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

welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday [Music] life I'm Andrew huberman and I'm a professor of neurobiology and Opthalmology at Stanford school of medicine today my guest is Dr Peter AA Dr AA is a physician who's focused on nutritional supplementation based behavioral prescription drug and other interventions that promote Health span and lifespan his expertise spans from exercise physiology to sleep physiology emotional and mental health and pharmacology today we talk about all those areas of Health starting with the very Basics such as how to evaluate one's own health status and how to define one's Health trajectory we also talk about the various sorts of interventions that one can take in order to optimize Vitality while also extending longevity that is lifespan Dr AA is uniquely qualified to focus on the complete depth and breadth of topics that we cover and indeed these are the same topics that he works with his patients on in his Clinic every day Dr AA 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 John's Hopkins Hospital in general surgery one of the Premier hospitals in the world where he was the recipient of several prestigious Awards including resident of the year he's been an author on comprehensive reviews of general surgery he spent two years at the National Institutes of Health as a Surgical Oncology fellow at the National Cancer Institute where his work focused on immune-based therapies for melanoma in the fields of science and medicine It is Well understood that we are much the product of our mentors and the mentoring we receive Dr AA has trained with some of the best and most Innovative lipidologists endocrinologist gynecologist sleep physiologists and Longevity scientists in the United States and Canada so the expertise that funnels through him and that he shares with us today is really harnessed from the best of the best and his extensive training and expertise by the end of today's episode you will have answers to important basic questions such as should you have blood work how often should you do blood work what specific things should you be looking for on that blood work that are either counterintuitive or not often discussed and yet that immediately and in the long term influence your lifespan and health span we talk about Hormone Health and hormone therapies for both men and women we talk about drug therapies that can influence the mind as well as the body and of course we talk about supplementation nutrition exercise and predictors of lifespan and healthspan it is an episode rich with information for some of you you may want to get out a pen and paper in order to take notes for others of you that learn better simply by listening just want to remind you that we have timestamped all this information so that you can go back to the specific topics most of interest to you I'm pleased to announce that the hubman Lab podcast is now partnered with momentus supplements we partnered with momentus for several important reasons first of all they ship intern nationally because we know that many of you are located outside of the United States second of all and perhaps most important the quality of their supplements is second to none both in terms of Purity and precision of the amounts of the ingredients third we've really emphasized supplements that are single ingredient supplements and that are supplied in dosages that allow you to build a supplementation protocol that's optimized for cost that's optimized for Effectiveness and that you can add things and remove things from your protocol in a way that's really system itic and scientific if you'd like to see the supplements that we partner with momentus on you can go to live.com huberman there you'll see those supplements and just keep in mind that we are constantly expanding the library of supplements available through momentus on a regular basis again that's li.com huberman before we begin I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford it is however part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme I i' like to thank the sponsors of today's podcast our first sponsor is thesis thesis makes custom neut Tropics that are designed for your unique needs to be honest I'm not a fan of the word neut tropics because neut Tropics means smart drugs and to be honest there is no such thing as a smart drug because there's no neural circuit for being smart there are neural circuits rather for being creative or for task switching or for focus and as we all know different sorts of Demands whether or not they are cognitive or physical require different types of cognitive and physical abilities thesis understands this and has 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to your unique sleep needs I've talked over and over again on this podcast and on another podcasts about the fact that sleep is the foundation of mental health physical health and performance there's just simply no other substitute for a quality night's sleep on a regular basis I've been sleeping on a helix mattress for well over a year now and it's the best sleep that I've ever had and that's in large part because the mattress was designed for me what you need to know however is what's the ideal mattress for you and you can do that by going to Helix site you can take their brief quiz which will ask you do you sleep on your side your back your stomach or maybe you don't know or maybe all three do you tend to run hot or cold in the night maybe you know maybe you don't at the end of that short quiz they will match you to the ideal mattress for you I match to the dusk the Duss mattress but again that's what I need that's not necessarily what you need in order to get your best night's sleep but if you're interested in upgrading your mattress go to helixsleep.com huberman take their two-minute sleep quiz and they'll match you to a customized mattress for you and you'll get up to $200 off any mattress order and two free pillows they have terrific pillows and you get to try out that mattress for 100 nights risk-free they'll even pick it up for you if you don't love it but I'm certain you will again if you're interested in you go to helixsleep.com huberman for up to $200 off your mattress order and two free pillows and now for my discussion with Dr Peter AA Peter thanks for joining me today thanks for having me man been looking forward to this for a very long time that's I I'm a huge fan of your podcast I know that you went to Stanford and worked with a number of people that are colleagues of mine so for me this is already a thrill just to just to be doing this yeah likewise I have a ton of questions uh but I want to start off with something that I wonder a lot about and that I know many other people wonder about which is how to assess their current health and their trajectory in terms of health and 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 how often do you get blood work done Etc yeah there's a lot there I mean the way I talk about this with patients is first taking everything back to the objective so what what what's the what's the what's the thing we're trying to optimize so if if a person says look I'm I'm trying to break 10 hours for an Iron Man I don't know that blood work is going to be a gamechanging aspect of their trajectory and their training you know they're going to Bene benefit much more from sort of functional analyses of performance so I'm assuming based on the question that you're really coming at this through the lens of living longer and living better through the lifespan Health span 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 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 it's it's pretty binary you're alive or you're not alive you're respiring or you're not you make ATP or you don't end of story so um what gets in the way of lifespan is essentially The Four Horsemen of disease right so atherosclerotic disease cancer neurodegenerative disease and metabolic disease which directly isn't the cause of many deaths but you know be basically creates the foundation to all of those other diseases um 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 atherosclerotic standpoint it's a very good predictor of risk if you know what to look for uh so primarily apob would be the single most important um lipoprotein that we care about I I can explain what that means in a second um and then also you know other markers of inflammation endothelial Health um 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 uh it's 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 epid epidemiologically we say obesity drives it what what it really means is metabolic poor health it's probably the hyperinsulinemia that comes with obesity that drives it so biomarkers help with that but there's still an enormous blind spot to cancer we could talk about liquid biopsies aside because those aren't really biomarker studies but put that away on the neurodegenerative side you know I don't think we have a lot of insight that comes to understanding Parkinson's disease but when it comes to dementia particularly Alzheimer's disease which is the most prevalent form of dementia I think the biomarkers can be quite helpful they overlap a lot with the atherosclerotic diseases so the same things that you know Drive the risk of heart disease are driving D driving the risk of dementia um and then there's some novel stuff as well if you include genetic testing which you can get out of a blood test we get a whole Suite of genes not just apoe but far more you know Nuance stuff than that that can also play a role so you can stratify risk in that sense so in aggregate I would say you know blood testing with biomarkers provides pretty good insight into lifespan when you get into Health span you have kind of the cognitive physical emotional domains I think here the 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 um are in line with the same things that you would do to reduce the risk of dementia so all the biomarkers that you would look to improve through dementia risk reduction you would be improving through cognitive Health on the physical side I mean outside of looking at hormone levels and which we look at extensively and understanding how those might um Aid in or prevent some of the metrics that matter it really is this is a biomarker aside thing I mean I'd be much more interested in a person's dexa cpet testing V2 max testing you know Zone 2 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 those other stuff matters right if you're a totally miserable human being your relationships suck I don't think any of this other stuff matters uh 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 or do you try and assess emotional state indirectly when you do an intake with one of your patients um probably not so much in the intake because I think it takes a while to form a relationship with a patient before that starts to become something that they're necessarily going to want to talk with you about but I definitely think of it as an important part of what we do and I think without it none of this other stuff really matters again the irony of thinking about how many years I spent sort of in pursuit of fully optimizing every detail of everything without any attention being paid to that Dimension is not lost on me and and look there are some patients who they that's just not something that that's something that's compartmentalized maybe they're you know they're doing well in that department or maybe they aren't but they just aren't willing to engage on that yet in terms of frequency of blood testing uh if somebody feels pretty good um and is taking a number of steps exercise nutrition Etc to try and extend lifespan and improve healthspan um is once a year frequent enough um and should a 20-year-old start getting blood work done just to get a window into what's going on assuming that they can afford it or their insurance can cover it yeah I mean look I I 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 littlea so unfortunately most Physicians don't know what LPA is and yet you know somewhere between 8 and 12% of the population has a high enough and depending on who you you know uh I had a recent guest on my podcast who suggested it could be as high as 20% have a high enough LP little a that it is contributing to atherosclerosis so to not want to know that when it's genetically determined right this is something that you know you're you're born with this and you only need to really check it once why we wouldn't want to know that in a 20-year-old when it can contribute to a lot of the early atherosclerosis we see in people uh 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 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 um you know a blood test is for the most part a static intervention uh it's a it's a it's a it's a look at a window in time and 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 there to to now check like hey you know we we gave this drug did it have the desired outcome um you know you put on three pounds of muscle and lost three pounds of fat did it have the desired outcome um speaking of tracking weight and um fat lean mass percentages is that something that you recommend your patients to pretty often I know people that step on the scale every day I know people like myself that frankly might step on the scale three times a year I don't really care I care I pay attention to other things that are far more subjective maybe I'm making a huge mistake what are your thoughts about um quantitative measurements of weight uh BMI uh for the typical person I think they're pretty crude um I think aexa I I'd rather take aexa annually um and then maybe follow weight a little bit more closely to get a sense of it and so with a dexa you're getting at least the way we look at the data four pieces of information now most people when they do aexa should I explain what that is I'm yeah I think some people might not know what dexa is I in fact I confess I have a crude understanding of what it is um my tell me of where I'm wrong and um hopefully where I'm part at least partially right my understanding is that there are a number of different ways to measure lean mass to non-lean mass ratio and there's one where they put you underwater there's one where they put you into some sort of non underwater chamber there's caliper Y and then there's the um looking in the mirror and and um pinching and and uh changing the lighting you know it's funny when if 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 six-pack or how bad the six-pack is what the leanness is and that's that's actually not a terrible uh way to do it there you know a bodybuilder 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 ABS um but basically a dexa scan is an x-ray um 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 there the denser the medium that the electrons are trying to go through uh the less of them that are collected so when you look at an x-ray as everybody's probably seen an x-ray that which is white is most dense so if you had you know a piece of metal in your pocket it would show up as a bright white thing that's why ribs and Bones show up as white and the things that are the least dense like the lungs where it's just air are the blackest and everything is a shade of gray in between so adexa 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 deck so 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 abjectly horrible we we've created our own templates so we have our own dashboard for how we do this because we've just given up on trying to use theirs but the first thing most people look at is what's my body fat and this is the gold standard outside of like MRI or something that's only used for research purposes so so adexa is going to produce a far better estimate of of body fat than calipers or uh buoyancy testing or things like that provided the Machinery is well calibrated and the operator knows how to use it um 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 offthe shelf Tech you know dexa is amazing you know of the four things that get spit out of the dexa we think that the body fat is the least interesting and so I would rank that as fourth on the list of what's gerine to your health the other three things that you get spit out are bone mineral density uh visceral fat and then the metrics that allow you to comput uh like to basically compute what's called appendicular lean mass index and fat-free mass index and so those three metrics are significantly more important than body fat and um the reason is as follows right so so bone mineral density basically speaks to your risk of osteoporosis um and osteopenia um and that doesn't sound very sexy to people our age you know 50-year-old guys listening to this it's like yeah big deal but for a 50-year-old woman this is a huge deal right a woman who's just about to go through menopause or has just gone through menopause is at an enormous risk for osteopenia and 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 of um Bones Work and why estrogen specifically is 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 oneyear morbidity is about 30 to 40% which again just to put that in English if you're 65 or older you fall and break your hip there's a 30 to 40% chance you're dead in a year wow bones matter um so we want to really get a sense of where you stack up for your age for your sex and if you're anywhere off the pace we have to ramp up our strategy and be super aggressive about how to increase