back to indexDr. Peter Attia: Exercise, Nutrition, Hormones for Vitality & Longevity | Huberman Lab Podcast #85
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Welcome to the Huberman Lab Podcast,
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where we discuss science and science-based tools
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for everyday life.
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I'm Andrew Huberman,
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and I'm a professor of neurobiology and ophthalmology
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at Stanford School of Medicine.
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Today, my guest is Dr. Peter Attia.
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Dr. Attia is a physician who's focused on nutritional,
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supplementation-based, behavioral, prescription drug,
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and other interventions that promote healthspan
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His expertise spans from exercise physiology
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to sleep physiology,
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emotional and mental health, and pharmacology.
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Today, we talk about all those areas of health,
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starting with the very basics,
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such as how to evaluate one's own health status
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and how to define one's health trajectory.
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We also talk about the various sorts of interventions
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that one can take in order to optimize vitality
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while also extending longevity, that is, lifespan.
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Dr. Attia is uniquely qualified
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to focus on the complete depth and breadth of topics
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And indeed, these are the same topics
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that he works with his patients on in his clinic every day.
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Dr. Attia earned his bachelor of science
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in mechanical engineering and applied mathematics
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and his MD from Stanford University School of Medicine.
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He then went on to train at Johns Hopkins Hospital
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in general surgery,
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one of the premier hospitals in the world,
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where he was the recipient of several prestigious awards,
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including resident of the year.
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He's been an author on comprehensive reviews
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of general surgery.
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He spent two years at the National Institutes of Health
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as a surgical oncology fellow
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at the National Cancer Institute,
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where his work focused on immune-based therapies
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In the fields of science and medicine,
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it is well understood that we are much the product
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of our mentors and the mentoring we receive.
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Dr. Attia has trained with some of the best
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and most innovative lipidologists, endocrinologists,
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gynecologists, sleep physiologists,
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and longevity scientists in the United States and Canada.
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So the expertise that funnels through him
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and that he shares with us today
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is really harnessed from the best of the best
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and his extensive training and expertise.
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By the end of today's episode,
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you will have answers to important basic questions
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such as, should you have blood work?
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How often should you do blood work?
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What specific things should you be looking for
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on that blood work that are either counterintuitive
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or not often discussed and yet that immediately
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and in the long-term influence your lifespan
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We talk about hormone health and hormone therapies
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for both men and women.
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We talk about drug therapies that can influence the mind
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as well as the body.
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And of course, we talk about supplementation, nutrition,
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exercise, and predictors of lifespan and health span.
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It is an episode rich with information.
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For some of you, you may want to get out a pen and paper
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in order to take notes.
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For others of you that learn better simply by listening,
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just want to remind you that we have timestamped
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all this information so that you can go back
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to the specific topics most of interest to you.
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I'm pleased to announce that the Huberman Lab Podcast
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is now partnered with Momentous Supplements.
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We partnered with Momentous for several important reasons.
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First of all, they ship internationally
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because we know that many of you are located
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outside of the United States.
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Second of all, and perhaps most important,
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the quality of their supplements is second to none,
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both in terms of purity and precision
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of the amounts of the ingredients.
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Third, we've really emphasized supplements
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that are single ingredient supplements
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and that are supplied in dosages that allow you
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to build a supplementation protocol that's optimized
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for cost, that's optimized for effectiveness,
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and that you can add things and remove things
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from your protocol in a way that's really systematic
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If you'd like to see the supplements
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that we partner with Momentous on,
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you can go to livemomentous.com slash Huberman.
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There you'll see those supplements and just keep in mind
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that we are constantly expanding the library
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of supplements available through Momentous
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on a regular basis.
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Again, that's livemomentous.com slash Huberman.
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Before we begin, I'd like to emphasize that this podcast
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is separate from my teaching and research roles at Stanford.
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It is, however, part of my desire and effort
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to bring zero cost to consumer information about science
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and science-related tools to the general public.
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In keeping with that theme,
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I'd like to thank the sponsors of today's podcast.
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Our first sponsor is Thesus.
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Thesus makes custom nootropics that are designed
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for your unique needs.
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And to be honest, I'm not a fan of the word nootropics
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because nootropics means smart drugs.
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And to be honest, there is no such thing as a smart drug
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because there's no neural circuit for being smart.
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There are neural circuits rather for being creative
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or for task switching or for focus.
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As we all know, different sorts of demands,
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whether or not they are cognitive or physical,
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require different types of cognitive and physical abilities.
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Thesus understands this and has created a kit
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of custom nootropics that are tailored to your needs.
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To get your own personalized nootropic starter kit,
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you can go to takethesus.com slash Huberman,
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take their three-minute quiz,
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and Thesus will send you four different formulas
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to try in your first month.
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That's takethesus.com slash Huberman
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and use the code Huberman at checkout
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to get 10% off your first box of custom nootropics.
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Today's episode is also brought to us by InsideTracker.
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InsideTracker is a personalized nutrition platform
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that analyzes data from your blood and DNA
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to help you better understand your body
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and help you reach your health goals.
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I've long been a believer in getting regular blood work done
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for the simple reason that many of the factors
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that impact your immediate and long-term health
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can only be assessed from a quality blood test.
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And nowadays with the advent of modern DNA tests,
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you can also analyze, for instance,
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what your biological age is and compare it
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to your chronological age.
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And obviously it's your biological age that really matters.
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The challenge with a lot of blood tests and DNA tests,
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however, is that you get information back
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about metabolic factors, hormones, and so forth,
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but you don't know what to do with that information.
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InsideTracker makes it very easy to know what to do
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with that information to optimize your health.
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They have a personalized platform.
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It's a dashboard that you go to.
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You can click on the level of any hormone,
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metabolic factor, lipid, et cetera,
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and it will tell you the various sorts of interventions
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based on nutrition, supplementation, et cetera,
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that you can use to bring those numbers
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into the ranges that are ideal for you.
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If you'd like to try InsideTracker,
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you can visit insidetracker.com slash Huberman
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to get 20% off any of InsideTracker's plans.
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That's insidetracker.com slash Huberman to get 20% off.
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Today's episode is also brought to us by Helix Sleep.
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Helix Sleep makes mattresses and pillows
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that are of the absolute highest quality.
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They also have some really unique features
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because they are customized to your unique sleep needs.
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I've talked over and over again on this podcast
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and on another podcast about the fact
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that sleep is the foundation of mental health,
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physical health, and performance.
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There's just simply no other substitute
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for a quality night's sleep on a regular basis.
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I've been sleeping on a Helix mattress
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for well over a year now,
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and it's the best sleep that I've ever had.
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And that's in large part
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because the mattress was designed for me.
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What you need to know, however,
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is what's the ideal mattress for you?
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And you can do that by going to Helix site.
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You can take their brief quiz, which will ask you,
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do you sleep on your side, your back, your stomach,
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or maybe you don't know, or maybe all three,
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do you tend to run hot or cold in the night?
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Maybe you know, maybe you don't.
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At the end of that short quiz,
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they will match you to the ideal mattress for you.
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I matched to the DUSK, the D-U-S-K mattress,
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but again, that's what I need.
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That's not necessarily what you need
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in order to get your best night's sleep.
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But if you're interested in upgrading your mattress,
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go to helixsleep.com slash Huberman,
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take their two-minute sleep quiz,
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and they'll match you to a customized mattress for you.
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They'll even pick it up for you if you don't love it,
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but I'm certain you will.
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Again, if you're interested in,
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you go to helixsleep.com slash Huberman
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for up to $200 off your mattress order and two free pillows.
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And now for my discussion with Dr. Peter Attia.
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Peter, thanks for joining me today.
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Thanks for having me, man.
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I've been looking forward to this for a very long time.
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I'm a huge fan of your podcast.
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I know that you went to Stanford
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and worked with a number of people
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that are colleagues of mine.
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So for me, this is already a thrill just to be doing this.
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Yeah, well, likewise.
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I have a ton of questions,
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but I want to start off with something
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that I wonder a lot about
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and that I know many other people wonder about,
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which is how to assess their current health
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and their trajectory in terms of health and wellbeing,
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specifically as it relates to blood work.
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So what are your thoughts on blood work?
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Is it necessary for the typical person?
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So this is somebody who's not dealing
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with some acute syndrome or illness.
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And at what age would you suggest
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people start getting blood work?
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How frequently should they get blood work?
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How often do you get blood work done, et cetera?
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Yeah, there's a lot there.
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I mean, the way I talk about this with patients
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is first taking everything back to the objective.
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So what's the thing we're trying to optimize?
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So if a person says,
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look, I'm trying to break 10 hours for an Ironman,
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I don't know that blood work is going to be
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a game-changing aspect of their trajectory
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and their training.
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They're going to benefit much more
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from sort of functional analysis of performance.
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So I'm assuming based on the question
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that you're really coming at this through the lens
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of living longer and living better
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through the lifespan, healthspan lens?
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Yeah, and just, I think most people have some sense
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of their vitality or lack of vitality,
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but I think everyone wonders
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whether or not they could feel better
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and whether or not blood work will give them a window
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into how they might go about feeling better.
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Yeah, I think it does to some extent,
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but I also think that it has a lot of blind spots.
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So I kind of break things down into the two vectors
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that make up longevity, which are lifespan and healthspan.
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So lifespan is the easiest of those vectors to understand
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because it's pretty binary, right?
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You're alive or you're not alive,
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you're respiring or you're not,
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you make ATP or you don't, end of story.
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So what gets in the way of lifespan
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is essentially the four horsemen of disease, right?
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So atherosclerotic disease, cancer, neurodegenerative disease
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and metabolic disease,
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which directly isn't the cause of many deaths,
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but basically creates the foundation
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to all of those other diseases.
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So if you're a non-smoker, what I just rattled off
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is about 80% of your death.
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So how does blood work help address those?
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So on the atherosclerotic standpoint,
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it's a very good predictor of risk
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if you know what to look for.
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So primarily ApoB would be the single most important
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lipoprotein that we care about.
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I gotta explain what that means in a second.
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And then also other markers of inflammation,
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endothelial health and metabolic health.
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When it comes to cancer, blood testing
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in the sense of biomarkers is not particularly helpful
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outside of knowing that the second leading environmental
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or modifiable cause of cancer
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is metabolic ill health after smoking.
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So we don't actually know a lot about cancer
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in the sense of what causes it.
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It's really stochastic and it's a lot of bad luck.
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So we know that smoking drives it
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and we know that even though epidemiologically
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we say obesity drives it,
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what it really means is metabolic poor health.
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It's probably the hyperinsulinemia
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that comes with obesity that drives it.
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So biomarkers help with that,
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but there's still an enormous blind spot to cancer.
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We could talk about liquid biopsies aside
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because those aren't really biomarker studies,
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but put that away.
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On the neurodegenerative side,
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I don't think we have a lot of insight
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that comes to understanding Parkinson's disease,
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but when it comes to dementia,
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particularly the Alzheimer's disease,
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which is the most prevalent form of dementia,
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I think the biomarkers can be quite helpful.
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They overlap a lot with the atherosclerotic diseases.
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So the same things that drive the risk of heart disease
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are driving the risk of dementia.
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And then there's some novel stuff as well.
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If you include genetic testing,
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which you can get out of a blood test,
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we get a whole suite of genes, not just APOE,
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but far more nuanced stuff than that
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that can also play a role.
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So you can stratify risk in that sense.
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So in aggregate, I would say blood testing of biomarkers
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provides pretty good insight into lifespan.
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When you get into healthspan,
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you have kind of the cognitive, physical, emotional domains.
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I think here the biomarkers are far less helpful,
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and here we kind of rely more on functional testing.
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So when it comes to sort of the cognitive piece,
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you can do cognitive testing.
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In terms of long-term risk,
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a lot of the things that imply good cognitive health
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as you age are in line with the same things
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that you would do to reduce the risk of dementia.
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So all the biomarkers that you would look to improve
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through dementia risk reduction,
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you would be improving through cognitive health.
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On the physical side, I mean,
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outside of looking at hormone levels and things,
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which we look at extensively,
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and understanding how those might aid in
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or prevent some of the metrics that matter,
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it really is, this is a biomarker aside thing.
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I mean, I'd be much more interested
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in a person's DEXA, CPET testing, VO2 max testing,
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zone two lactate testing, fat oxidation,
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those what I would consider more functional tests
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that give me far more insight into that.
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And then of course the emotional piece,
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which depending on who you are,
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might be the single most important piece
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without which none of this other stuff matters,
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right, if you're a totally miserable human being,
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your relationships suck.
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I don't think any of this other stuff matters.
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And certainly there's nothing that I'm looking at
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in biomarkers that's giving me great insight into that.
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Do you ask about emotional state
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or do you try and assess emotional state indirectly
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when you do an intake with one of your patients?
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Probably not so much in the intake
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because I think it takes a while
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to form a relationship with a patient
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before that starts to become something
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that they're necessarily gonna wanna talk with you about.
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But I definitely think of it
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as an important part of what we do.
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And I think without it,
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none of this other stuff really matters.
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Again, the irony of thinking about
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how many years I spent sort of in pursuit
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of fully optimizing every detail of everything
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without any attention being paid to that dimension
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is not lost on me.
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And look, there are some patients who,
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that's just not something that,
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that's something that's compartmentalized.
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Maybe they're doing well in that department
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or maybe they aren't,
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but they just aren't willing to engage on that yet.
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In terms of frequency of blood testing,
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if somebody feels pretty good
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and is taking a number of steps,
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exercise, nutrition, et cetera,
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to try and extend lifespan and improve health span,
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is once a year frequent enough?
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And should a 20-year-old start getting blood work done
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just to get a window into what's going on,
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assuming that they can afford it
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or their insurance can cover it?
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Yeah, I mean, look,
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I certainly think everybody should be screened early in life
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because if you look at like what's the single most prevalent
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genetic driver of atherosclerosis is Lp little a.
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So unfortunately, most physicians don't know
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what Lp little a is,
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and yet somewhere between 8 and 12% of the population
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has a high enough,
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and depending on who you,
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I had a recent guest on my podcast
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who suggested it could be as high as 20%
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have a high enough Lp little a
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that it is contributing to atherosclerosis.
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So to not want to know that
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when it's genetically determined, right?
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This is something that you're born with this
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and you only need to really check it once.
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Why we wouldn't want to know that in a 20-year-old
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when it can contribute
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to a lot of the early atherosclerosis we see in people.
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It's leaving money on the table, in my opinion.
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The frequency with which you need to test
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really comes down to the state of interventions.
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I don't think it makes sense to just do blood tests
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for the sake of doing blood tests.
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There has to be kind of a reason.
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Is something changing?
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A blood test is, for the most part, a static intervention.
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It's a look at a window in time,
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and there's benefit in having a few of those
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over the course of a year if you're unsure about a level.
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So if something comes back and it doesn't look great,
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yeah, it might make sense just to recheck it
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without reacting to it.
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But typically, in patients,
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we might check blood two to four times a year,
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but we're also probably doing things in there
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to now check, like, hey, we gave this drug.
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Did it have the desired outcome?
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You put on three pounds of muscle
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and lost three pounds of fat.
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Did it have the desired outcome?
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Speaking of tracking weight and fat lean mass percentages,
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is that something that you recommend
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your patients do pretty often?
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I know people that step on the scale every day.
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I know people like myself that, frankly,
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I might step on the scale three times a year.
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I don't really care.
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I pay attention to other things
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that are far more subjective.
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Maybe I'm making a huge mistake.
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What are your thoughts about quantitative measurements
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of weight BMI for the typical person?
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I think they're pretty crude.
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I think a DEXA, I'd rather take a DEXA annually
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and then maybe follow weight a little bit more closely
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to get a sense of it.
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And so with a DEXA, you're getting,
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at least the way we look at the data,
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four pieces of information.
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Now, most people, when they do a DEXA,
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should I explain what that is?
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Yeah, I think some people might not know what DEXA is.
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In fact, I confess I have a crude understanding
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Tell me where I'm wrong
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and hopefully where I'm at least partially right.
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My understanding is that there are a number of different ways
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to measure lean mass to non-lean mass ratio.
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And there's one where they put you underwater.
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There's one where they put you
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into some sort of non-underwater chamber.
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There's calipering.
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And then there's the looking in the mirror
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and pinching and changing the lighting.
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It's funny, if you've done it enough,
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I can sort of tell my body fat by my abs, right?
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So I can sort of tell by how good the six pack
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or how bad the six pack is, what the leanness is.
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And that's actually not a terrible way to do it.
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A bodybuilder, for example, which I've never been,
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can tell you the difference between being 6%, 7%, 8%, 10%,
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just based on the degree of visibility within the abs.
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But basically a DEXA scan is an X-ray.
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So it's the same principle as just getting a chest X-ray
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where ionizing radiation is passed through the body
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and there's a plate behind the body
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that collects what comes through.
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And the denser the medium
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that the electrons are trying to go through,
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the less of them that are collected.
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So when you look at an X-ray,
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as everybody's probably seen an X-ray,
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that which is white is most dense.
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So if you had a piece of metal in your pocket,
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it would show up as a bright white thing.
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That's why ribs and bones show up as white.
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And the things that are the least dense,
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like the lungs where it's just air, are the blackest.
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And everything is a shade of gray in between.
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So a DEXA is just doing that effectively,
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but it's a moving X-ray.
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So you lay down on a bed and it takes maybe 10 minutes
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and this little very low power X-ray
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kind of goes over your body.
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And the plate beneath it is collecting information
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that is basically allowing it to differentiate
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between three things.
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Bone mineral content, fat, other.
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And the other is quantified as lean body mass.
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So that's organs, muscles, everything else.
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So when most people do a DEXA,
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they get the report back and the reports are horrible.
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I've yet to see one company that can do this
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in a way that isn't abjectly horrible.
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We've created our own templates.
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We have our own dashboard for how we do this
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because we've just given up on trying to use theirs.
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But the first thing most people look at
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is what's my body fat?
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And this is the gold standard outside of like MRI
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or something that's only used for research purposes.
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So a DEXA is going to produce a far better estimate
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of body fat than calipers or buoyancy testing
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or things like that, provided the machinery
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is well calibrated and the operator knows how to use it.
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I've heard some people argue that in the hands
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of the guy who's been doing calipers his whole life,
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it could probably be comparable with calipers.
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But nevertheless, for an off the shelf tech,
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Of the four things that get spit out of the DEXA,
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we think that the body fat is the least interesting.
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And so I would rank that as fourth on the list
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of what's germane to your health.
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The other three things that you get spit out
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are bone mineral density, visceral fat,
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and then the metrics that allow you to basically compute
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what's called appendicular lean mass index
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and fat free mass index.
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And so those three metrics are significantly
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more important than body fat.
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And the reason is as follows, right?
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So bone mineral density basically speaks
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to your risk of osteoporosis and osteopenia.
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And that doesn't sound very sexy to people our age,
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you know, 50 year old guys listening to this,
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it's like, yeah, big deal.
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But for a 50 year old woman, this is a huge deal, right?
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A woman who's just about to go through menopause
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or has just gone through menopause is at an enormous risk
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for osteopenia and then ultimately osteoporosis.
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Because estrogen is the single most important hormone
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in regulating bone mineral density.
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And we can come back and talk about why that's the case,
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but it's very interesting how the biomechanics
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of bones work and why estrogen specifically is so important.
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And this is a huge cause of morbidity, right?
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So, you know, if you're over the age of 65
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and you fall and break your hip,
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your one year morbidity is about 30 to 40%.
