative to a nonsmoker and however smoker. Yeah so it's important to distinguish doesn't mean your life span is going to be 40 percent less. It means that 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 that catches up high blood pressure. It's about a 20 to 25% increase in all-cause mortality. You take something really extreme like end-stage kidney disease.
So these are patients that are on dialysis waiting for an organ. And again there's a confounder there because there's what's the underlying condition that leads you to that. It's you know, profound hypertension, you know significant type 2 diabetes. It's been uncontrolled. You know, that's enormous that's about a hundred and seventy five percent increase in a CM so the hazard ratios like 2.75. Type 2 diabetes is probably about a one point two five as well. So, 25 percent increase. So now the question is, like, how do you improve? So what are the things?
That improve those. So now here we do this, by comparing low to high, Achievers, and other metrics. So if you look at low muscle mass versus high muscle mass, what is the Improvement and it's pretty significant. It's about 3 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 3 x Hazard Ratio or 200% increase in all-cause mortality. Now if you look at the data more carefully you realize that
That it's probably less than muscle mass fully doing that and it's more the high association with strength. And when you start to tease out strength, you can realize that strength could be probably three and a half X as a hazard ratio. Meaning about 250 percent greater risk. If you have low strength to high strength,
high strength is the ability to move loads at 80 to
90. It's all, it's all defined by given studies. So some the most
Things that are used or actually, you know, they're used for the purposes of experiments that make it easy to do and I don't think they're the best metrics. So they're usually using like grip, strength leg extensions and like wall sits squats. Things like that. Okay. 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 smas. Oh, 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 the like, how long can you dead in your body weight? Stuff like that. So we're trying to be more granular in that Insight but tie it back to these principles. If you look at cardiorespiratory Fitness, it's even more profound. So if you look at people who were 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 2X difference, roughly in, in, in the risk of a CM. If you compare the bottom 25% to the top two point five percent, so you're talking about, you know, bottom quarter to the elite for a given age. You're talking about five x, four hundred percent difference in all-cause mortality. That's probably the single strongest Association I've seen for any.
Modifiable
Behavior incredible. So when you sail eat, 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 vo2max would be in the elite for my age group, my VO2 max, you know, but again, it's the I'm training, very deliberately to make sure that it's in that. So, I wouldn't consider myself a lead at anything anymore, but I still maintain a VO2 max that is Elite for my
age. I consider you an elite physician and and guy all around but true
um,
But in terms of,
okay, so for the point is like you don't have to be a world-class athlete to be allowed here, yet,
got it. So maybe we could talk a little bit about the specifics around the training to get into that, you know, 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 some
of them be and that's, you know, like this is my whole pet peeve in life, right? It's like I just can't get enough.
Off of the mash in dating and arguing about this supplement versus that supplement and I feel like you shouldn't be having those arguments until you have your exercise house. In order. You know, you shouldn't be arguing about your this Nuance of your carnivore diet. Versus this Nuance of your paleo diet versus this new one. So if you're vegan diet like until you can deadlift, your body weight for 10 reps, like then you then you can come and talk about the things or something like, let's just roll with some metrics. Like,
Till your VO2, max is at least to the 75th percentile and you're able to dead hang for at least a minute and are 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 like me,
just, we can make that
rule don't want to listen to it. I
don't know about that we can make whatever rules we want. We can call the AT&T has rule. One thing I've done before. In this podcast 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's. I'm going to call it a Tia's rule until you can do the following things. Don't
talk. Please refrain from talking about supplements and
nutrition. Here it is.
You're after thought of referred to and referenced as a tea has rule. I coined the phrase not him, so there's no ego involved, but it is now a t as rule watch out hashtag a Tio's rule. Oh God, Wikipedia entry Matias 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 that's our goal. I think we have a minute and a half is the goal for a 40 year old woman 2 minutes is the goal for 40 year old man so we adjust them up and down.
Based on age and
gender great. And then the wall sit, what's, what are
some differences? A while. So we do as just a straight squat air squat at 90 degrees and I believe, two minutes is the standard for both men and women at 40
great. And then because for some people thinking, in terms of VO2, max is a little more complicated. They might not have access to the equipment or the measure it etcetera. What can we talk about thing about? In terms of cardiovascular said, run a mile at 7 minutes or less 8 minutes or less.
Good question.
There are VO2, there are really good. VO2 max estimators online and you can plug in your activity dish or so would be at a bike run or rowing machine and it can give you a sense of that and I don't remember I used to know all of those, 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 great and and I think
Somewhere in my podcast realm. I've got all those charged charts posted of like this is by age by sex. This is what the VO2 max is in. Each of those buckets,
traffic will provide links to those will have our people find those links and then you mentioned dead lifting body, weight. 10
times, I just made that one up. I don't, that's not one that we include, but but something something like that. We used, we use farmer carries. So, we'll say, for a male, you should be able to farm or carry your body.
For I think we have two minutes so that's half your body weight in each hand. You should be able to walk with that for two minutes for women. I think we're doing 75 percent of body weight or something like that. Yeah,
great I love it. As indirect measures of how healthy and yeah huge we are and how long were going to
live. It's basically grip strength, its 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
Oh, it's it's really trying to capture and it's an evolution, right? Like I think the the test is going to get only more and more involved as we as we as we get involved. Because it took us about a year Beth Lewis did the majority of the work to develop this Beth, runs our strength and stability program in the practice and their basic. I just asked 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 back.
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 Etc 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 loose connections between neurons is to stop that animal from moving or 2D and Rich its environment to private of some sensory input or
all 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? And I think it's 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 pal, HR and I said, dad, 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 almost 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, damn, 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 because 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.
One, insulin, signaling, all these things. Like, 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 isaacsohn, who is a neurologist that we work with really closely on Alzheimer's prevention? And you know, ultimately turned into a paper that we wrote basically you know about this about this topic and a few others. Because again I thought are you sure it's not EPA and DHA? Like that's got to have a bigger impact and
Again, there's 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, you will get the maximum benefit comes going from nothing to something. So if you go from being completely sedentary to doing 15 met hours,
Week, you'll get probably a 50 percent reduction in Risk. So, I met our 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 would be about one met. You know walking really briskly would be about five Mets. So 15 met hours per week would be 3. 1 Hour really brisk walks. That's not a lot of work but just going from doing nothing to do.
Doing that would give you 50% of the benefit that you would get from going all the way. Now, I think and 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 in can truly capture that but look, you know, there's, 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 healthspan gets back to the functional piece. We opened with which is what do you want to be doing in your marginal decade, you want to
The pick up a great grandkid. If they come running at you, you won't be able to get up off the floor, going to be able to play on the floor, with the kid and then get
up on your own. And I think most people are thinking final years of life, they're trying thinking, how can they take themselves to the bathroom there, thinking how can they sit up off the toilet? And I mean yeah really basil 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 too,
Two actual methods and behaviors and protocols. That one should be doing on a daily basis. I'll use an account data as it's now called to site. 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 90's. So I'll name them because I'm complimenting them for what they've done, not just their work but what I'm about to describe Sir, Eric kandel at Columbia Nobel Prize going for work on memory tourist. Visa work on neural plasticity.