that or at a minimum prevent any further Decay and are there age related charts for these sorts of things yeah this is this all gets spit out into what's called a zcore so when you're looking at your bmd it's going to give you a zcore so a zcore of zero means uh and you understand this but it's like it's zcore referring to a probability distribution in a standard mode so zcore of zero it means you're at the 50th percentile for your age in sex as ccore of plus one you're one standard deviation above minus one below Etc um there's also a t-core which is doing the same thing but comparing you to a young person and so the t-core is technically used to make the diagnosis of osteop osteoporosis we we tend to look more at the zcore and basically say look if your zcore right now is minus one in four years I want your zcore to be zero not necessarily because you've increased that entire way but maybe you've increased slightly while it's expected that you would have declined I see what are some things that we can do to improve bone mineral density at any age so it turns out there's a real critical window in which we are malleable so depending on the age at which someone's listening to us discuss this um you know if you're if you're under 2025 you are still in that time of your life when you are able to reach your potential so um 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 oh 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 was probably the best thing you could do um and I think once you understand how Bones Work it became more clear which is you know powerlifting is really putting more of a sheer force from the muscle via the tendon onto the bone and that's what the bones are really sensing they're sensing that sheer force that's being applied through the bone in in a compressive way depending on the bone of course and that's what's basically activating the osteoblasts which are the cells that are you know allowing bone to be built so it's this is this turns out to be probably more important for females um 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 inh inhaled steroids during that period of their life because let's say they had really bad asthma or patients who needed large amounts of corticosteroids for some other immune related condition so during their critical window of development they were taking a drug that was impairing this process so you know we have some patients like that in our practice and that's you know just an enormous liability that we're working really hard to overcome you know with nutrition with hormones with drugs with training um and you know it's you know it's just something you have to be aware of I wasn't aware that um inhalence uh for asthma and things of that sort can impair bone mineral density yeah they're steroid based some of them of course are just beta agonists and they're fine so anything corticosterone like yep interesting and then I always get asked this question and I I always reflexively want to say no but I don't really know the answer so I don't reply what about topical um corticosterone you know people put cortisone cream to me it seems almost inconceivable that it would have a systemic effect but then again what do I know it's all it's all dose and it's all dose and 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 um but but certainly with enough of it put on I mean it is absorbed so um it could be an issue but that's not typically what we're concerned with I mean we're mostly concerned with people that are you know taking even modest amounts of prazone for months years at a time um 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's on a steroid inhaler they shouldn't be you have to solve the most important problem and if asthma is the most important problem so be it I think you just want to turn that into okay well how much more imperative is it that our kid is doing things that are putting a high amount of stress on their bones and Via their muscles to make sure that they're in that maximal capacity to build do you think that somebody in their 30s or 40s or 50s could still benefit from strength training in terms of bone mineral density and Longevity um as it relates to Bone mineral density um given that there's this of key window earlier they might have missed that window oh yeah no no this is essential for the rest of life because you're now trying to prevent the fall off so so basically the way it works is you you're sort of from from birth to say 20 you're on you're in growth from 20 to 50 you plateau at 50 Men start to decline but it's really small women start to decline and it's precipitous and it's related to the drop in estrogen associated with menopause or premenopause correct and and can we get into any of the broad uh Contours of of what that strength training looks like we had Dr Andy Galpin on the show he talked a lot about ways to build strength versus hypertrophy versus endurance Etc I think there's pretty good agreement across the fields of you know Physiotherapy Etc physiology and and Medicine in terms of how to do that but my understanding is fairly low repetition ranges so this is anywhere from 1 to six repetitions typically not aiming for you know a pump hypertrophy that sort of thing but heavy loads that are hard to move 80% of one repetition maximum or more done with long rest periods um three two to you know three times a week type thing is that about right yeah if you if you look at the literature on this it's going to tell you if 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 lift weights in her life who we now have to get lifting I mean we could get her to deadlift but I I 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 um you know it's not as pure a movement as a deadlift but who cares right we can still put her at a heavy load for her and do so safely so um now that said I mean there was a study that was done in Australia um 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 results I could send it to you after and it's it's just amazing they took a group of you know older women they looked like they were 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 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 ke up off the ground I mean just staggering sums of weight for these women who have never done anything and their bone health is improving at this age so um 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 um 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 instance um let's say that well my mother is in her late 70s um she actually used to be really strong when we were kids she could move this fish tank that was in my room long before I could move it and um always she's really strong over the years um 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 are the effects all local meaning if she were to just train her legs or just do push-ups um would it only be the loads applied to the limbs and and muscles and tissues I think that's where the bulk of it is yeah 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 and the lumbar spine so um you know that's just the convention by which we make the diagnosis and and I think part of that has to do with that's where the majority of the insults occur now not all of the insults I've seen people that have you know because of horrible bone density they're they're you know they're fracturing ankles and tibia fibula like they're having low tib fib fractures just walking um 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 so this is a systemic issue um but the majority of the response is a local response because it really comes down to putting a load directly on that bone and then having that bone in kind respond by laying down more bone before we continue with today's discussion i' like to just briefly acknowledge our sponsor athletic greens now called ag1 athletic greens AKA ag1 is an all-in-one vitamin mineral probiotic drink that also has adaptogens and digestive enzymes I've been taking athletic greens since way back in 2012 so I'm delighted that they're sponsoring the podcast the reason I started taking athletic greens and the reason I still drink athletic greens twice a day is that it supplies total foundational coverage of my vitamin mineral needs and IT Supplies important nutrients that I need to support my gut microbiome the gut microbiome as many of you know supports the immune system it also supports the so-called gut brain axis which is vital for mood for energy levels for regulating focus and many other features of our mental health and physical health that impact our daily performance and high performance in any Endeavors we might be involved in if you'd like to try athletic greens you can go to athletic greens.com huberman and claim a special offer they're giving away five free travel packs plus a year supply of vitamin D3 K2 with every order and of course vitamin D3 K2 are 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 um health related effects of just having weak bones that are not just about falling and breaking a bone and dying a year later even that's obviously very severe um because I think when people hear about that some people might think well I'll just be more careful I'll just move more slowly I'll sit in a wheelchair if I need to if um even though I might be able to walk if it keeps me from falling some people I think adopt that mentality what are some of the benefits of having um 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 you have to sort of be able to articulate what it is you want in your marginal decade so we we use this thing in our practice called the marginal decade marginal decade is the last decade of your life so everyone will have a marginal decade that's the only thing I can tell you with absolute certainty right I believe you there's no immortality there's no hidden Elixir that's going to help us live to be you know whatever I mean we're all going to be in our last decade at some point um and outside of people who die suddenly or through an accident um 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 um lay out what their marginal decade should look like wow that's a serious exercise it's a very serious exercise right like what tell me everything that is going to happen in your marginal decade I don't know when it's going to be Andrew it could be 87 to 97 if we're doing well right it might be 79 to 89 I don't know but I I you know it would really be an 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 it is that they want to be doing in that last decade you can't design a program to get them there I mean think about it you know someone wants to do an Iron Man we take it for granted that we know what the objective is I have to be able to swim two and a half miles I have to be able to get out take my 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 Andrew I'm going to have you do an athletic event in a year start training I'm not g to tell you what it is right just do it right could be playing basketball you know it could be swimming to Catalina Island it could be running a 100 miles you wouldn't be able to do it so similarly if we don't know what our marginal decade is meant to be there's no way to train for it do you think this is a good exercise for anyone and everyone to do on their own regardless of age here I'm hearing this thinking I need to think about when my last decade might be and what I want that to look like absolutely I mean when I say we do it with our patients that's only because that's the population I work with but there's simply no reason everybody shouldn't be going through this exercise and then you you sort of back script from there figure out what people should be doing given their current health status exactly right we call it backcasting so the first step we do is once we've really delineated what the objective function looks like we then say okay how do you break down that into uh metrics that we can measure so you know you described doing a whole bunch of things okay just to let you know to do that will require a V2 Max of 30 milliliters of oxygen per minute per kilogram and the person will say okay what does that mean we'll say well that's a measure of your maximal uptake of oxygen and that declines at about 8% to 10% per decade so if you have to be at 30 and let's just assume you're going to be doing that at 90 so what do you need to be at 80 70 60 50 okay here's what it would need to be at 50 okay what are you now ah there's a big gap you're below where you need to be now so you're obviously higher than 30 now but if you're only at 42 now and you need to be at 30 and 40 years you're not going to cut it you have to be a lot fitter okay now let's do the same exercise around strength and stability and without exception most people when they do this exercise will find out they're well below where they need to be so the gravity of Aging is more vicious Than People realize and therefore the height of your glider needs to be much higher than you think it is when you're our age if you want to be able to do the things we probably want to be able to do when we're 90 I absolutely love this approach I've never done it in terms of my health I've always thought about what I want to accomplish in the next three to six months or next year or so and by the way that's a great approach that's forecasting forecasting is fantastic forecasting is really good at short-term things it doesn't work for long-term things long-term you have to do backcasting this backcasting approach really appeals to me because in my career well I never anticipate oop excuse me I never anticipated I'd be podcasting um but that that's what I did at some point as an undergraduate I look professors I that looks like a pretty good life they seem pretty happy I talked to a few of them and then I figured out what I need to do at each stage in order to get to that next rung on the ladder and just kind of figured it out in uh in a backcasting kind of way you refer to it uh I think this is incredibly useful because it puts all the questions about blood work and how often to get blood work and what to measure in in a really nice context that's highly individualized I've never heard of this before so um and I should give a nod to Annie Duke I used to always refer to this is reverse engineering but in Annie Duke's book she wrote about this exact thing and called it backcasting and I was like I like the term backcasting better it I think it's more intuitive than reverse engineering yeah there's a Real Genius to it and I think it because it sets so many things into the appropriate bins and trajectories I've heard you talk before about some of the Prime movers for longevity and allrisk morality um and I'd love for you to review a little bit of that for us um I think we all know that we shouldn't smoke because it's very likely that we'll die earlier if we smoke nicotine uh I'm neither a marijuana nor a nicotine smoker so I feel on stable ground there but anytime we see smoking nowadays people want really want to distinguish between cannabis and and nicotine um so I am curious about any differences there in terms of um impact on longevity but in that context what are the things that anyone and everyone can do should do to to live longer basically how long you got well you tell me you tell me um I'd like to live to be I'd like my final decade to be between 90 and 100 oh no I meant how long I'm just kiding just and will we spend from now until your well there's a risk of that but um top Contour is fine I know you've done a lot of content on this and we we will give people links to some of that more in-depth content but you know let's say we were on a short flight from here to San Diego uh we're in Los Angeles now um and we've got takeoff in landing and we don't want to Kink our neck too much by doing this thing so if I just said hey you know give me the the the extended version of the 3x5 card uh yeah what does that look like um so so let's start with a couple of the things that you've already highlighter it's so smoking how much does smoking increase your risk of all cause mortality and and the reason we like to talk about what's called ACM or all cause mortality is it's really agnostic to how you die and that doesn't always make sense I mean if you're talking about you know a very specific intervention like a anti-cancer therapeutic you really care about cancer specific mortality or heart specific mortality but when we talk about these sort of broad things we like to talk about ACM so you know using smoking smoking is approximately a 40% increase inre in the risk of ACM what does that translate to and um that means I'm I'm shortening My Life by 40% no 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 a never smoker yeah yeah so it's important to distinguish it doesn't mean your lifespan is going to be 40% less it means at any point in time standing there your risk of death is 40% higher um and by the way that'll catch up with you right at some point that that catches up um high blood pressure it's about a 20 to 25% increase in all cause mortality um you take something really extreme like endstage kidney disease so these are patients that are on dialysis waiting for an organ and again there's a confounder there because there's what's the underlying condition that leads you to that it's you know profound hypertension you know significant type two diabetes that's been uncontrolled you know that's enormous that's about 175% increase in ACM so the hazard ratio is like 2.75 um type two diabetes is probably about a 1.25 as well so 25% increase so now the