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Which again, just to put that in English,
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if you're 65 or older, you fall and break your hip,
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there's a 30 to 40% chance you're dead in a year.
link |
So we want to really get a sense of where you stack up
link |
for your age, for your sex, and if you're anywhere
link |
off the pace, we have to ramp up our strategy
link |
and be super aggressive about how to increase that
link |
or at a minimum, prevent any further decay.
link |
And are there age related charts for these sorts of things?
link |
Yeah, this all gets spit out into what's called a z-score.
link |
So when you're looking at your BMD,
link |
it's gonna give you a z-score.
link |
So a z-score of zero means, and you understand this,
link |
but it's z-score referring to a probability distribution
link |
in a standard mode.
link |
So z-score of zero means you're at the 50th percentile
link |
for your age and sex.
link |
A z-score of plus one, your one standard deviation above,
link |
minus one below, et cetera.
link |
There's also a t-score, which is doing the same thing,
link |
but comparing you to a young person.
link |
And so the t-score is technically used to make the diagnosis
link |
of osteopenia or osteoporosis.
link |
We tend to look more at the z-score and basically say,
link |
look, if your z-score right now is minus one in four years,
link |
I want your z-score to be zero.
link |
Not necessarily because you've increased that entire way,
link |
but maybe you've increased slightly
link |
while it's expected that you would have declined.
link |
What are some things that we can do
link |
to improve bone mineral density at any age?
link |
So it turns out there's a real critical window
link |
in which we are malleable.
link |
So depending on the age at which someone's listening
link |
to us discuss this, if you're under 20, 25,
link |
you are still in that time of your life
link |
when you are able to reach your potential.
link |
So it turns out that strength training is probably
link |
the single best thing you can do.
link |
And this was a surprise to me,
link |
because we did an AMA on this topic a little while ago,
link |
and that's when I got really deep on this with our analysts.
link |
My assumption was running must be the best.
link |
Some sort of impact must be the best thing you can do.
link |
I assumed running would be better than swimming and cycling,
link |
but it turned out that powerlifting
link |
was probably the best thing you could do.
link |
And I think once you understand how bones work,
link |
it became more clear, which is,
link |
powerlifting is really putting more of a shear force
link |
from the muscle via the tendon onto the bone.
link |
And that's what the bones are really sensing.
link |
They're sensing that shear force that's being applied
link |
through the bone, in a compressive way,
link |
depending on the bone, of course.
link |
And that's what's basically activating the osteoblasts,
link |
which are the cells that are allowing bone to be built.
link |
So this turns out to be probably more important for females,
link |
because how high you can get
link |
during that period of development,
link |
say till you're 20 or 25,
link |
basically sets your trajectory for the rest of your life.
link |
So where we get into real trouble is with patients who,
link |
for example, used large amounts of inhaled steroids
link |
during that period of their life,
link |
because let's say they had really bad asthma.
link |
Or patients who needed large amounts of corticosteroids
link |
for some other immune-related condition.
link |
So during their critical window of development,
link |
they were taking a drug that was impairing this process.
link |
So we have some patients like that in our practice,
link |
and that's just an enormous liability
link |
that we're working really hard to overcome,
link |
with nutrition, with hormones, with drugs, with training.
link |
And it's just something you have to be aware of.
link |
I wasn't aware that inhalants for asthma
link |
and things of that sort can impair bone mineral density.
link |
Yeah, they're steroid-based.
link |
Some of them, of course, are just beta agonists,
link |
So anything corticosterone-like, interesting.
link |
And then I always get asked this question,
link |
and I always reflexively want to say no,
link |
but I don't really know the answer, so I don't reply.
link |
What about topical corticosterone?
link |
People will put cortisone cream.
link |
To me, it seems almost inconceivable
link |
that it would have a systemic effect,
link |
but then again, what do I know?
link |
It's all docent and time-related.
link |
So if you're talking about like,
link |
I've got a little rash under my skin,
link |
I'm gonna put corticosteroids on, probably not.
link |
But certainly with enough of it put on,
link |
I mean, it is absorbed, so it could be an issue.
link |
But that's not typically what we're concerned with.
link |
I mean, we're mostly concerned with people
link |
that are taking even modest amounts of prednisone
link |
for months, years at a time,
link |
or like I said, kids that are using steroid inhalers
link |
for years and years and years.
link |
Again, I'm not suggesting that if your kid's
link |
on a steroid inhaler, they shouldn't be.
link |
You have to solve the most important problem,
link |
and if asthma is the most important problem, so be it.
link |
I think you just want to turn that into,
link |
okay, well, how much more imperative is it
link |
that our kid is doing things that are putting
link |
a high amount of stress on their bones
link |
and via their muscles to make sure
link |
that they're in that maximal capacity to build?
link |
Do you think that somebody in their 30s or 40s or 50s
link |
could still benefit from strength training
link |
in terms of bone mineral density and longevity
link |
as it relates to bone mineral density,
link |
given that there was this key window earlier,
link |
they might've missed that window?
link |
Oh yeah, no, no, this is essential for the rest of life
link |
because you're now trying to prevent the fall off.
link |
So basically the way it works is you're sort of,
link |
from birth to say 20, you're in growth.
link |
From 20 to 50, you plateau.
link |
At 50, men start to decline, but it's really small.
link |
Women start to decline, and it's precipitous.
link |
And it's related to the drop in estrogen
link |
associated with menopause or pre-menopause?
link |
And can we get into any of the broad contours
link |
of what that strength training looks like?
link |
We had Dr. Andy Galpin on the show.
link |
He talked a lot about ways to build strength
link |
versus hypertrophy versus endurance, et cetera.
link |
I think there's pretty good agreement across the fields
link |
of physiotherapy, et cetera, of physiology and medicine
link |
in terms of how to do that.
link |
But my understanding is fairly low repetition ranges.
link |
So this is anywhere from one to six repetitions,
link |
typically not aiming for a pump hypertrophy,
link |
that sort of thing, but heavy loads that are hard to move.
link |
80% of one repetition maximum or more
link |
done with long rest periods,
link |
two to three times a week type thing.
link |
Is that about right?
link |
Yeah, if you look at the literature on this,
link |
it's going to tell you,
link |
it's going to differentiate powerlifting from weightlifting.
link |
In other words, yeah, you do need to be kind of moving
link |
against a very heavy load.
link |
Now, again, that can look very different
link |
depending on your level of experience.
link |
I really like deadlifting.
link |
Now, I can count the number of days left in my life
link |
when I'm going to want to do sets over 400 pounds,
link |
but I'll pick and choose the days that I do.
link |
But I grew up doing those things.
link |
I'm comfortable with those movements.
link |
If I had a 60-year-old woman who's never lifted weights
link |
in her life who we now have to get lifting,
link |
we could get her to deadlift,
link |
but I think I wouldn't make perfect the enemy of good.
link |
I'd be happy to put her on a leg press machine
link |
and just get her doing that.
link |
It's not as pure a movement as a deadlift, but who cares?
link |
We can still put her at a heavy load for her
link |
Now, that said, there was a study that was done in Australia
link |
and hopefully we can find a link to it.
link |
There's a video on YouTube that actually kind of has the PI
link |
sort of walking through the results.
link |
I could send it to you.
link |
And it's just amazing.
link |
They took a group of older women.
link |
They looked like they were in their 60s or 70s
link |
who had never lifted weights in their life,
link |
who had osteopenia,
link |
and some probably already had osteoporosis.
link |
And they basically just put them
link |
on a strength training protocol.
link |
And it is remarkable to watch these women.
link |
They're doing good mornings.
link |
They're doing deadlifts.
link |
They're picking heavy things up off the ground.
link |
I think one woman was picking up,
link |
God, I want to say she was picking like 50, 60 kilos up
link |
I mean, just staggering sums of weight
link |
for these women who have never done anything.
link |
And their bone health is improving at this age.
link |
So the goal, frankly, is to just never get to the point
link |
where you have to do this for the first time.
link |
Strength training is such an essential part of our existence
link |
that it's never too late to start,
link |
but you should never stop.
link |
I love that advice.
link |
Is it a systemic effect or a local effect?
link |
So for instance, let's say that,
link |
well, my mother is in her late 70s.
link |
She actually used to be really strong when we were kids.
link |
She could move this fish tank that was in my room
link |
long before I could move it.
link |
And she's really strong.
link |
Over the years, I wouldn't call her frail by any means,
link |
but I certainly think she could benefit
link |
from some strength training.
link |
Let's say she were to start doing some leg presses
link |
or start even with air squats
link |
and maybe work up to some pushups.
link |
Are the effects all local?
link |
Meaning if she were to just train her legs
link |
or just do pushups, would it only be the loads
link |
applied to the limbs and muscles and tissues
link |
that were involved?
link |
I think that's where the bulk of it is, yeah.
link |
So you need to train the whole body, essentially.
link |
Yeah, now keep in mind,
link |
the diagnosis of osteopenia and osteoporosis
link |
is based on only three locations,
link |
the left hip, the right hip, and the lumbar spine.
link |
So that's just the convention
link |
by which we make the diagnosis.
link |
And I think part of that has to do with
link |
that's where the majority of the insults occur.
link |
Now, not all of the insults.
link |
I've seen people that have,
link |
because of horrible bone density,
link |
they're fracturing ankles and tibia, fibula,
link |
like they're having low-tib fib fractures just walking.
link |
So clearly bone density outside of those regions
link |
does matter, but much of it is really focused on,
link |
and by the way, you fall, you break a wrist.
link |
So this is a systemic issue,
link |
but the majority of the response is a local response
link |
because it really comes down to putting a load
link |
directly on that bone and then having that bone in kind
link |
respond by laying down more bone.
link |
Before we continue with today's discussion,
link |
I'd like to just briefly acknowledge our sponsor,
link |
Athletic Greens, now called AG1.
link |
Athletic Greens, aka AG1,
link |
is an all-in-one vitamin, mineral, probiotic drink
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that also has adaptogens and digestive enzymes.
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I've been taking Athletic Greens since way back in 2012,
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so I'm delighted that they're sponsoring the podcast.
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The reason I started taking Athletic Greens
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and the reason I still drink Athletic Greens twice a day
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is that it supplies total foundational coverage
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of my vitamin, mineral needs,
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and it supplies important nutrients that I need
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to support my gut microbiome.
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The gut microbiome, as many of you know,
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supports the immune system.
link |
It also supports the so-called gut-brain axis,
link |
which is vital for mood, for energy levels,
link |
for regulating focus, and many other features
link |
of our mental health and physical health
link |
that impact our daily performance and high performance
link |
in any endeavors we might be involved in.
link |
If you'd like to try Athletic Greens,
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you can go to athleticgreens.com slash Huberman
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plus a year supply of vitamin D3K2 with every order.
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And of course, vitamin D3K2 are vital
link |
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and metabolic health and K2 for cardiovascular health
link |
and calcium regulation.
link |
Again, you can go to athleticgreens.com slash Huberman
link |
to claim that special offer.
link |
You mentioned falling and the problems with falling
link |
and breaking things and mortality related to that.
link |
I wonder whether or not there are also
link |
health-related effects of just having weak bones
link |
that are not just about falling and breaking a bone
link |
and dying a year later.
link |
Even though that's obviously very severe,
link |
because I think when people hear about that,
link |
some people might think, well, I'll just be more careful.
link |
I'll just move more slowly.
link |
I'll sit in a wheelchair if I need to,
link |
even though I might be able to walk
link |
if it keeps me from falling.
link |
Some people, I think, adopt that mentality.
link |
What are some of the benefits of having
link |
high bone mineral density for men and women
link |
that are perhaps independent of risk of injury?
link |
Well, I think it's actually the inverse
link |
of what you just said, right?
link |
It's sort of like, you have to sort of
link |
be able to articulate what it is you want
link |
in your marginal decade.
link |
So we use this thing in our practice
link |
called the marginal decade.
link |
Marginal decade is the last decade of your life.
link |
So everyone will have a marginal decade.
link |
That's the only thing I can tell you
link |
with absolute certainty, right?
link |
There's no immortality.
link |
There's no hidden elixir that's gonna help us live
link |
to be, you know, whatever.
link |
I mean, we're all gonna be in our last decade at some point.
link |
And outside of people who die suddenly
link |
or through an accident, most of us know
link |
when we're in that marginal decade.
link |
You might not know the day you enter it,
link |
but most people who are old enough,
link |
if you tell them, are you in the last decade of your life?
link |
They probably have a sense that they are.
link |
So I think the exercise that we like to go through
link |
with our patients very early on
link |
is have them in exquisite detail,
link |
more detail than they've ever considered.
link |
So we have to prompt them with like 50 questions,
link |
lay out what their marginal decade should look like.
link |
That's a serious exercise.
link |
It's a very serious exercise, right?
link |
Like what, tell me everything that is going to happen
link |
in your marginal decade.
link |
I don't know when it's gonna be, Andrew.
link |
It could be 87 to 97 if we're doing well, right?
link |
It might be 79 to 89.
link |
But it would really be a very nuanced
link |
exploration of that topic.
link |
And I think until you do that,
link |
all of this other stuff is just abstract
link |
and kind of nonsense.
link |
You know, until a person can tell you
link |
what it is that they want to be doing in that last decade,
link |
you can't design a program to get them there.
link |
I mean, think about it.
link |
You know, someone wants to do an Ironman,
link |
we take it for granted that we know what the objective is.
link |
I have to be able to swim two and a half miles.
link |
I have to be able to get out, take my wetsuit off,
link |
hop on my bike, ride 112 miles, get off my bike,
link |
take the bike shoes off, put the run shoes on,
link |
run 26.2 miles, like we get it.
link |
We know what the objective is.
link |
And only by knowing that can you train.
link |
Can you imagine if I said to you,
link |
Andrew, I'm going to have you do an athletic event
link |
in a year, start training.
link |
I'm not gonna tell you what it is, just do it.
link |
It could be playing basketball.
link |
You know, it could be swimming to Catalina Island.
link |
It could be running a hundred miles.
link |
You wouldn't be able to do it.
link |
So similarly, if we don't know what our marginal decade
link |
is meant to be, there's no way to train for it.
link |
Do you think this is a good exercise for anyone
link |
and everyone to do on their own, regardless of age here?
link |
I'm hearing this and I'm thinking,
link |
I need to think about when my last decade might be
link |
and what I want that to look like.
link |
I mean, when I say we do it with our patients,
link |
that's only because that's the population I work with,
link |
but there's simply no reason
link |
everybody shouldn't be going through this exercise.
link |
And then you sort of back script from there,
link |
figure out what people should be doing
link |
given their current health status.
link |
Exactly right, we call it backcasting.
link |
So the first step we do is once we've really delineated
link |
what the objective function looks like, we then say,
link |
okay, how do you break down that
link |
into metrics that we can measure?
link |
So, you know, you described doing a whole bunch of things.
link |
Okay, just to let you know, to do that will require
link |
a VO2 max of 30 milliliters of oxygen
link |
per minute per kilogram.
link |
And the person will say, okay, what does that mean?
link |
We'll say, well, that's a measure
link |
of your maximal uptake of oxygen.
link |
And that declines at about 8% to 10% per decade.
link |
So if you have to be at 30,
link |
and let's just assume you're gonna be doing that at 90,
link |
so what do you need to be at 80, 70, 60, 50?
link |
Okay, here's what it would need to be at 50.
link |
Okay, what are you now?
link |
Ah, there's a big gap.
link |
You're below where you need to be now.
link |
So you're obviously higher than 30 now,
link |
but if you're only at 42 now,
link |
and you need to be at 30 in 40 years,
link |
you're not gonna cut it.
link |
You have to be a lot fitter.
link |
Okay, now let's do the same exercise
link |
around strength and stability.
link |
And without exception, most people,
link |
when they do this exercise, will find out
link |
they're well below where they need to be.
link |
So the gravity of aging is more vicious than people realize,
link |
and therefore the height of your glider
link |
needs to be much higher than you think it is
link |
when you're our age if you wanna be able to do the things
link |
we probably wanna be able to do when we're 90.
link |
I absolutely love this approach.
link |
I've never done it in terms of my health.
link |
I've always thought about what I wanna accomplish
link |
in the next three to six months or next year or so.
link |
And by the way, that's a great approach.
link |
That's forecasting.
link |
Forecasting is fantastic.
link |
Forecasting is really good at short-term things.
link |
It doesn't work for long-term things.
link |
Long-term, you have to do backcasting.
link |
This backcasting approach really appeals to me
link |
because in my career, well, I never anticipate, excuse me,
link |
I never anticipated I'd be podcasting,
link |
but that's what I did.
link |
At some point as an undergraduate, I looked,
link |
professors, I'm like, that looks like a pretty good life.
link |
They seem pretty happy.
link |
I talked to a few of them and then I figured out
link |
what I need to do at each stage
link |
in order to get to that next rung on the ladder
link |
and just kind of figured it out
link |
in a backcasting kind of way, as you refer to it.
link |
I think this is incredibly useful
link |
because it puts all the questions about blood work
link |
and how often to get blood work
link |
and what to measure in a really nice context
link |
that's highly individualized.
link |
I've never heard of this before, so.
link |
And I should give a nod to Annie Duke.
link |
I used to always refer to this as reverse engineering,
link |
but in Annie Duke's book,
link |
she wrote about this exact thing and called it backcasting,
link |
and I was like, I like the term backcasting better.
link |
I think it's more intuitive than reverse engineering.
link |
Yeah, there's a real genius to it,
link |
and I think it, because it sets so many things
link |
into the appropriate bins and trajectories.
link |
I've heard you talk before about some of the prime movers
link |
for longevity and all-risk mortality.
link |
And I'd love for you to review a little bit of that for us.
link |
I think we all know that we shouldn't smoke
link |
because it's very likely that we'll die earlier
link |
if we smoke nicotine.
link |
I'm neither a marijuana nor a nicotine smoker,
link |
so I feel unstable ground there,
link |
but anytime we see smoking nowadays,
link |
people really want to distinguish
link |
between cannabis and nicotine.
link |
So I am curious about any differences there
link |
in terms of impact on longevity, but in that context,
link |
what are the things that anyone and everyone can do,
link |
should do to live longer, basically?
link |
Well, you tell me.
link |
I'd like to live to be,
link |
I'd like my final decade to be between 90 and 100.
link |
Oh, no, I meant how long do you, but yeah, yeah, yeah.
link |
And will we spend from now until you're 90
link |
talking about this?
link |
Well, there's a risk of that,
link |
but top contour is fine.
link |
I know you've done a lot of content on this
link |
and we will give people links
link |
to some of that more in-depth content,
link |
but let's say we were on a short flight
link |
from here to San Diego, we're in Los Angeles now,
link |
and we've got takeoff and landing,
link |
and we don't want to kink our neck too much
link |
by doing this thing.
link |
So if I just said, hey, give me the extended version
link |
of the three by five card, what does that look like?
link |
So let's start with a couple of the things
link |
that you've already highlighted, so smoking.
link |
How much does smoking increase your risk
link |
of all-cause mortality?
link |
And the reason we like to talk about what's called ACM
link |
or all-cause mortality is it's really agnostic
link |
to how you die, and that doesn't always make sense.
link |
I mean, if you're talking about a very specific intervention
link |
like an anti-cancer therapeutic,
link |
you really care about cancer-specific mortality
link |
or heart-specific mortality,
link |
but when we talk about these sort of broad things,
link |
we like to talk about ACM.
link |
So using smoking, smoking is approximately
link |
a 40% increase in the risk of ACM.
link |
And what does that translate to?
link |
And that means I'm shortening my life by 40%?
link |
No, it means at any point in time,
link |
there's a 40% greater risk that you're going to die
link |
relative to a non-smoker and a never-smoker.
link |
Yeah, yeah, so it's important to distinguish.
link |
It doesn't mean your lifespan is going to be 40% less.
link |
It means at any point in time standing there,
link |
your risk of death is 40% higher.
link |
And by the way, that'll catch up with you, right?
link |
At some point, that catches up.
link |
High blood pressure, it's about a 20 to 25% increase
link |
in all-cause mortality.
link |
You take something really extreme
link |
like end-stage kidney disease.
link |
So these are patients that are on dialysis
link |
waiting for an organ.
link |
And again, there's a confounder there
link |
because what's the underlying condition
link |
that leads you to that?
link |
It's profound hypertension, significant type 2 diabetes
link |
that's been uncontrolled.
link |
That's about 175% increase in ACM.
link |
So the hazard ratio is like 2.75.
link |
Type 2 diabetes is probably about a 1.25 as well.
link |
So now the question is like, how do you improve?
link |
So what are the things that improve those?
link |
So now here we do this by comparing low to high achievers
link |
and other metrics.
link |
So if you look at low muscle mass versus high muscle mass,
link |
what is the improvement?
link |
And it's pretty significant.
link |
So if you compare low muscle mass people to high muscle mass
link |
people as they age,
link |
the low muscle mass people have about a 3x hazard ratio
link |
or a 200% increase in all-cause mortality.
link |
Now, if you look at the data more carefully,
link |
you realize that it's probably less the muscle mass
link |
and it's more the high association with strength.
link |
And when you start to tease out strength,
link |
you can realize that strength could be probably 3.5x
link |
as a hazard ratio,
link |
meaning about 250% greater risk
link |
if you have low strength to high strength.
link |
And high strength is the ability to move loads
link |
at 80 to 90% of one repetition.
link |
It's all defined by given studies.
link |
So the most common things that are used are actually,
link |
they're used for the purposes of experiments
link |
that make it easy to do.
link |
And I don't even think they're the best metrics.
link |
So they're usually using like grip strength,
link |
leg extensions, and like wall sits, squats,
link |
So how long can you sit in a squatted position
link |
at 90 degrees without support
link |
would be a great demonstration of quad strength,
link |
how much weight can you hold for how long
link |
relative to body weight, things like that.
link |
We have a whole strength program
link |
that we do with our patients.
link |
We have something called the SMA.
link |
So it's the strength metrics assessment.
link |
And we put them through 11 tests that are really difficult,
link |
like a dead hang is one of them.
link |
Like how long can you dead hang your body weight,
link |
So we're trying to be more granular in that insight,
link |
but tie it back to these principles.
link |
If you look at cardio respiratory fitness,
link |
it's even more profound.
link |
So if you look at people who are in the bottom 25%
link |
for their age and sex in terms of VO2 max,
link |
and you compare them to the people
link |
that are just at the 50th to 75th percentile,
link |
you're talking about a two X difference roughly
link |
in the risk of ACM.