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. Richards, younger compared to the other, two, all three of them either swim jog or play, tennis or racquetball, I think is Richards thing multiple times per week. Eric was there all cognitively still extremely sharp still interested in the Arts doing science, curious about science, running Laboratories writing books, going on podcast and it's incredible.
Well again that's anecdotal 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 or early on linked that to their some of their intellectual Vigor. Over time I will want to just also use as a jumping-off point to ask about one kind of Niche thing but it comes up. I don't know man out which one of those told me this but one of those three individuals choose an excessive amount of Nicorette use
Be a smoker and I asked him, why? And he said, because in his estimation its protective against Parkinson's and Alzheimer's, or at least the nicotinic acetylcholine, augmentation of nicotine is nicotine is a CO calling 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 is going to shorten your life, just terrible.
All idea, addictive Etc, in my opinion. But what are your thoughts about augmenting? Acetylcholine through the use of nicotine in order to keep the brain healthy and focused again? This is one Nobel Prize winner, so it's a truly n of 1, but he's so convinced that this matches up with the mechanistic data, on a seat of choline 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 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. It sounds like a funny story about this. So our mutual acquaintance, David Sinclair?
Mentioned to compete company to me.
A year ago, he's like, hey, have you heard of this company and I forget the name of the company, but he gave me some name. So I go online and it's like this company selling nicotine. And I'm like, I wonder why he's asking me to do this. Well, I'll just order a bunch and then we'll figure out why, because we were, you know, there was some reason we were doing this potentially through investment. So I get up like, literally ordered like a lifetime supply of this stuff and it's pretty good. It's actually it's a really nice little patch because I the thing I didn't like about the gum was, I hated just the the
Of it. So then the next week I'm talking to David, I'm like, by the way, I ordered all that nicotine stuff. You told me about he's like, what? And he goes oh oh the company's name was something else. It's totally unrelated. It's like 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. No, it's not addictive, everybody. I personally experienced know.
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 Dos, truthfully. I mean, remember one cigarette is about 1 mg of nicotine and a lot of these laws inches will plow 428 mg 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 flak when I did this am a 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, you know, I apologize for that but on the list of things that you can do to
Make your brain a little more focused. I would consider this infinitely safer than what a lot of people are doing, which is using stimulants. I mean, to me, I, you know, I just helped patients out, right? Like, we are under no circumstance, prescribing stimulants, I mean those are still. Yeah, we're just 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 and
Using that as a tool to enhance, you know, concentration and cognitive performance is not something we're comfortable doing.
Yeah, it's rampant on college campuses. I can only imagine our modafinil modafinil, which are slightly different, of course, but it's a non clinical use of not prescribed for ADHD, but just, it's rampant, recreational use study based use, but
data. I've seen on modafinil, suggest that it only really provides a nootropic benefit in someone who is deprived of sleep, is there data that in a totally? Well,
Arrested person. There is a nootropic benefit of
modafinil. I don't know. I have one experience with our modafinil where I took a half. A recommended doses, was prescribed by a doctor. I went to give a talk, this isn't 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 lasered in that. I kind of forgot the context. I'm a little bit.
A kind of a tunnel vision OCD type anyway, but one that was all it took. I never, I never took any more of it. It was a powerful, stimulant I take 300 mg 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. This is
an example of where you know we're talking about exercise versus sort of nutrition and
It's 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, 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, 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 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. Well like I'll pick up my phone, every 20 minutes to look and see if I miss the text message or something stupid. That's pretty
infrequent. I did a episode on habits and looking at the data, it seems that people are getting interrupted or interrupting themselves about once every three minutes in the typical workplace. And now that typical is changed with a lot more people working at home. I do put my phone away,
Try and work that nothing focuses. Me like a deadline bit of fear-based urgency. That's, that's it Grant deadlines. You have drop deadlines as I call them or podcast. We're going to record today. The 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 the that augmenting the acetylcholine system, which is what nicotine does and its various forms and some related
Ated type pharmacology, does enhance focus and pretty potent Lee. So I think it's gonna 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 in the data around menopause. He's very interested in these findings that I think I'm gonna get this right that whether or not women benefit from estrogen therapy to offset, menopause really
It's on when that therapy is initiated 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 our male versus female. And what age is those patients are, of course. But what are your thoughts about estrogen?
Poppy for women, menopause and hormone therapies generally for women maybe even testosterone therapy, 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 screwup 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, another
Giants. 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. Then 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.
Phones 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?
Really worth mentioning a bit of the top Contour. Some of them might be familiar with that. We done episodes on estrogen testosterone but frankly, 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 or progesterone or FSH, LH her testosterone horse, excellent, binding globulin, all these things but based on the unit's, 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 your body than estrogen.
Interesting. Yeah,
I did not know that. Then again, I've never been a woman getting my hormone profile.
Yeah. So, even though a woman's testosterone is much less than in men than a man's level, it's still more than she has estrogen in her body. So phenotypically right. Estrogen is the hormone that's dominating and test. So it's that, you know, she has much higher estrogen than a man and much lower testosterone than a man. But in absolute amounts, she has more testosterone and estrogen just worth pointing that out incredible. So,
So what's happening to a woman from the age? She starts magistrate 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. We're at the beginning of her period, we call that day 0, 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 hormone called follicle-stimulating hormone.
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 5 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
And a 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 called her philic a hair 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
Mining 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 I think this is a, this is a legitimate thing, right? I mean it's not like oh she's crazy because
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. 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 the donor says
Looking at RNA and sore, where genes and proteins ought to be expressed in the human brain by using actual human brain tissue sections, as opposed to just my. So I'll take a look at think some insight into here's what that progesterone emotionality link. Might be and where it might exist, neural circuit
was 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, you know, well known in the 50s that okay. A woman's going to stop menstruating at some point, her estrogen goes down. Why don't we just give her estrogen because that's clearly going to help with some of the symptoms of menopause. So what do women experience when they go through menopause? The first symptoms are, what are called vasomotor symptoms. So this is usually in the form of night, sweats, hot flashes. So and depending on the women, 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.
You 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 or osteoporosis. A lot of women will complain complain, a 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
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 the nineteen, call it the 1970s, if the standard for for HRT,
So, in the early 1990s, the NIH said, look, we haven't really studied this. You know, we have a ton of epidemiology that says, giving women hormones seems to be doing really good things, they feel better. So they're all their symptoms, go away. They seem to have a lower risk of heart disease, lower risk of, you know, cardiovascular disease, permeate 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. The 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 are 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 you need to Long? Yeah, you got away 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 that 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 percent 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 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 patient's. 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, I make 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 ask 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 Aquinas estrogen and MPA, which is a synthetic form of progesterone horse? Yes, I will choose a horse. Its horse urine is they collect horse urine.