question is like how do you improve so what are the things that improve those so now here we do this by comparing low to high Achievers and other metrics so if you look at low muscle mass versus high muscle mass what is the Improvement and it's pretty significant it's about 3x so if you compare low muscle mass people to high muscle mass people as they age the low muscle mass people have about a three X Hazard Ratio or 200% increase in all cause mortality now if you look at the data more carefully you realize that it's probably less the muscle mass fully doing that and it's more the high association with strength and when you start to teas out strength you can realize that strength could be probably 3 and a half X as a hazard ratio meaning about 250% greater risk if you have low strength to high strength high strength is the ability to move loads at 80 to 90 it's all defined by given studies so some the most common things that are used are actually you know they're used for the purposes of experiments that make it easy to do and I don't even think they're the best metrics so they're usually using like grip strength um 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 um you know how much weight can you hold for how long relative to body weight things like that um you know we we have a whole strength program that we do with our patients we have something called the SMA so it's the strength metrics assessment and we put them through 11 tests that um are really difficult you know like a dead hang is one of them like how long can you dead hang your body weight stuff like that so we're trying to be more granular in that Insight but tie it back to these principles if you look at cardiorespiratory Fitness it's even more profound so um if you look at people who are in the bottom 25% for their age and sex in terms of V2 Max and you compare them to the people that are just at the 50th to 75th percentile um you're talking about a 2X difference roughly in um in in in the risk of ACM if you compare the bottom 25% to the top 2.5% so you're talking about you know bottom quarter to the elite for a given age um you're talking about 5X 400% difference in all cause mortality that's probably the single strongest Association I've seen for any modifiable Behavior incredible so uh when you say Elite these are uh people that are running marathons at a pretty rapid clip not necessarily it's just like what the V2 Max is for that like my V2 Max would be in the elite for my age group uh my V2 Max you know but but again it's I'm training very deliberately to make sure that it's in that so I wouldn't consider myself Elite at anything anymore but I still maintain a V2 Max that is Elite for my age i' i' consider you an elite physician and podcast and guy all around but true um but in terms of okay so but the point is like you don't have to be a worldclass athlete to be elite here yeah got it um so maybe we could talk a little bit about the specifics around the training to get into that um 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 around let's just say supplement a or supplement B and that's you know like this is my whole pet peeve life right it's like I just can't get enough of the masting 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 um you know you shouldn't be arguing about your this Nuance of your carnivore diet versus this Nuance of your paleo diet versus this Nuance of your vegan diet like until you can deadlift your body weight for 10 reps like then then you can come and talk about those things or something like let's just go with some metrics like until your V2 Max is at least to the 75th percentile and you're able to dead hang for at least a minute and you're able to wall it for at least two like we could rattle off a bunch of relatively loow hanging fruit I wish there was a rule that said like you couldn't talk about anything else health related like you just we can make that rule no one will listen to it I don't know about that we can make whatever rules we want we called aa's 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 um but it's totally appropriate to name things after other people so I'm going to call it a Tia's rule until you can do the following things um don't talk about please refrain from talking about supplements and nutrition here it is Hereafter thought of referred to and referenced as aa's rule I coin the phrase not him so there's no ego involved but it is is now aa's rule watch out # aa's rule oh god um Wikipedia entry aa's rule in all seriousness and I am serious about that um dead hang for about a minute seems like a 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 two minutes is the goal for 40-year old man so we adjust them up and down based on uh age and gender great and then uh the walls sit what's what are some numbers we don't use a walls sit we do as just a straight squat squat at 90° um and I believe 2 minutes is the standard for both men and women at 40 great and then uh because for some people thinking in terms of V2 Max is a little more complicated they might not have access to the equipment or the to measure it Etc um what can we talk about think about in terms of cardiovascular so run a mile at uh seven minutes or less eight minutes or less that's a good question so there are V2 there are really good V2 Max estimators online and you can plug in your activity dour so would be at a bike run or rowing machine and it can give you a sense of of that and I I don't I used to know all of those but now that I just actually do the testing I don't recall them but it's exactly that line of thinking like can you run a mile in this time if you can your V2 Max is approximately this great and and and and I think somewhere in my podcast realm I've got all those charart charts posted of like this is by age by sex this is what the V2 Max is in each of those buckets trfic we'll provide links just to those we'll have our people find those links and then um you mentioned deadlifting body weight 10 times I just made that one up we don't that's not one that we include but but something something like that um we use we use farmer carries so we'll say for a male you should be able to Farmer carry your body weight for I think we have two minutes so that's half your body weight in each hand um you should be able to walk with that for for two minutes um for women I think we're doing 75% of body weight or something like that yeah great I I love it um as indirect measures of how healthy and we are and how long we're going to live it's basically grip strength it's Mobility I mean again walking with that much weight for for some people initially is really hard um you know we use different things like vertical jump ground contact time if you're jumping off a box things like that so it's it's really trying to capture and it's 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 um Beth runs our strength and stability program in the practice and you know basically I just tasked her with like hey go out to the literature and come up with all of the best movements that we think are proxies for what you need to be like the most Kick-Ass you know what we call centenarian to cathete which is the person living in their marginal decade at the best well what I'm about to say is certainly a mechanistic leap but if you look at the literature on exercise related neurogenesis in mice um or brain atrophy or brain hypertrophy Etc um in animal models it's very clear that the best way to get a nervous system to atrophy to lose neurons shrink neurons and or lose connections between neurons is to stop that animal from moving yep or to De enrich its environment dep deprive it of some sensory input or multiple sensory inputs and the best way to enhance um the size of neurons the number of connections between neurons and maybe even the number of neurons is to enrich its environment and get it moving while enriching that environment you know Andrew I think it's it's very difficult for me to say that the same is not true in humans and and so the first time this became clear to me was in 2014 um I had an analyst Dan pichar and I said Dan I'm gonna give you a project that is vexing me to no end which is um 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 we iterated a lot on this together um and he came back with kind of an amazing presentation that took I don't know nine months to a year of work and what amazed me was when he came back to it he said the single greatest efficacy we can point to is exercise and I was like damn that's got to be nonsense dude there's '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 disposal and 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 I think you're missing something Dan I think you're missing something and then finally in the end looped in Richard Isaacson who's a neurologist that we work with really closely on Alzheimer's prevention and you know ultimately it turned into a paper that we wrote basically on you know about this about this this topic and and and and a few others because again I thought oh are you sure it's not EPA and DHA like that's got to have a bigger impact and um again there are a lot of things that I think do matter and there's a whole host of things that we do for Alzheimer's prevention but I think you're absolutely right there's not one thing that I'll tell patients is more important than exercising and by the way it's not the sort of pathetic recommendations that are made like it's you have to exercise a lot more if you want to get this maximum benefit you will you will get you know the maximum benefit comes going from nothing to something so if you go from being completely sedentary to doing 15 met hours per week you'll get probably a 50% reduction in Risk wow uh so a met hour a met just for people who don't know is a metabolic equivalent so we're we're exerting about 1.3 Mets sitting here talking if we were sitting here being quiet it would be about one met um you know walking really briskly would be about five Mets so 15 met hours per week would be three one hour really brisk walks that's not a lot of work but just going from doing nothing to doing that would give you 50% of the benefit that you would get from going all the way now I again I think I'm personally a little skep IAL of how much that's I think it's probably a bit less than that I think there's more upside Than People appreciate but the studies I don't think can can truly capture that but look you know there's there's no reason to not be exercising more than that and and capture more benefit even though the rate at which you acrw it is less and it also speaks to the health span side of this which is not necessarily captured in those data the health span gets back to the functional piece we opened with which is what do you want to be doing in your marginal decade do you want to be able to pick up a great grandkid if they come running at you do you want to be able to get up off the floor do you want to be able to play on the floor with a kid and then get up on your own and I think most people are thinking final years of life they're trying to think you know how can they um take themselves to the bathroom they're thinking how can they sit up off the toilet I mean got really Bas vegetative type functions right um at some level I love this again this idea of marginal decade and using that as a way to Fat cast to uh uh to actual methods and behaviors and um protocols that one should be doing on a daily basis uh I'll use anic data as it's now called um to cite just I know three Nobel Prize winners which doesn't mean anything except that they did beautiful work but the point is that they're all in their 90s so I I'll I'll name them because I'm I'm complimenting them for what they've done not just their work but what I'm about to describe so Eric kandell at Columbia Nobel Prize we for work on memory Toren and visel work on neuroplasticity and then uh Axel who's also at Columbia Noel prize winning work for molecular biology of smell and and molecular biology generally all three of them still alive Richard's younger compared to the other two all three of them either swim jog or play tennis or racketball I think is Richard's thing multiple times per week Eric was they're all cognitively still extremely sharp still interested in the Arts doing science curious about science running Laboratories writing books going on podcast I me it's incredible again that's anic dat but I was kind of surprised to learn that colleagues that were so intellectually strong were also so obsessed with exercise I mean that they really are obsessed with their exercise routine and early on linked that to their um some of their intellectual Vigor over time I want to just also use that as a jumping off point to ask about one kind of Niche thing but it comes up um I don't think I'm gonna out which one of those told me this but one of those three individuals um choose an excessive amount of Nicorette used to be a smoker and I asked him why and he said because in his estimation it's protective against Parkinson's and Alzheimer's or at least the nicotinic acetycholine augmentation of nicotine because nicotine is acetycholine receptor obviously um is known to create a state of focus and and neural enhancement what are your thoughts about not smoking let's just I want to be really clear people don't smoke nicotine Vape nicotine that's going to shorten your life just terrible idea add 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 truly n of one but he's so convinced that this matches up with the mechanistic data on acet ofine 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 C nitive enhancement piece of it and actually did an AMA on this uh probably a year ago where I went into all of the Gory details of it and talked about my own use of 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 uh I used to use the gum I don't like the gum anymore so now I like these little lozenges um that uh I'll tell you a funny story about this so our mutual acquaintance David Sinclair mentioned a comp 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 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 got 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 cuz I the thing I didn't like about gum was I hated just the the the taste of it um so then the next week I'm talking to David and I'm like by the way I ordered all that nicotine stuff you told me about he's like what and he goes oh oh the company's name was something else it was totally unrelated it's like oh god um so um the short answer is I think this stuff is absolutely a concentration um enhancing substance um it is addictive and people need to be wary of that now it's not addictive to everybody I personally experience no um 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 um you have to be careful with the dose truthfully I mean remember one cigarette is about one milligram of nicotine and a lot of these lozenges will plow four to eight milligrams into you in one shot and for someone who is you know naive to that like I am four milligrams is a lot of nicotine in one Bolis so you just have to be very mindful of it um I got a lot of flak when I did this AMA for obvious reasons but people were like how can you as a doctor encourage people to use nicotine and I was like first of all I'm not encouraging anybody to use it I just want to be able to talk about the biochemistry of it um and if disclosing that I use it from time to time is is an endorsement then you know I apologize for that um 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 I I you know I just tell patients outright like we are under no circumstance prescribing stimulants I mean yeah we're just we're not giving anybody Aderall we're not giving anybody viance or any of these things um 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 and and using that as a tool to enhance you know concentration in cognitive performance is not something we're comfortable doing yeah it's rampant on college campuses I can only imagine um arm modao modao which are slightly different of course but uh so non clinical use not prescribed for ADHD but just it's rampant recreational use study based use now the data I've seen on mafel suggests that it only really provides a not Tropic benefit in someone who is deprived of sleep is there data that in a totally well-rested person there is a not Tropic benefit of mapel I don't know I have one experience with armodafinil where I took a half a recommended dose this was prescribed by a doctor um I went to give a talk this is in Hawaii and um four hours into the talk my uh co-speaker came up to me and just said well first of all you got a little bit of uh spit in the corner of your mouth and second of all you haven't blinked in three minutes and third um there's only two people left in the audience I was so lasered in that I I forgot the context I'm a little bit of a kind of a tunnel vision OCD type uh anyway but one that was all it took I never I never took any more of it it was a powerful stimulant I take uh 300 milligrams of alpha GPC now and again before some cognitive work sometimes before workouts and I do subjectively feel that it Narrows my focus in a in a nice way um 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 how we're talking about versus sort of nutrition and supplements for longevity I think there may be a whole bunch of things that are kind of interesting around Focus but nothing would compare to changing our environment like I think that if I compare my focus today to my focus when I was in college there's no