link |
If you compare the bottom 25% to the top 2.5%,
link |
so you're talking about bottom quarter to the elite
link |
for a given age, you're talking about five X,
link |
400% difference in all cause mortality.
link |
That's probably the single strongest association
link |
I've seen for any modifiable behavior.
link |
So when you say elite, these are people
link |
that are running marathons at a pretty rapid clip?
link |
It's just like what the VO2 max is for that.
link |
Like my VO2 max would be in the elite for my age group.
link |
My VO2 max, but again, I'm training very deliberately
link |
to make sure that it's in that.
link |
So I wouldn't consider myself elite at anything anymore,
link |
but I still maintain a VO2 max that is elite for my age.
link |
I consider you an elite physician
link |
and possibly an end guy all around.
link |
But in terms of, okay, so for the-
link |
But the point is like you don't have to be
link |
a world-class athlete to be elite here, yeah.
link |
So maybe we could talk a little bit about the specifics
link |
around the training to get into the top two tiers there,
link |
because it seems that those are enormous positive effects
link |
of cardiovascular exercise,
link |
far greater than the sorts of numbers that I see around,
link |
let's just say supplement A or supplement B.
link |
And that's, you know,
link |
like this is my whole pet peeve in life, right?
link |
It's like, I just can't get enough of the machinating
link |
and arguing about this supplement versus that supplement.
link |
And I feel like you shouldn't be having those arguments
link |
until you have your exercise house in order.
link |
You know, you shouldn't be arguing about
link |
this nuance of your carnivore diet
link |
versus this nuance of your paleo diet
link |
versus this nuance of your vegan diet,
link |
like until you can deadlift your body weight for 10 reps.
link |
Like then you can come and talk about those things
link |
or something like, let's just go up with some metrics.
link |
Like until your VO2 max is at least to the 75th percentile
link |
and you're able to dead hang for at least a minute
link |
and you're able to wall sit for at least two,
link |
like we could rattle off
link |
a bunch of relatively low-hanging fruit.
link |
I wish there was a rule that said,
link |
like you couldn't talk about anything else, health related.
link |
We can make that rule.
link |
No one will listen to it.
link |
I don't know about that.
link |
We can make whatever rules we want.
link |
We can call it Atiyah's rule.
link |
One thing I've done before in this podcast
link |
and on social media is just borrowing
link |
from the tradition in science,
link |
which is it's inappropriate to name something
link |
after yourself unless you were a scientist before 1950.
link |
But it's totally appropriate to name things
link |
after other people's.
link |
I'm going to call it Atiyah's rule
link |
until you can do the following things.
link |
Don't talk about supplements.
link |
Please refrain from talking about supplements and nutrition.
link |
Hereafter, thought of, referred to,
link |
and referenced as Atiyah's rule.
link |
I coined the phrase, not him.
link |
So there's no ego involved, but it is now Atiyah's rule.
link |
Watch out, hashtag Atiyah's rule.
link |
Wikipedia entered Atiyah's rule.
link |
In all seriousness, and I am serious about that,
link |
dead hang for about a minute.
link |
Seems like a really good goal for a lot of people,
link |
I think we have a minute and a half
link |
is the goal for a 40-year-old woman.
link |
Two minutes is the goal for a 40-year-old man.
link |
So we adjust them up and down based on age and gender.
link |
And then the wall sit, what are some numbers?
link |
We don't use a wall sit.
link |
We do just a straight squat, air squat, at 90 degrees.
link |
And I believe two minutes is the standard
link |
for both men and women at 40.
link |
And then, because for some people,
link |
thinking in terms of EO2 max is a little more complicated.
link |
They might not have access to the equipment
link |
or to measure it, et cetera.
link |
What can we talk about, think about
link |
in terms of cardiovascular?
link |
So run a mile at seven minutes or less,
link |
eight minutes or less?
link |
That's a good question.
link |
So there are really good VO2 max estimators online,
link |
and you can plug in your activity du jour.
link |
So be it a bike, run, or rowing machine,
link |
and it can give you a sense of that.
link |
And I used to know all of those,
link |
but now that I just actually do the testing,
link |
I don't recall them, but it's exactly that line of thinking.
link |
Like, can you run a mile in this time?
link |
If you can, your VO2 max is approximately this.
link |
And I think somewhere in my podcast realm,
link |
I've got all those charts posted of like,
link |
this is by age, by sex.
link |
This is what the VO2 max is in each of those buckets.
link |
We'll provide links to those.
link |
We'll have our people find those links.
link |
And then you mentioned deadlifting body weight 10 times.
link |
I just made that one up.
link |
That's not one that we include, but something like that.
link |
We use farmer carries.
link |
So we'll say for a male,
link |
you should be able to farmer carry your body weight for,
link |
I think we have two minutes.
link |
So that's half your body weight in each hand.
link |
You should be able to walk with that for two minutes.
link |
For women, I think we're doing 75% of body weight
link |
or something like that, yeah.
link |
As indirect measures of how healthy we are
link |
and how long we're going to live.
link |
It's basically grip strength, it's mobility.
link |
I mean, again, walking with that much weight
link |
for some people initially is really hard.
link |
We use different things like vertical jump,
link |
ground contact time if you're jumping off a box,
link |
So it's really trying to capture,
link |
and it's an evolution, right?
link |
I think the test is going to get only more and more involved
link |
as we get involved, because it took us about a year.
link |
Beth Lewis did the majority of the work to develop this.
link |
Beth runs our strength and stability program in the practice
link |
and basically I just tasked her with like,
link |
hey, go out to the literature and come up with
link |
all of the best movements that we think are proxies
link |
for what you need to be like the most kick-ass,
link |
you know, what we call centenarian decathlete,
link |
which is the person living in their marginal decade
link |
Well, what I'm about to say is certainly a mechanistic leap,
link |
but if you look at the literature on
link |
exercise-related neurogenesis in mice
link |
or brain atrophy or brain hypertrophy, et cetera,
link |
in animal models, it's very clear that the best way
link |
to get a nervous system to atrophy, to lose neurons,
link |
shrink neurons, or lose connections between neurons,
link |
is to stop that animal from moving
link |
or to de-enrich its environment,
link |
deprive it of some sensory input or multiple sensory inputs,
link |
and the best way to enhance the size of neurons,
link |
the number of connections between neurons,
link |
and maybe even the number of neurons
link |
is to enrich its environment and get it moving
link |
while enriching that environment.
link |
You know, Andrew, I think it's very difficult for me
link |
to say that the same is not true in humans.
link |
And so the first time this became clear to me
link |
was in 2014, I had an analyst, Dan Pelletier,
link |
and I said, Dan, I'm gonna give you a project
link |
that is vexing me to no end, which is
link |
I want you to look at all of the literature that we have,
link |
both mechanistic and clinical trial data,
link |
that talks about Alzheimer's prevention.
link |
And I wanna know every single type of input,
link |
and I wanna have a clear sense of via what mechanism
link |
does it offer, what mode of protection.
link |
And it took Dan, and this was obviously,
link |
we iterated a lot on this together,
link |
and he came back with kind of an amazing presentation
link |
that took, I don't know, nine months to a year of work.
link |
And what amazed me was when he came back to it,
link |
he said, the single greatest efficacy
link |
we can point to is exercise.
link |
And I was like, Dan, that's gotta be nonsense, dude.
link |
There's no way exercise is the single best thing
link |
you can do for the brain.
link |
There has to be some drug you've missed.
link |
There has to be some other thing that you've missed.
link |
And he's like, no, this is hands down the best thing,
link |
because it's not just what it's doing to BDNF,
link |
it's not just what it's doing to vascular endothelium,
link |
it's not just what it's doing to glucose disposal
link |
and insulin signaling, all these things.
link |
It's just touching every aspect of the brain.
link |
And I was very skeptical for about six months,
link |
kind of really pushed on him, and I was like,
link |
I think you're missing something, Dan,
link |
I think you're missing something.
link |
And then finally, in the end, looped in Richard Isaacson,
link |
who's a neurologist that we work with really closely
link |
on Alzheimer's prevention, and ultimately,
link |
it turned into a paper that we wrote, basically,
link |
about this topic, and a few others.
link |
Because again, I thought, are you sure it's not EPA and DHA?
link |
That's gotta have a bigger impact.
link |
And again, there are a lot of things that I think do matter,
link |
and there's a whole host of things that we do
link |
for Alzheimer's prevention,
link |
but I think you're absolutely right.
link |
There's not one thing that I'll tell patients
link |
is more important than exercising.
link |
And by the way, it's not the sort of
link |
pathetic recommendations that are made.
link |
Like, you have to exercise a lot more
link |
if you wanna get this maximum benefit.
link |
You will get, you know, the maximum benefit
link |
comes going from nothing to something.
link |
So if you go from being completely sedentary
link |
to doing 15 met hours per week,
link |
you'll get probably a 50% reduction in risk.
link |
So a met hour, a met, just for people who don't know,
link |
is a metabolic equivalent.
link |
So we're exerting about 1.3 mets sitting here talking.
link |
If we were sitting here being quiet,
link |
it would be about one met.
link |
You know, walking really briskly would be about five mets.
link |
So 15 met hours per week would be
link |
three one-hour really brisk walks.
link |
That's not a lot of work.
link |
But just going from doing nothing to doing that
link |
would give you 50% of the benefit
link |
that you would get from going all the way.
link |
Now, again, I think I'm personally a little skeptical
link |
of how much that's,
link |
I think it's probably a bit less than that.
link |
I think there's more upside than people appreciate.
link |
But the studies, I don't think, can truly capture that.
link |
But look, you know, there's no reason
link |
to not be exercising more than that
link |
and capture more benefit,
link |
even though the rate at which you accrue it is less.
link |
And it also speaks to the healthspan side of this,
link |
which is not necessarily captured in those data.
link |
The healthspan gets back to the functional piece
link |
we opened with, which is what do you want to be doing
link |
in your marginal decade?
link |
Do you want to be able to pick up a great grandkid
link |
if they come running at you?
link |
Do you want to be able to get up off the floor?
link |
Do you want to be able to play on the floor with a kid
link |
and then get up on your own?
link |
And I think most people are thinking final years of life,
link |
they're trying to think, you know,
link |
how can they take themselves to the bathroom?
link |
They're thinking, how can they sit up off the toilet?
link |
I mean, you've got really basic,
link |
vegetative-type functions, right, at some level.
link |
I love this, again, this idea of marginal decade
link |
and using that as a way to backcast
link |
to actual methods and behaviors and protocols
link |
that one should be doing on a daily basis.
link |
I'll use ANIC data, as it's now called,
link |
to cite just, I know, three Nobel Prize winners,
link |
which doesn't mean anything
link |
except that they did beautiful work,
link |
but the point is that they're all in their 90s.
link |
because I'm complimenting them for what they've done,
link |
not just their work, but what I'm about to describe.
link |
So Eric Kandel at Columbia,
link |
Nobel Prize-winning for work on memory,
link |
Torrance and Wiesel, work on neuroplasticity,
link |
and then Richard Axel, who's also at Columbia,
link |
Nobel Prize-winning work for molecular biology of smell
link |
and molecular biology generally.
link |
All three of them still alive.
link |
Richard's younger compared to the other two.
link |
All three of them either swim, jog, or play tennis,
link |
or racquetball, I think is Richard's thing,
link |
multiple times per week.
link |
Eric was, they're all cognitively still extremely sharp,
link |
still interested in the arts, doing science,
link |
curious about science, running laboratories,
link |
writing books, going on podcasts.
link |
I mean, it's incredible.
link |
Again, that's ANIC data,
link |
but I was kind of surprised to learn that colleagues
link |
that were so intellectually strong
link |
were also so obsessed with exercise.
link |
I mean, they really are obsessed with their exercise routine
link |
and early on linked that
link |
to some of their intellectual vigor over time.
link |
I want to just also use it as a jumping off point
link |
to ask about one kind of niche thing, but it comes up.
link |
I don't think I'm going to out which one of those
link |
told me this, but one of those three individuals
link |
choose an excessive amount of Nicorette.
link |
Used to be a smoker and I asked him why.
link |
And he said, because in his estimation,
link |
it's protective against Parkinson's and Alzheimer's,
link |
or at least the nicotinic acetylcholine augmentation
link |
of nicotine, because nicotine is an acetylcholine receptor,
link |
obviously, is known to create a state of focus
link |
and neural enhancement.
link |
What are your thoughts about not smoking?
link |
Let's just, I want to be really clear.
link |
People don't smoke nicotine, vape nicotine.
link |
It's going to shorten your life.
link |
Just terrible idea, addictive, et cetera, in my opinion.
link |
But what are your thoughts about augmenting acetylcholine
link |
through the use of nicotine
link |
in order to keep the brain healthy and focused?
link |
Again, this is one Nobel Prize winner,
link |
so it's truly N of one,
link |
but he's so convinced that this matches up
link |
with the mechanistic data on acetylcholine and cognition
link |
that I'd love to get your thoughts on it.
link |
So I can't speak to the AD prevention component of it.
link |
I'd have to run that by a couple of my colleagues
link |
who I collaborate with on that,
link |
but I can definitely speak
link |
to the cognitive enhancement piece of it.
link |
And I actually did an AMA on this probably a year ago
link |
where I went into all of the gory details of it
link |
and talked about my own use of nicotine,
link |
which I'll cycle on and off.
link |
I've been doing it for the last 10 years.
link |
What form do you take it in?
link |
I used to use the gum.
link |
I don't like the gum anymore,
link |
so now I like these little lozenges.
link |
I'll tell you a funny story about this.
link |
So our mutual acquaintance, David Sinclair,
link |
mentioned a company to me a year ago.
link |
He's like, hey, have you heard of this company?
link |
And I forget the name of the company,
link |
but he gave me some name.
link |
and it's like this company selling nicotine.
link |
And I'm like, I wonder why he's asking me to do this.
link |
Well, I'll just order a bunch,
link |
and then we'll figure out why,
link |
because there was some reason
link |
we were doing this potentially through investment.
link |
So I literally ordered a lifetime supply of this stuff,
link |
and it's pretty good.
link |
It's a really nice little patch,
link |
because the thing I didn't like about the gum
link |
was I hated just the taste of it.
link |
So then the next week I'm talking to David,
link |
and I'm like, by the way,
link |
I ordered all that nicotine stuff you told me about.
link |
And he goes, oh, oh, the company's name was something else.
link |
It was totally unrelated.
link |
I was like, oh, God.
link |
So the short answer is I think this stuff
link |
is absolutely a concentration-enhancing substance.
link |
It is addictive, and people need to be wary of that.
link |
Now, it's not addictive to everybody.
link |
I personally experience no addiction to it whatsoever.
link |
So I could do it every day for 30 days
link |
and stop and experience no withdrawal.
link |
I could forget about it.
link |
It doesn't really seem to matter.
link |
You have to be careful with the dose, truthfully.
link |
I mean, remember, one cigarette
link |
is about one milligram of nicotine,
link |
and a lot of these lozenges will plow
link |
four to eight milligrams into you in one shot.
link |
And for someone who is naive to that like I am,
link |
four milligrams is a lot of nicotine in one bolus.
link |
So you just have to be very mindful of it.
link |
I got a lot of flack when I did this AMA
link |
for obvious reasons, but people were like,
link |
how can you, as a doctor, encourage people to use nicotine?
link |
And I was like, first of all,
link |
I'm not encouraging anybody to use it.
link |
I just wanna be able to talk about the biochemistry of it.
link |
And if disclosing that I use it from time to time
link |
is an endorsement, then I apologize for that.
link |
But on the list of things that you can do
link |
to make your brain a little more focused,
link |
I would consider this infinitely safer
link |
than what a lot of people are doing,
link |
which is using stimulants.
link |
I mean, to me, I just tell patients outright,
link |
we are under no circumstance prescribing stimulants.
link |
I mean, we're not giving anybody Adderall.
link |
We're not giving anybody Vyvanse or any of these things.
link |
Not to say they don't have an appropriate clinical use,
link |
but they should be prescribed under the care
link |
of somebody who's really monitoring the use case for it.
link |
And using that as a tool to enhance concentration
link |
and cognitive performance
link |
is not something we're comfortable doing.
link |
Yeah, it's rampant on college campuses.
link |
I can only imagine.
link |
Our modafinil, modafinil,
link |
which are slightly different, of course,
link |
so non-clinical use, not prescribed for ADHD,
link |
but just it's rampant, recreational use, study-based use.
link |
But the data I've seen on modafinil suggests
link |
that it only really provides a nootropic benefit
link |
in someone who is deprived of sleep.
link |
Is there data that in a totally well-rested person,
link |
there is a nootropic benefit of modafinil?
link |
I have one experience with R-modafinil
link |
where I took a half a recommended dose.
link |
This was prescribed by a doctor.
link |
I went to give a talk.
link |
This is in Hawaii.
link |
And four hours into the talk,
link |
my co-speaker came up to me and just said,
link |
well, first of all, you got a little bit of a spit
link |
in the corner of your mouth.
link |
And second of all, you haven't blinked in three minutes.
link |
And third, there's only two people left in the audience.
link |
I was so lasered in that I kind of forgot the context.
link |
I'm a little bit of a kind of a tunnel vision OCD type
link |
anyway, but that was all it took.
link |
I never took any more of it.
link |
It was a powerful stimulant.
link |
I take 300 milligrams of alpha-GPC now and again
link |
before some cognitive work, sometimes before workouts.
link |
And I do subjectively feel that it narrows my focus
link |
in a nice way, but I don't take it more
link |
than once or twice a day and more than once or twice a week.
link |
So this is an example of where,
link |
you know how we're talking about exercise
link |
versus sort of nutrition and supplements for longevity.
link |
I think there may be a whole bunch of things
link |
that are kind of interesting around focus,
link |
but nothing would compare to changing our environment.
link |
Like I think that if I compare my focus today
link |
to my focus when I was in college, there's no comparison.
link |
Like in college, I was truly a robot,
link |
but I think a large part of it was there was no distraction.
link |
There was no email, there was no social media,
link |
there was no internet.
link |
I mean, I was in college when Mosaic launched
link |
in the early 90s, and you had to walk like a mile
link |
to get to the computer lab on a big sun workstation
link |
to do anything in some computer code language.
link |
So when you're sitting in your room studying,
link |
there was no distraction.
link |
And I think that's a far greater component
link |
of what it means to be focused
link |
than the challenges we have today.
link |
So my thoughts on this would be if we really wanted
link |
to return to a state of focus,
link |
we're gonna have to individually do something
link |
about our environment.
link |
And I don't know what the answer is.
link |
Like I've tried every little trick I can think of,
link |
like closing my browsers when I'm writing and stuff,
link |
but I'm just not strong enough willed.
link |
Like I'll pick up my phone every 20 minutes
link |
to look and see if I miss the text message
link |
or something stupid.
link |
That's pretty infrequent.
link |
I did a episode on habits and looking at the data.
link |
It seems that people are getting interrupted
link |
or interrupting themselves about once every three minutes
link |
in the typical workplace.
link |
Now that typical has changed
link |
with a lot more people working at home.
link |
I do put my phone away when I try and work,
link |
that nothing focuses me like a deadline,
link |
a little bit of a fear-based urgency.
link |
Grant deadlines, drop deadlines as I call them,
link |
or podcasts we're gonna record today
link |
that nothing works quite like it,
link |
Well, thanks for that offshoot about nicotine.
link |
Again, you're not recommending it.
link |
I'm not recommending it,
link |
but it's clear that augmenting the acetylcholine system,
link |
which is what nicotine does in its various forms
link |
and some related type pharmacology does enhance focus
link |
and pretty potently.
link |
So I think it's gonna be an interesting area
link |
for real clinical trials and things of that sort.
link |
Love to chat about hormone therapies and hormones generally.
link |
When Robert Sapolsky came on the podcast,
link |
we talked a little bit about menopause
link |
and the data around menopause.
link |
He's very interested in these findings that,
link |
I think I'm gonna get this right,
link |
that whether or not women benefit from estrogen therapy
link |
to offset menopause really depends
link |
on when that therapy is initiated.
link |
I don't know if you're aware of those data,
link |
but he claimed that if they begin estrogen therapy
link |
in the middle to tail end of menopause,
link |
the outcomes can be quite bad.
link |
Whereas if they initiate those estrogen therapies
link |
as they enter menopause or even before menopause,
link |
then the outcomes can be quite good.
link |
I don't know what percentage of the patients you treat
link |
are male versus female
link |
and what ages those patients are, of course,
link |
but what are your thoughts about estrogen therapy
link |
for women, menopause, and hormone therapies
link |
generally for women, maybe even testosterone therapy.
link |
You hear about that these days.
link |
And then we'll talk about men.
link |
So our practice is probably 70, 30 male, female.
link |
So we have lots of women and this is a very important topic.