They're getting the, it says,
do your innate a lot or at least when they urinate, it seems like a large volume of urine from what I've
observed. You have a lot of experience with this.
No. But, you know, my sister rode horses for a little while, my high school girlfriend, had a horse. And that thing, I mean, the the peas were legendary male horse.
Yeah, so yeah. So the conjugated equine estrogen is the estrogen that's collected from from female horses, and then I'd say synthetic progesterone,
And I said to the Press, I said, well, why didn't you use what we use today? Which is bioidentical estrogen and progesterone like today, when we put women on estrogen, we use a, it's an FDA product called the Bevelle. 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 bioidentical progesterone and she said,
Well, at the time we just wanted to test what was currently being used. I said totally makes sense. But again now you have four considerations that you have to keep in mind, okay? So despite those four considerations, I'm going to make a case for you, why I think the MPAA 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 C e+ MPA in the group with the uterus, had a higher incidence of breast cancer and that basically became the headline that never went away though. It turned out not to be true.
Let's talk about the numbers. What was the increase in the risk of breast cancer? In that group? Which gets to my one of my? If you know you've ever listening on a podcast rail on something
as an I have about 3,800 pet peeves and counting. My laboratory staff knows he's know a good number of them. So here I'll deny, I do not have to apologize for having many pet peeves because as long as they have experience in data to support them, it
provides a one of my biggest pet peeves is a, my team knows this. Because sometimes, they'll occasionally, you know,
I'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, so what does that look like? So the relative risk increase of breast cancer in the estrogen, plus MP a group versus the placebo was 25, 27 percent, and that became the only headline,
HRT increases risk of breast cancer by 27 percent. 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 1000 and it's true going from for in 1000 25 and 1000 is a 25 percent 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, we're 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 and serious was.
So I'll bring this Meandering to a
Those 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 bioidentical hormones. And if your upper bound risk of breast cancer is one case in 1000, 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 loaded 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 in small increase in the risk of heart disease.
In a small increase, in the risk of breast cancer. But consider the other group, we forgot about the group that didn't have a uterus. Because remember, those women got estrogen, only versus placebo. What was the difference in breast cancer there? Well, this is interesting because it didn't reach the testicle significance. But it's p-value was .06 or .07? So it came very close, but it was in the opposite direction.
It was a 24 percent risk reduction about 1 in 1,000 as well. So when you had estrogen plus MP a, you had a, barely statistically significant, the p-value is 0.05. So it just hit statistical, significance, one in 1,000, cases for breast cancer and then you had one in a thousand cases but p-value of .07 for reduction of risk of breast cancer, which to me suggests that the MPAA, the synthetic progesterone was playing more of
Role than anything else. The second thing I point out is oral estrogen which we no longer use does increase coagula ability. 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 me.
Stations and things like Factor 5, 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 5 Leiden? You know, we don't typically
test people for Factor 5. My wife actually has it, but we didn't learn it until she had helped 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
were about
So your reflex nowadays is to put women on these topical,
estrogen therapy, basically have the discussion right now. So here's where we still struggle, right? Is, you know, we if it were up to me, I'd prefer for a woman's HRT to be provided by her GYN because we want to be able to work in partnership with the GYN who we would like to see an endometrial ultrasound done every year. That's you know, some would argue that's Overkill but you know, we think she be having a
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, under is, today we now realize that not all women can tolerate estrogen, pardon me progesterone. So you have to be careful. So assuming, again, a woman still has her uterus. The estrogen solves most of the problems, but then you have to decide, can she tolerate the progesterone? And it needs to be, if given systemically like 100 to 200 milligrams and for some women, that is a life-saving
Mention. 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 coded IUD. So then you get the local progesterone in the uterus for protection and the systemic estrogen.
Fascinating. What about oral contraception
For it in women. So the use of estrogen chronically through walls, you know college Years or twenties thirties. Maybe even teens, who knows what's known about the long-term effects? If any, I got
to be honest, I don't think I know enough to comment on it. It's not, it's not something that really impacts my patient population. You know, at least in what I see more women are using iuds for for, for contraception than OCS, I mean, we use OCS sometimes
In women who are premenopausal for symptomatic control, but will typically use like a low low estrogen. So a very low synthetic estrogen, which I don't like using these very much, but if it's the only thing that we can get to control certain symptoms and we'll use it like half her cycle but it's typically not something we're that experienced with.
What about testosterone because you mentioned that, you know, nanogram per Mill. When you said
Thing to the same, you know, I guess it's nanograms per deciliter. Is it would be to kind of normalize? Thank you for a mole, right? Yeah, and so yeah, that's what Peter has pointed out before is that you look at your charts and they're all in these different measures and so, when you normalized testosterone is actually the 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 in, you, prescribe them
testosterone when it comes to estrogen and testosterone and women don't have that data. And I'd
Love to see that trial done. So how what's the what's the Sweet Spot? How do we, how do we reconcile that? So it's not something I consider standard and basically if a woman is for testosterone, first of all is staggeringly low. And again, even though her testosterone is low compared to a male, we still have a range. So if it's really at the bottom of that range, she's really having difficulty putting on muscle mass and really complaining of low libido. I think in that situation will 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 hear things like that, like, those are real symptoms that you have to be aware of. But you know, like clitoral and large men, and things like that. Like, that doesn't happen under physiologic normal conditions.
Love to talk a little bit about hormone replacement.
In therapy in men when one looks on social media and the internet, there seems to be a younger and younger cohort of guys, people in their teens and 20s showing up to the table thinking that injecting testosterone sippy and a door. Taking anavar, whatever it is is going to be right idea. They're mainly seem to be focused on cosmetic effects. I'm not a physician, so I can't say whether or not they were actually have a gonadal, etc, but it seems to me you can correct me if I'm wrong, but it seems to me.
That similar to the atilla'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 etc, etc. 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 the sleeping, exercise, Social connections, Etc. So I do want to acknowledge that, but with that in mind, how do you think about? I'm perhaps, occasionally, prescribed 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 test, 300
DL. I think on the low end now in the u.s. all the way up to 900 or 12:00, 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 the range is you gay bar for total testosterone, of course, and we don't spend a lot of time. Looking at that, the way we used the way we, you know, I used to spend more time looking at total and free when I had
had 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 what it was a low dose of anavar in that context.
Ten milligrams, sub-link two to three times a
week and of are basically being DHT.
It oxandrolone, exactly, exactly. Exactly. And again, we're not recommending. This is actually if you're playing a competitive sport, can get you banned from that
Spirit. Yeah, you can
also get. You can also get you banned from having children if you do it
incorrectly. Yeah. So we're 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.
Testosterones. 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 one percent free, a guy should be about, two percent free tea, so that dude should be closer to 16 to 18.
A grams per deciliter. So in that situation that I just gave you, his shbg is really high, it's shbg is probably in the 80 to 90
range. That's very high because I think the upper range is somewhere around 55 56.