comparison like in college I was truly a robot but I think a large part of it was there was no distraction there's no email there's no social media there's no internet I mean I was in college when Mosaic launched in the early 90s like I you know and you had to walk like a mile to get to the computer lab on a big sun workstation to do anything in you know some computer code language so when you're sitting in your room studying there was no distraction and I think that's a far greater component of what it means to be focused than the challenges we have today so you know my thoughts on this would be if we really wanted to return to a state of focus we're going to have to individually do something about you know our Environ and and I I don't know what the answer is like I've tried every little trick I can think of like closing my browsers when I'm writing and stuff but you know I'm just not strong enough willed like I'll pick up my phone every 20 minutes to look and see if I miss a text message or something stupid that's pretty infrequent I did a episode on habits and looking at the data um it seems that U people are getting interrupted or interrupting themselves about once every 3 minutes in the typical workplace now that typical has changed with a lot more people working at home I do put my phone away when I try and work that nothing focuses me like a deadline a little bit of uh fear-based urgency that's it Grant deadlines you know drop deadlines as I call them or podcasts we're going to record today that nothing works quite like it but such as life um well thanks for that um offshoot about nicotine um again uh 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 it's very ious forms and some related type pharmacology does enhance focus and pretty potently so I think it's going to be an interesting area for real clinical trials and things of that sort love to chat about hormone therapies and hormones generally uh when Robert spolski came on the podcast we talked a little bit about menopause and the data around menopause he's very interested in um these findings that I think I'm going to get this right that whether or not women benefit from estrogen therapy to offset menopause really depends on when that therapy is initiated I don't know if you're aware of those data but uh he claimed that if they begin estrogen therapy in the middle to tail end of menopause the outcomes can be um quite bad whereas if they initiate those estrogen therapies as they enter menopause or even before menopause then the outcomes can be quite good I don't know what percentage of the patients you treat are male versus female and what ages those patients are of course but um what are your thoughts about estrogen therapy for women menopause and um hormone therapies generally for women maybe even testosterone therapy you hear about that these days and then we'll talk about men so so our practice is probably 703 male female so we have lots of women and this is a very important topic um it's also probably let me think I just want to make sure I'm not being hyperbolic when I say this yep I don't think I am it's hands down the biggest screw up of the entire medical field in the last 25 years now again it's possible in the next hour I'll think of nope there's a bigger screw up another another giant screw up but but I don't think I will I I'm pretty confident that I won't be able to think of a bigger Act of incompetence than what happened with the Women's Health Initiative in the late 90s and early 2000s which is effectively the study that turned the entire medical field off hormone replacement therapy for women so it's important I think to explain what the study looked at so this was a a study that was conducted in response to the widely held belief in the 70s and 80s that women should be placed on hormones as they're uh 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 probably worth mentioning a bit of the top Contour some of them might be familiar with it we've done episodes on estrogen and testosterone but frankly as I think back to those we didn't really go into the biology of estrogen testosterone enough yeah so I mean actually an interesting aside that I always tell my female patients who get a kick out of this um when you look at a woman's Labs you'll see her estrogen her progesterone her FSH her LH her testosterone her sexor binding globulin all these things but based on the units they're reported in it's very distorting picture of what the most common Androgen is in her body if you actually convert them to the same units she has much more testosterone in her body than estrogen interesting yeah I did not know that yeah then again I've never been a woman getting my hormone profile though yeah so even though a woman's testosterone is much less than a man uh than than a man's level um it's still more than she has estrogen in her body wow so phenotypically right estrogen is the hormone that's dominating and T so it's the you know she has much higher estrogen than a man and much lower testosterone than a man but in absolute amounts she has more testosterone than estrogen just worth pointing that out incredible so um so so you know what what's happening to a woman from the age she starts menstruating until she goes through menopause outside of pregnancy and birth control and stuff like that is she has this cycle you know roughly every 28 days but it can vary where uh at the beginning of her period we call that day Zero her basic her estrogen and progesterone are very low you can't measure that and then what happens is the uh estrogen level starts to rise and it rises in response to a hormone called follicle stimulating hormone follicle stimulating hormone FSH that is getting her ready to ovulate and she ovulates at about the midpoint of her cycle so if we're just going to make the math easy on day 14 she's going to release a follicle from one of her ovaries and the estrogen level is sort of rising Rising Rising we love to measure hormones on day five because I want to have a standardized way in which I measure her hormones so our women know if we're in the business of trying to understand her hormones the day her period starts even if it's just a day of spotting that becomes our Benchmark and then day five I want to see every hormone on that day and if everything is going well I know what her FSH LH estrad 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 uh uterus for uh the lining to accommodate a pregnancy so now you start to see estradi go back but now for the first time progesterone goes up so progesterone has been doing nothing for 14 days and now it starts to rise and actually progesterone is the hormone that's dominating the second half which is called her fic her ludal cycle so the first 14 days is the folicular cycle second is the lud ludal 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 G most of the time she's not going to be pregnant so the body says oh I don't need this lining that I've been preparing I'm going to shed it so now progesterone and estrogen start crashing and the lining is what is being shed and that is the Menses by the way it's that last seven days of that cycle that in a susceptible woman is what creates those PMS symptoms so it's the actually this is something that you would probably have a better understanding of than me there is something about this in a susceptible woman where the enormous reduction of progesterone so quickly is probably impacting something in her brain so I think this is a this is a legitimate thing right I mean you know it's not like oh she's crazy because she's having all these PMS symptoms no um 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 ludal phase and sometimes we would just do it for the entire ludal 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 um brain Institute now has beautiful data of Inu hybridization which for folks that don't understand is looking at RNA and so where genes and uh proteins ought to be expressed in the human brain by using actual human brain tissue sections as opposed to just mice so I'll take a look I think some insight into what that um progesterone emotionality link might be and where where it might exist neural circuit wise so then when the estrogen and progesterone reach their nater 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 menstrating 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 what do women experience when they go through menopause the first symptoms are what are called Vasa motor symptoms so this is usually in the form of um night sweats hot flashes so and depending on the woman this can be really significant right these are women who can have a hard time sleeping they can be having hot flashes during the middle of the day they can wake up soaked in a pool of sweat um those tend to pass after a couple of years and then they get into sort of the more long-term complications of menopause so what we call vaginal atrophy vaginal dryness and then the stuff that we talked about a while ago which is the osteopenia osteoporosis uh a lot of women will compan complain of brain fog um 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 um and the reason for that is if you just give estrogen with no progesterone to to antagonize it you will thicken the endometrium endlessly and you will increase the risk of hyperplasia well you'll you'll definitely undergo hyperplasia and then ultimately dysplasia dysplasia is pre-cancerous and ultimately uh we were seeing that so people figured out well actually if you want to give estrogen to a woman who still has her uterus you have to give her progesterone as well you have to be able to have a hormone to oppose the estrogen and then that became effectively in the 19 call it the 1970s is the standard for um for HRT so in the early 1990s uh 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 their all their symptoms go away uh they seem to have lower risk of heart disease lower risk of you know uh cardiovascular pardon me lower risk of cardiovascular dise lower risk of bone fractures um 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 uh 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 um there were probably a several reasons for that but one of them is and I think this is a a legitimate reason they wanted hard outcomes they wanted to know death rates and if you're doing this on women in their 50s you just weren't going to get it right you couldn't wait too long yeah you gotta wait too long and this was only going to be like a seven to 10 year study so they had to do this on women who were much older they also disproportionately took much sicker women I believe the prevalence and again I'm going to get some of these numbers wrong and people are going to get all phosphorilated but you know I mean I'm in the ballpark right something like 40% of these women were smokers the prevalence of obesity diabetes was enormous so they they 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 um 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 patients you're interested in treating so they also treated no patients who were symptomatic the rationale being if we include in the study patients who are symptomatic those who are randomized to Placebo will drop out okay I it makes sense in terms of study design makes no sense if the study design is um intended to mimic the real world that's right so now let's just keep track of the three issues we have a disproportionately unhealthy patient population who are not symptomatic and we're starting them more than 10 years after menopause the next thing that they did which again I understand why they did it but it's now the fourth strike against this study is and I've spoken with the pi of the study and asked this question Point Blank I'm actually going to have her on my podcast at some point soon to go over this in more detail um is why did you use conjugated equin estrogen and MPA which is a synthetic form of progesterone horse yes estrogen horse it's horse urine is like they collect horse urine so they're getting the it's horses do urinate a lot or at least when they urinate it seems like a large volume of urine from what I've observed 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 the peas were legendary it's male horse yeah yeah yeah so yeah so so the the conjugated equine estrogen is the estrogen that's collected from from female horses and then it say sythetic progesterone uh and I said to to uh to to the person 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 Vel dot so it's a patch that you just put on and it's estrad but it's bioidentical estrad and we use what's called micronized progesterone so bioid itical progesterone and she said well at the time we just wanted to test what was currently being used and I said totally makes sense but again now you have four considerations that you have to keep in mind okay so despite those four considerations and I'm going to make a case for you why I think the mpa created a real problem in that study the synthetic progesterone when the preliminary results were first made available but not yet reviewed and not yet published there was a huge Fiasco huge press announcement about it suggesting that the women receiving the CE plus MPA in the uh uh group with the uterus had a higher incidence of breast cancer and that basically became the headline that never went away though it turned out not to be true let's talk about the numbers what was the increase in the risk of breast cancer in that group which gets to one of my if you know you've ever listened to me on the podcast rail on something listen I have about 3800 pet peeves and counting my laboratory staff know these um know a good number of them so you do not have to apologize for having many pet peeves because as long as they have um experience and data to support them it provides one of my biggest pet peeves is uh and my my team knows this because sometimes they'll occasionally you know they'll do this and I'll have to remind them you never talk about a relative risk change without an absolute risk accommodating it right right so so what does that look like so the the relative risk increase of breast cancer in the estrogen plus MPA group versus the placebo was 25 27% and that became the only headline HRT increases risk of breast cancer by 27% now I don't think that's true at all today but let's even look at the data what was the ARR what was the absolute risk increase it was a difference between five cases per thousand and four cases per thousand so the ARR was 0.1% one case in a thousand and it's true going from 4 in a th000 to 5 in a thousand is a 25% increase but it's a completely inappropriate context I agree and I feel like headlines of that sort which have come up recently around various dietary interventions we won't go there at least not for the time being um are nothing short of criminal because they really distort people's thinking but also they steer the course of science and medicine for as you pointed out for decades if not longer and they can really take us off our health track in serious ways so I'll bring this Meandering to a close which is to say even though I could spend the next hour talking about all of the ways in which this study was flawed and all of the very unethical things that were done by 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 upperbound risk of breast cancer is one one case in a thousand you should at least weigh that against all of the other benefits which I'll talk about now there's something else I want to say because a moment ago I alluded to the fact that I think the mpa might have been the biggest issue in that study so there were two findings in that study that were negative one was the in small increase in the risk of heart disease and a small increase in the risk of breast cancer but consider the other group we forgot about the group that didn't have a uterus because remember those women got estrogen only versus placebo what was the difference in breast cancer there well this is interesting because it didn't reach statistical significance but it's p value was 006 or 007 so it came very close but it was in the opposite direction it was a 24% risk reduction about one in a thousand as well so when you had estrogen plus MPA you had a barely statistically significant the P value was 005 so it just hit statistical significance one in a thousand cases for breast cancer and then you had one in a thousand cases but P value of 007 for red reduction of risk of breast cancer which to me suggests that the mpa the synthetic progesterone was playing more of a role than anything else the second thing I point out is oral estrogen which we no longer use does increase coagulability it does increase the ability of the blood to clot a little bit and when we look at the more recent data on HRT using topical estrogen or patches of estrogen we don't see that at all in fact we see the opposite now so now we see the risk of heart disease going down in women with estrad and some women will be arriving to those treatments with uh mutations and things like Factor 5 light and and other clotting factors is it uh appropriate to say that everyone both male and female should know whether or not they have mutant forms of factor 5 lien you know we don't typically test people for Factor 5 uh my wife actually has it but we didn't learn it until she had help syndrome giving birth to our first daughter um but um you know we we kind of look for more family history reason to be test things like that uh we take a pretty detailed family history so we'll kind of look for clotting