link |
It's also probably, let me think.
link |
I just want to make sure I'm not being hyperbolic
link |
Yeah, I don't think I am.
link |
It's hands down the biggest screw up
link |
of the entire medical field in the last 25 years.
link |
Now again, it's possible in the next hour,
link |
I'll think of, there's a bigger screw up.
link |
Another giant screw up.
link |
Yeah, but I don't think I will.
link |
I'm pretty confident that I won't be able to think
link |
of a bigger act of incompetence than what happened
link |
with the Women's Health Initiative in the late 90s
link |
and early 2000s, which is effectively the study
link |
that turned the entire medical field
link |
off hormone replacement therapy for women.
link |
So it's important, I think, to explain
link |
what the study looked at.
link |
So this was a study that was conducted in response
link |
to the widely held belief in the 70s and 80s
link |
that women should be placed on hormones
link |
as they're going through menopause, right?
link |
Menopause is, I guess maybe I'll even take a step back.
link |
I don't know how much your audience is familiar
link |
with how estrogen and progesterone work.
link |
Is it worth going into that stuff?
link |
Yeah, probably worth mentioning a bit of the top contour.
link |
Some of them might be familiar with it.
link |
We've done episodes on estrogen and testosterone,
link |
but frankly, as I think back to those,
link |
we didn't really go into the biology
link |
of estrogen, testosterone, you know.
link |
Yeah, so, I mean, actually an interesting aside
link |
that I always tell my female patients
link |
who get a kick out of this,
link |
when you look at a woman's labs,
link |
you'll see her estrogen, her progesterone, her FSH, her LH,
link |
her testosterone, her sex hormone binding globulin,
link |
all these things, but based on the units they're reported in
link |
it's a very distorting picture
link |
of what the most common androgen is in her body.
link |
If you actually convert them to the same units,
link |
she has much more testosterone in her body than estrogen.
link |
Interesting. Yeah.
link |
I did not know that. Yeah.
link |
Then again, I've never been a woman
link |
getting my hormone profile done.
link |
Yeah, so even though a woman's testosterone
link |
is much less than a man's level,
link |
it's still more than she has estrogen in her body.
link |
So phenotypically, right, estrogen is the hormone
link |
that's dominating and so it's the, you know,
link |
she has much higher estrogen than a man
link |
and much lower testosterone than a man,
link |
but in absolute amounts,
link |
she has more testosterone than estrogen.
link |
Just worth pointing that out.
link |
So, you know, what's happening to a woman
link |
from the age she starts menstruating
link |
until she goes through menopause,
link |
outside of pregnancy and birth control and stuff like that,
link |
is she has this cycle, you know,
link |
roughly every 28 days, but it can vary,
link |
where at the beginning of her period,
link |
we call that day zero,
link |
her estrogen and progesterone are very low.
link |
You can't measure them.
link |
And then what happens is the estrogen level starts to rise
link |
and it rises in response to a hormone
link |
called follicle stimulating hormone, FSH,
link |
that is getting her ready to ovulate
link |
and she ovulates at about the midpoint of her cycle.
link |
So if we're just gonna make the math easy,
link |
on day 14, she's going to release a follicle
link |
from one of her ovaries.
link |
And the estrogen level is sort of rising, rising, rising.
link |
We love to measure hormones on day five
link |
because I wanna have a standardized way
link |
in which I measure her hormones.
link |
So our women know if we're in the business
link |
of trying to understand her hormones,
link |
the day her period starts,
link |
even if it's just a day of spotting,
link |
that becomes our benchmark.
link |
And then day five, I wanna see every hormone on that day.
link |
And if everything is going well,
link |
I know what her FSH, LH, estradiol,
link |
and progesterone should be on that day.
link |
So the estrogen rises,
link |
starts to come down a little bit as she ovulates,
link |
and then the luteinizing hormone kicks on
link |
because it's now going to prepare her uterus
link |
for the lining to accommodate a pregnancy.
link |
So now you start to see estradiol go back,
link |
but now for the first time, progesterone goes up.
link |
So progesterone has been doing nothing for 14 days,
link |
and now it starts to rise.
link |
And actually, progesterone is the hormone
link |
that's dominating the second half,
link |
which is called her luteal cycle.
link |
So the first 14 days is the follicular cycle,
link |
second is the luteal cycle.
link |
So once you get to about the halfway point of that,
link |
which is now, just to do the math, 21 days in,
link |
the body has figured out if she's pregnant or not.
link |
And again, most of the time she's not gonna be pregnant,
link |
so the body says, oh, I don't need this lining
link |
that I've been preparing, I'm going to shed it.
link |
So now progesterone and estrogen start crashing,
link |
and the lining is what is being shed,
link |
and that is the menses.
link |
By the way, it's that last seven days of that cycle
link |
that in a susceptible woman
link |
is what creates those PMS symptoms.
link |
So it's the, actually, this is something
link |
that you would probably have
link |
a better understanding of than me.
link |
There is something about this in a susceptible woman
link |
where the enormous reduction of progesterone so quickly
link |
is probably impacting something in her brain.
link |
So I think this is a legitimate thing, right?
link |
I mean, it's not like, oh, she's crazy
link |
because she's having all these PMS symptoms, no.
link |
We know that that's the case
link |
because if you put women on progesterone
link |
for those seven days, those symptoms go away.
link |
So if you can stabilize their progesterone
link |
during the last half of their luteal phase,
link |
and sometimes we would just do it
link |
for the entire luteal phase,
link |
just put them on a low dose of progesterone,
link |
all PMS symptoms vanish.
link |
I'll have to look up where the progesterone receptors
link |
are located in the brain.
link |
The Allen Brain Institute now has beautiful data
link |
of in situ hyperization,
link |
which for folks that don't understand
link |
is looking at RNA and sort of where genes
link |
and proteins ought to be expressed in the human brain
link |
by using actual human brain tissue sections
link |
as opposed to just mice.
link |
So I'll take a look.
link |
I think some insight into what that
link |
progesterone emotionality link might be
link |
and where it might exist neural circuit-wise.
link |
So then when the estrogen and progesterone
link |
reach their nadir again, that starts the cycle.
link |
So that cycle is happening over and over and over again.
link |
Okay, so it became well known in the 50s
link |
that okay, a woman's gonna stop menstruating at some point.
link |
Her estrogen goes down.
link |
Why don't we just give her estrogen?
link |
Because that's clearly gonna help
link |
with some of the symptoms of menopause.
link |
So what do women experience when they go through menopause?
link |
The first symptoms are what are called vasomotor symptoms.
link |
So this is usually in the form of night sweats,
link |
hot flashes, and depending on the woman,
link |
this can be really significant, right?
link |
These are women who can have a hard time sleeping.
link |
They can be having hot flashes during the middle of the day.
link |
They can wake up soaked in a pool of sweat.
link |
Those tend to pass after a couple of years,
link |
and then they get into sort of the more
link |
long-term complications of menopause.
link |
So what we call vaginal atrophy, vaginal dryness,
link |
and then the stuff that we talked about a while ago,
link |
which is the osteopenia, osteoporosis.
link |
A lot of women will complain of brain fog.
link |
So I mean, clearly this was an issue,
link |
and it was recognized 70 years ago.
link |
Why don't we give women estrogen back
link |
to replace that hormone?
link |
And so that went on for a couple of decades,
link |
maybe less, maybe a decade, and then it was realized,
link |
wait a minute, we were driving up the risk of uterine cancer.
link |
And the reason for that is if you just give estrogen
link |
with no progesterone to antagonize it,
link |
you will thicken the endometrium endlessly,
link |
and you will increase the risk of hyperplasia.
link |
Well, you'll definitely undergo hyperplasia,
link |
and then ultimately dysplasia.
link |
Dysplasia is precancerous,
link |
and ultimately we were seeing that.
link |
So people figured out, well, actually,
link |
if you want to give estrogen to a woman
link |
who still has her uterus,
link |
you have to give her progesterone as well.
link |
You have to be able to have a hormone
link |
to oppose the estrogen.
link |
And then that became effectively, call it the 1970s-ish,
link |
the standard for HRT.
link |
So in the early 1990s, the NIH said,
link |
look, we haven't really studied this.
link |
We have a ton of epidemiology that says
link |
giving women hormones seems to be doing really good things.
link |
They feel better, so all their symptoms go away.
link |
They seem to have lower risk of heart disease,
link |
lower risk of cardiovascular disease,
link |
lower risk of bone fractures.
link |
Everything seems to get better, lower risk of diabetes.
link |
But we haven't tested this
link |
in a randomized prospective trial, so let's do this.
link |
So that became the WHI.
link |
And it randomized, it had two parallel arms.
link |
So it had a group for women who did not have a uterus.
link |
So these are women that had undergone hysterectomy
link |
for some other reason.
link |
And then it had a group for women
link |
that did have their uterus.
link |
In the first group, there was a placebo arm
link |
and then an estrogen-only arm.
link |
And in the other group, there was a progesterone
link |
plus estrogen versus a placebo.
link |
Everything about the way this study was done
link |
Some of it is justifiable,
link |
but it's important to understand.
link |
First, the women were all way outside of menopause.
link |
So none of these women were started
link |
when you would normally start HRT.
link |
And there were probably several reasons for that,
link |
but one of them is, and I think this is a legitimate reason,
link |
they wanted hard outcomes.
link |
They wanted to know death rates.
link |
And if you're doing this on women in their 50s,
link |
you just weren't gonna get it, right?
link |
You gotta wait too long.
link |
Yeah, you gotta wait too long.
link |
There was only gonna be like a seven to 10-year study.
link |
So they had to do this on women who were much older.
link |
They also disproportionately took much sicker women.
link |
I believe the prevalence,
link |
and again, I'm gonna get some of these numbers wrong
link |
and people are gonna get all phosphorylated,
link |
but I mean, I'm in the ballpark, right?
link |
Something like 30, 40% of these women were smokers.
link |
The prevalence of obesity, diabetes was enormous.
link |
So they really disproportionately picked
link |
the most unhealthy population they could
link |
that was pretty advanced in age.
link |
And again, I think part of that was to say,
link |
look, we wanna make sure that after seven years,
link |
we really know if there's a difference
link |
in these causes of death.
link |
The other thing is, this is kind of weird,
link |
although again, I understand their rationale for it,
link |
but this is a great example of be very careful
link |
when you look at a clinical trial
link |
that it remotely represents the patients
link |
you're interested in treating.
link |
So they also treated no patients who were symptomatic.
link |
The rationale being, if we include in the study
link |
patients who are symptomatic,
link |
those who are randomized to placebo will drop out.
link |
Okay, it makes sense in terms of study design,
link |
makes no sense if the study design
link |
is intended to mimic the real world.
link |
So now let's just keep track of the three issues.
link |
We have a disproportionately unhealthy patient population
link |
who are not symptomatic,
link |
and we're starting them more than 10 years after menopause.
link |
The next thing that they did,
link |
which again, I understand why they did it,
link |
but it's now the fourth strike against this study is,
link |
and I've spoken with the PI of the study
link |
and asked this question point blank.
link |
I'm actually gonna have her on my podcast
link |
at some point soon to go over this in more detail,
link |
is why did you use conjugated equine estrogen and MPA,
link |
which is a synthetic form of progesterone?
link |
It's horse urine, they collect horse urine.
link |
So they're getting the-
link |
Horses do urinate a lot, or at least when they urinate,
link |
it seems like a large volume of urine
link |
from what I've observed.
link |
You have a lot of experience with this?
link |
No, but you know, my sister rode horses for a little while.
link |
My high school girlfriend had a horse and that thing,
link |
I mean, the peas were legendary.
link |
It's a male horse.
link |
So yeah, so the conjugated equine estrogen
link |
is the estrogen that's collected from female horses,
link |
and then it's a synthetic progesterone.
link |
And I said to the person, I said,
link |
well, why didn't you use what we use today,
link |
which is bioidentical estrogen and progesterone?
link |
Like today, when we put women on estrogen,
link |
we use a, it's an FDA product called the Vivel Dot.
link |
So it's a patch that you just put on and it's estradiol,
link |
but it's bioidentical estradiol,
link |
and we use what's called micronized progesterone,
link |
so bioidentical progesterone.
link |
And she said, well, at the time,
link |
we just wanted to test what was currently being used.
link |
I said, totally makes sense.
link |
But again, now you have four considerations
link |
that you have to keep in mind.
link |
Okay, so despite those four considerations,
link |
and I'm gonna make a case for you
link |
why I think the MPA created a real problem in that study,
link |
the synthetic progesterone.
link |
When the preliminary results were first made available,
link |
but not yet peer reviewed and not yet published,
link |
there was a huge fiasco, huge press announcement about it,
link |
suggesting that the women receiving the CEE plus MPA
link |
in the group with the uterus
link |
had a higher incidence of breast cancer.
link |
And that basically became the headline that never went away,
link |
though it turned out not to be true.
link |
Let's talk about the numbers.
link |
What was the increase in the risk of breast cancer
link |
Which gets to my, if you've ever listened to me
link |
on the podcast, rail on something.
link |
Listen, I have about 3,800 pet peeves and counting.
link |
My laboratory staff know these, know a good number of them.
link |
So you do not have to apologize for having many pet peeves,
link |
because as long as they have experience
link |
and data to support them, it provides a better life.
link |
So one of my biggest pet peeves is,
link |
and my team knows this,
link |
because sometimes they'll occasionally,
link |
they'll do this and I'll have to remind them.
link |
You never talk about a relative risk change
link |
without an absolute risk accommodating it, right?
link |
So what does that look like?
link |
So the relative risk increase of breast cancer
link |
in the estrogen plus MPA group versus the placebo
link |
was 25, 27%, and that became the only headline.
link |
HRT increases risk of breast cancer by 27%.
link |
Now, I don't think that's true at all today,
link |
but let's even look at the data.
link |
What was the absolute risk increase?
link |
It was a difference between five cases per thousand
link |
and four cases per thousand.
link |
So the ARR was 0.1%, one case in a thousand.
link |
And it's true, going from four in a thousand
link |
to five in a thousand is a 25% increase,
link |
but it's a completely inappropriate context.
link |
I agree, and I feel like headlines of that sort,
link |
which have come up recently
link |
around various dietary interventions,
link |
we won't go there, at least not for the time being,
link |
are nothing short of criminal
link |
because they really distort people's thinking,
link |
but also they steer the course of science and medicine
link |
for, as you pointed out, for decades, if not longer.
link |
And they can really take us off our health track
link |
So I'll bring this meandering to a close,
link |
which is to say, even though I could spend the next hour
link |
talking about all of the ways in which this study was flawed
link |
and all of the very unethical things
link |
that were done by a number of the investigators
link |
who went out of their way to mask the truth of this study
link |
from the world, I'll tell a woman today,
link |
we're gonna start you on this
link |
when you're going through menopause,
link |
we're using bioidentical hormones,
link |
and if your upper bound risk of breast cancer
link |
is one case in 1,000, you should at least weigh that
link |
against all of the other benefits, which I'll talk about.
link |
Now there's something else I wanna say,
link |
because a moment ago I alluded to the fact
link |
that I think the MPA might have been the biggest issue
link |
So there were two findings in that study that were negative.
link |
One was the small increase in the risk of heart disease
link |
and the small increase in the risk of breast cancer.
link |
But consider the other group.
link |
We forgot about the group that didn't have a uterus,
link |
because remember, those women got estrogen only
link |
What was the difference in breast cancer there?
link |
Well, this is interesting
link |
because it didn't reach statistical significance,
link |
but its P value was 0.06 or 0.07.
link |
So it came very close, but it was in the opposite direction.
link |
It was a 24% risk reduction, about one in 1,000 as well.
link |
So when you had estrogen plus MPA,
link |
you had a barely statistically significant,
link |
the P value was 0.05,
link |
so it just hit statistical significance,
link |
one in 1,000 cases for breast cancer,
link |
and then you had one in 1,000 cases,
link |
but P value of 0.07 for reduction of risk of breast cancer,
link |
which to me suggests that the MPA,
link |
the synthetic progesterone, was playing more of a role
link |
than anything else.
link |
The second thing I point out is oral estrogen,
link |
which we no longer use, does increase coagulability.
link |
It does increase the ability of the blood
link |
to clot a little bit.
link |
And when we look at the more recent data on HRT
link |
using topical estrogen or patches of estrogen,
link |
we don't see that at all.
link |
In fact, we see the opposite now.
link |
So now we see the risk of heart disease
link |
going down in women with estradiol.
link |
And some women will be arriving to those treatments
link |
with mutations and things like factor V Leiden
link |
and other clotting factors.
link |
Is it appropriate to say that everyone,
link |
both male and female, should know whether or not
link |
they have mutant forms of factor V Leiden?
link |
You know, we don't typically test people for factor V.
link |
My wife actually has it,
link |
but we didn't learn it until she had help syndrome,
link |
giving birth to our first daughter.
link |
But we kind of look for more family history reason
link |
to be testing things like that.
link |
We take a pretty detailed family history,
link |
so we'll kind of look for clotting issues there.
link |
What about, so your reflex nowadays is to put women
link |
on these topical estrogen therapies.
link |
Well, it's to basically have the discussion, right?
link |
So here's where we still struggle, right?
link |
Is, you know, we, if it were up to me,
link |
I'd prefer for a woman's HRT to be provided by her GYN
link |
because we want to be able to work in partnership
link |
with the GYN who we would like to see
link |
an endometrial ultrasound done every year.
link |
That's, you know, some would argue that's overkill,
link |
but you know, we think she'd be shoving
link |
a pap smear every year as well.
link |
So if we're looking at the cervix,
link |
we want to look at the endometrium.
link |
We want to make sure the lining isn't too thick.
link |
The other thing I should say, Andrew,
link |
is today we now realize that not all women
link |
can tolerate, pardon me, progesterone.
link |
So you have to be careful.
link |
So assuming, again, a woman still has her uterus,
link |
the estrogen solves most of the problems,
link |
but then you have to decide,
link |
can she tolerate the progesterone?
link |
And it needs to be, if given systemically,
link |
like 100 to 200 milligrams.
link |
And for some women, that is a life-saving intervention.
link |
I mean, they start sleeping better,
link |
their hair gets thicker, they feel better,
link |
but for some women, it literally drives them crazy.
link |
It's probably the reciprocal of what we were seeing
link |
in the case of women with PMS.
link |
So in those situations, we say, great,
link |
we're done with oral progesterone.
link |
We just use a progesterone-coated IUD.
link |
So then you get the local progesterone in the uterus
link |
for protection in the systemic estrogen.
link |
What about oral contraception in women?
link |
So the use of estrogen chronically through college years
link |
or 20s, 30s, maybe even teens, who knows?
link |
What's known about the long-term effects, if any?
link |
I got to be honest with you.
link |
I don't think I know enough to comment on it.
link |
It's not something that really impacts
link |
my patient population.
link |
You know, at least in what I see,
link |
more women are using IUDs for contraception than OCs.
link |
I mean, we use OCs sometimes in women
link |
who are premenopausal for symptomatic control,
link |
but we'll typically use like a low, low estrogen,
link |
so a very low synthetic estrogen,
link |
which I don't like using these very much,
link |
but if it's the only thing that we can get
link |
to control certain symptoms,
link |
and we'll use it like half her cycle.
link |
But it's typically not something we're that experienced with.
link |
What about testosterone?
link |
Because you mentioned that nanogram per mil,
link |
when you set everything to the same,
link |
I guess it's nanogram per deciliter,
link |
as it would be to kind of normalize everything.
link |
First picogram per mole.
link |
Right, yeah, and so what Peter was pointing out before
link |
is that you look at your charts
link |
and they're all in these different measures,
link |
and so when you normalize,
link |
testosterone is actually higher than estrogen
link |
in women, that's a surprise to me.
link |
Do you prescribe testosterone therapy to women ever?
link |
We do sometimes, but I do it with much more caution
link |
because I don't have the data, right?
link |
So what we'll say is, look,
link |
I mean, we're now really outside of an area
link |
where I can point to a lot of data.
link |
Like when it comes to estrogen and progesterone,
link |
I'll happily go toe to toe with anybody
link |
who wants to make the case that it's dangerous.
link |
Similarly, when it comes to using testosterone in men,
link |
I'll spend all day, and I can go through that literature
link |
until the other person cries
link |
and wants to just call uncle, right?
link |
And then you prescribe them testosterone.
link |
When it comes to estrogen in,
link |
testosterone in women don't have that data,
link |
and I'd love to see that trial done.
link |
So what's the sweet spot?
link |
How do we reconcile that?
link |
So it's not something I consider standard,
link |
and basically, if a woman is,
link |
if her testosterone, first of all, is staggeringly low,
link |
and again, even though her testosterone is low
link |
compared to a male, we still have a range.
link |
So if it's really at the bottom of that range,
link |
she's really having difficulty putting on muscle mass
link |
and really complaining of low libido,
link |
I think in that situation,
link |
we'll go ahead and use topical testosterone
link |
and replace her to a level
link |
that is still physiologically normal.
