This episode is brought to you by eight sleep. My God, am I in love with eight sleep? Good. Sleep is the Ultimate Game Changer more than 30 percent of Americans struggle with sleep. And I'm a member of that, sad group temperature is one of the main causes of poor sleep. And heat has always been my Nemesis. I've suffered for decades tossing and turning throwing blankets off, putting them back on and repeating Ad nauseam. But now, I am falling asleep in record time, faster than ever, why? Because I'm using a simple device.
Called the Pod Pro cover by eight sleep. It's the easiest. And fastest way to sleep at the perfect temperature, it pairs Dynamic cooling and heating with biometric tracking to offer the most advanced but most user friendly Solution on the market. I pulled, all of you guys on social media, about the best tools for Sleep, enhancing sleep. And eat sleep, was by far and away the crowd favorite. I mean, people were just raving fans of this, so I used it and here we are.
Add the Pod Pro cover to your current mattress and start sleeping as cool as 55 degrees Fahrenheit or as hot as a hundred and ten degrees Fahrenheit. It also splits your bed in half, so your partner can choose a totally different temperature. My girlfriend runs hot all the time. She doesn't need cooling. She loves the Heat and we can have our own bespoke temperatures on either side which is exactly what we're doing now for me. And for many people, the result eight sleep users fall asleep up to 32 percent faster, reduce sleep interruptions.
By up to 40% and get more restful sleep. Overall, I can personally attest to this because I track it in all sorts of ways. It's the total solution for enhanced recovery so you can take on the next day. Feeling refreshed. And now my dear listeners. That's you guys, you can get 250 dollars off of the Pod Pro cover. That's a lot. Simply go to eight, sleep.com Tim or use code Tim that's a tall. Spelled out. TIG HT, sleep.com Tim, or use.
Code. Tim TI M8. Sleep.com, Tim for $200 off your pod, Pro cover.
This episode is brought to you by Aura. Oh, you are a, it is the only wearable that I wear on a daily basis, or is the company behind the smart ring, that delivers personalized, sleep and health insights, to help you optimize just about everything and I've tried every device out there that you can imagine. This one really makes the cut. I've been using it religiously for at least, six months now and I was introduced to it by dr. Peter attia, who's also vetted just about everything with Advanced sensors.
Or pack state-of-the-art heart rate, heart rate variability HRV super important to me temperature activity and sleep monitoring technology into a convenient non-invasive ring. It's tiny it weighs less than 6 grams and focuses on three key, insights sleep Readiness and activities, so I can use it to help Focus my attention, on the type volume intensity of exercise that I should do any given day. I use it to determine how certain types of alcohol at different times of the day affect my
Eep, which they do and I can see all of that in graph form. Trended over time, there are tons of actionable insights that have come from using this ring for me. They have a number of incredible people on their team. Dr. Matthew Walker, a professor of neuroscience and psychology at UC Berkeley and also author of why we sleep. The mega-hit is or as Chief science advisor, as just one example, the aura ring is one of the most accurate wearables available because it measures your vitals directly from your
So it's not deducing that or making a best guesstimate based on a bunch of other things and trying to triangulate compared to a medical grade. Electrocardiogram, the ordering is 99.9% accurate for resting heart rate, and 98.4% accurate for heart rate, variability. And I work with HRV doctors and they recommend that I use the ordering. So try yourself. It is super cool, and super practical very actionable. The aura ring comes in two Styles. And
Three colors, silver, black, and matte black. I use matte black for $299 you can give or get the gift of Health by visiting Aura. Ring.com that's oh you are a are ing.com. Again, that's Aura. Ring.com this altitude. I can run flat out for a half mile before my hands start shaking another answer the question.
I'm a cybernetic organism living tissue over metal endoskeleton.
Hello boys and girls ladies and germs, this is Tim Ferriss and welcome to another episode of the Tim Ferriss show. This is very special edition. I am in the cave of Peter, Tia dr. Peter Tia, and we'll get back to his bio in a second. We have the incredible videographer who is trapped inside a closet to monitor levels. Everything is spin fitted to Perfection and that all makes sense. Shortly, dr. Peter, it's you who can be found at Peter, Atia ATT. I am, d.com is a former Ultra endurance athlete. So
And swimming races of 25 or so Miles. Maybe more a compulsive self experimenter emphasis on compulsive and one of the most fascinating human beings, I know he is one of my go-to doctors. I would say the go to doctor for me for anything performance or longevity related, but here's, the official bio to do him Justice. Peter is a physician focusing on the applied science of longevity, his practice deals extensively with nutritional interventions exercise, physiology sleep, physiology emotional, and mental health, and pharmacology to increase.