issues there what about um so your reflex nowadays is to put women on uh these topical EST to basically have the discussion right so so 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 um 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 endometrial ultrasound done every year um that's you know some would argue that's Overkill but you know we think sheep having a papsmear 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 estrog uh 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 needs to be if given systemically like 100 to 200 milligrams and for some women that is a life-saving intervention I mean they start sleeping better their hair gets thicker they feel better but for some women it literally drives them crazy it it's probably the reciprocal of what we were seeing in the case of women with PMS so in those situations we say great we're done with oral progesterone we just use a progesterone coated IUD so then you get the local progesterone in the uterus for protection and the system estrogen fascinating what about um oral contraception um for in women uh so the use of estrogen chronically through people's you know college Years or the 20s 30s maybe even teens who knows um what's known about the long-term effects if any I gotta be honest with I don't I don't think I know enough to comment on it it's not it's not something that really impacts my patient population um you know at least in what I see more women are using iuds for uh for for contraception than than OC's I mean we use OC's sometimes in women who are pre-menopausal for symptomatic control but we'll typically use like a low low Estrin so a very low um synthetic estrogen which I don't like using these very much but if it's the only thing we can get to control certain symptoms and we'll use it like half her cycle um but it's typically not something we're we're that experienced with what about to stop from because you mentioned that you know nanogram per Mill uh when you said everything to the same um you know I guess it's nanogram per deciliter as it would be to to kind of normalize per mole right yeah and so yeah that's what Peter was pointing out before is that you look at your charts and they're all in these different measures and so when you normalize testosterone is actually higher than estrogen in women that's a surprise to me um do you prescribe testosterone therapy to 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 I'll I'll happily go toe-to-toe with anybody who wants to make the case that it's dangerous uh similarly when it comes to using testosterone in men I'll 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 then you prescribe them testosterone when it comes to estrogen in testosterone in women don't have that data and I'd love to see that trial done so how what's the what's the Sweet Spot how do we how do we reconcile that so um it's not something I consider standard and basically if a woman is if her testosterone first of all is staggeringly low and again even though her testosterone is low compared to a male we still have a range so if it's really at the bottom of that range she's really having difficulty putting on muscle mass and really complaining of low beo I think in that situation we'll go ahead and use topical testosterone um and 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 I've never seen a single symptom in a single woman that I've put testosterone on in terms of like acne body hair things like that like those are real symptoms that you have to be aware of but you know like clitoral enlargement and things like that like that doesn't happen under physiologic normal conditions I'd love to talk a little bit about hormone replacement therapy in men um 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 uh that injecting testosterone cypionate or taking anavar or whatever it is is going to be the right idea they mainly seem to be focused on cosmetic effects I'm not a physician so I can't say whether or not they were actually hypogonadal Etc but it seems to me again correct me if I'm wrong but it seems to me that similar to the aa'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 anti-depressants there is a kind of a cliff after which uh low enough testosterone or low enough serotonin prevents people from sleeping exercise Social connection Etc so I do want to acknowledge that but with that in mind how do you think about and perhaps occasionally prescribe uh 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 uh what sorts of levels do you think are meaningful because the range is tremendous in terms of blood test 300 nanograms per deciliter I think on the low end now in the US all the way up to 900 or 12200 that's an enormous range what are some of the other hormones you like to look at estrogen DHT and so on so um lot lot to unpack there so um let's start with the ranges right so um the the the ranges you gave are for total testosterone of course and and we don't spend a lot of time looking at that uh the way we used the way we you know I used to spend more time looking at total and free when I had when I used more tricks to modulate it so I 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 do of anavar to lower SBG in a person who had normal testosterone but lowf free testosterone what what was um a low dose of anavar in that context 10 milligrams suing two to three times a week anavar basically being DHT it oxandrolone exactly and again we're not recommending this this actually if you're playing a competitive sport can get you banned from that sport no yeah can also get it can also get you banned from having children if you do it incorrectly yeah so so a micro dose of this has to be small enough that it doesn't impair your body's ability to make testosterone but anavar has such a high affinity for shbg that it basically distracts your shbg from binding your testosterone freeing up testosterone that's exactly right so so the goal was how do I just give you more free testosterone so if if patient shows up and they've got a 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 know8 nanograms per deciliter so that's pretty bad that means you're less than 1% free a guy should be about 2% free te so that dude should be closer to 16 to 18 nanograms per deciliter so in that situation that I just gave you his shbg is really high his shbg is probably in the 80 to 90 range that's very high because I think the upper range is somewhere around 55 56 exactly so we would first back stall for what's driving his shbg so there's basically three hormones so genetics plays a huge role on 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 shpg is like kind of in the 30s 20s to 30s um but from a hormone perspective there's basically three hormones that run it so estrad being probably the most important insulin and thyroxine so we're going to look at all of those and decide if any of those are playing a role so insulin suppresses it so this is actually the great irony of helping a person get metabolically healthy is in the short run you can actually lower their free testosterone all things equal because as insulin comes down shbg goes up and if testosterone hasn't gone up with it you're lowering free testosterone so somebody who goes on a very low carbohydrate diet and attempt to drop some water and d drop some weight is going to increase their shbg yeah if their insulin goes up testosterone less free testosterone um I can I could tell the carnivore diet people are going to be coming after me with um with bone marrow in hand but then again after this discussion extends a little further I'm sure the vegans will be coming after me with celery stocks so it's a uh so then the same as with estrad so except in the opposite direction so higher estrad is higher shbg um so again occasionally you'll see a guy with incred normal testosterone but he's a very high aromatase activity person so he has a lot of the enzyme that converts testosterone into estradiol you can lower estradiol a bit with an aromatase inhibitor that can bring down shbg now again these things individually are rarely enough to move the needle uh the last is is thyroxine so if you have a person whose thyroid is out of whack you have to fix that before you if their T4 is out of whack you're going to interfere with that hpg there are also some supplements which I think you've probably talked about these on the podcast I feel like I've heard you talk about these on the podcast yeah there are a few that will adjust you know there is this idea now there's a a much better review that just came out I'll send it to you I'd love your thoughts on it and I've been perusing it line by line but I love input from experts Like You on the use of Tonga Ali for reducing H hbg in my experience it does free up some testosterone by which mechanism it isn't exactly clear and the effects aren't that dramatic yeah right they're probably multiple effects uh for all we know it increases libido and it does generally by way of increasing estrogen slightly which can also increase libido in some individuals so we don't know the exact mode of of action so we've talked about a few the one that few years back people were claiming cling could reduce shbg was um uh stinging nle um stinging nettle well just urine seems to be urinating seems to be coming up multiple times on this podcast for whatever reason uh sting nettle extract I took the the the most pronounced effect of that was you could basically urinate over a car when taking shbg what the underlying mechanism of that was I do not know I took it for a short while it didn't drop my shbg very much um but it did drop my DHT sufficiently so that stop taking it I do not like anything that impedes DHT I I don't care if my hairline Retreats I don't care about any of that DHT to me is something to be um coveted and held on to because you feel so much better when your DHT is in the appropriate range and love your thoughts on that yeah again it really depends on the guy and it depends on what risk you're trying to manage right so prostate size starts to become one of the issues with DHT luckily my prostate physic antigen is low um DHT um the things that I know can reduce it are things like finasteride Propecia things like right things to that people take to try and avoid hair loss can um dramatically reduce DHT and lead to all sorts of terrible sexual side effects mood-based side effects Etc but um yeah so I'm not aware of anything that can be taken in supplement form that can really profoundly drop 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 in the end I think they were just like dude just what do I need to take um 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 estradi and sorry didn't trby you said if you look at your total testosterone you want the free tea to be about 2% of your total it should be right I can't I might not change that anymore so in other words if a guy's at 1% then I know I have to really boost his total testosterone if he's only going to get one to one and a half% of it converted to free I need to boost him and that's why I don't care if he's outside the range like I'll have a guy who's free tea to I might have to get a guy's Total Tea up to 1500 to get his free tea to 18 I see so free tea is the target I like is what we treat and do you still use anavar uh um sorry to try and lower shbg it's because it's too potent no because it's just too complicated for patients you know you know it's a it's a it's a drug that can't be taken orally so have to take it under the tongue like atro or something right but then you know I had one patient once who even though we told him about 87 times that he was like swallowing the anavar and his liver function and he was like we're talking 10 milligrams three times a week is a tiny dose and three months of him or whatever two months of him swallowing that every time tripled his liver function test so it's like it's just I was like you know it's just not worth the hassle of doing this um for you know Perfection uh in reality we can fix this another way so 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 ranges um 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 um two years ago was it two years ago or maybe a year ago very good study came out that looked at pre-diabetic men you've probably talked about this study and looking at insulin resistance and glucose uh disposal with and without testosterone and the evidence was overwhelmingly clear um testosterone improves glycemic control testosterone improves insulin signaling this shouldn't be surprising by the way given the role muscles play as a glucose Reservoir and a glucose sync so now I include that as one of the things that we will consider as a factor for using testosterone now again it's not the only one so you can accomplish that with exercise you can accomplish that with these other things but then you get into a little bit of the Vicious Cycle of will having a normalized testosterone facilitate you doing those things better so uh let's just assume we come to the decision that this this this person is uh a good candidate for 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 uh we used to use a lot of Clomid in our practice um and have you talked about Clomid on the podast I don't talk too much about it I'm um no we've talked a little bit about the fact that some people taking things like an asrol 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 and even fat accumulation so if estrogen is too low you you'll you can develop osity in a way that you wouldn't otherwise there's a great New England Journal paper it's probably 10 years old now that looked at F I believe it was five different doses of testosterone cypionate so these men were chemically castrated and divided into 10 groups it's pretty remarkable somebody signed up for this study yeah so you were with and without an asrol and five doses of testosterone okay 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 estradi 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 were were less significant and this is 30 to 50 nanograms per desile or not 30 to 50% of your of one's testosterone okay great um okay no we haven't talked but Clomid is you know we have not talked a lot about Clomid I'd love to get your thoughts on Clomid so chopine is a fertility drug it's a synthetic hormone it's actually two drugs mcline and I forget the other one and it tells the pituitary uh to secrete FSH and LH so uh you and so the advantage of of Clomid is it's oral and it's meant to be taken orally so you know a typical starting dose would be like 50 milligrams three times a week and if you do that you'll notice in most men especially young men FSH LH goes up in any man the FSH and LH go up but if a man still has testicular Reserve he'll make lots of testosterone in response to that um 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 I just want to point out again correct me if I'm wrong but my understanding is that a lot of the drugs that we're talking about um the synthetic compounds testosterone estrogen things uh related to growth hormone Etc were discovered and designed in order to treat and excuse me in order to isolate and treat exactly these kinds of syndromes whether or not it was the hypothalamus the pituitary or the target tissue the O 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-year-old guy whose testosterone is low but you can demonstrate that it's low because he's not getting enough of a signal from the pituitary why would you bother giving him more testosterone when he has the Capac he has the lading cells and the ceruli cells to make testosterone he just needs the signal um sometimes though 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 Mill uh 50 milligrams three times a week for a short course and then yeah we would do that for 8 to 12 weeks and then we re-evaluate and estrogen and testosterone will increase in in parallel yes and again it depends you know aromatase activity is dependent on how much body fat you have and genetics um and if estrad gets too high we think if it gets over about 55 60 we will give micro does of an asol but it has to be real micro does I mean you cannot pound people with an astol to to give you perspective the the the sort of on label use like if you just go to a pharmacy and order an asosal you're going to get one milligram tablets like we can't give anybody a milligram they'll feel like garbage we we have to have it compounded at 0.1 milligrams and we might give a patient .12 three times a week that would be a big dose of an asol yeah I think that the typical trt Clinic out there is giving 200 milligrams per Mill one mil 200 milligrams of testosterone once every two weeks and then hitting people with um multiple milligrams of an astol and they're all over the place I I I've never really understood I mean I guess I shouldn't be surprised but it's kind of blows my mind that these trt clinics are up all over the place given how bad I mean I see the results because I have patients that come from them and I don't understand like why they're so incompetent I actually think it's worse than that I think that they simply don't understand and don't care because it's a um pill Mill and it's a money Mill I think that nowadays it seems almost everybody who's doing trt is taking lower doses more frequently every other day or twice a week dividing the dose and being very very careful with these estrogen or aromat taste blockers um we we we most of our patients do not take aromatase Inhibitors it's not needed it's really only the high aromatizer that need it um