link |
Yeah, that's key, because when people hear HRT,
link |
they think about super physiological,
link |
seems to be the term-
link |
Yeah, like I've never seen a single symptom
link |
in a single woman that I've put testosterone on
link |
in terms of acne, body hair, things like that.
link |
Those are real symptoms that you have to be aware of,
link |
but clitoral enlargement and things like that,
link |
that doesn't happen under physiologic normal conditions.
link |
I'd love to talk a little bit
link |
about hormone replacement therapy in men.
link |
When one looks on social media and the internet,
link |
there seems to be a younger and younger cohort of guys,
link |
people in their teens and 20s, showing up to the table,
link |
thinking that injecting testosterone,
link |
sapienate or taking Anavar or whatever it is,
link |
is going to be the right idea.
link |
They mainly seem to be focused on cosmetic effects.
link |
I'm not a physician, so I can't say whether or not
link |
they were actually hypogonadal, et cetera,
link |
but it seems to me, again, correct me if I'm wrong,
link |
but it seems to me that similar to the Atiyah's rule
link |
as it relates to longevity,
link |
that we could come up with a broad contour rule
link |
in which if a male of any age
link |
is not trying to get decent sleep, exercise appropriately,
link |
appropriate nutrition, minding their social connections,
link |
et cetera, et cetera,
link |
the idea of going straight to testosterone
link |
seems like a bad idea.
link |
That said, just like with depression and antidepressants,
link |
there is a kind of a cliff after which
link |
low enough testosterone or low enough serotonin
link |
prevents people from sleeping, exercise,
link |
social connection, et cetera.
link |
So I do want to acknowledge that.
link |
But with that in mind, how do you think about,
link |
and perhaps occasionally prescribe and direct your patients
link |
in terms of hormone replacement therapy in men,
link |
person in their thirties, person in their forties,
link |
who's doing almost all the other things correctly?
link |
What sorts of levels do you think are meaningful?
link |
Because the range is tremendous in terms of blood tests,
link |
300 nanograms per deciliter,
link |
I think on the low end now in the US,
link |
all the way up to 900 or 1200, that's an enormous range.
link |
What are some of the other hormones you like to look at?
link |
Estrogen, DHT, and so on.
link |
So a lot to unpack there.
link |
So let's start with the ranges, right?
link |
So the ranges you gave are for total testosterone,
link |
of course, and we don't spend a lot of time looking at that.
link |
I used to spend more time looking at total and free
link |
when I used more tricks to modulate it.
link |
So I'm actually far more simple in my manipulation
link |
of testosterone today than I was six or seven years ago.
link |
Six or seven years ago, I mean, we were,
link |
we would use a microdose of Anovar to lower SHBG
link |
in a person who had normal testosterone,
link |
but low free testosterone.
link |
What was a low dose of Anovar in that context?
link |
10 milligrams, subling, two to three times a week.
link |
Anovar basically being DHT.
link |
Oxandrolone, yeah, exactly.
link |
And again, we're not recommending this.
link |
This is actually, if you're playing a competitive sport,
link |
can get you banned from that sport.
link |
It can also get you banned from having children
link |
if you do it incorrectly.
link |
Yeah, so a microdose of this has to be small enough
link |
that it doesn't impair your body's ability
link |
to make testosterone, but Anovar has such a high affinity
link |
for SHBG that it basically distracts your SHBG
link |
from binding your testosterone.
link |
Freeing up testosterone.
link |
That's exactly right.
link |
So the goal was how do I just give you more free testosterone?
link |
So if a patient shows up and they've got a total
link |
testosterone of 900 nanograms per deciliter,
link |
which would place them at, depending on the scale
link |
you look at, the scale we look at,
link |
that would place you at about the 70th percentile,
link |
but your free testosterone is eight nanograms
link |
So that's pretty bad.
link |
That means you're less than 1% free.
link |
A guy should be about 2% free T.
link |
So that dude should be closer to 16 to 18 nanograms
link |
So in that situation that I just gave you,
link |
his SHBG is really high.
link |
His SHBG is probably in the 80 to 90 range.
link |
Because I think the upper range is somewhere around 55, 56.
link |
So we would first back stall for what's driving his SHBG.
link |
So there's basically three hormones.
link |
So genetics plays a huge role in this.
link |
There's no question that just out of the box,
link |
people have a different set point for SHBG.
link |
Mine is incredibly low.
link |
My SHBG is like kind of in the 30s, 20s to 30s.
link |
But from a hormone perspective, there's
link |
basically three hormones that run it.
link |
So estradiol being probably the most important,
link |
insulin, and thyroxine.
link |
So we're going to look at all of those
link |
and decide if any of those are playing a role.
link |
So insulin suppresses it.
link |
So this is actually the great irony
link |
of helping a person get metabolically healthy,
link |
is in the short run, you can actually
link |
lower their free testosterone, all things equal.
link |
Because as insulin comes down, SHBG goes up.
link |
And if testosterone hasn't gone up with it,
link |
you're lowering free testosterone.
link |
So somebody who goes on a very low carbohydrate diet
link |
in an attempt to drop some water and drop some weight
link |
is going to increase their SHBG.
link |
Yeah, if their insulin goes down, they're tough.
link |
Bind up testosterone, less free testosterone.
link |
I can tell the carnivore diet people
link |
are going to be coming after me with bone marrow in hand.
link |
But then again, after this discussion
link |
extends a little further, I'm sure the vegans
link |
will be coming after me with celery stalks.
link |
So it's, so then the same as with estradiol.
link |
So except in the opposite direction.
link |
So higher estradiol is higher SHBG.
link |
So again, occasionally you'll see a guy
link |
with incredible, normal testosterone,
link |
but he's a very high aromatase activity person.
link |
So he has a lot of the enzyme
link |
that converts testosterone into estradiol.
link |
You can lower estradiol a bit with an aromatase inhibitor,
link |
and that can bring down SHBG.
link |
Now again, these things individually
link |
are rarely enough to move the needle.
link |
The last is thyroxine.
link |
So if you have a person whose thyroid is out of whack,
link |
you have to fix that before you,
link |
if their T4 is out of whack,
link |
you're going to interfere with SHBG.
link |
There are also some supplements,
link |
which I think you've probably talked about these
link |
I feel like I've heard you talk about these on the podcast.
link |
Yeah, there are a few that will adjust.
link |
You know, there is this idea.
link |
Now there's a much better review that just came out.
link |
I'll send it to you.
link |
I'd love your thoughts on it.
link |
And I've been perusing it line by line,
link |
but I love input from experts like you
link |
on the use of Tonga Ali for reducing SHBG.
link |
In my experience, it does free up some testosterone
link |
by which mechanism it isn't exactly clear,
link |
and the effects aren't that dramatic, right?
link |
There are probably multiple effects.
link |
For all we know, it increases libido,
link |
and it does generally by way of increasing estrogens slightly
link |
which can also increase libido in some individuals.
link |
So we don't know the exact mode of action.
link |
So we've talked about a few.
link |
The one that a few years back people were claiming
link |
could reduce SHBG was stinging nettles.
link |
Stinging nettle, well, urine seems to be,
link |
urinating seems to be coming up multiple times
link |
on this podcast for whatever reason.
link |
Stinging nettle extract,
link |
I took the most pronounced effect of that
link |
was you could basically urinate over a car
link |
What the underlying mechanism of that was, I do not know.
link |
I took it for a short while.
link |
It didn't drop my SHBG very much,
link |
but it did drop by DHT sufficiently
link |
so that I stopped taking it.
link |
I do not like anything that impedes DHT.
link |
I don't care if my hairline retreats.
link |
I don't care about any of that.
link |
DHT to me is something to be hoveted and held onto
link |
because you feel so much better
link |
when your DHT is in the appropriate range.
link |
And I'd love your thoughts on that at some point.
link |
Yeah, again, it really depends on the guy
link |
and it depends on what risk you're trying to manage, right?
link |
So prostate size starts to become
link |
one of the issues with DHT.
link |
Luckily, my prostate-specific antigen is low, and DHT,
link |
the things that I know can reduce it
link |
are things like finasteride, Propecia, things like that.
link |
So things that people take to try and avoid hair loss
link |
can dramatically reduce DHT
link |
and lead to all sorts of terrible sexual side effects,
link |
mood-based side effects, et cetera.
link |
But yeah, so I'm not aware of anything
link |
that can be taken in supplement form
link |
that can really profoundly drop SHBG.
link |
Yeah, we don't spend much attention on it anymore.
link |
Basically, I used to have
link |
a much more complicated differential diagnosis
link |
I would drive patients nuts
link |
with the whiteboard diagrams I would draw for them,
link |
when in the end, I think they were just like,
link |
dude, just what do I need to take?
link |
Today, we take a much more simple approach.
link |
So the first question is,
link |
should you or should you
link |
have your free testosterone being higher?
link |
That's the metric I care about,
link |
is free testosterone is the first most important,
link |
the second most important is estradiol.
link |
And sorry to interrupt,
link |
but you said if you look at your total testosterone,
link |
you want the free T to be about 2% of your total.
link |
Well, it should be, right?
link |
Now, I might not change that anymore.
link |
So in other words, if a guy's at 1%,
link |
then I know I have to really boost his total testosterone.
link |
If he's only going to get
link |
one to one and a half percent of it converted to free,
link |
I need to boost him.
link |
And that's why I don't care if he's outside the range.
link |
Like I'll have a guy who's free T,
link |
I might have to get a guy's total T up to 1,500
link |
to get his free T to 18.
link |
I see, so free T is the target.
link |
I like this approach. Free T is what we treat.
link |
And do you still use Anavarix?
link |
I don't use Anavarix.
link |
Sorry, to try and lower SHBG?
link |
Because it's too potent?
link |
No, because it's just too complicated for patients.
link |
You know, it's a drug that can't be taken orally,
link |
so you have to take it under the tongue.
link |
Like a troche or something.
link |
Right, but I had one patient once who,
link |
even though we told him about 87 times that,
link |
he was like swallowing the Anavars and his liver function.
link |
And he was like, we're talking 10 milligrams
link |
three times a week is a tiny dose.
link |
And three months of him, or whatever,
link |
two months of him swallowing that every time
link |
tripled his liver function test.
link |
So it's like, I was like, you know,
link |
it's just not worth the hassle of doing this for perfection.
link |
In reality, we can fix this another way.
link |
So the first order question is,
link |
do we believe clinically you will benefit
link |
from normalizing your free testosterone?
link |
Or taking it to a level that's call it
link |
80th to 90th percentile.
link |
So upper normal limit of physiologic ranges.
link |
That's the first order question.
link |
And that's going to come down to symptoms,
link |
and that's going to come down to some biomarkers.
link |
I think there's two years ago, was it two years ago,
link |
or maybe a year ago, a very good study came out
link |
that looked at prediabetic men,
link |
you've probably talked about this study,
link |
and looking at insulin resistance and glucose disposal
link |
with and without testosterone.
link |
And the evidence was overwhelmingly clear.
link |
Testosterone improves glycemic control.
link |
Testosterone improves insulin signaling.
link |
This shouldn't be surprising, by the way,
link |
given the role muscles play as a glucose reservoir
link |
in a glucose sink.
link |
So now I include that as one of the things
link |
that we will consider as a factor for using testosterone.
link |
Now, again, it's not the only one,
link |
so you can accomplish that with exercise,
link |
you can accomplish that with these other things,
link |
but then you get into a little bit of the vicious cycle
link |
of will having a normalized testosterone
link |
facilitate you doing those things better?
link |
So let's just assume we come to the decision
link |
that this person is a good candidate
link |
for testosterone replacement therapy.
link |
The next question is what's the method
link |
that we're going to do it?
link |
Are we going to do it indirectly or directly?
link |
Now, we used to use a lot of Clomid in our practice,
link |
and have you talked about Clomid on the podcast?
link |
I haven't talked too much about it.
link |
No, we've talked a little bit about the fact
link |
that some people taking things like anastrozole
link |
to reduce aromatase activity can potentially run
link |
into trouble because they think,
link |
oh, well, more testosterone good, lower estrogen bad,
link |
and then they end up with issues like joint pain,
link |
memory issues, and severe drops in libido,
link |
and I think a lot of the reason why.
link |
And even fat accumulation.
link |
So if estrogen is too low, you can develop adiposity
link |
in a way that you wouldn't otherwise.
link |
There's a great New England Journal paper,
link |
it's probably 10 years old now,
link |
that looked at, I believe it was five different doses
link |
of testosterone siponate.
link |
So these men were chemically castrated
link |
and divided into 10 groups.
link |
It's pretty remarkable.
link |
Somebody signed up for this study.
link |
Yeah, so you were with and without anastrozole
link |
and five doses of testosterone.
link |
So now you basically had five testosterone levels,
link |
plus or minus high or low estradiol.
link |
And the results were really clear
link |
that the higher your testosterone
link |
and the more your estradiol was in kind of
link |
that 30 to 50 range, the better you were.
link |
So if estrogen was too low,
link |
even in the presence of high testosterone,
link |
the outcomes were less significant.
link |
And this is 30 to 50 nanograms per deciliter,
link |
not 30 to 50% of one's testosterone.
link |
Okay, so we haven't talked, but Clomid is,
link |
no, we have not talked a lot about Clomid.
link |
I'd love to get your thoughts on Clomid.
link |
So Clomiphene is a fertility drug.
link |
It's a synthetic hormone.
link |
It's actually two drugs, M-Clomiphene
link |
and I forget the other one.
link |
And it tells the pituitary to secrete FSH and LH.
link |
So the advantage of Clomid is it's oral
link |
and it's meant to be taken orally.
link |
So a typical starting dose would be like 50 milligrams
link |
three times a week.
link |
And if you do that, you'll notice in most men,
link |
especially young men, FSH, LH goes up.
link |
In any man, the FSH and LH go up.
link |
But if a man still has testicular reserve,
link |
he'll make lots of testosterone in response to that.
link |
Because that's the first order question
link |
we're trying to answer is do you,
link |
is your failure to make testosterone central or peripheral?
link |
Yeah, and I think just one point out again,
link |
correct me if I'm wrong, but my understanding
link |
is that a lot of the drugs that we're talking about,
link |
the synthetic compounds, testosterone, estrogen,
link |
things related to growth hormone, et cetera,
link |
were discovered and designed in order to treat
link |
and excuse me, in order to isolate and treat
link |
exactly these kinds of syndromes,
link |
whether or not it was the hypothalamus, the pituitary
link |
or the target tissue, the ovaries or the testes, correct?
link |
I mean, I think the easiest way to go about doing this
link |
is just give the hormone that's missing
link |
without attention to where the deficiency is.
link |
Why this becomes relevant is if you have a 35-year-old guy
link |
whose testosterone is low, but you can demonstrate
link |
that it's low because he's not getting enough
link |
of a signal from the pituitary,
link |
why would you bother giving him more testosterone
link |
when he has the, he has the Leydig cells
link |
and the Sertuli cells to make testosterone,
link |
he just needs the signal.
link |
Sometimes, though not always,
link |
just a course of Clomid can wake him up
link |
and he's back to making normal testosterone.
link |
So he'll do this three times a week,
link |
50 milligrams three times a week for a short course
link |
and then- Yeah, we would do it
link |
for eight to 12 weeks and then we reevaluate.
link |
And estrogen and testosterone will increase in parallel.
link |
Yes, and again, it depends.
link |
Aromatase activity is dependent on how much body fat
link |
you have and genetics and if estradiol gets too high,
link |
we think if it gets over about 55, 60,
link |
we will give microdoses of an estradiol.
link |
But it has to be real microdoses.
link |
I mean, you cannot pound people with an estradiol.
link |
To give you perspective, the sort of on-label use,
link |
like if you just go to a pharmacy and order an estradiol,
link |
you're gonna get one milligram tablets.
link |
Like we can't give anybody a milligram.
link |
They'll feel like garbage.
link |
We have to have it compounded at 0.1 milligrams
link |
and we might give a patient 0.1 two to three times a week.
link |
That would be a big dose of an estradiol.
link |
Yeah, I think that the typical TRT clinic out there
link |
is giving 200 milligrams per mil,
link |
one mil, 200 milligrams of testosterone once every two weeks
link |
and then hitting people with multiple milligrams
link |
of an estradiol and they're all over the place.
link |
I've never really understood.
link |
I mean, I guess I shouldn't be surprised,
link |
but it kind of blows my mind that these TRT clinics
link |
are up all over the place given how bad,
link |
I mean, I see the results
link |
because I have patients that come from them
link |
and I don't understand like why they're so incompetent.
link |
I actually think it's worse than that.
link |
I think that they simply don't understand
link |
and don't care because it's a pill mill
link |
and it's a money mill.
link |
I think that nowadays it seems almost everybody
link |
who's doing TRT is taking lower doses more frequently
link |
every other day or twice a week dividing the dose
link |
and being very, very careful with these estrogen
link |
or aromatase blockers.
link |
Most of our patients do not take aromatase inhibitors.
link |
It's really only the high aromatizers that need it.
link |
And so, yeah, when we'll talk about testosterone,
link |
we'll talk about dosing there because I agree,
link |
the more frequently you can take it, the better.
link |
And frankly, you don't need to go more frequently
link |
than twice a week.
link |
Because it's so slow.
link |
Yeah, the half-life of the drug is,
link |
I think it's about three and a half days
link |
is the plasma half-life or something like that.
link |
It could be off a little bit,
link |
but twice week dosing is really nice.
link |
So if you go to like a testosterone clinic
link |
that's giving you 200 every two weeks,
link |
50 twice a week is the same total dose,
link |
which by the way, is a physiologic dose.
link |
That's not going to give somebody
link |
any of the side effects you would see.
link |
You're not gonna get acne with that.
link |
You're not gonna get gynecomastia.
link |
You're not gonna get any things.
link |
The only real side effect you get from that
link |
is you will get testicular atrophy.
link |
That is enough to suppress.
link |
Yeah, to maintain fertility,
link |
what do you typically do for them?
link |
Well, so this is where,
link |
so I'll finish the story on Clomid
link |
because we currently do not use Clomid.
link |
And that's due to a really interesting observation
link |
that we made that I don't think has been reported
link |
in the literature yet,
link |
which is that Clomid was increasing levels of a sterol
link |
that we also happen to measure called desmosterol.
link |
I'm not familiar with that.
link |
So in the way that cholesterol is made,
link |
it's made by, there's two pathways that make cholesterol.
link |
So it starts like with two carbon subunits,
link |
like acetyl-CoA, and it kind of marches down a pathway,
link |
bifurcates, and cholesterol is the finished product of both.
link |
But in one of those pathways,
link |
the molecule right before cholesterol is called desmosterol.
link |
In the other pathway, it's called lithosterol.
link |
So we constantly measure lithosterol and desmosterol
link |
because we want to know how much cholesterol
link |
is being synthesized in the body,
link |
not just what your cholesterol is.
link |
We wanna know how much cholesterol you reabsorb.
link |
And those markers are really important to us
link |
when we're looking at cardiovascular disease risk.
link |
So when we gave patients Clomid,
link |
we were noticing a almost universal rise
link |
in their desmosterol levels.
link |
Now, the most obvious explanation for that,
link |
though the last time I looked,
link |
I couldn't find clear explanation for this
link |
in any of the clinical trials
link |
that led to the approval of Clomid.
link |
So I don't know if it was described.
link |
In fact, maybe it wasn't known.
link |
I suspect it is inhibiting the enzyme,
link |
which I think is called Delta 24 desaturase,
link |
that turns desmosterol into cholesterol.
link |
Makes sense if you inhibit that enzyme,
link |
you're gonna see a rise in desmosterol.
link |
This wouldn't have been a concern to me
link |
if not for the fact that Tom Dayspring,
link |
who's one of the physicians we work with,
link |
who's one of the world's experts in lipids,
link |
pointed out a very obscure story,
link |
which was that the very first drug ever approved
link |
to treat cardiovascular disease,
link |
at least to treat hypercholesterolemia,
link |
was a drug that attacked the same enzyme.
link |
So this was in the early 1960s, I believe,
link |
maybe the mid-60s, this drug was approved
link |
and it lowered cholesterol.
link |
And it was approved on the basis of lowering cholesterol.
link |
Now, today, no drug for ASCVD is approved
link |
on the basis of it lowering cholesterol.
link |
That's not a high enough bar.
link |
You have to reduce events.
link |
They actually have to show that you're preventing
link |
heart attacks and death.
link |
But at the time, it was like, hey, it lowers cholesterol,
link |
it's gotta be good.
link |
Well, in the late 60s, it was pulled from the market
link |
because events were going up.
link |
So cholesterol was coming down, events were going up.
link |
How could that be?
link |
What we are suspecting is that desmostrol,
link |
which is still a sterol, was potentially more damaging
link |
and created more oxidative stress in the endothelium,
link |
in the subendothelial space than cholesterol.