Exactly. So we would first box tall for what's driving is 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 sh
EG 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,
Goes up and if testosterone hasn't gone up with it, you're lowering free
testosterone. So, somebody who goes on a very low carbohydrate diet and attempt to drop some water and drum drop, some weight is going to increase their shbg after insulin goes lined up, testosterone less free testosterone. I can't, I could tell the carnivore diet. People are going to be coming after me with, with bone marrow in hand. But then again, that 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 the same as Westward. I also accept the opposite direction. So higher estradiol is higher shbg. So, again, occasionally, you'll see a guy with Incredible normal testosterone but he's a very high aromatase activity person. So he has a lot of the enzyme that converts testosterone into estrogen dial. 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 who's thyroid is out of whack, you have to fix that before you. If they're 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 this on the podcast. I feel like I've heard you talk about this on the podcast.
Yeah, there are few that will adjust it. You know, there is 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 Tonga Ali for reducing Edge hpg in. My experience, it does free up some testosterone by which mechanism, it isn't exactly clear and the effects aren't that good?
Yeah, right there, 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 motive of action. So we've talked about a few, the one that few years back people were claiming could reduce shbg was stinging, nettle, stinging nettle, I'll just urine seems to be covered urinating seems to be coming up multiple times on this podcast for whatever reason, stinging nettle abstract, I took the the most pronounced
Effective, that was you could basically urinate over a car and 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 by DHT sufficiently so that I stopped taking it. I do not like anything that impedes DHT, I don't care. If my hairline Retreats, I don't care about any of that. DHT to me is something to be avoided and held onto, because you feel so much better when you're
DHT is in the appropriate range and love your thoughts on that.
Yeah. I guess 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 I know can reduce, it are things like finasteride, Propecia, things like to write things too, 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 Etc.
But yeah. So I'm not aware of anything that can be taken in supplement form that can really profoundly
Dropout, 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, I mean, it was, I would drive patients nuts with the Whiteboard diagrams, I would draw for them when they and 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 trouble. You said, if you look at your total testosterone, you want the free to be about 2% of your village should be
somewhere. 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 one-and-a-half percent of it converted to free, I need to boost them. And that's why I don't care if he's outside the range. Like now, have a guy who's free tea, I might have to get a guy's total T up to 1500 to get his free tea to 18.
I see. So free. T is the target. I like to hear.
We treat. And do you still use antibiotics Alexandra, sorry to try and lower shbg. Do it because it's too potent now because it's just
too complicated for patients, you know, you know it's a it's a drug that can't be taken orally. So you have to take it under the tongue like Rocher some 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 and of ours and his liver function, and he was a, we're talking ten milligrams three times a week, is a tiny dose and three months of him or
Whatever, two months of him swallowing that everytime tripled his liver function tests. So it's like, it's just, I was like, you know, it's just not worth the hassle of doing this for, you know, perfection in reality, we can fix this another way. So, the first order question is, do we believe clinically you will benefit from normalizing? Your free testosterone or taking it to a level? That's call it 80th to 90th percentile. So upper normal limit of physiologic range
ages, 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 probably talked about this study and looking at insulin resistance and glucose, disposal with. And without testosterone in the evidence was overwhelmingly clear testosterone, improves glycemic control, testosterone, improves, insulin signaling, this shouldn't be surprising.
Thing by the way, given the role muscles play as a glucose Reservoir, glucose sing. 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 unit, compare some of these other things, but then you get into a little bit of the Vicious Cycle of will having a normalized testosterone, facilitate you doing those things better. So let's just assume we come to the decision that this person is a good candidate for testosterone replacement therapy.
The next question is, what's the method we're going to do it? Are we going to do it indirectly or directly now? We used to use a lot of Clomid in our practice. And have you talked about climate on the phone,
talk too much about it. I know we talked a little bit about the fact that some people taking things like Anastrozole to reduce aromatase activity, run 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 even fat accumulation. So if estrogen is too low, you'll you can develop adiposity in a way that you wouldn't otherwise there's a great New England Journal paper, probably 10 years old. Now that looked at thought I'd lose five different doses of testosterone sippy innate. So these men were chemically castrated and divided into ten groups. It's pretty remarkable.
Somebody setting 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 deciliter, not 30, or 50 percent of your of one's testosterone. Okay great. Okay, so we haven't talked,
Ahmed is no, we have not talked a lot about Clomid, I'd love to get your thoughts on common.
So clomiphene is a fertility drug. It's a synthetic hormone, it's actually, who drugs and 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 its oral and it's meant to be taken orally. So, you know, a typical starting dose would be like 50 milligrams, three times a week.
And if you do that, you'll notice in most men, especially young men FSH LH goes up in any man, the FSH and LH go up. But if a man still has testicular Reserve, he'll make lots of testosterone in response to that because that's the first order question, we're trying to answer is do you is your failure to make testosterone Central or
peripheral? Yeah, and I think just one point out again, correct me if I'm wrong, but my understanding is that a lot of the drugs that were talking about
On the synthetic compounds just tossed, her own estrogen things related to growth hormone etcetera, were discovered in 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, 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 that's missing without attention to where it's where the deficiency is, why this becomes relevant is. If you have a 35
Five year old guy, whose testosterone is low, but you can demonstrate that it slow because he's not getting enough of a signal from the pituitary. Why would you bother giving him more testosterone when he has the capacity? He has the latest cells in the sertoli cells to make testosterone. He just needs the signal. Sometimes they're not always just a course of Clomid can wake him up and he's he's back to making normal testosterone.
So he'll do this three times a week. 50 million, 50 milligrams, three times a week for a short course. And
they said we would do it for 8 to 12.
Of weeks and then we
reevaluate an 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 microdose. Has, I mean, you cannot pound people with Anastrozole, to give you perspective, the, the sort of
On label. Use like if you just go to a pharmacy in order, Anastrozole you're going to get one milligram tablets like we can't give anybody a milligram and they'll feel like garbage. We have to have a compounded at Point 1 mg and we might give a patient point. One, 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 mg per Mill, 1 Mill. 200 milligrams of testosterone once every two weeks and then hitting people with multiple.
Mg 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's kind of blows my mind that these trt clinics are up all over the place. Given how bad? I mean, I see the results because I have Nations 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.
Isis more frequently every other day, or twice a week dividing the dose and being very, very careful with these estrogen or Aroma taste blockers.
We most of our patients do not take aromatase Inhibitors. It's not needed, it's really only the high aromatize errs. That need it. And so yeah, when we'll talk about testosterone will talk about dosing there because I agree, the more frequently you can take it the better and run, frankly you don't need to go more frequently than twice a week because it's so stiff. Like yeah. The half-life of the drug is I think it's about three and a half days is the place.
Half-Life or something like that. Could be off a little bit, but, but twice, week dosing is really nice. So if you're, if you, if you go to like, you know, testosterone Clinic, that's giving you two hundred 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 to stickler, atrophy, that's enough.