and so yeah when we'll talk about testosterone we'll talk about dosing there because I agree the more frequently you can take it the better and and frankly you don't need to go more frequently than twice a week because it's so slow yeah the halflife of the drug is I think it's about three and a half days is the plasma half life or something like that it could be off a little bit but but twice week dosing is is really nice so if you're if you if you go to like you know a testosterone Clinic that's giving you 200 every two weeks 50 twice a week is the same total dose which by the way is a physiologic dose that's not going to give somebody any of the side effects you would see you're not going to get acne with that you're not going to get gynecomastia you're not going to get any the only real side effect you get from that is you will get testicular atrophy that is enough to supress yeah to maintain um 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 um due to a really interesting observation that um we we made that I don't think has been reported in the literature yet which is that Clomid was increasing levels of a sterol that we also happen to measure called desol I'm not familiar with that so in the in the in the way that cholesterol is made uh it's made by um there's two Pathways that make cholesterol so it starts like with you know two carbon subunits like acetal COA and it kind of marches down a pathway bifurcates and cholesterol is the finished product of both but one of those Pathways the the the molecule right before cholesterol is called desol in the other pathway it's called lathosterol so we constantly measure lathosterol and desol 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 desol 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 desol into cholesterol makes sense if you inhibit that enzyme you're going to see a rise in desol this wouldn't have been a concern to me if not for the fact that Tom dpring who's one of the Physicians we work with who's one of the world's experts in lipids pointed out a very obscure story which was that the very first drug ever approved to treat cardiovascular disease at least to treat hypercholesterolemia was a drug that attacked the same enzyme um so this this this was in the early 1960s I believe maybe the mid 60s this drug was approved and it lowered cholesterol and it was approved on the basis of lowering cholesterol now today no drug for ascvd is approved on the basis of it lowering cholesterol that's not a high enough bar you have to reduce events you actually have to show that you're preventing heart attacks and death but at the time it was like Hey it lowers cholesterol it's got to be good well in the late 60s it was pulled from the market because events were going up so cholesterol was coming down events were going up how could that be we don't know what we are suspecting is that desol which is still a stero was potentially more damaging and created more oxidative stress in the endothelium in the subendothelial space than cholesterol I see which would at least suggest to us and again we're taking a lot of leaps here that maybe having high dmol very high dmol is 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 um 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 uh knock over the little uh bottle it's basically gone bad travel with it is is very can't travel with it um it's a needle you know it's an injection subq so easy to administer it's not IM or anything like that but it's just more of a hassle Factor um but that said it has the benefit that Clomid does which is it preserves testicular function it preserves testicular volume so you know bodybuilders will often use this in their post-cycle therapy as a way to kind of recover function and we would just use it now as ongoing therapy for a guy who still has TSC Reserve so on its own no testosterone no aromatase inhibitor nothing just a way to crank out a more testosterone from the testes maybe some additional estrogen HCG is a different model HCG is just an analog of lutenizing hormone so it's basically like giving them luteinizing hormone so it's going to crush endogenous luteinizing hormone levels right because of actually um yeah and it and it and it um 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 uh just as a mention and here I'm not making recommendations but one One supplement I've talked a lot about uh publicly is fogia grus which is this weird Nigerian shrub that that um talk about this on Tim's podcast on Tim's podcast and Joe's podcast and um you know there was a bit of a backlash because it does turn out that at high doses in rodent studies it can cause uh some toxicity to the testes but um at lower doses it does seem to increase lutenizing hormone and after talking about this a number of people went out there did pre- and post blood work and the the 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 and be like oh you know their their balls are getting bigger and so they get all excited that something good is happening um but we don't know the long-term safety and efficacy of something like fogia whether or not needs to be cycle this is why I'm 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 I you know I think the FDI the FDA has a lot of faults uh 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 Tong God FID doia was to provide some intermediate discussion between doing all the correct things but no supplementation or hormone therapy and then going straight to hormone therapy it's sort of like the leap from I can't focus very well to ridin right without a 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 are worked out empirically on an individual basis and there aren't randomized control trials they're they're just aren't yeah and and and you know have kind of like a a seven uh this is another Peter Principle right so I got a lot of patients that come into the practice and you know during our intake we go through what what drugs and supplements are you taking right now and you know a lot of people come in I'm not taking anything Peter I just you're 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 uh we're going to need an extra few pages for this part of the documentation people who travel with a suitcase that you can hear as they walk through the airport from all the pills and um so I give these patients a little homework exercise which is you have to answer these seven questions for every supplement you take and here's the spreadsheet and let's talk about it and it basically just runs through like you know it's it's basically walking you through the logic of why do you take this molecule and um I think for many people it's when they do that it's very sobering right they kind of a lot of them will come back and be like you know what I don't think I can come up with any reason along this really rigorous line of thinking as to why I'm taking 80% of this stuff well I know people and actually we know some of the same people are fanatic about like red life red light on the testes sunning their testes um 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 teses is pretty remarkable and that said um among some of the women I know the number of things that they're doing to try and promote longevity and fertility and in particular skin Health hair health and nail health is also kind of outrages everything from collagen to Red Light therapies which may actually have some efficacy in certain cases but um as an interesting there's hunger there right oh for sure um one of the things that I hope gets a lot more attention is the use of Ramy for preserving ovarian health so the animal literature on this is pretty pretty impressive right so in Mouse models rap ay will preserve OV ovarian life and so it makes sense right I mean it totally makes sense why the most potent geroprotective molecule we have would also preserve and extend ovarian life at least in my so um I'd love to see the clinical trials done in in in women to test this hypothesis I definitely want to come back to this because that's a key thing I know a lot of people are interested in female fertility out there um including their male Partners so um going back to so now I understand why you don't prescribe chopine because of this um dmol uh potential dmol link um what about testosterone therapy so less less frequent lower doses um less less or no estrogen inhibition or aromatase inhibition only only we're only using an aromatase blocker and we use Arimidex when we do it's just to it's just to get that estral into the range we want I like to see it between 30 and 50 that that that's The Sweet Spot and uh 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 do of an asrol to get into that range most do not um and I'd rather on the side of being a little high than a little low so I never really want to be below 25 if unless sometimes it's just below 25 and it is it is what it is that's fine but but if we're suppressing it to below 25 I never want to be in that zone um and then yes so trt is ultimately you know giving testosterone cypionate is usually what we use injectable so it's supposed to creamer pellet correct um I used to use pellets with women um for some who were really adamant about the convenience of it but for a bunch of reasons I I just I'm I'm mostly not doing that and I've never been a fan of pellets in men um you can't control the dosage once it's in if you know the dose yeah that's obviously a problem but I don't think there's a big difference between putting a pellet into a man and a woman so when you're putting a estrogen pellet into a woman it's like it's that big when you're putting enough pellets into a man for six months of testosterone it's too sums of pellets that are longer than my finger so you're putting like a vshape you're putting it into the Glu fat so it's just it's just a more morbid procedure and I I don't think it's necessary I think if you if you know how to manage it you know through through sort of the injections and Nows are no big deal yeah well especially now if you're doing you know we're having them do subq 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 um once to twice a week depending on and by the way they're real needle phobes we use zad which is a pre-loaded pen and are you having all men take HCG to maintain fertility in test they want to got it yeah and by the way we do not like to use trt in men who we don't like to use testosterone specifically in men who still want to maintain fertility we just steer them away from that because total sperm count goes down yeah we just say why risk it like we'd rather use HCG just on its own yeah just wait just wait till you're done reproducing Bank sperm wait till you're done reproducing before we go to testosterone um what are some of the benefits and what are some of the uh 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 um people what it generally people report how do they feel uh what does it allow them to do that they couldn't um do or feel before and then in terms of what are the markers to look for is it LDL blood pressure water retention acne those kinds of things are there some other things as well it depends on the doses right I mean again we're using these in really low doses so it's pretty rare that we'd have a patient on more than 100 milligrams a week of testosterone um I think for comparison like a bodybuilder could easily take 500 to a thousand during a high growth phase I know some of these guys they they go ballistic or they're doing moderate levels of testosterone cbate but they're also taking dianab bolic androne uh you know sarms 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 are D like crazy in that sport right now it's outside of physiology yeah and I think for 99% of people listening they just they look they hear bodybuilder and they just go like why would somebody do that anyway I think that's the typical response so so the point is a lot of but but we owe those guys a great deal of gratitude because they've shown us the boundaries including the women that's right right yeah yeah yeah and so so so those those body builders have taught us a lot about like what happens and so yeah the 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 output my understand it's a physiologic dose I mean the reality of it is it's enough for most people I mean there's probably the highest we've ever had to go is maybe 70 twice a week what's the youngest patient you've ever had to put um on TR actual testosterone M probably that's a good question I'm think about 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 unless you're doing everything else right and you're still hypogonadal and you're really struggling put that put that time off because also the fertility issue you want to delay delay well again it depends if when we say trt if you're in your 20s and there's no other way I would I would hope you would be steered toward HCG to at least preserve Toc function now again we don't actually know if after being on HCG for 10 years your pituitary will still work right you won't be able to make your own lutenizing exactly so so it might be the case that you're going to need something Upstream of that like Clomid to Kickstart it and then we're but again I 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 it I was my concern over this became like if you're going to be on this for 10 years is it problematic not if you're using this for a course of IVF or something like that so so again if if if we felt that someone's pituitary was not working I would be happy to put three months of Clone it on them to kind of try to see if we could blast it back do you have men cycle on and off testosterone at these low dosages are they taking a month vacation from it every yeah totally depends you know I was talking to a patient yesterday where we're going to do we just decided to change the cycle eight weeks on then eight weeks on HCG eight weeks on then 8 weeks on HCG so that's going to be a cycle that maintains his testosterone level but fluctuates between endogenous exogenous endogenous exogenous sometimes we'll just do testosterone on off on off and there it's like how much can he replenish naturally but understanding his 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 anavar right if you one could just drop hbg just the tiniest bit it seems like one could adjust the free t um in a in a way that would be great I don't know why that molecule is so hard to Target but somebody ought to do it the chemistry can't be that hard I talked with Patrick Arnold about this many many years ago um I wish I could remember what his idea he he he had a comment about this that at the time made sense and I don't remember what it was because I I had that thought too like man the when especially for that subset of guys who have normal testosterone but they're just overbinding it I'm really glad that you brought up this issue of total testost versus fre tea and the reason is um ever since going on podcast and talking about this stuff and talking about on this podcast uh people will send me their numbers they'll send me their charts and then they'll send photos of themselves and I can tell you while I'm not a clinician and I haven't done fancy statistics on it there's very little correlation between someone's absolute testosterone and how they appear I mean some of these guys look you know really lean really strong they'll say oh total testosterone is 550 480 right and then other people you know testosterone is 860 but they you look at them and you think oh they kind of have a kind of a doughy look to them and so it's got to be this free testosterone thing plus estrogen Etc training and nutrition too right I mean I just think I think for all this talk about testosterone which I enjoy talking about and you know I enjoy talking about the data on you know long-term Health consequences of testosterone because it's another controversial topic um I also think people kind of overstate its importance I agree um and I think there 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 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 insane physique like my best performance on a dexa scan would have been 30 I was 38 years old by dexa I was 7% body fat my fat-free mass index was like 23.2 23 3 kilog per meter squared I mean I was huge strong and totally ripped my testosterone was in the toilet I was overtraining like crazy I was you know exercising probably 26 hours a week killing it in the gym swimming like a banshee cycling like my life dependent on it grossly overtrained low tea but you know I mean physically look like twice the guy I am today you know today my tea is probably twice as high as it was then so you know now you could say well Peter what if you took tea back then how much better could you have been sure um but but again I think the take-home is just giving somebody tea doesn't do much of anything it probably helps on the insulin resistance front without any other thing but to me that's a waste like that's squandering the gift that it is giving you which is the ability to do more work and you know capture the benefit of it via muscle protein synthesis I agree and I think that the psychological effect of testosterone whether or not it's exogenous or endogenous is it makes effort feel good yeah at some level it really seems to do that and saoli tells me the main reason or mechanistically the main reason that it can do that is by adjusting levels of activity in the amydala and so there's some interesting Imaging there I'd love to chat more about the cholesterol pathway