link |
Which would at least suggest to us,
link |
and again, we're taking a lot of leaps here,
link |
that maybe having high desmostrol,
link |
very high desmostrol, is not a good thing.
link |
And so once we kind of pieced all that together
link |
a few years ago, we were like, yeah,
link |
we're just not gonna prescribe Clomid anymore.
link |
And we then switched to HCG,
link |
which we used to use sometimes instead of Clomid,
link |
but it's more cumbersome to work with.
link |
It needs to be refrigerated.
link |
It's a much more fragile molecule.
link |
Yeah, I think we talked about this once.
link |
It's almost like if you accidentally knock over
link |
the little bottle, it's basically gone bad.
link |
Travel with it is very challenging.
link |
Can't travel with it.
link |
It's an injection, sub-Q.
link |
So easy to administer.
link |
It's not IM or anything like that,
link |
but it's just more of a hassle factor.
link |
But that said, it has the benefit that Clomid does,
link |
which is it preserves testicular function.
link |
It preserves testicular volume.
link |
So bodybuilders will often use this
link |
in their post-cycle therapy
link |
as a way to kind of recover function.
link |
And we would just use it now as ongoing therapy
link |
for a guy who still has testicular reserve.
link |
So on its own, no testosterone,
link |
no aromatase inhibitor, nothing,
link |
just a way to crank out a bit more testosterone
link |
from the testes, maybe some additional estrogen also.
link |
And HCG is a different model.
link |
HCG is just an analog of luteinizing hormone.
link |
So it's basically like giving them luteinizing hormone.
link |
So it's gonna crush endogenous luteinizing hormone levels,
link |
right, because it's-
link |
It's really, yeah, and it,
link |
you don't really see much of an impact on LH,
link |
but you do see endogenous testosterone production go down.
link |
Actually, no, I correct that.
link |
Both FSH and LH will go down on a high enough dose, yep.
link |
Just as a mention, and here I'm not making recommendations,
link |
but one supplement I've talked a lot about publicly
link |
is Fidogia agrestis, which is this weird Nigerian shrub
link |
that does- You're talking about this
link |
On Tim's podcast and Joe's podcast,
link |
and there was a bit of a backlash
link |
because it does turn out that at high doses
link |
in rodent studies, it can cause some toxicity to the testes,
link |
but at lower doses,
link |
it does seem to increase luteinizing hormone.
link |
And after talking about this,
link |
a number of people went out there,
link |
did pre and post blood work,
link |
and the consistent effect seems to be an increase
link |
in luteinizing hormone.
link |
There's a noticeable effect on testicular size and volume.
link |
So a lot of people will take this and be like,
link |
oh, you know, their balls are getting bigger,
link |
and so they get all excited
link |
that something good is happening.
link |
But we don't know the long-term safety and efficacy
link |
of something like Fidogia,
link |
whether or not it needs to be cycled.
link |
Yeah, this is why I'm also very leery
link |
of the supplements in this space,
link |
because at least when we're using HCG or testosterone,
link |
like we have so many years of data.
link |
You have to remember how many women are using this stuff
link |
for reproductive medicine.
link |
So, you know, I think the FDA has a lot of faults.
link |
I think I have an entire podcast devoted
link |
to the corruption of the FDA
link |
and all of the mistakes that have been made
link |
with respect to their oversight in especially generic drugs,
link |
but it's way more regulated than the wild, wild west
link |
of nutty supplement land.
link |
I think that the reason for talking about things
link |
like Tonga and Fidogia was
link |
to provide some intermediate discussion
link |
between doing all the correct things,
link |
but no supplementation or hormone therapy,
link |
and then going straight to hormone therapy.
link |
It's sort of like the leap from,
link |
I can't focus very well to Ritalin, right,
link |
without a real diagnosis of ADHD,
link |
to, oh, well, maybe some things like alpha-GPC
link |
low doses of nicotine, right?
link |
But I agree entirely.
link |
I mean, the sourcing is important.
link |
The dosages are worked out empirically on an individual basis
link |
and there aren't randomized control trials.
link |
There just aren't.
link |
Yeah, and, you know, have kind of like a seven,
link |
this is another Peter principle, right?
link |
So I've got a lot of patients that come into the practice
link |
and, you know, during our intake, we go through,
link |
what drugs and supplements are you taking right now?
link |
And, you know, a lot of people come in,
link |
I'm not taking anything, Peter.
link |
I just, you're in charge now.
link |
Like, tell me what you think.
link |
And then you get a lot of people that come in
link |
and they're like, we're gonna need an extra few pages
link |
for this part of the documentation.
link |
Right, the people who travel with a suitcase
link |
that you can hear as they walk through the airport
link |
from all the pills that I like.
link |
Right, and so I give these patients
link |
a little homework exercise,
link |
which is you have to answer these seven questions
link |
for every supplement you take.
link |
And here's the spreadsheet and let's talk about it.
link |
And it basically just runs through,
link |
like, you know, it's basically walking you through
link |
the logic of why do you take this molecule?
link |
And I think for many people,
link |
when they do that, it's very sobering, right?
link |
They kind of, a lot of them will come back and be like,
link |
you know what, I don't think I can come up with any reason
link |
along this really rigorous line of thinking
link |
as to why I'm taking 80% of this stuff.
link |
Well, I know people, and actually we know some
link |
of the same people were fanatic about like red light
link |
on the testes, sunning their testes,
link |
putting ice packs on their testes.
link |
It's kind of all over the place.
link |
The number of things that people are trying and doing
link |
in order to increase testosterone output
link |
from their testes is pretty remarkable.
link |
And that said, among some of the women I know,
link |
the number of things that they're doing
link |
to try and promote longevity and fertility,
link |
and in particular skin health, hair health,
link |
and nail health is also kind of outrageous.
link |
Everything from collagen to red light therapies,
link |
which may actually have some efficacy in certain cases.
link |
But there's a hunger there, right?
link |
One of the things that I hope gets a lot more attention
link |
is the use of rapamycin for preserving ovarian health.
link |
So the animal literature on this is pretty impressive, right?
link |
So in mouse models, rapamycin will preserve ovarian life.
link |
And so it makes sense, right?
link |
I mean, it totally makes sense
link |
why the most potent, zero protective molecule we have
link |
would also preserve and extend ovarian life, at least in mice.
link |
So I'd love to see the clinical trials done in women
link |
to test this hypothesis.
link |
I definitely want to come back to this
link |
because it's a key thing.
link |
I know that a lot of people are interested
link |
in female fertility out there,
link |
including their male partners.
link |
So going back to, so now I understand
link |
why you don't prescribe clomiphene
link |
because of this potential dysmosterol link.
link |
What about testosterone therapy?
link |
So less frequent, lower doses,
link |
less or no estrogen inhibition or aromatase inhibition?
link |
Yeah, we're only using an aromatase blocker,
link |
and we use Arimidex when we do.
link |
It's just to get that estradiol into the range we want.
link |
I like to see it between 30 and 50.
link |
That's the sweet spot.
link |
And I don't know, I would say like a third,
link |
maybe not even a third, I'd say probably 20% of men
link |
require a microdose of anastrozole to get into that range.
link |
And I'd rather err on the side
link |
of being a little high than a little low.
link |
So I never really want to be below 25.
link |
If, unless, sometimes it's just below 25 and it is,
link |
it is what it is, that's fine.
link |
But if we're suppressing it to below 25,
link |
I never want to be in that zone.
link |
And then yes, so TRT is ultimately,
link |
giving testosterone, cipunate is usually what we use.
link |
Injectable, so as opposed to cream or pellet.
link |
I used to use pellets with women for some
link |
who were really adamant about the convenience of it.
link |
But for a bunch of reasons, I just,
link |
I'm mostly not doing that.
link |
And I've never been a fan of pellets in men.
link |
You can't control the dosage once it's in, right?
link |
Well, even if you know the dose,
link |
yeah, that's obviously a problem.
link |
But I don't think, there's a big difference
link |
between putting a pellet into a man and a woman.
link |
So when you're putting an estrogen pellet into a woman,
link |
it's like, it's that big.
link |
When you're putting enough pellets into a man
link |
for six months of testosterone,
link |
it's two sums of pellets that are longer than my finger.
link |
So you're putting like a V-shape,
link |
you're putting it into the gluteal fat.
link |
So it's just a more morbid procedure
link |
and I don't think it's necessary.
link |
I think if you know how to manage it,
link |
through sort of the injections and now,
link |
yeah, well, especially now if you're doing,
link |
we're having them do sub-Q injections anyway.
link |
So it's not IM, they're using a five eighths inch
link |
to a one inch 25 gauge needle,
link |
which is about the smallest needle
link |
you can push the oil through once to twice a week,
link |
depending on, and by the way,
link |
if they're real needle phobes,
link |
we use Zyosted, which is a preloaded pen.
link |
And are you having all men take HCG
link |
to maintain fertility and test their killer size?
link |
Only if they want to.
link |
And by the way, we do not like to use TRT in men who,
link |
we don't like to use testosterone specifically
link |
in men who still want to maintain fertility.
link |
We just steer them away from that.
link |
Because total sperm count goes down.
link |
Yeah, we just say, why risk it?
link |
Like we'd rather use HCG.
link |
Yeah, just wait, just wait until you're done reproducing.
link |
Bank sperm, wait till you're done reproducing
link |
before we go to testosterone.
link |
What are some of the benefits
link |
and what are some of the cautionary notes
link |
with appropriate TRT, meaning of the kind of contour
link |
that we're talking about here,
link |
a lower dose with the yes or no low estrogen control?
link |
People, what generally people report, how do they feel?
link |
What does it allow them to do
link |
that they couldn't do or feel before?
link |
And then in terms of what are the markers to look for?
link |
Is it LDL, blood pressure, water retention, acne,
link |
those kinds of things?
link |
Are there some other things as well?
link |
Yeah, it depends on the doses, right?
link |
I mean, again, we're using these in really low doses.
link |
So it's pretty rare that we'd have a patient
link |
on more than 100 milligrams a week of testosterone.
link |
I think for comparison,
link |
like a bodybuilder could easily take 500 to 1,000
link |
during a high growth phase.
link |
I know some of these guys, they go ballistic
link |
or they're doing moderate levels of testosterone sibonate,
link |
but they're also taking dianabolic, sandralone,
link |
SARMs and a bunch of other things.
link |
I mean, their stacks are kind of ridiculous.
link |
I mean, no disrespect to that sport,
link |
but I mean, people are dying like crazy
link |
in that sport right now.
link |
It's outside of physiology.
link |
Yeah, and I think for 99% of people listening,
link |
they just, they look, they hear bodybuilder
link |
and they just go like, why would somebody do that anyway?
link |
I think that's the typical response.
link |
So the point is a lot of,
link |
but we owe those guys a great deal of gratitude
link |
because they've shown us the boundaries.
link |
Including the women.
link |
That's right, yeah.
link |
And so those bodybuilders have taught us a lot
link |
about like what happens.
link |
And so, yeah, the bloating, the water retention,
link |
acne, hair loss, hair growth, all of those things,
link |
we understand the truth of it is
link |
we just don't see those things in our patients.
link |
But 100 milligrams per week is a very low output.
link |
My understanding is-
link |
But it's a physiologic dose.
link |
I mean, the reality of it is it's enough for most people.
link |
I mean, there's probably the highest we've ever had to go
link |
is maybe 70 twice a week.
link |
What's the youngest patient you've ever had to put on TRT?
link |
Actual testosterone?
link |
Probably, that's a good question.
link |
I'm thinking about maybe 40.
link |
I think that's great for people to hear
link |
because I know that a lot of guys in their 20s
link |
are thinking TRT is the way to go, and I would argue,
link |
unless you're doing everything else right
link |
and you're still hypogonadal and you're really struggling,
link |
put that time off because also the fertility issue,
link |
you want to delay delay delay.
link |
Well, again, it depends if when we say TRT,
link |
if you're in your 20s and there's no other way,
link |
I would hope you would be steered toward HCG
link |
to at least preserve testicular function.
link |
Now, again, we don't actually know
link |
if after being on HCG for 10 years,
link |
your pituitary will still work.
link |
Right, you won't be able to make your own luteinizing.
link |
Exactly, so it might be the case
link |
that you're gonna need something upstream of that,
link |
like Clomid to kickstart it.
link |
But again, I don't want anybody who's listening to this
link |
who's using Clomid for fertility
link |
to think that there's anything wrong with it.
link |
My concern over this became like,
link |
if you're gonna be on this for 10 years, is it problematic?
link |
Not if you're using this for a course of IVF
link |
or something like that.
link |
So again, if we felt that someone's pituitary
link |
was not working, I would be happy to put three months
link |
of Clomid on them to kind of try to see
link |
if we could blast it back.
link |
Do you have men cycle on and off testosterone
link |
at these low dosages?
link |
Are they taking a month vacation from it every once in a while?
link |
Yeah, it totally depends.
link |
You know, I was talking to a patient yesterday
link |
where we just decided to change the cycle.
link |
Eight weeks on, then eight weeks on HCG.
link |
Eight weeks on, then eight weeks on HCG.
link |
So that's gonna be a cycle
link |
that maintains his testosterone level
link |
but fluctuates between endogenous, exogenous,
link |
endogenous, exogenous.
link |
Sometimes we'll just do testosterone on, off, on, off.
link |
And there it's like, how much can he replenish naturally
link |
but understanding his T will dip during those off cycles.
link |
It seems to me there's a tremendous incentive
link |
for somebody to develop a molecule
link |
that can directly target SHBG,
link |
besides oxyandryl and ANIMAR, right?
link |
If one could just drop SHBG just the tiniest bit,
link |
it seems like one could adjust the free T
link |
in a way that would be great.
link |
I don't know why that molecule is so hard to target
link |
but somebody ought to do it.
link |
The chemistry can't be that hard.
link |
I talked with Patrick Arnold about this
link |
many, many years ago.
link |
I wish I could remember what his ID,
link |
he had a comment about this that at the time made sense
link |
and I don't remember what it was.
link |
Cause I had that thought too, like, man,
link |
especially for that subset of guys
link |
who have normal testosterone
link |
but they're just overbinding it.
link |
I'm really glad that you brought up this issue
link |
of total testosterone versus free T.
link |
And the reason is ever since going on podcasts
link |
and talking about this stuff
link |
and talking about it on this podcast,
link |
people will send me their numbers,
link |
they'll send me their charts
link |
and then they'll send photos of themselves.
link |
And I can tell you, while I'm not a clinician
link |
and I haven't done fancy statistics on it,
link |
there's very little correlation
link |
between someone's absolute testosterone and how they appear.
link |
I mean, some of these guys look really lean, really strong
link |
and they'll say, oh, total testosterone is 550, 480, right?
link |
And then other people, you know, testosterone is 860
link |
but you look at them and you think,
link |
oh, they kind of have a kind of a doughy look to them.
link |
And so it's gotta be this free testosterone thing
link |
plus estrogen, et cetera.
link |
And so cosmetically-
link |
Well, but also training and nutrition too, right?
link |
I mean, I just think, I think for all this talk
link |
about testosterone, which I enjoy talking about
link |
and I enjoy talking about the data
link |
on long-term health consequences of testosterone
link |
because this is another controversial topic.
link |
I also think people kind of overstate its importance.
link |
And I think there's a group of people who think
link |
if I could just fix my testosterone,
link |
everything will be better.
link |
And it's sort of like, no, actually that's not true at all.
link |
Really, the only purpose in my mind of fixing testosterone
link |
is to give you the capacity to work harder.
link |
It's really going to help you recover more
link |
from your workouts.
link |
This should just give you a greater ability
link |
to experience muscle protein synthesis.
link |
So, you know, if I just give you a bunch of testosterone
link |
and you sit on the couch and your nutrition doesn't change
link |
and you're not exercising anymore,
link |
you're not gonna experience any benefits of this thing.
link |
I mean, my testosterone level has fluctuated quite a bit
link |
throughout my life.
link |
And when I think about as an adult,
link |
not sort of including when I was sort of
link |
a fanatical teenager, but as an adult,
link |
when was I at my absolute most insane physique?
link |
Like my best performance on a DEXA scan
link |
would have been 30, I was 38 years old.
link |
By DEXA, I was 7% body fat.
link |
My fat-free mass index was like 23.2,
link |
23.3 kilograms per meter squared.
link |
I mean, I was huge, strong, and totally ripped.
link |
My testosterone was in the toilet.
link |
I was over-training like crazy.
link |
I was exercising probably 26 hours a week,
link |
killing it in the gym, swimming like a banshee,
link |
cycling like my life depended on it,
link |
grossly over-trained, low T, but, you know,
link |
I mean, physically looked like twice the guy I am today.
link |
You know, today my T is probably
link |
twice as high as it was then.
link |
So, you know, now you could say, well, Peter,
link |
what if you took T back then?
link |
How much better could you have been?
link |
But again, I think the take home is
link |
just giving somebody T doesn't do much of anything.
link |
It probably helps on the insulin resistance front
link |
without any other thing, but to me, that's a waste.
link |
Like that's squandering the gift that it is giving you,
link |
which is the ability to do more work
link |
and, you know, capture the benefit of it via muscle protein
link |
I agree, and I think that the psychological effect
link |
of testosterone, whether or not it's exogenous or endogenous
link |
is it makes effort feel good.
link |
At some level, it really seems to do that.
link |
And Sapolsky tells me the main reason,
link |
or mechanistically the main reason that it can do that
link |
is by adjusting levels of activity in the amygdala.
link |
And so there's some interesting imaging there.
link |
I'd love to chat more about the cholesterol pathway.
link |
And I know this is a huge landscape as well,
link |
but I think we're doing a good job of diving in deep,
link |
but not getting stuck in the underlying currents at all.
link |
There's tremendous debate about whether or not
link |
dietary cholesterol directly relates to,
link |
or does not relate to serum cholesterol, LDL and HDL.
link |
Well, let me put it this way.
link |
There are people that argue, I'm certainly not arguing.
link |
There are people that argue that if one eats a ton
link |
of saturated fat, that LDL goes up and HDL goes down.
link |
Okay, but that's not dietary cholesterol per se.
link |
No, not dietary cholesterol per se.
link |
But, and then there are people that argue
link |
that any increase in saturated fat intake
link |
is going to be bad, that you already synthesize
link |
enough cholesterol for hormone production, et cetera.
link |
I'd like to talk about this in terms
link |
of how one should read their charts.
link |
My LDL is in what I'm told is healthy range.
link |
My HDL is in what I'm told is healthy range.
link |
I do try and not overeat things like butter, cheese,
link |
and red meat, but I do eat some of those things
link |
and I feel pretty good.
link |
But most people are operating under the assumption
link |
that eating saturated fat is bad
link |
and you only do it in so far as you want to taste it.
link |
And then of course, there's a small group of people
link |
that love to eat organs and meats and really pack
link |
cholesterol and would argue that it doesn't matter
link |
if your LDL is 870, it's not going to impact your health.
link |
What's the reality around LDL, HDL, dietary cholesterol,
link |
saturated fat, at least in your view?
link |
So first, let's differentiate between cholesterol and fat,
link |
just for the listener, because we use them,
link |
I don't want to make sure people understand.
link |
So cholesterol is a really complicated molecule.
link |
So it's a ringed molecule.
link |
I used to know exactly what its structure was,
link |
but it could have 36 carbons for all I remember.
link |
It is a lipid, so it is a hydrophobic molecule
link |
that is synthesized by every cell in the human body.
link |
It is so important that without it,
link |
if you look at sort of genetic conditions
link |
that impair cholesterol synthesis,
link |
depending on their severity, they can be fatal in utero.
link |
So in other words, anything that really interferes
link |
with our ability to produce cholesterol
link |
is a threat to us as a species.
link |
And the reason for that is cholesterol makes up
link |
the cell membrane of every cell in our body.
link |
So as you know, but maybe the listeners don't,
link |
even though a cell is a spherical thing,
link |
it has to be fluid, right?
link |
It's not just a rigid like sphere,
link |
like a blow up ball, right?
link |
It's gotta be able to kind of move in this way
link |
to mesh with other cells.
link |
It also has to accommodate having porous structures
link |
that traverse its membrane to allow ions
link |
and things like that to go across.
link |
And it's cholesterol that gives the fluidity
link |
It's also, as you're alluding to, the backbone
link |
of some of the most important hormones in our body,
link |
estrogen, progesterone, testosterone, cortisol.
link |
So we have this thing, super important.
link |
Okay, then let's talk about does cholesterol,
link |
can you get cholesterol in your diet?
link |
Yes, you can eat foods that are rich in cholesterol.
link |
What was known in 1960,
link |
but somehow escaped everybody's imagination
link |
until finally the American Heart Association acknowledged
link |
this a few years ago, is that the cholesterol you eat
link |
does not really make it into your body.
link |
And the reason for that is it's hysterified.
link |
So we have, and not to get too nerdy,
link |
but I think people, I really think it's important
link |
people understand how this thing works.