Lifespan. That is how long you live while simultaneously improving Health Span. In other words, how well you live Peter trained for five years at the Johns. Hopkins Hospital in general surgery, where he was the recipient of several prestigious Awards, including resident of the year and the author of a comprehensive review of general surgery. He also spent two years at NIH as a Surgical Oncology fellow at the National Cancer Institute where his research focused on immune based therapies for melanoma. He has since been mentored by some of the most experienced.
And Innovative lipid ologists, endocrinologists gynecologists, sleep, physiologists and Longevity scientists in the United States and Canada. Peter earned, his MD from Stanford University and holds a Bachelor's of Science and mechanical engineering and Applied Mathematics. Last but not least, and this would explain the immaculate video and audio setup that I am enjoying today. Peter also hosts the drive a weekly Deep dive podcast and I do mean Deep dive focusing on maximizing longevity and all that goes into
To that, including physical, cognitive and emotional health. It features topics including fasting, ketosis Alzheimer's disease, cancer, mental health, and much more. You can subscribe on Apple podcast Spotify overcast or wherever you listen to podcasts. You can find him all over the interwebs Peter, a TM d.com on Twitter at Peter, Atia, MD, Instagram, Sam, Sam, Peter TMD Facebook, you got it Peter, Tia MD, and then on YouTube, Peter Atia, M.D Peter
Welcome back to the show. It's quite an interesting. It was an incredibly comprehensive I could have shown up a little later for this. So we've we've had frequent flyer miles on podcasts, including on this show and last time we used a format that I quite enjoyed in part because it required minimal preparation for me. And that was going through categories. Excited about changed my mind about and stupid things or absurd things.
Things that you do. And I know that you have a number of things that you are excited about. So we may spend more time in that category. So why don't you kick us off? However, you like,
so, yes. So the nice thing about this is I get to prepare a little bit and I jotted down a few bullet points on each. So I think one of the things I'm really excited about is a very recent thing. In that, it's come to Market really recently. It's been in the works for about five years and it's something called a liquid biopsy. And the reason this is interesting is that, when you
But this sort of major chronic diseases, which is the diseases of atherosclerosis or heart disease, stroke, cancer, and Alzheimer's disease. We don't have a lot of great tools at detecting cancer early, so cancer, screening is a somewhat controversial topic. Most people are probably familiar with things like mammograms, colonoscopies, and PSA testing. There are two or three others that rise to the level of having evidence to suggest that we do them for example, pap smears. But when it comes to some of the really bad actors of cancer, we
Don't really have great screening tools and so what a liquid biopsy does is it draws a sample of blood and through that tries to predict whether or not you have cancer cells in your body and tries to do. So, of course, when you have very, very few of them because the evidence is overwhelming that all things being equal a cancer when caught early at an early stage is eminently more curable than a cancer caught at a later stage and probably the most compelling explanation for that. Is that the longer a cancer gets to
In your body, the more chance it has to develop mutations and the more mutations it, generates the more difficult it is to Target later on. So there are a number of companies that have been doing this. But to me the most interesting by far is a company called Grail because of the method that they've gone about doing this, and the method is using something called the cell-free DNA as opposed to, tumor
DNA, and just for those listening Grail as in holy grail, this is exactly
coming out big
As a little side note, Grail was recently acquired by another company called alumina alumina. Being the largest company that does DNA sequencing. And a very interesting note is the FTC has sued alumina for antitrust violations. In this acquisition which if you understand the science of it and we don't have to get into it in. Great detail is literally the dumbest thing I've ever heard so that the FTC has done this, in my opinion is actually a tragedy because it is actually going to cost lives. It's going
Tens of thousands of lives in delay. If this acquisition does not go through because alumina has the power to scale this up, like no other company would putting that aside for a moment, what a cell-free DNA, because that's really at the heart of this said that when we're done, what is cell free DNA cell, free DNA
CLL - free. Yeah,
as in DNA, that's not in a Cell. So most of the DNA in your body is contained within cells, but when a cell breaks down or sometimes, even when cells spontaneously like red,
Red cells are actually typically monocytes white, blood cells, make DNA and then spontaneously release it from them. You can capture these small amounts of cell free DNA. So if you draw somebody's blood, whether or not they have cancer or not, they're going to have a certain amount of this cell free DNA floating around, you have signatures on DNA called methylations.
So a methyl group is
just a carbon with three hydrogen's on it. It's one of the most basic building blocks of organic
chemistry and as DNA acquired,
These signatures. So remember, DNA is made up of these four nucleotides. When they start binding these little
methods really actg exactly
actg as they start acquiring these methyl groups, that tells a bit of a story and even though there's not a lot of cell free DNA, when you look at it, the best analogy. And one of my analysts actually came up with this analogy is it's sort of like looking at meteor fragments that would land in the desert and being able to understand what type of an asteroid they came from. So,
Even though the asteroid is enormous and it shed, big chunks of meteor down to earth. And by the time they actually hit the Earth or just small rocks, a chemical analysis of that would give you a greater idea where it came from. So this type of test can actually detect up to 50 different types of cancers. There are certain ones that it's not very good at detecting such as prostate cancer, which is not bad, because we have other tools that are so good at detecting prostate cancer, but when you do this blood test, you basically get a readout, which says no cancer detected or the following him.