and I know this is a huge landscape as well but I think we're doing a good job of diving in deep but not getting stuck in the underlying currents at all there's tremendous debate about whether or not dietary cholesterol directly relates to or does not relate to serum cholesterol LDL and HDL here's my is there I think well let me put it this way there are people that argue I'm certainly not arguing there are people that argue that if one eats a ton of saturated fat that LDL goes up and HL go 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 um you know any increase in saturated fat intake is going to be bad that you already synthesize enough cholesterol for hormone production Etc I'd like to talk about this in terms of how one should read their charts um my LDL is in what I'm told is healthy range my HDL is in what I'm told is healthy range I do try and not overeat things like butter cheese and red meat but I do eat some of those things and I feel pretty good but most people are operating under the assumption that eating saturated fat is bad and you only do it in so far as you want to taste it um and then of course there's a small group of people that love to eat organs and meats and and really pack cholesterol um and would argue that doesn't matter if your LDL is 870 um it's not going to impact your health what's the reality around LDL HDL dietary cholesterol saturated fat uh at least in your view uh so first let's differentiate between cholesterol and fat just for the listener um because we use them so you know I don't want to make sure people understand so so cholesterol is a is a really complicated molecule so it's a ringed molecule um God I used to know exactly what its structure was but like it could have 36 carbons for all I remember um it is a lipid so it is a hydrophobic molecule that is synthesized by every cell in the human body uh it is so important that without it uh if you look at sort of genetic uh 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 uh 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 uh like a you know blowup ball right it's got to be able to kind of move in this way to mesh with other cells it also has to accommodate having porous structures that Traverse its membrane to allow ions and things like that to go across and it's cholesterol that gives the fluidity to that membrane it's also as you're alluding to the backbone of some of the most important hormones in our body estrogen progesterone testosterone cortisol um so we have this thing super important okay then let's talk about does cholesterol can you get cholesterol in your diet yes you can eat foods that are rich in cholesterol what was known in 1960 but somehow escaped everybody's imagination until finally the American Heart Association acknowledged this a few years ago is that the cholesterol you eat does not really make it into your body and the reason for that is it's hyeri 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 ocytes 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 Neiman pic C1 like one transporter the second is called the ATP binding cassette G5 G8 okay the Neiman pixie1 like one transporter will bring in any stero cholesterol Ze stero phytosterol any stero that fits through the door will come in virtually all all of that is the cholesterol we produce that gets taken back to the liver that the liver packages in bile and secretes so that's that's what AIDS in our digestion which is another thing I should have mentioned earlier in addition to using cholesterol for cell membranes and hormones we wouldn't be able to digest our food without cholesterol because it's what makes up the bile salts so our own cholesterol is basically recirculated in a pool throughout our body and this is the way it gets back into the body it's through this Neiman pixie1 like one transporter when it gets in there the body this is the checkpoint of Regulation this is where the body says do you have enough cholesterol in the body yes or no if yes I will let that cholesterol make its way into the circulation so it'll go off the basil lateral side of the cell not the luminal side into the body alternatively the body says you know what we have enough cholesterol I'm going to let you poop this out and now the ATP binding cassette will shoot it out it'll go back into the luminal side in a way it goes the so all of the cholesterol in our body is not aerified meaning it doesn't have that big bulky side chain attached to it the cholesterol you eat is aerified and an aerified cholesterol molecule simply can't physically pass through that Neiman pix C1 L one transporter now we probably manage to deify 10 to 15% of our dietary cholesterol so in other words there are small amounts of dietary cholesterol that do make their way into our circulation but it represents a small fraction of our total body's pool of cholesterol again this was known even by anel Keys the the the guy who turned fat into the biggest Boogeyman of all time anel 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 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 satat 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 what is saturated fat so saturated fat of course is a fatty acid just so people understand totally different molecule from cholesterol cholesterol is this very complicated ring structure multiple Rings stuck together SFA saturated fat is just a longchain fatty acid that is fully saturated meaning it has no double bonds and it can exist in isolation it can exist in a triglyceride triog glyceride or you know 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 um but again now it makes because if we're going to start talking about LDL we have to explain what LDL is this is another one of those things that's just so gross misunderstood that it's uh uh it makes having discussions about this very complicated um 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 it's water plasma is water so now you have this problem which is I want to transport cargo that is hydrophobic in a hydrophilic medium can't do it so if you think about all the things that we transport in our blood sodium electrolytes 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 A 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 electropheresis plate you'll you'll identify different densities the density is a function of how much protein and how much lipid is in it so the highest density of this is called a high density lipoprotein and the lowest density of this is called a very low density lipoprotein a LDL and then next to that you have an LDL a low density lipo protein and then next to that you have an IDL an intermediate density lipo protein so um you know it actually goes vldl IDL LDL but anyway so um when people say my LDL is high or my LDL is 100 what are they saying they're saying the cholesterol concentration of my LDL particles is 100 milligrams per deciliter so the total cholesterol concentration you have in your circulation is that number that says total cholesterol so if someone's blood panel says my total cholesterol is 200 it means that if you take all the lipoproteins in their circulation bust them open and measure the cholesterol content it's 200 milligrams per deciliter and for all intents and purposes because the idls are so short-lived that's basically the sum of your LDL cholesterol your vldl cholesterol and your HDL cholesterol those three things sum to your total cholesterol what about LDL little a that you mentioned earlier LP little a is 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 APO lipoprotein on it called APO lipoprotein little a got it um the other thing I'll just say on this because earlier I mentioned apob there are two broad families of lipoproteins there are those that are wrapped in apobs and those that are wrapped in APO as the apoa family is the HDL family the APO B family is the vdl IDL LDL family I see so for somebody who let's say their total cholesterol is let's just stay with 200 for Simplicity uh what do you like to see in terms of the HDL LDL ratio couldn't care less I only care about apob I only care about apob I care about the causitive agent of atherosclerosis APO 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 um what it depends 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 a 100 assuming some taper if you tell me you want to live to be 100 you're going to need to keep your apob below 30 Mill per deciliter let's say I want to live to be 100 but I ALS well how about I 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 it that way because if you're going to tell me that I'm in order to achieve that live to a 100 level I'm going to have to uh give up my personal life and my and my my brain functioning then then I'm not really interested in sure but but to to get LDL levels and really again people think of it as LDL it's really apob right apob is this total concentration of LDL and vldl and that's what matters those are the big arthrogenic particles LDL also includes um 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 apob and basically what it comes down to is you want apob to be as close to the level as it was when you were born so we start developing heart disease when we're born that's just the way it is um the autopsy studies make this abundantly clear when you look at autopsies of young people who are dying in their 20s and this was first done in the 1970s it was again repeated again it's always done after we have a war right so in the 1970s it was done on people you know who died in Vietnam in the early 2000s it was done on mostly young men but some young women who were you know dying in in Iraq and Afghanistan and we saw without any ambiguity that cardiovascular disease is already taking hold in people who are 18 19 20 years old wow and to be clear they aren't going to die of atherosclerosis at that age they're still 40 50 years away from it but this is a lifelong disease and we also know that the disease can't really develop until apob reaches a certain threshold and that's the threshold that most of us get to by the time we're 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 atherosclerosis so apob is necessary but not sufficient to develop ascvd now that go ahead oh I'm sorry I was just going to ask what are some of the top behavioral nutritional supplementation if any based and prescription drug based ways to Target apob well nutritionally you basically have two big tools right and it depends 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 clinically this is readily apparent to anyone who treats patients if you restrict carbohydrates you will reduce triglycerides that that just happens all day long but if you reduce triglycerides by raising fat intake so much it can still raise apob 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 apob while lowering carbohydrate and then see what you can get but here's the reality of it is there's nobody with dietary intervention that's going to get to a level of 30 milligrams per deciliter I mean I've never seen anything pure dietary intervention yeah so what are the other things be pharmacologic at this point Statin type inter well now you have multiple classes of drugs so the tried and true is the Statin so statins work by inhibiting cholesterol synthesis and the net effect of that is that the so the liver is really sensitive to cholesterol levels it doesn't want too much it doesn't want too little when you inhibit cholesterol synthesis the liver says I want more cholesterol so it puts more LDL receptors on its surface and it pulls the LDL out of circulation that's what lowers the LDL in the circulation um so you know again nine statins in use today we typically use four of them um the side effect profile contrary to kind of all the sort of Statin hating propaganda out there very benign right 5% of people experience muscle soreness which reverses upon cessation uh you know cognitive effects again I think it's ve in terms of actual comparing it and a placebo no effect whatsoever right so does that mean that you put a patient on it they won't complain of something no but if you look at clinical trials there's no evidence whatsoever that statins impair cognition there's also no evidence in clinical trials that they accelerate the risk of neurod degenerate disease in fact it's the opposite now we will there's a there's a very nuanced case we make Andrew which is we'll look at patients with highly suppressed desol levels we will back off we we do want to maintain desol above a certain level um because of some evidence that is still I think very preliminary but enough for us that we say why take the chance we have so many other tools to lower cholesterol why would we overs supress synthesis in a susceptible individual um so the next tool you look at is a drug that blocks the absorption or the reabsorption of cholesterol that remember that Neiman pixie one like one transporter so that guy has um a drug called aetam that just mechanically blocks it so in people and that's why I mentioned earlier we me we measure all those sterols in people so we also measure things called phytosterols and the phytosterols give us an indication of how active that transporter is so the higher your phytosterols the more likely you are to respond to zmod next class of drugs is a drug that blocks cholesterol synthesis but only in the liver so the Statin does it globally uh the this other drug called bidic 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 bidic acid bidic 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 uh is responsible for the degrad of LDL receptors this was first discovered in people who had a condition called familial hyper cholesterolemia or FH so these are people that have incredibly high cholesterol typically their CH total cholesterol level is 300 their LDL cholesterol is typically you know north of 200 milligrams per deciliter this is a disease that is defined by the phenotype not the genotype so the phenotype has a very clear definition which I basically just gave you the genotype is there's a million paths to get there there's over 3,000 mutations that are known to produce that phenotype this was discovered to be one of them in people who had hyperfunctioning PCI uh pcsk pcsk9 this protein was just constantly hammering and destroying the LDL receptors and so their LDL would be huge and by extension their total cholesterol would be so in 19 sorry in 2006 Helen Hobbs and colleagues discovered an opposite group of population people who had LDL cholesterol naturally of 10 to 20 milligrams per deciliter which would be an apob of about 20 milligrams per deciliter um and who never got heart disease they were immune to heart disease no matter how long they live and they had the opposite they had hypofunctioning pcsk9 and so that was 2006 the New England Journal of Medicine that basically got a whole bunch of drug companies Hot on the trail of producing a drug to mimic it so now we have these antibodies and they're wildly effective what percentage of your patients over 45 uh do you have on either a Statin or on one of these other well often it's in combinations and I would say 80% eight Z 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 say cardiovascular and and like how close is it so the the last year before co co kind of messes up these numbers a little bit but if you go to 20 2019 18.6 million people died of heart disease number two cancer 10 million like like nothing's 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 ascvd an orphan disease so so the question why more why don't hear more about this I realize there's some Nuance it's it's it's not straightforward it's not as simple as saying eat less cheese red meat and and watch your LDL get on a Staten but why do we hear so little about apob in the general discussion I'm not social media is such a a skewed landscape as we know um people shouting into tunnels of of uh varying uh Clarity you know some are beautiful bronze tunnels with clean walls and others are sewer lines right um and they all converge in the same place right as we know um but why do we hear so little about this I mean I'm not on a Statin um but now I'm beginning to think that maybe that might be a good idea to consider one of these other compounds I don't know the last time I looked at my apob specifically I'm guessing my physician did but um why don't we hear more about this this is this sounds so important sounds like the most important conversation because all the hormone stuff and all the stuff about um smoking and head injuries and ADHD and all the rest I mean is is irrelevant if you're dead right yeah um it's a great question I don't think I have a great insight as to why this isn't more front and center um I I think the bigger problem is why don't we even understand how to think about it I mean the the the and 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 causitive agent instead we look at uh modifying 10year risk so that's the fundamental difference between what I call medicine 2.0 and Medicine 3.0 medicine 2.0 which is what we're generally practicing today when it comes to ascvd says look we will treat you we will lower that LDL cholesterol they still don't talk about apob but that's a very American thing if you go outside of the United States everybody's talking about apob it's in the guidelines in Europe and Canada 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 um but but um but the the Paradigm is when your 10year risk reaches 5% when there's a 5% chance that you're going to have a heart attack stroke or die in the next 10 years