link |
So we have cells in our gut, enterocytes,
link |
they're the endothelial cells of our gut.
link |
They have, each one of them has basically
link |
two transporters on them.
link |
So the first is called the Niemann-Pick C1-Like1 transporter.
link |
The second is called the ATP-Binding cassette G5-G8.
link |
Okay, the Niemann-Pick C1-Like1 transporter
link |
will bring in any sterile, cholesterol,
link |
zosterol, phytosterol, any sterile
link |
that fits through the door will come in.
link |
Virtually all of that is the cholesterol we produce
link |
that gets taken back to the liver,
link |
that the liver packages in bile and secretes.
link |
So that's what aids in our digestion,
link |
which is another thing I should have mentioned earlier.
link |
In addition to using cholesterol
link |
for cell membranes and hormones,
link |
we wouldn't be able to digest our food without cholesterol
link |
because it's what makes up the bile salts.
link |
So our own cholesterol is basically recirculated
link |
in a pool throughout our body,
link |
and this is the way it gets back into the body.
link |
It's through this Niemann-Pick C1-Like1 transporter.
link |
When it gets in there, the body,
link |
this is the checkpoint of regulation.
link |
This is where the body says,
link |
do you have enough cholesterol in the body, yes or no?
link |
If yes, I will let that cholesterol
link |
make its way into the circulation.
link |
So it'll go off the basolateral side of the cell,
link |
not the luminal side, into the body.
link |
Alternatively, the body says,
link |
you know what, we have enough cholesterol.
link |
I'm gonna let you poop this out.
link |
And now the ATP binding cassette will shoot it out.
link |
It'll go back into the luminal side, and away it goes.
link |
So all of the cholesterol in our body is not esterified,
link |
and it doesn't have that big,
link |
bulky side chain attached to it.
link |
The cholesterol you eat is esterified,
link |
and an esterified cholesterol molecule
link |
simply can't physically pass
link |
through that Niemann-Pick C1-Like1 transporter.
link |
Now, we probably manage to de-esterify
link |
10 to 15% of our dietary cholesterol.
link |
So in other words, there are small amounts
link |
of dietary cholesterol
link |
that do make their way into our circulation,
link |
but it represents a small fraction
link |
of our total body's pool of cholesterol.
link |
Again, this was known even by Ancel Keys,
link |
the guy who turned fat into the biggest bogeyman of all time.
link |
Ancel Keys acknowledged this in the 1960s.
link |
Dietary cholesterol plays no role in serum cholesterol.
link |
Again, it took the American Heart Association
link |
another 60 years to figure that out,
link |
but even now, they acknowledge that.
link |
Dietary cholesterol has no bearing.
link |
So why is it that it's pretty easy to find studies,
link |
or at least people who are highly credentialed
link |
from good institutions,
link |
claiming that eating saturated fat, cheese-
link |
Saturated fat's different.
link |
Saturated fat and red meat,
link |
things that are rich in cholesterol,
link |
to be more specific, is bad for us
link |
in terms of our eventual LDL.
link |
So this is two different things.
link |
So saturated fat consumption in many people
link |
will raise LDL cholesterol.
link |
So it's important to differentiate
link |
between what is saturated fat.
link |
So saturated fat, of course, is a fatty acid,
link |
just so people understand.
link |
Totally different molecule from cholesterol.
link |
Cholesterol is this very complicated ring structure,
link |
multiple rings stuck together.
link |
SFA, saturated fat, is just a long-chain fatty acid
link |
that is fully saturated, meaning it has no double bonds,
link |
and it can exist in isolation.
link |
It can exist in a triglyceride, triacylglyceride,
link |
or a phospholipid, or all sorts of things like that.
link |
So when we eat foods that contain fat,
link |
basically there are three distinctions for that fat.
link |
Is it monounsaturated, one double bond?
link |
Or is it polyunsaturated, two or more double bonds?
link |
The observation that eating saturated fat
link |
raises cholesterol is generally correct.
link |
But again, because if we're gonna start talking about LDL,
link |
we have to explain what LDL is.
link |
This is another one of those things
link |
that's just so grossly misunderstood
link |
that it makes having discussions about this very complicated.
link |
Let's go back to the cholesterol problem.
link |
So every cell in our body makes cholesterol.
link |
And almost without exception, they make enough.
link |
There are a handful of times, however,
link |
when a cell needs to borrow cholesterol from another cell.
link |
Okay, so how would you do this, right?
link |
So if you're playing God for a minute
link |
and you wanna design a system,
link |
you have to be able to transport cholesterol
link |
from one cell to another.
link |
The most logical place you would transport this
link |
is through the circulation.
link |
And the problem with circulation is it's water.
link |
So now you have this problem,
link |
which is I want to transport cargo
link |
that is hydrophobic in a hydrophilic medium.
link |
So if you think about all the things
link |
that we transport in our blood,
link |
sodium, electrolytes, glucose, things like that,
link |
they're water soluble.
link |
They just move back and forth in our blood with no chaperone.
link |
But when you wanna move cholesterol,
link |
you have to package it in something that's hydrophilic.
link |
That something is called a lipoprotein.
link |
So we have these spherical molecules
link |
that are lipid on the inside,
link |
protein on the outside, lipoprotein.
link |
And inside, they contain cholesterol and triglycerides.
link |
So now you've got the spherical thing,
link |
triglyceride, cholesterol on the inside,
link |
and it's chaperoned by a hydrophilic molecule
link |
that allows it to move through our circulation.
link |
And those lipoproteins exist in different densities.
link |
So if you run these out on a gel electrophoresis plate,
link |
you'll identify different densities.
link |
The density is a function of how much protein
link |
and how much lipid is in it.
link |
So the highest density of this
link |
is called a high density lipoprotein.
link |
And the lowest density of this
link |
is called a very low density lipoprotein, a VLDL.
link |
And then next to that, you have an LDL,
link |
a low density lipoprotein.
link |
And then next to that, you have an IDL,
link |
an intermediate density lipoprotein.
link |
So, you know, it actually goes VLDL, IDL, LDL.
link |
But anyway, so when people say my LDL is high
link |
or my LDL is 100, what are they saying?
link |
They're saying the cholesterol concentration
link |
of my LDL particles is 100 milligrams per deciliter.
link |
So the total cholesterol concentration you have
link |
in your circulation is that number
link |
that says total cholesterol.
link |
So if someone's blood panel says
link |
my total cholesterol is 200,
link |
it means that if you take all the lipoproteins
link |
in their circulation, bust them open
link |
and measure the cholesterol content,
link |
it's 200 milligrams per deciliter.
link |
And for all intents and purposes,
link |
because the IDLs are so short-lived,
link |
that's basically the sum of your LDL cholesterol,
link |
your VLDL cholesterol, and your HDL cholesterol.
link |
Those three things sum to your total cholesterol.
link |
What about LDL little A that you mentioned earlier?
link |
LP little A is another, yeah, yeah.
link |
He's another actor.
link |
He is a special type of LDL that, again,
link |
in sort of 10 to 20% of the population
link |
is a really bad actor.
link |
So that's an LDL that has another apolipoprotein on it
link |
called apolipoprotein little A.
link |
The other thing I'll just say on this,
link |
because earlier I mentioned apoB,
link |
there are two broad families of lipoproteins.
link |
There are those that are wrapped in apoBs
link |
and those that are wrapped in apoAs.
link |
The apoA family is the HDL family.
link |
The apoB family is the VLDL, IDL, LDL family.
link |
So for somebody who, let's say,
link |
their total cholesterol is,
link |
let's just stay with 200 for simplicity.
link |
What do you like to see in terms of the HDL LDL ratio?
link |
Couldn't care less.
link |
I only care about apoB.
link |
I only care about apoB.
link |
I care about the causative agent of atherosclerosis.
link |
apoB is the thing that drives atherosclerosis.
link |
And what levels are attractive or repulsive for you?
link |
When you see levels of apoB that are blank,
link |
you get really concerned.
link |
It depends on the person's objectives.
link |
So again, we take a very different view.
link |
I mean, we have...
link |
Vitality now, and I want to live to be 100.
link |
Yeah, so if you tell me you want to live to be 100,
link |
you're going to need to keep your apoB
link |
below 30 milligrams per deciliter.
link |
Let's say I want to live to be 100,
link |
but I also, well, how about I don't care how long I live,
link |
but I want to feel great while I live.
link |
Again, it depends, right?
link |
Like anybody who's had a heart attack
link |
is going to be compromised in their ability
link |
to feel well after, right?
link |
I guess I say it that way,
link |
because if you're going to tell me that,
link |
I mean, in order to achieve that live to 100 level,
link |
I'm going to have to give up my personal life
link |
and my brain functioning,
link |
then I'm not really interested in it.
link |
Sure, but to get LDL levels,
link |
and really, again, people think of it as LDL.
link |
It's really apoB, right?
link |
ApoB is this total concentration of LDL and VLDL,
link |
and that's what matters.
link |
Those are the big atherogenic particles.
link |
LDL also includes the Lp little a,
link |
although the concentration of Lp little a
link |
is relatively speaking so small
link |
that it doesn't generally show up as much in the apoB.
link |
So we treat apoB, and basically what it comes down to
link |
is you want apoB to be as close to the level
link |
as it was when you were born.
link |
So we start developing heart disease when we're born.
link |
That's just the way it is.
link |
The autopsy studies make this abundantly clear.
link |
When you look at autopsies of young people
link |
who are dying in their 20s,
link |
and this was first done in the 1970s,
link |
it was again repeated.
link |
Again, it's always done after we have a war, right?
link |
So in the 1970s, it was done on people who died in Vietnam.
link |
In the early 2000s, it was done on mostly young men
link |
but some young women who were dying
link |
in Iraq and Afghanistan.
link |
And we saw without any ambiguity
link |
that cardiovascular disease is already taking hold
link |
in people who are 18, 19, 20 years old.
link |
And to be clear, they aren't gonna die of atherosclerosis
link |
They're still 40, 50 years away from it,
link |
but this is a lifelong disease.
link |
And we also know that the disease can't really develop
link |
until apoB reaches a certain threshold.
link |
And that's the threshold that most of us get to
link |
by the time we're sort of in our teens.
link |
So it's this really young apoB level
link |
of kind of 20 to 30 milligrams per deciliter
link |
that makes it impossible to get atherosclerosis.
link |
So apoB is necessary
link |
but not sufficient to develop ASCVD.
link |
Now that, go ahead.
link |
Oh, I'm sorry, I was just gonna ask
link |
what are some of the top behavioral nutritional
link |
supplementation, if any, based
link |
and prescription drug based ways to target apoB?
link |
Well, nutritionally, you basically have two big tools, right?
link |
And it depends on what's driving up apoB.
link |
So apoB, remember, is the concentration of LDL
link |
and VLDL particles.
link |
And what do they carry?
link |
Cholesterol and triglycerides.
link |
So anything that reduces cholesterol
link |
and reduces triglycerides is going to reduce apoB.
link |
Triglycerides are generally driven by carbohydrate intake.
link |
So more insulin resistance, more carbohydrate intake,
link |
more triglycerides.
link |
So we, I mean, clinically, this is readily apparent
link |
to anyone who treats patients.
link |
If you restrict carbohydrates,
link |
you will reduce triglycerides.
link |
That just happens all day long.
link |
But if you reduce triglycerides by raising fat intake
link |
so much, it can still raise apoB.
link |
So you have to be able to think about it.
link |
So in an ideal world, it's can you lower saturated fat,
link |
which tends to be the one that is most driving apoB,
link |
while lowering carbohydrate and then see what you can get.
link |
But here's the reality of it is,
link |
there's nobody with dietary intervention
link |
that's going to get to a level
link |
of 30 milligrams per deciliter.
link |
I mean, I've never seen any.
link |
Pure dietary intervention.
link |
So what are the other things that can move the-
link |
It's gotta be pharmacologic at this point.
link |
Statin type interventions.
link |
Well, now you have multiple classes of drugs.
link |
So the tried and true is the statin.
link |
So statins work by inhibiting cholesterol synthesis.
link |
And the net effect of that is that the,
link |
so the liver is really sensitive to cholesterol levels.
link |
It doesn't want too much.
link |
It doesn't want too little.
link |
When you inhibit cholesterol synthesis,
link |
the liver says, I want more cholesterol.
link |
So it puts more LDL receptors on its surface
link |
and it pulls the LDL out of circulation.
link |
That's what lowers the LDL in the circulation.
link |
So, you know, again, nine statins in use today.
link |
We typically use four of them.
link |
The side effect profile, contrary to kind of all the
link |
sort of statin hating propaganda out there, very benign.
link |
5% of people experience muscle soreness,
link |
which reverses upon cessation, you know.
link |
Cognitive effects.
link |
Again, I think it's, in terms of actual comparing it
link |
at a placebo, no effect whatsoever, right?
link |
So does that mean that you put a patient on it,
link |
they won't complain of something?
link |
No, but if you look at clinical trials,
link |
there's no evidence whatsoever
link |
that statins impair cognition.
link |
There's also no evidence in clinical trials
link |
that they accelerate the risk of neurodegenerative disease.
link |
In fact, it's the opposite.
link |
Now we will, there's a very nuanced case we make.
link |
Andrew, which is we'll look at patients
link |
with highly suppressed desmostrol levels.
link |
We do want to maintain desmostrol above a certain level
link |
because of some evidence that is still,
link |
I think, very preliminary,
link |
but enough for us that we say, why take the chance?
link |
We have so many other tools to lower cholesterol.
link |
Why would we over suppress synthesis
link |
in a susceptible individual?
link |
So the next tool you look at is a drug
link |
that blocks the absorption or the reabsorption
link |
Remember that Niemann-Pixie-1-like-1 transporter?
link |
So that guy has a drug called ezetimibe
link |
that just mechanically blocks it.
link |
So in people, and that's why I mentioned earlier,
link |
we measure all those sterols in people,
link |
so we also measure things called phytosterols,
link |
and the phytosterols give us an indication
link |
of how active that transporter is.
link |
So the higher your phytosterols,
link |
the more likely you are to respond to ezetimibe.
link |
Next class of drugs is a drug
link |
that blocks cholesterol synthesis, but only in the liver.
link |
So the statin does it globally.
link |
This other drug called benbedoic acid
link |
does it only in the liver.
link |
So it has a very similar mechanism to statins,
link |
different enzyme, not quite as potent,
link |
but way fewer side effects.
link |
So any patient that's having a response to statins
link |
that's adverse will try this other thing.
link |
What's it called one more time?
link |
The most potent drug of the lot is the PCSK9 inhibitor.
link |
So PCSK9, it's a protein that was discovered
link |
in the late 90s, I believe,
link |
is responsible for the degradation of LDL receptors.
link |
This was first discovered in people
link |
who had a condition called
link |
familial hypercholesterolemia, or FH.
link |
So these are people that have incredibly high cholesterol.
link |
Typically, their total cholesterol level is 300.
link |
Their LDL cholesterol is typically
link |
north of 200 milligrams per deciliter.
link |
This is a disease that is defined by the phenotype,
link |
So the phenotype has a very clear definition,
link |
which I basically just gave you.
link |
The genotype is there's a million paths to get there.
link |
There's over 3,000 mutations
link |
that are known to produce that phenotype.
link |
This was discovered to be one of them.
link |
In people who had hyperfunctioning PCSK9,
link |
this protein was just constantly hammering
link |
and destroying the LDL receptors,
link |
and so their LDL would be huge.
link |
And by extension, their total cholesterol would be.
link |
So in 19, sorry, in 2006, Helen Hobbs and colleagues
link |
discovered an opposite group of population,
link |
people who had LDL cholesterol naturally
link |
of 10 to 20 milligrams per deciliter,
link |
which would be an ApoB of about 20 milligrams per deciliter,
link |
and who never got heart disease.
link |
They were immune to heart disease,
link |
no matter how long they lived.
link |
And they had the opposite.
link |
They had hypofunctioning PCSK9.
link |
And so that was 2006 in the New England Journal of Medicine.
link |
That basically got a whole bunch of drug companies
link |
hot on the trail of producing a drug to mimic it.
link |
So now we have these antibodies,
link |
and they're wildly effective.
link |
What percentage of your patients over 45
link |
do you have on either a statin
link |
or on one of these other classes?
link |
Well, often it's in combinations, and I would say 80%.
link |
We have to remember what our objective is.
link |
We're in the business of trying to make sure
link |
people live as long as possible.
link |
And you have to take a sort of worldview of this, right?
link |
If you, like, what's the most prevalent
link |
cause of death globally?
link |
It's the cardiovascular disease.
link |
Yeah, and like, how close is it?
link |
So the last year before COVID,
link |
COVID kind of messes up these numbers a little bit,
link |
but if you go to 2019, 18.6 million people
link |
died of heart disease.
link |
Number two, cancer, 10 million.
link |
Like, nothing's in the zip code of atherosclerosis.
link |
And if you remember what I just said,
link |
if you took everybody in their 20s
link |
and reduced them to a level of that of a child,
link |
you'd make ASCBD an orphan disease.
link |
So the question is, can you do that?
link |
Why don't we hear more about this?
link |
I realize there's some nuance.
link |
It's not straightforward.
link |
It's not as simple as saying eat less cheese, red meat,
link |
and watch your LDL get on a statin.
link |
But why do we hear so little about ApoB
link |
in the general discussion?
link |
Social media is such a skewed landscape, as we know.
link |
People shouting into tunnels of varying clarity.
link |
Some are beautiful bronze tunnels
link |
with clean walls and others are sewer lines, right?
link |
And they all converge in the same place, as we know.
link |
But why do we hear so little about this?
link |
I mean, I'm not on a statin,
link |
but now I'm beginning to think
link |
that maybe that might be a good idea to consider
link |
one of these other compounds.
link |
I don't know the last time I looked
link |
at my ApoBs specifically.
link |
I'm guessing my physician did.
link |
But why don't we hear more about this?
link |
This sounds so important.
link |
It sounds like the most important conversation
link |
because all the hormone stuff and all the stuff
link |
about smoking and head injuries and ADHD and all the rest,
link |
I mean, is irrelevant if you're dead, right?
link |
Yeah, it's a good question.
link |
I don't think I have a great insight
link |
as to why this isn't more front and center.
link |
I think the bigger problem
link |
is why don't we even understand how to think about it?
link |
I mean, and there's a whole chapter in my book
link |
I'm working on that really gets to this problem
link |
of why aren't we looking at atherosclerosis
link |
in terms of treating the causative agent?
link |
Instead, we look at modifying 10-year risk.
link |
So that's the fundamental difference
link |
between what I call Medicine 2.0 and Medicine 3.0.
link |
Medicine 2.0, which is what we're generally practicing today,
link |
when it comes to ASCBD says, look, we will treat you.
link |
We will lower that LDL cholesterol.
link |
They still don't talk about ApoB,
link |
but that's a very American thing.
link |
If you go outside of the United States,
link |
everybody's talking about ApoB.
link |
It's in the guidelines in Europe and Canada,
link |
The United States is very stubborn on this,
link |
and it's due to a couple of really weird personalities
link |
in the lipid world.
link |
But the paradigm is when your 10-year risk reaches 5%,
link |
and there's a 5% chance that you're gonna have
link |
a heart attack, stroke, or die in the next 10 years,
link |
now it's time to treat you.
link |
Medicine 3.0 says that's not the way to think about it.
link |
You treat the causative agent.
link |
If there's a causative agent, you treat it.
link |
If blood pressure raises the risk of heart disease,
link |
you lower blood pressure.
link |
If smoking raises the risk of something, you treat smoking.
link |
And the reason that the risk model is so bad
link |
when you're looking at 10-year risk
link |
is age is the biggest driver of risk, I mean, bar none.
link |
So if you take a 70-year-old with perfect lipids
link |
and perfect blood pressure and perfect everything,
link |
their 10-year risk of ASCVD is probably four
link |
to five times higher than the most unhealthy 30-year-old.
link |
It's not even close.
link |
Yeah, there's a lot like eye disease.
link |
There are exceptions, of course,
link |
but you always say that the biggest risk factor
link |
for going blind from glaucoma is being an older person.
link |
An older person, frankly.
link |
Right, so if you could identify
link |
what the risk factors are for glaucoma,
link |
imagine if the paradigm was we're only gonna treat it
link |
when your risk of blindness reaches 5%,
link |
which isn't triggered until you're old enough.
link |
Anyway, wouldn't you rather know that when you're 30
link |
and say, wait, if maybe being in the sun without sunglasses
link |
or using this type of eye drop or something like that
link |
has a negative impact, I would rather know that sooner.
link |
So that's the fundamental difference.
link |
It's a philosophical difference with respect to prevention.
link |
And I will acknowledge that in one element of prevention,
link |
I make no consideration.
link |
I am only coming at this through the lens of the individual.
link |
I am never coming at this through the lens of society.
link |
That makes my life easier
link |
and it makes the problem I'm solving easier.