To
suppress. Yeah, to maintain fertility. What do you typically do for
well? So this is where, so, I'll finish the story on Clomid because we currently do not use Clomid. And that's 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 sterile that we also happen to measure called Des master. All I'm not familiar with that. So in the, in the, in the way that cholesterol is made,
It's made by there's two Pathways that make cholesterol. So it starts like with, you know, to carbon subunits like acetylcholine and it kind of Marches On A pathway bifurcates and cholesterol is the finished product of both, but in one of those Pathways that the molecule right before, cholesterol is called does master all in the other pathway. It's called Le faster all. So we constantly measure with Oscar all and does master all 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 Des master all levels.
Now, the most obvious explanation for that, though. I 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 does master all into cholesterol, make sense. If you inhibit that enzyme you're going to see a rise in does master all
this wouldn't have been a concern to me if not for the fact that Tom Dayspring is 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 treat hypercholesterolemia was a drug that attacked the same enzyme
So this this 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 a s cvd is approved on the basis of it. Lowering cholesterol. That's not a high enough bar. You have to reduce events except is 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 close.
For always coming down events were going up. How could that be? We don't know what we are. Suspecting is that does Monster all which is still a sterile was potentially more damaging and created more oxidative stress in the endothelium in the sub endothelial space than cholesterol. I see which would at least suggest to us and again we're taking a lot of leaps here that may be having high does master all very high does Master. Rahl 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 if you accidentally knock over the little model it's basically gone bad. Yeah well with it is very
challenging, it's a needle, you know it's an injection Sub-Q, so easy to administer. It's not im or anything like that but it's just more of a hassle Factor. But that said,
It has the benefit that Clomid does which is it preserves testicular function. It preserves testicular volume. So you know, bodybuilders will often use this in their post Psychotherapy 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
reserved. So on its own, no testosterone, no aromatase inhibitor, nothing just a way to crank out a bit more testosterone from the testes may be some
additional action and also HCG is a different model.
HCG is just an analog of luteinizing hormone, so it's basically like giving them luteinizing
hormone, so it's going to crush in dodging us, luteinizing, hormone levels, right?
Because actually yeah and it, you don't really see much of an impact on LH, but you do see endogenous testosterone production go down. Actually, no, I correct that both FSH and LH will go down on a high enough dose.
Yep, just as a mention in here, I'm not making recommendations. But one supplement I've talked a lot about publicly is Fado G aggressiveness which is this weird.
Nigerian shrub. That that does put us on Tim's podcast on iTunes, podcast and Joe's podcast. And, you know, there was a bit of a backlash because it does turn out that at high doses. In rodent studies, it can cause some toxicity to the testes, but at lower doses, it does seem to increase luteinizing hormone and after talking about this, a number of people went out there, did pre and post blood work and they consistent effect seems to be an increase in luteinizing hormone. There's a noticeable effect on test testicular size and volume. So, a lot of people take this
Go, 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 Fado Gia whether or not needs to be
cycle. 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 FDI, the FDA has a lot of faults.
I think I have an entire podcast devoted to the corruption of the FDA and all of the mistakes that have been made with respect to their oversight in, especially generic drugs, but it's way more regulated than the wild wild west of nutty supplement
land. Absolutely. I think that the reason for talking about things like tongue got a dojo 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, sort of like the leap from. I
Focus very well to Ritalin right without a real diagnosis of ADHD to, oh well. Maybe some things like Alpha, GPC, low, doses of nicotine, right? But I agree entirely, I mean, the sourcing is important. The dosages are worked out empirically on an individual basis and there aren't randomized, controlled trials there just aren't.
Yeah. And and, you know, have kind of like a
Seven. This is another Peter Principle, right? So I'll get a lot of patients that come into the practice. And, you know, during our intake, we go through what drugs and supplements are you taking right now? And a lot of people come in, I'm not taking anything. Peter, I just you're in charge. Now like tell me what you think, and then you get a lot of people that come in and they're like, we're going to need an extra few pages for this part of the
documentation blue travel with a suitcase that you can hear as they walk through the airport and all the pills Rattle. And
so I give these patients a little homework exercise which is you have to answer these seven questions.
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,
why? No people and actually, we know some of the same people were
fanatic about like red light 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 Care Health and nail health is also kind of outrageous. Everything from college into red light therapies, which may actually have some
Because the in certain cases, but as an interest, there's a
fire there right now. 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 it makes sense, right? I mean it totally makes sense why the most potent gyro 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 because it's a key thing. I know that a lot of people are interested in female fertility out there including their male Partners, so going back to. So now I understand why you don't prescribe clomiphene because of this, this monster all potential. This monster all linked. What about testosterone therapy? So less cement frequent lower doses, less
Less or no estrogen inhibition or aromatisse, inhibition,
we only. And we're only using an aroma taste blocker and we use a room at X when we do. It's just, it's just to get that estradiol into the range, we want. I like to see it between 30 and 50, that, that 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
The side of being a little higher than a little low. So I never really want to be below 25. If unless it's sometimes it's just below 25 and it is it is what it is, that's fine. But 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 sippy innate is usually what we
use injectibles 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.
Can't control the dosage once it's in there. I know
the dose. Yeah, that's obviously a problem. But I don't think there's a big difference in 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 too.
Sums of pellets that are longer than my finger, so you're putting like a VA putting this, you're putting it into the gluteal fat. So, it's just, it's just a morbid procedure and I do mean it's necessary. I think if you, if you know how to manage it, you know, through through sort of the injections and now Cesaro pick. Yeah. Well especially now if you're doing, you know, we're having them do Sub-Q injections anyway so it's not IM, they're using a 5/8 inch to a 1-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
Needle. Phobes we use Z instead which is a pre-loaded
pain and are you having all men? Take HCG to maintain fertility and totally got it.
And by the way, we do not like to use trt and 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 to. Yeah, we just say why risk it like we'd rather use HCG just on its own. Yeah, just wait. Just wait till you're done. Reproducing Bank, sperm. Wait till you're done reproducing before we go to testosterone.
What are some of the benefits? And what are some of the cautionary notes with appropriate trt, meaning of the kind of Contour that we're talking about here, a lower dose with the yes or no low, estrogen control? People what it generally people report, how do they feel? What does 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?
Tension acne, those kinds of things are there. Some other things as well?
The dose is right. I mean, again, we're using these in really low doses. So, it's pretty rare that we have a patient on more than 100 mg a week of testosterone. I think for comparison like a bodybuilder, could easily take 500 to 1,000 during a high growth
phase? I know some of these guys, they go ballistic or they're doing moderate levels of testosterone sipping a, but they're also taking Dianabol oxandrolone, you know,
storms and a bunch of other things. I mean, their Stacks are kind of ridiculous. I mean, not no disrespect to that sport but I mean people that system like crazy in that Sports outside of physiology. Yeah, and I think for 99% of people listening, they just they look with a here bodybuilder and they just go like, why would somebody do that? Anyway, right. I think that's the typical with it. So
the point is a lot of but we owe those guys. A great deal of gratitude because they've shown us the boundaries including the women. That's right. Yeah, yeah. And so so so those those body builders
Have taught us a lot about, like what happens. And so, yeah, the 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 100 milligrams per week is a very low. I'll put my understand
physiologic do is I mean you're really but 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.