now it's time to treat you uh medicine 3.0 says that's not the way to think about it you treat the causitive agent if there's a causitive 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 you treat smoking um and the reason that the risk model is so bad when you're looking at 10year risk is age is the biggest driver of risk I mean Bar None right so if you take a 70y old with perfect lipids and perfect blood pressure and perfect everything their 10-year risk of ascvd is probably four to five times higher than the most unhealthy 30-year-old it's not even close a lot like eye disease you know you there are exceptions of course but you always say that the biggest risk factor for going blind from glaucoma is being an older person frankly you know 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 sunglasses or you know using this type of ey or something like that has a negative impact I would rather know that sooner so that's the fundamental difference it's a philosophical difference with respect to prevention and I will acknowledge that in one element of prevention I make no consideration I am only coming at this through the lens of the individual I am never coming at this through the lens of society that makes my life easier and it makes the problem I'm solving easier I don't have to answer the quality adjusted lifeear problem I don't have to ask the question is it economical to treat people at 30 I don't know the answer to that question but I I also know that when you're trying to solve really complicated problems the more you can simplify the better so I've just acknowledged openly not solving that if you want to criticize me for it that's fine let's be transparent but all I care about is the person I'm sitting across from and in that situation it's really their decision if they can justify the cost of treatment an esoteric question and then a less esoteric question the esoteric question relates to something that I think is a little bit Niche but not necessarily so which is um 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 were I have to just tell you really thoughtful and I really appreciate that you're willing to share your own um tissue Rehabilitation experience and point people that because this is a landscape that a lot of people are in and they don't know how to navigate it and a mutual friend of ours not to be named sent me a text and said I'm going to be talking to AA and what do you know about studies on things like bpc157 this gastric peptide that anecdotally again anecdotally people report getting injections of this into shoulder knee Etc and feeling so much better so much faster but there really aren't good studies controlled studies and you hear all the same sorts of things about platelet rich plasma PRP which if someone tells you there are a lot of stem cells in in them they're lying there not a lot of stem cells in them and you also hear 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 Colombia and getting injections and what is your understanding or experience with things like bpc 157 specifically because peptides is a huge landscape we should probably do a whole episode on peptides um things like PRP um PRP is now approved for I mean women are get injections of this into their ovaries to improve uh follicle count we know this um people are getting injections of PRP into every tissue and organ in Hell men are getting injected in their penis so I hear um for all sorts of reasons that are unclear to me um what's the deal with PRP bpc157 and stem cells do you ever see interesting effects are you curious about these um compounds do you prescribe or direct people towards these the FDA approved ones of course yeah so 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 uh PRP less so uh 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 rap ay as an example right I'm a huge proponent of rap ayon and you can say well Peter how can you take or prescribe rap ay for geroprotective effects when we do not have a human clinical trial demonstrating that it lengthens life and the answer is because I have 84 other pieces of data that all point in the same direction across every model organism going back more than a billion years and that's really different from Joey Sammy and Sally did this thing and I think it works and they just can't be compared now I have no idea if stem cells work I have no idea if bpc157 works I have no no idea frankly if PRP even works though it might seem to have some efficacy and some indications for example maybe when it comes to early hair loss maybe when it comes to you know certain joint um issues um but the reality of it is like I think we just have to accept the fact that everything we do has an opportunity cost and that opportunity cost is sometimes Financial but I actually find a lot of times it's in time and effort and energy that goes into something now when I was you know waiting to get my shoulder surgery this is an injury that I've had forever right this is an injury you know I've I 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 tells you how long I've had this injury um 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 would in infusing a million stem cells into it work um and in speaking with as many orthopedic surgeons as I could the answer was kind of unambiguously no and by the way it doesn't mean you wouldn't feel better if I injected a bunch of stem cells into your shoulder there are a lot of reasons that might make you feel better just like there are a bunch of reasons you can feel better if somebody injects saline directly into your joint yeah so so the 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 if you took a thousand people with my particular injury and injected them with stem cells it wouldn't do a thing because of the nature of my injury I had a complete laboral tear um 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 10% of your patient population that was the right patient population to get that so you know will we ever get there I don't know because I don't see what the incentive is right you have people who are making money Handover fist doing procedures on the basis of I'm not sure what what would their motivation or incentive be to to sort of see this legitimized uh you'd really have to be able to say well there there really needs to be sort of a Pharma angle to this um it it's sort of one of the wishes I had right like if I was if I was a a billionaire I feel like the way I would probably waste all of my money would be running clinical trials on stuff nobody cared about yeah it just likewise I join you because that would be there yesterday we courted a sit down with somebody from Caltech who works on uh 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 on to a long description of why none of these drugs exist on the market for the treatment of psychiatric illness and yet probably would work um and what's missing is a billionaire or a billion dollar company that is willing to invest in something that very likely will work but the market value isn't quite there or it failed in a previous trial and so no one wants to touch it with a 10-ft pole um hopefully someone listening to this will be incentivized to provide this sort of a venue for that uh the kind of work that we're talking about I have to ask but but I want to make one other point Andrew which is to me the problem with a lot of these things is it gets it it's a crutch you know it's sort like what we talked about with like hey just fix my tea man and everything's going to be fine and it's like no that's just the beginning you know what I worry about when I see people who are clamoring for this stuff is a lot of times they don't realize that whether it's psychologically or otherwise they sort of say well now that I've had this thing done I don't have to do the hard work of the real rehab I mean if I've learned anything through my shoulder surgery and I'm now three and a half months out how'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 dead lifs I mean I don't know maybe 9 months but it's you know I'm not there yet but what I learned through a really amazing prehab and Rehab process is like you just got to do the work and it's freaking hard shoulders are the most tedious boring thing in the world I mean three days a week I am doing four days a week I am doing one hour of just dedicated stuff for this shoulder that is super super uncomfortable super boring super frustrating um but I I mean I have faith in the methodology right and and I think a lot of people are saying just shoot the stem cells into me and I don't have to do any of that stuff and the reality of it is I I think that's a very dangerous place to be have you ever tried bpc 157 um yeah we tried it um we had you know again maybe seven eight years ago we had a bunch of patients ask about it so you you know my view is okay I was prettyy 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 we did it for I don't know a couple months I didn't notice a single thing interesting well thank you for that um shifting to a less esoteric but uh and I think probably more important topic overall metabolomics talking about this before we sat down to record what what is what are metabolomics why should we be thinking about them uh I have some idea of what it might be about uh but most people I think are not thinking about metabolomics at all and for those that are I'm sure they could learn more so tell us about metabolomics and what you'd like to see more of in the world of metabolomics yeah so omix is just the term that we use to describe the study of of of something so genomics right is like the broad steady of genes and uh you know proteomics the broad steady of proteins and things like that so so metabolomics is the study of metabolites and metabolites unlike a lot of these other things they they're a relatively finite number of these things uh many of which are known but some of which are not known so glucose is a metabolite acetyl COA is a metabolite lactate is a metabolite and so the 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 so let's use two extreme examples like exercise everybody understands the data are unambiguously clear exercise produces about the most favorable phenotype imaginable so if you wanted to take a genomics approach to understanding that you might look at is there a change in the genome when you exercise the answer is you know probably not but maybe maybe if you looked at the you know methylation patterns in epigenome you could look at epigenomic studies um but you might instead look at kind of the proteomic side of that like what is gene expression doing and there you would see a lot of changes well what I don't think people are really understanding although there was a very interesting paper that just came out um two weeks ago that looks for novel metabolites that are changing is there a huge signal in a metabolomic profile that looks different in the state of exercise versus non-exercise and could that represent part of how exercise is transmitting its benefit through the body um you know people always talk about the Holy Grail of metabolomics would be can you find a pill to mimic exercise and I think the answer that question is going to be undoubtedly no um for 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 metabolomics is is you know relatively untapped um and and I think you know potentially the next sort of Frontier speaking of Frontiers I hear a lot nowadays about gp1 and pharmacology that prescription drugs that mimic or increase gp1 directly um glucagon like peptide uh 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 uh favorably since the discussions of fenfen when I was in college and then of course fenfen was pulled from the market um because people were dying uh not left and right but enough people died that they pulled it from the market which by the way is an interesting uh story you know it was the en anomer that they chose to use that was the wrong en anomer and what it result Ed in was um God I think it was like a mitro valve collapse was an MVP yeah it was something in the mitro valve um yeah I think the cord tendon were rupturing in the mitol valve um and and and it was mostly young women I think were getting you know horrible pulmonary disease as a result of it probably pulmonary hypertension or something like that um but there were you know there were two en anomers of the drug and had they just used the other one this issue wouldn't have happened and there was a stupid reason why they made the choice to use the one they did and it's one of those things where once you make the mistake you're never going back it's not like that company could say okay we want to do over but we're going to do it with the right version so uh it's a tragic outcome uh but but you're absolutely right I think the glp1 agonists are have more efficacy um and you know for all intensity and for everything we can see certainly seems 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 uh they're not they're not Miracle drugs right they come with s 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 just sent all the the uh Jim jockeys running from semag gluten and all that's all you have to say all you have to say nowadays about something is that it's going to drop testosterone lower fertility change someone's skin hair or nails and it's like people it could extend life to being 250 years old and people are gone humans are humans that's a that's a neuroscience and psychology issue not a not a a biology medicine issue um but I'm 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 about them it takes a while to get people up to dose so if you're looking at semaglutide the dose that was studied um so did a one-year trial or maybe was a little over that maybe 60 weeks but it took about 16 weeks to get the patients comfortably up to 2.4 milligrams weekly which was the dose that they ultimately stayed on in our experience when we use it we don't even usually go up to 2.4 milligram we can usually get enough benefit between 1 and 2 Mig and we usually move people along a little bit quicker but we've definitely had our share of patients who can't tolerate it due to the nausea interesting which might be part of how it's working right is the sort of suppression of appetite which if taken to an extreme can produce nausea interesting yeah I think most of the effective of semaglutide is Central not peripheral huh so I don't know I saw one paper that uh glp1 is acting both on cells in in the periphery um to cause gut distension in some ways or sort of make people feel full through promotion of of literally mechano receptors that make people feel as if their stomach is distended even though their stomach is empty and then perhaps some Central hypothalamic effects is that yeah I I think it's doing I would bet 80% of it's in the hypothalamus um 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 um versions of these that seem to be more longlasting so right now if you look at coming off semaglutide you're going to see a weight regain so there's newer versions that seem to preserve the weight loss even off the drug so it begs the ultimate question which is like what's the What's the total use case for this going to be is this going to be a drug you cycle on and off or is it going to be a drug that a person has to stay on indefinitely and if so will they become tachy filac 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 describ testosterone and estrogen therapies that it would allow people to do more of the behavioral work that's absolutely required for health span and lifespan yep and we've also seen on the flip side of that you can cheat through semaglutide right 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 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 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 um 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 of the drug that way interesting I so appreciate your aners today first of all they were incredibly thorough um and pointed towards real world application um I also just want to thank you more broadly for the work that you do because obviously you have this um incredible clinical experience and 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 I did you do a PhD as well no but I consider you a scientist clinician clinician scientist is the appropriate wording of that of course in the way that you really still drill into studies in detail I know a lot of clinicians not all of them do that um for sure and the fact that you're so hungry for the new incoming knowledge as well as the the old literature so uh it's an incredibly Rich data set in that brain of yours and I really appreciate you sharing it with us both in your podcast in the upcoming book which I think that we'll certainly have you on here again um in anticipation of that but I know I and a ton of other people are really excited for the book and in the way that you approach social media and 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 AA all about the things that we can do in order to maximize our lifespan and health span I highly recommend people check out Dr aa's podcast the drive it is excellent as you can imagine based on today's conversation and it's easily available on Apple podcast Spotify overcast and Google please also check out Dr aa's website it's Peter aam md.com there you can find links to his podcast episodes as well as a sign up for his excellent Weekly Newsletter that newsletter provides terrific information 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