link |
I don't have to answer
link |
the quality-adjusted life-year problem.
link |
I don't have to ask the question,
link |
is it economical to treat people at 30?
link |
I don't know the answer to that question.
link |
But I also know that when you're trying to solve
link |
really complicated problems,
link |
the more you can simplify, the better.
link |
So I've just acknowledged openly, not solving that.
link |
If you wanna criticize me for it, that's fine.
link |
Let's be transparent.
link |
But all I care about is the person I'm sitting across from.
link |
And in that situation, it's really their decision
link |
if they can justify the cost of treatment.
link |
An esoteric question and then a less esoteric question.
link |
The esoteric question relates to something
link |
that I think is a little bit niche,
link |
but not necessarily so,
link |
which is peptides and stem cells and PRP.
link |
I don't wanna go off on too much of a tangent on rehab,
link |
but I know you've done a number of posts
link |
on social media recently
link |
that I have to just tell you are really thoughtful
link |
and I really appreciate that you're willing to share
link |
your own tissue rehabilitation experience
link |
and point people to that,
link |
because this is a landscape that a lot of people are in
link |
and they don't know how to navigate it.
link |
And a mutual friend of ours, not to be named,
link |
sent me a text and said, I'm gonna be talking to Atiyah
link |
and what do you know about studies
link |
on things like BPC-157, this gastric peptide,
link |
that anecdotally, again, anecdotally,
link |
people report getting injections of this
link |
in the shoulder, knee, et cetera,
link |
and feeling so much better, so much faster,
link |
but there really aren't good studies, controlled studies.
link |
And you hear all the same sorts of things
link |
about platelet-rich plasma, PRP,
link |
which someone tells you there are a lot of stem cells in them
link |
they're lying, there are not a lot of stem cells in them.
link |
And you also hear about stem cells,
link |
which are not FDA approved,
link |
at least for most uses in this country,
link |
but are certainly people are flying down to Columbia
link |
and getting injections.
link |
And what is your understanding or experience
link |
with things like BPC-157 specifically,
link |
because peptides is a huge landscape,
link |
we should probably do a whole episode on peptides,
link |
PRP is now approved for, I mean,
link |
women are getting injections of this into their ovaries
link |
to improve follicle count, we know this.
link |
People are getting injections of PRP
link |
into every tissue and organ in it.
link |
Hell, men are getting injected into their penis,
link |
so I hear, for all sorts of reasons that are unclear to me.
link |
What's the deal with PRP, BPC-157, and stem cells?
link |
Do you ever see interesting effects?
link |
Are you curious about these compounds?
link |
Do you prescribe or direct people towards these?
link |
The FDA approved ones, of course.
link |
Yeah, so short answer is I'm definitely curious about them
link |
and I'd love to see the work done,
link |
but I also think this is about
link |
as wild, wild west as it gets.
link |
PRP less so, but certainly stem cells and peptides.
link |
And I just think if you're gonna do something
link |
without a clinical trial,
link |
you gotta show up with a lot more data.
link |
So let's use rapamycin as an example.
link |
I'm a huge proponent of rapamycin,
link |
and you can say, well, Peter,
link |
how can you take or prescribe rapamycin
link |
for zero protective effects
link |
when we do not have a human clinical trial
link |
demonstrating that it lengthens life?
link |
And the answer is because I have 84 other pieces of data
link |
that all point in the same direction
link |
across every model organism
link |
going back more than a billion years.
link |
And that's really different from Joey, Sammy, and Sally
link |
did this thing, and I think it works.
link |
And they just can't be compared.
link |
Now, I have no idea if stem cells work.
link |
I have no idea if BPC157 works.
link |
I have no idea, frankly, if PRP even works,
link |
though it might seem to have some efficacy
link |
and some indications.
link |
For example, maybe when it comes to early hair loss,
link |
maybe when it comes to certain joint issues.
link |
But the reality of it is like,
link |
I think we just have to accept the fact
link |
that everything we do has an opportunity cost,
link |
and that opportunity cost is sometimes financial.
link |
But I actually find a lot of times
link |
it's in time and effort and energy that goes into something.
link |
Now, when I was waiting to get my shoulder surgery,
link |
this is an injury that I've had forever, right?
link |
This is an injury,
link |
this injury was actually probably the greatest source
link |
of discomfort I had swimming the Catalina Channel
link |
the last time in 2009.
link |
So that tells you how long I've had this injury.
link |
But I sort of knew at some point like,
link |
I'm gonna have to have it fixed.
link |
And I sort of went down this rabbit hole like,
link |
hey, is there anything I can do to avoid having surgery?
link |
Would infusing a million stem cells into it work?
link |
And in speaking with as many orthopedic surgeons as I could,
link |
the answer was kind of unambiguously no.
link |
And by the way, it doesn't mean you wouldn't feel better
link |
if I injected a bunch of stem cells into your shoulder.
link |
There are a lot of reasons that might make you feel better.
link |
Just like there are a bunch of reasons you can feel better
link |
if somebody injects saline directly into your joint.
link |
So the question is, is it going to fix the underlying
link |
problem and if so, will it do so by what mechanism?
link |
So I'm pretty sure that if you took a thousand people
link |
with my particular injury and injected them with stem cells,
link |
it wouldn't do a thing because of the nature of my injury.
link |
I had a complete labral tear.
link |
Are there some injuries that might benefit from it?
link |
So the question is, how would you design the trial
link |
to narrow down your patient population correctly
link |
so that you might see a signal?
link |
Because the other risk of doing a trial is,
link |
you have too much of a heterogeneous patient population,
link |
you don't know what the heck you're really doing
link |
and you get meaningless results.
link |
You get a null result when in fact there's a small signal
link |
but you were underpowered to pick it up
link |
because you only had 10% of your patient population
link |
that was the right patient population to get that.
link |
So will we ever get there?
link |
I don't know because I don't see what the incentive is.
link |
You have people who are making money hand over fist
link |
doing procedures on the basis of, I'm not sure what,
link |
what would their motivation or incentive be
link |
to see this legitimized.
link |
You'd really have to be able to say,
link |
well, there really needs to be a pharma angle to this.
link |
It's one of the wishes I had.
link |
If I was a billionaire,
link |
I feel like the way I would probably waste all of my money
link |
would be running clinical trials
link |
on stuff nobody cared about.
link |
Likewise, I would join you because that would be,
link |
yesterday we recorded a sit down with somebody from Caltech
link |
who works on aggression and rage
link |
and other things related to that
link |
and has identified peptides that are approved the FDA
link |
for other reasons that seem to adjust anxiety,
link |
might even adjust aggression and pathologic aggression
link |
and went off onto a long description
link |
of why none of these drugs exist on the market
link |
for the treatment of psychiatric illness
link |
and yet probably would work.
link |
And what's missing is a billionaire
link |
or a billion dollar company
link |
that is willing to invest in something
link |
that very likely will work,
link |
but the market value isn't quite there
link |
or it failed in a previous trial
link |
and so no one wants to touch it with a 10 foot pole.
link |
Hopefully someone listening to this will be incentivized
link |
to provide this sort of a venue for that,
link |
the kind of work that we're talking about.
link |
But I wanna make one other point, Andrew,
link |
which is to me the problem with a lot of these things
link |
is it gets, it's a crutch.
link |
It's sort of like what we talked about with like,
link |
hey, just fix my T-man and everything's gonna be fine
link |
and it's like, no, that's just the beginning.
link |
What I worry about when I see people
link |
who are clamoring for this stuff
link |
is a lot of times they don't realize
link |
that whether it's psychologically or otherwise,
link |
they sort of say, well, now that I've had this thing done,
link |
I don't have to do the hard work of the real rehab.
link |
I mean, if I've learned anything through my shoulder surgery
link |
and I'm now three and a half months out-
link |
I mean, look, I still can't do a lot of stuff.
link |
It's gonna be a while.
link |
I haven't even been able to shoot a bow yet
link |
and it'll probably be a year before I'll go back
link |
to long dead hangs and heavy dead lifts.
link |
I mean, I don't know, maybe nine months,
link |
but I'm not there yet.
link |
But what I learned through a really amazing
link |
rehab and rehab process is you just gotta do the work
link |
and it's freaking hard.
link |
Shoulders are the most tedious, boring thing in the world.
link |
I mean, three days a week, I am doing,
link |
four days a week, I am doing one hour
link |
of just dedicated stuff for this shoulder
link |
that is super uncomfortable, super boring,
link |
super frustrating, but I mean,
link |
I have faith in the methodology, right?
link |
And I think a lot of people are saying,
link |
just shoot the stem cells into me
link |
and I don't have to do any of that stuff.
link |
And the reality of it is I think
link |
that's a very dangerous place to be.
link |
Have you ever tried BPC157?
link |
Yeah, we tried it.
link |
We had, again, maybe seven, eight years ago,
link |
we had a bunch of patients ask about it.
link |
So my view is, okay, I was pretty convinced
link |
that there was no safety downside to it.
link |
So I was like, well, I wouldn't prescribe it to a patient
link |
unless I tried it myself.
link |
So me and another doc in the practice, Ralph,
link |
we did it for, I don't know, a couple of months.
link |
I didn't notice a single thing.
link |
Well, thank you for that.
link |
Shifting to a less esoteric,
link |
and I think probably more important topic overall,
link |
metabolomics, we're talking about this
link |
before we set down to record.
link |
What is, what are metabolomics?
link |
Why should we be thinking about them?
link |
I have some idea of what it might be about,
link |
but most people I think are not thinking
link |
about metabolomics at all.
link |
And for those that are, I'm sure they could learn more.
link |
So tell us about metabolomics and what you'd like
link |
to see more of in the world of metabolomics.
link |
Yeah, so omics is just the term that we use
link |
to describe the study of something.
link |
So genomics, right, is like the broad study of genes
link |
and proteomics, the broad study of proteins
link |
and things like that.
link |
So metabolomics is the study of metabolites,
link |
and metabolites, unlike a lot of these other things,
link |
they're a relatively finite number of these things,
link |
many of which are known, but some of which are not known.
link |
So glucose is a metabolite, acetyl-CoA is a metabolite,
link |
lactate is a metabolite.
link |
And so the question is, what do we know
link |
about these things and how they work?
link |
And more importantly, what do we know
link |
about certain physiologic states
link |
and the metabolomic profile that results from them?
link |
So let's use two extreme examples, like exercise.
link |
Everybody understands, the data are unambiguously clear,
link |
exercise produces about the most
link |
favorable phenotype imaginable.
link |
So if you wanted to take a genomics approach
link |
to understanding that, you might look at,
link |
is there a change in the genome when you exercise?
link |
And the answer is probably not,
link |
but maybe if you looked at the methylation patterns
link |
in epigenome, you could look at epigenomic studies.
link |
But you might instead look
link |
at kind of the proteomic side of that,
link |
like what is gene expression doing?
link |
And there you would see a lot of changes.
link |
Well, what I don't think people are really understanding,
link |
although there was a very interesting paper
link |
that just came out two weeks ago,
link |
that looks for novel metabolites that are changing.
link |
Is there a huge signal in a metabolomic profile
link |
that looks different in the state of exercise
link |
versus non-exercise, and could that represent
link |
part of how exercise is transmitting
link |
its benefit through the body?
link |
People always talk about the holy grail of metabolomics
link |
would be can you find a pill to mimic exercise?
link |
And I think the answer to that question
link |
is going to be undoubtedly no, for a couple reasons.
link |
One, even if you could mimic the longevity,
link |
sort of lifespan parts of it,
link |
you could never mimic the healthspan parts of it.
link |
But what if you could do both, right?
link |
What if there were small molecules
link |
that can replicate some of the protective benefits
link |
of exercise, and you could combine those with exercise?
link |
What if those could be treatments
link |
for other disease states, like diabetes, things like that?
link |
So that's why I think this field of metabolomics
link |
is relatively untapped, and I think,
link |
potentially the next sort of frontier.
link |
Speaking of frontiers, I hear a lot nowadays
link |
about GLP-1 and pharmacology, prescription drugs
link |
that mimic or increase GLP-1 directly.
link |
Glucon, like peptide, people are talking about this
link |
as the blockbuster obesity drug.
link |
I haven't heard this much talk about a drug
link |
to adjust human body weight favorably
link |
since the discussions of Fen-Phen when I was in college,
link |
and then of course, Fen-Phen was pulled from the market
link |
because people were dying, not left and right,
link |
but enough people died that they pulled it from the market.
link |
Which, by the way, is an interesting story.
link |
It was the enantiomer that they chose to use
link |
that was the wrong enantiomer,
link |
and what it resulted in was, God, I think it was like.
link |
So mitral valve, prolapse.
link |
It was an MVP, yeah, it was something in the mitral valve.
link |
Yeah, I think the chordae tendineae were rupturing
link |
in the mitral valve, and it was mostly young women,
link |
I think, were getting horrible pulmonary disease
link |
as a result of it, probably pulmonary hypertension
link |
or something like that.
link |
But there were two enantiomers of the drug,
link |
and had they just used the other one,
link |
this issue wouldn't have happened,
link |
and there was a stupid reason why they made the choice
link |
to use the one they did, and it's one of those things
link |
where once you make the mistake, you're never going back.
link |
It's not like that company could say,
link |
okay, we want to do over,
link |
but we're gonna do it with the right version.
link |
So it's a tragic outcome, but you're absolutely right.
link |
I think the GLP-1 agonists have more efficacy,
link |
and for all intensity and for everything we can see,
link |
it certainly seems safer.
link |
Are you excited about them?
link |
I mean, I think we're just seeing
link |
the kind of tip of the iceberg.
link |
They're not miracle drugs, right?
link |
They come with problems, right?
link |
Which is, they're catabolic across the board,
link |
so patients are losing fat,
link |
but they're losing muscle as well, so.
link |
You just sent all the Jim jockeys running
link |
from semaglutinol, and that's all you have to say.
link |
All you have to say nowadays about something
link |
is that it's gonna drop testosterone,
link |
lower fertility, change someone's skin, hair, or nails,
link |
and it's like people,
link |
it could extend life to being 250 years old
link |
and people are gone.
link |
Humans are humans.
link |
That's a neuroscience and psychology issue,
link |
not a biology medicine issue.
link |
But I'm pleased to hear that you're excited by them
link |
because I hear a lot of excitement.
link |
I haven't heard anything disastrous about them.
link |
It takes a while to get people up to dose,
link |
so if you're looking at semaglutide,
link |
the dose that was studied,
link |
so they did a one-year trial,
link |
or maybe it was a little over that, maybe 60 weeks,
link |
but it took about 16 weeks to get the patients comfortably
link |
up to 2.4 milligrams weekly,
link |
which was the dose that they ultimately stayed on.
link |
In our experience, when we use it,
link |
we don't even usually go up to 2.4 milligrams.
link |
We can usually get enough benefit
link |
between one and two milligrams,
link |
and we usually move people along a little bit quicker,
link |
but we've definitely had our share of patients
link |
who can't tolerate it due to the nausea.
link |
Which might be part of how it's working, right,
link |
is sort of suppression of appetite,
link |
which if taken to an extreme can produce nausea.
link |
Yeah, I think most of the effect of semaglutide
link |
is central, not peripheral.
link |
Huh, so I don't know.
link |
I saw one paper that GLP-1 is acting both on cells
link |
in the periphery to cause gut distension in some ways,
link |
or sort of make people feel full
link |
through promotion of literally mechanoreceptors
link |
that make people feel as if their stomach is distended,
link |
even though their stomach is empty,
link |
and then perhaps some central hypothalamic effects.
link |
Is that what you think?
link |
Yeah, I think it's doing,
link |
I would bet 80% of it's in the hypothalamus.
link |
It is also improving insulin sensitivity in the periphery,
link |
but I don't think that that's accounting
link |
for much of its benefit.
link |
Super interesting.
link |
And there's next-gen versions of these
link |
that seem to be more long-lasting.
link |
So right now, if you look at coming off semaglutide,
link |
you're going to see a weight regain.
link |
So there's newer versions that seem to preserve
link |
the weight loss, even off the drug.
link |
So it begs the ultimate question, which is like,
link |
what's the total use case for this going to be?
link |
Is this going to be a drug you cycle on and off,
link |
or is it going to be a drug
link |
that a person has to stay on indefinitely?
link |
And if so, will they become tachyphylactic?
link |
Will they gain a resistance to it?
link |
So it's still super early days on these things.
link |
My hope is that it would be a little bit like
link |
the way that you described testosterone
link |
and estrogen therapy is that it would allow people
link |
to do more of the behavioral work
link |
that's absolutely required for healthspan and lifespan.
link |
Yep, and we've also seen on the flip side of that,
link |
you can cheat through semaglutide, right?
link |
People who, you know, you can drink a lot of calories
link |
and sort of get around the drug.
link |
So, you know, for example, like, you know,
link |
we always encourage patients who want to lose weight
link |
to really just eliminate alcohol.
link |
Like that's the cheapest, easiest trick to lose weight.
link |
And so if you're still drinking a lot of alcohol,
link |
which is incredibly caloric,
link |
and just drinking a lot of caloric stuff,
link |
we've seen that that's less,
link |
this is just anecdotal with our patients,
link |
but we've seen that it's easier to get around
link |
the benefits of the drug that way.
link |
I so appreciate your answers today.
link |
First of all, they were incredibly thorough
link |
and pointed towards real-world application.
link |
I also just want to thank you more broadly
link |
for the work that you do,
link |
because obviously you have this incredible
link |
clinical experience and patient population
link |
that you work very closely with.
link |
But I see you really as one of the few,
link |
both clinicians, and I realize you're an MD.
link |
Did you do a PhD as well?
link |
No, but I consider you a scientist clinician,
link |
a clinician scientist is the appropriate wording
link |
of that, of course,
link |
in the way that you really still drill
link |
into studies in detail.
link |
I know a lot of clinicians,
link |
not all of them do that for sure.
link |
And the fact that you're so hungry
link |
for the new incoming knowledge,
link |
as well as the old literature.
link |
So it's an incredibly rich data set
link |
in that brain of yours.
link |
And I really appreciate you sharing it with us,
link |
both in your podcast and the upcoming book,
link |
which I think that we'll certainly have you on here again
link |
in anticipation of that.
link |
But I know I and a ton of other people
link |
are really excited for the book.
link |
And in the way that you approach social media
link |
and podcasts and going on podcasts.
link |
Thank you so much.
link |
I know everyone learned a ton.
link |
Great to be here, man.
link |
Thank you for joining me today for my discussion
link |
with Dr. Peter Attia,
link |
all about the things that we can do
link |
in order to maximize our lifespan and health span.
link |
I highly recommend people check out Dr. Attia's podcast,
link |
The Drive, it is excellent,
link |
as you can imagine based on today's conversation.
link |
And it's easily available on Apple Podcasts,
link |
Spotify, Overcast and Google.
link |
Please also check out Dr. Attia's website.
link |
It's PeterAttiaMD.com.
link |
There you can find links to his podcast episodes,
link |
as well as a sign up for his excellent weekly newsletter.
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That newsletter provides terrific information
link |
related to health that anyone can benefit from.
link |
If you're learning from and are enjoying this podcast,
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please subscribe to our YouTube channel.
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That's a simple zero cost way to support us.
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Please also subscribe to the podcast on Spotify and Apple.
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And on both Spotify and Apple,
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up to a five-star review.
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If you have questions or comments or suggestions
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link |
or guests you'd like us to interview
link |
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We do read all those comments and we do take them to heart.
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Please also check out the sponsors mentioned
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And check out Momentus Supplements,
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our new partners in the supplement space,
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and check out Athletic Greens.
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That's the best way to support this podcast.
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If you're not already following us on social media,
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We are Huberman Lab on Twitter,
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and we are also Huberman Lab on Instagram.
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And both places I cover science and science-related tools,
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some of which overlap with the content
link |
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but much of which is unique from the content
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Again, that's Huberman Lab on Instagram
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and Huberman Lab on Twitter.
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Please also check out our Neural Network monthly newsletter.
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This is a newsletter that has summaries of podcast episodes.
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It also includes a lot of actionable protocols.
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It's very easy to sign up for the newsletter.
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You go to HubermanLab.com, click on the menu,
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Again, just go to HubermanLab.com
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I'd also like to point out that the Huberman Lab Podcast
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link |
So these are brief clips, anywhere from three to 10 minutes,
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that encompass single concepts and actionable protocols
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related to sleep, to focus, interviews with various guests.
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We talk about things like caffeine,
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when to drink caffeine relative to sleep,
link |
alcohol, when and how,
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and if anyone should ingest it relative to sleep,
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dopamine, serotonin, mental health, physical health,
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all the things that relate to the topics
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You can find that easily by going to YouTube,
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look for Huberman Lab clips in the search area,
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Subscribe, and we are constantly updating those
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This is especially useful, I believe,
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which admittedly can be rather long.
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And last, but certainly not least,
link |
thank you for your interest in science.
link |
I'll see you in the next one.