Probably ask you a question about maybe maybe, maybe 40,
I think that's great for people to hear because I know that a lot of guys in their 20s are thinking trt is the way to go. And I would argue less, you're doing everything else, right? And you're still hypokinetic, when you're really struggling put that, put that time off because also the fertility issue you want to delay
delivery. Well again, it depends if when we say trt, if you're in your 20s and there's no other way, I would, 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
G for 10 years, you are pituitary will
still work. You won't be able to make your own
luteinizing. Exactly. So it might be the case that you're going to need something Upstream of that like Clomid to kick, start it and then we're but again I don't want to I don't want anybody who's listening to this who's using Clomid for fertility to think that there's anything wrong with 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's Cycle on and off testosterone at these low dosages? Are they taking a month vacation from it?
Everyone totally depends. You know, talking to Patient yesterday where we're going to do, we just decided to change the cycle, eight weeks on than eight weeks, on HCG eight weeks on than 8 weeks on HCG. So that's going to be a cycle. That maintains his testosterone level. But fluctuates between endogenous, exogenous and endogenous or exogenous sometimes we'll just do testosterone on off on off.
And there. It's like, how much can he replenished naturally? But understanding his tea 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 animal, right? If you wanted could just drop a stitch PG, just the tiniest bit. It seems like one could adjust the free tea in a way that would be great. I don't know why that molecule so hard to Target but somebody ought to
To do it. The chemistry camping that I talked
with Patrick Arnold about this many, many years ago. I wish I could remember what his i.d. He had a comment about this that at the time made sense and I don't remember what it was because I had that thought to like man the 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 tea and the reason is ever since going on podcast and talking about this stuff and I'm on this
Just people will send me their numbers, they'll send me their charts, and then they'll send photos of themselves. And I can tell you while I'm not a clinician and I haven't done fancy statistics on it. There's very little correlation between someone's absolute testosterone and how they appear. I mean some of these guys look, really lean really strong. And they'll say, oh, total testosterone is 554 80, right? And then other people, you know, testosterone is 860 but they, you look at them and you think, oh, they kind of gavel, kind of a doughy.
Look to them. And so it's got to be this free testosterone, that was estrogen etcetera. Well so called
training training and nutrition tips, right? I mean, I just think, I think
For all this talk about testosterone, which I enjoy talking about and, you know, I've enjoyed talking about the data on, you know, long-term Health consequences of testosterone because there's another controversial topic. I also think people kind of overstate its importance, I agree and I think there's a, there's a, 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 not sort of, including when I was sort of a fanatical teenager, but as an adult, when was I at my absolute most?
Most insane physique like my best performance on a dexa. Scan would have been
30. It is 38 years old by dexa. I was 7% body fat. My fat free mass index was like twenty three point two twenty three point, three 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 might he's probably twice as high as it was then. So you know, now you could say, well Peter, what if you look 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
Wandering. 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 exoticness 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 first. 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 I think. Well, let me put it this way.
There are people that argue, I'm certainly not arguing. Yeah, there are people that argue that, if one eats a ton of saturated fat, that LDL goes up and
it's yellow and down. 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 synthesized enough cholesterol for hormone production, Etc. 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 those 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 in so far 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, and really pack cholesterol and would argue that doesn't matter if your LDL is, 870 does not going to impact your health. What's the reality around, LDL HDL, dietary cholesterol saturated fat, at least in your view.
So first, let's differentiate between cholesterol and fat just for the listener because we use them. So, you know, that I want to make sure people understand. So, so cholesterol is a, is a really complicated molecule. So it's a ringed molecule got. I used to know exactly what its structure was, but like, it could have thirty six 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.
It 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 will 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, blow up. All 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 does cholesterol. Can you get cholesterol in your diet? Yes, you can eat foods that are rich in cholesterol,
What was known in 1960 but somehow escaped everybody's imagination until finally, the American Heart Association acknowledge this a few years ago is that the cholesterol you eat? Does not really make it into your body and the reason for that is it's esterified. So we have and not to get too nerdy. But I think people I think, if I really think it's important, people understand how this thing works. So we have cells in our gut and enterocytes that 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. See one like one transporter, the second is called the atp-binding cassette G5 G 8. Okay, the niemann-pick see, one like one transporter will bring in any sterile cholesterol Zoo sterile phytosterols any sterile 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 deliver packages in bile and secretes. So that's what AIDS in our digestion, which is another thing I should have mentioned earlier, in addition to using cholesterol for cell membranes and hormones, we wouldn't be able to digest our food without cholesterol because it's what makes up the bile salts. So our own cholesterol is basically recirculated in a pool throughout our body and this is the way it gets back.
To the body, it's through this niemann-pick see one like one transport. 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 luminol 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.
The so all the cholesterol in our body is not esterified any, it doesn't have that big bulky side chain attached to it. The cholesterol you eat is esterified and and esterified cholesterol molecule simply can't physically pass through that. Niemann-pick see one like one transporter. Now, we probably manage to Dias terrify 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 bodies pool of cholesterol again. This was known even by ancel keys, the guy who turn fat into the biggest boogie man 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 with who are highly credentialed from good institutions claiming that eating saturated
fat. That'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 raise LDL cholesterol, so it's important to differentiate between the what is saturated fat. So saturated fat, of course, is a fatty acid. Just so people understand, totally different molecule from cholesterol. Cholesterol is very complicated, ring structure, multiple Rings stuck together. SFA saturated fat is just a long chain fatty acid that is fully saturated.
Meaning has no double bonds and it can exist in isolation. It can exist in a triglyceride try. So glyceride or a, you know, a phospholipid or all sorts of things like that. So when we eat foods that contain fat basically, there are three distinctions for that fat. Is it saturated? Is it monounsaturated one double bond? Or is it polyunsaturated, two or more? Double bonds.
The observation that eating saturated fat raises cholesterol is generally correct. But again, now it makes because if we're gonna start talking about LDL, we have to explain what LDL is. This is another one of those things. That's just so grossly, misunderstood that it'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 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 its water, plasma is water. So now you have this problem, which is I want to transport cargo. That is hydrophobic in hydrophilic medium. Can't do it.
So if you think about all the things that we transport in our blood sodium electrolytes, you know, 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 lipoprotein. So they have these. We have these spherical molecules that are lipid on the inside protein, on the outside lipoprotein. And inside they
contain cholesterol and triglycerides.
So now you've got the spherical thing triglyceride, cholesterol on the inside, and it's chaperoned by a hydrophilic. Molecule that allows it to move through our circulation and those lipoproteins exist in different densities. So, if you run these out on a gel electrophoresis plate, you'll identify different densities. The density is a function of how much protein and how much lipid is in it. So the highest density of this is called a high density lipoprotein and the lowest density of this is
The 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 idea an intermediate density lipoprotein.
so,
You know, it actually goes vldl, I dll deal. But anyway, so when people say, my LDL is, I or my LDL is 100. What are they saying? They're saying the cholesterol concentration of my LDL particles is 100 milligrams per deciliter, so the total cholesterol concentration you have in your circulation. Is that number that says total cholesterol. So if someone's blood panel, says my total cholesterol is 200. It means that if you take all the lipoproteins in their circulation,
Shannon, bust them open and measure the cholesterol content. It's 200 milligrams per deciliter and for all intents and purposes, because the ideals are so short-lived. That's basically the sum of your LDL cholesterol, your V LDL cholesterol, and your HDL cholesterol, those three things, some to your total cholesterol.
What about LDL little a that you mentioned early LP little a zealous. 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 April lipoprotein on it called a polite, but protein, little a, the other thing, I'll just say on this because earlier, I mentioned a poby, there are two broad families of lipoproteins there are, those that are wrapped in a bow BS and those that are wrapped in a bow. A ways, the, a Poe a family is the HDL family. The apob family is the vldl IDL LDL family.
So for somebody who
It's a their total cholesterol is. Let's just stay with 200. Your 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 a poby. 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 a levels of apob that are blank, you get really concerned
And what
the ratings on the person's objectives. So, again, we take a very different view. I mean, we have
Vitality now live to and I want to live to be 100. Yeah. So if you assuming some
tape, if you tell me you want to live to be 100, you're going to need to keep your apob below 30 milligrams per deciliter.
Let's say I want to live to be 100 but I also. Well how about I don't care how long I live but I want to feel great while I
live again, it depends.
Right, like anybody who's had a heart attack is going to be compromised in their ability, to feel well after, right? So
I guess I point, I make say that way because if you're going to tell me that I'm in order to achieve that live to 100 level, I'm going to have to give up my personal life and my no, no, it might be getting functioning than I'm not really
interested. Sure. But take to get LDL levels and really again, people think of it as LDL. It's really a poby right? A bobi is this total concentration of LDL and vldl
LDL and that's what matters. Those are the big atherogenic. Particles LDL also includes the the lp little a, although the concentration of LP little a is relatively speaking so small that it doesn't generally show up as much in the apob. So we treat a poby and basically what it comes down to is you want a poby 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
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 dying in Iraq and Afghanistan. And we saw without any ambiguity, the cardiovascular disease is already taking hold in people who are 18 19, 20 years old. And to be clear, they aren't going to die of atherosclerosis at that.
At 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 a poby reaches a certain threshold and that's the threshold that most of us get to by the time were you know 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 out the risk LaRosa's. So apob is necessary but not sufficient to develop a scpd.
Now the go
ahead 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 a poby.
Well, nutritionally you basically have two big pools 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 a poby. So so you have to be able to think about it. So, so, in an ideal world, it's can you lower saturated fat, which tends to be the one that is most driving a poby while lowering carbohydrate and then see what you can get. But here's the reality of it is there's nobody with dietary intervention. That's going to get to a level of 30 milligrams per deciliter. I mean, I've never
seen any other dietary intervention. Yeah. So what are the other things going to be pharmacologic at this
point Staton type interventions have multiple classes of drugs so the
Tried and true is the Staten. So statins, work by inhibiting cholesterol synthesis and the net effect of that is that the so the liver is really sensitive to cholesterol levels. It doesn't want too much. It doesn't want too little when you inhibit cholesterol synthesis, the liver says, I want more cholesterol so it puts more LDL receptors on its surface and it pulls the LDL out of circulation, that's what lowers the LDL in the circulation. So again,
Nine statins in use today. We typically use four of them side effect profile. Contrary to kind of all the sort of Statin hating propaganda out there very benign, right? 5% of people experience muscle soreness, which reverses upon cessation, you know
cognitive effects.
Again, I think it's very in terms of actual. Comparing it at a placebo, no effect whatsoever, right? So does that mean that you put a patient on it? They won't complain if 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 this there's a very nuanced case we make entry which is we'll look at patients with highly suppressed as master all levels. We will back off. We do want to maintain does master all above a certain level because of some evidence that is still. I think very preliminary but enough for
Russ that we say, why? Take the chance we have so many other ghouls 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 that remember that niemann-pick see one like one transporter. So that guy has a drug called ezetimibe that just mechanically blocks it.
So in people, and that's why I mentioned earlier, we meant when we measure all those sterols and 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 is that Ahmad next class of drugs, is a drug that blocks cholesterol synthesis but only in the liver. So the Statin does it globally? The this other drug called Benedict 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, Bend pandemic acid, and lactic 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 cholesterol, cholesterol level is 300, their LDL cholesterol is typically you know, north of 200 milligrams per deciliter. This is a disease that is defined by the phenotype, not the genotype. So the phenotype has a very clear definition, which I basically just gave you. The genotype is there's a million paths to get there. There's over 3,000.
That are known to produce that phenotype. This was discovered to be one of them in people who had hyper functioning PCI a PCS K 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 nineteen. 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 APO be 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 hypo functioning pcsk9. And so that was 2006. And we won 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
often it's in combinations. And I would say 80%, we 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, it's like cardiovascular. And and I like how close is it? So the last year before covid covid kind of messes up these numbers little bit but if you go to 2,000 1918
point, six million people died of heart disease. Number two, cancer, 10 million like like nothing is in the zip code of atherosclerosis. And if you remember what I just said, if you, if you had, if you took everybody in their 20s and reduced them to a level of that of a child, you'd make a SC b d, an orphan disease.
So to the question who you more, why don't we hear more about this? I realized there's some Nuance, it's not straightforward, it's not as simple as saying. Eat less cheese, red meat and and watch your LDL get on a Statin. But why do we hear so little about a poby in the general discussion, I'm not social me is such a skewed landscape, as we know people shouting into tunnels of varying Clarity, you know, some are beautiful.
Ron's tunnels with clean walls and others are sewer lines, right? And they all converge in the same place, 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 a bow be specifically. I'm guessing my physician did. But why don't we hear more about this? This is the sounds. So important. Sounds like the most important conversation because all the hormones stuff and all this stuff about
out, 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 the end, there's a whole chapter in my book, I'm working on that really gets to this problem of why 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 a scpd 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. 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
but the the Paradigm is, when you're ten year risk reaches five percent and 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 seventy-year-old with perfect lipids and perfect blood pressure and perfect everything, their 10-year risk of a s cvd is probably four to five times higher than the most unhealthy thirty-year-old. It's not even
close is a lot like eye disease, you know?
There are exceptions. Of course. We always say that the biggest risk factor for going blind from glaucoma is being an older person.
Frankly,
you know? And 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 and say, wait, if maybe being in the sun without sun glasses or, you know, using this type of I drop or something like that. Has a negative impact, I'd rather know that sooner. So that's the fundamental difference. It's a philosophical difference with respect.
Backed 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 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
Which is peptides and stem cells in 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 we have to show you a really thoughtful. And I really appreciate that. You're willing to share your own tissue Rehabilitation experience. And point people that because this is a landscape that a lot of people are in and they don't know how to navigate it and a mutual friend of ours, not to be named, send me a text and said, I'm going to be talking to a TIA. And what do you know about studies on things like bpc?
E 157 is gastric peptide, that anecdotally again. Anecdotally people report, getting injections of this into shoulder, knee etcetera, 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 someone tells you they're a lot of stem cells in them, they're lying, they're not allowed stem cells and them and you here also, here about stem cells which are not FDA approved, at least in this, you know,
For most uses in this country. But are certainly, people are flying down to Columbia and getting injections. And what is your understanding or experience with things like bpc 157 specifically? Because peptides is a huge landscape. We should probably do a whole episode of peptides things like PRP or PRP is now approved for, I mean, women are getting Jackson's of this into their ovaries to improve follicle count. We know this people are getting injections of PRP into every tissue and organ and help men are getting injected in their penis. So I
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?
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 is an example, right? I'm a huge proponent of rapamycin and you can say, well, Peter, how can you take or prescribed rapamycin for gyro 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 that you did, they just can't be compared now. I have no idea if stem cells work. I have no idea if PPC 157 works, I have no idea. Frankly, if PRP even works though, it might seem to have some efficacy in 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? There's an injury, you know? I this this injury was actually probably
the greatest source of discomfort. I had swimming the Catalina channel the last time in 2009. So that's the 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 know.
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, a lot of reasons that might make you feel better. Just like there are a bunch of reasons you can feel better if somebody inject 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 1000 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 did a complete labral tear.
Are there some injuries that might benefit from it? Yeah, possible. So the question is, how would you design the trial to narrow down your patient population correctly? So that you might see a signal because the other risk of doing a trial, is, you have too much of a heterogeneous patient population. It's, 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 ten percent
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 legitimised 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
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
if I just like wise, join you. Because that would be yesterday, we recorded a sit-down with somebody from Caltech who works on aggression and rage and think 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 onto 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 ten-foot pole. Hopefully, someone listening to this will be incentivized to provide this sort of venue for that.
The kind of work that we're talking about.
I have to
ask but I want to make one other point injury, which is to me the problem with a lot of these things. Is it gets it's a crutch, you know, it's early. But we talked about with like, hey, just fix my team 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.
If I've learned anything through my shoulder surgery, and I'm now three and a half months out, how's it feel? Amazing. I mean, look, I still can't do a lot of stuff. It's going to be, you know, a while, I haven't even been able to shoot a bow yet and it'll probably be a year before I'll go back to, you know, long-dead hangs and heavy deadlifts. I mean, I don't know, maybe nine months but it's, you know, I'm not there yet. But what I learned through a really amazing prehab and Rehab process is
Like, you just got to do the work. And it's freaking hard. Shoulders are the most tedious boring thing in the world. I mean, three days a week I am doing for four days a week. I am doing one hour of just dedicated stuff for this shoulder. That is super disc 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. 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 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 asked 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 metabolomic School talking about this before we sat down to record, what, what is what are metabolomic speech? 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 metabolomic 60.
All and for those that are sure they could learn more. So tell us about metabolomic sand. What you'd like to see more of in the world of
metabolomic Soo. Mix 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 so metabolomic Siz just study of metabolites and metabolites unlike a lot of these other things. There are relatively finite number of these things, many of which are known, but some of which are not
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.
A verbal phenotype imaginable. So, if you want to take a genomics approach to understanding that you might look at, is there a change in the genome when you exercise? The answer is probably not but maybe maybe if you looked at the, you know, 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 there? You would see a lot of changes. Well, what I don't think people are really understanding.
Oh, there's a very interesting paper that just came out two weeks ago. That looks for novel metabolites that are changing as 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 metabolomic should be. Can you find pill?
Mimic exercise. And I think the answer that question is going to be undoubtedly, know, for a couple 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 metabolomic.
This is, you know, relatively untapped and and I think you know 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
some mitral valve prolapse, it
was an MVP. Yet was something in the mitral valve. Yeah, I think the chordae tendineae were ruptured.
During and the mitral valve and and it was mostly young women. I think we're getting, you know, horrible pulmonary diseases, 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 use 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, who want to do over, but we're going to do it with the right version. So it's a tragic outcome.
But but you're absolutely right. I think the glp-1 agonists are have more efficacy and you know, for all intensity and for everything we can see, certainly seemed
safer. Are you excited about them?
Yeah, I am. Yeah. I mean I think I think we're just seeing the kind of tip of the iceberg. They're not they're not Miracle drugs, right? They come with problems right which is you know they're they're they're catabolic across the board so patients are losing fat but they're losing muscle as well. So you
know you sent all the the
Jim jockeys running from some, a glutton and Tall. 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 nails. And that's like people, it could extend life to being 250 years old and people are gone. Humans are humans. That's a that's a neuroscience and psychology issue. Not a not a biology medicine issue but I'm pleased to hear that you're excited by them because I hear a lot of excitement. Yeah I haven't heard anything disastrous.
Out them,
it takes a while to get people up to do. So if you're looking at some Igloo tied, the dose that was studied. So there are 1 year trial or maybe it was a little over that maybe 60 weeks, but it took about 16 weeks to get the patient's comfortably up to 2.4 mg 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 mg. We can usually get enough benefit between 1 and 2 mg, and we usually move people along a little bit quicker, but we've definitely had our
A 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 effective of semi glue Titus 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 distension in some ways, they're sort of make people feel full through.
Motion of literally mechanoreceptors that make people feel as if their stomach is distended, even though their stomach is empty and then, perhaps some Central hypothalamic effects
is that? Yeah, I think it's doing, I would bet 80% of its 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 some
My glute, I'd you're going to see a weight regain. So there's newer versions that seemed to preserve the weight loss even off the drug. So it begs the ultimate question which is like, what's the What's the total use case for this going to be, is this going to be a drug use 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 tacky for lactic? Will they gain, you know, a resistance to it. So it's still super early days on these
things. My hope is that it would be a little bit like the way that you described testosterone and estrogen therapies that it would allow people to do more of the behavior.
A real work. That's absolutely required for health spending last minute.
Yep. And we've also seen in the flip side of that, you can cheat through some Igloo type, right? People who, you know, 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. Like 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 in our with our patients, but we've seen that that's it's easier to get around the benefits of the drug, that way.
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.
Mission 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 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 the will certainly have you on here, again, in anticipation of that. But I
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 podcast and going on podcast. 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 Atia, all about the things that we can do in order to maximize our lifespan and healthspan. I highly recommend people check out dr. Arati as podcast, the drive is excellent as you can imagine. Based on today's conversation
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