Detected. And it does this with about a 50 percent sensitivity and about a 97 to 99 percent specificity. Now, to explain what that means in context, requires a little bit of math and it's worth going into. So sensitivity is the probability that a cancer is truly there. If detected by the test and specificity is the probability that the cancer is not there, if not detected by the test. So sensitivity speaks
Stu true positives and specificity speaks to True negatives. Now, at first, 50 percent sensitivity doesn't sound that good, but you have to remember. It depends on what we call. The pretest probability is so pretest. Probability says, what is the probability that you have cancer before I test you? And that's a function of many things. It's a function of the prevalence of that cancer. It's a function of your age, it's a function of other behaviors. So for example, to people being otherwise, identical, except one being a smoker and one not,
A smoker are going to have very different pretest probabilities, but when you start to think about, for example, you what's your pretest probability of having pancreatic cancer? It's quite low. Fortunately, even though pancreatic cancer is one of the most lethal cancers out there. So in a low probability environment, a modest sensitivity of 50%, and a very high specificity produces incredible, what we call positive and negative predictive value. So what do those things mean so positive predictive
Devalue is. It sounds means what's the probability that if you get a positive test you truly have cancer and negative predictive value. Is of course, if you have a negative test, what's the probability? It's A- these numbers end up being well north of 90%. In fact, the negative predictive value is about 99.7%. The positive predictive value is in the ballpark of about 97 percent. So these are really exciting tests. Especially when you pair them with some of the other things that we do in our practice such as relying on a very special type of
MRI technology that uses something called diffusion weighted Imaging that adds sort of a functional Dimension. To
MRI quick, note there people can if they really want to Deep dive into that subject matter, you have a guest on your podcast and I've listened to this episode it does get quite technical by. That's right. What is the guest name for people who want to go on a search?
Raj are AJ and how do you spell his last name? Attr a
A wal of course I can't spell in my head but if you just search Raj MRI it'll pop up and the. Yes that's that's an episode. We usually make our patients listen to before they go and get one of those MRIs so they understand
it follow-up to that unrelated but related to Grail. What is it that happened? Or what technology was developed? Its suddenly made this possible where it was not possible before or what realization why did this suddenly come to fruition?
And or only now become available. I think the
major insight and I will be doing a podcast on this, but I need to wait until this FTC issue is resolved a little bit because the person that I really want to interview for the podcast, who is one of the people that had the biggest hand in developing, this is actually now the chief scientific officer at alumina. So for him to be able to speak about it, obviously it would need to make sense that aluminum actually owns the technology. Again, I would say in this might change as I get deeper into understanding there.
A journey. I think it was the realization that tumor DNA was not the place to go. So at the outset of this process, people didn't know what to look for. Would you look for RNA of tumors? Because RNA is the template that's telling you to make the protein. And that didn't really pan out because RNA is so unstable by itself. So then pivoting to DNA The Logical Choice was. Well, let's look for the tumor DNA, you know, if you have pancreatic cancer and we can find the DNA of a pancreatic cancer cell, that would be a good place to
Start. But you have to be looking for cell-free DNA by definition when you're doing a liquid biopsy, because you're not going to sample the organ and it turns out the tumor DNA represents about 0.1% of cell free DNA. So I think the big aha for Grail was realizing. No, let's look at cell free DNA, which is much more abundant, but instead look at the methylation patterns and then specifically figure out what those methylation patterns were so that was the real
puzzle. Yeah. The the forensic science yo,
That's very cool. I don't know if I interrupted a train of thought that had more to say about Grail. Do you want to say more about Grail? Or do you want to hop to another?
Yeah, no. I mean, I just think that this is I have been waiting for this like I said for five years because I think that I'm just less bullish on the idea that we're going to quote unquote cure cancer, right? If you put cancer in perspective, the overall survival for people with metastatic cancer has improved
About 5% in 50 years and virtually all of that Improvement has come with a handful of very specific types of cancers. For example, something called the GI stromal tumor and a certain type of testicular cancer for which there's been like very specific behaviors of these that have rendered them quite sensitive to certain chemotherapies. But when it comes to, you know, lung cancer, when it comes to pancreatic cancer when it comes to colon cancer breast cancer, once you
You don't catch it early, you're sort of in the same situation you were in about 1970, that's pretty depressing. When you consider how much progress has been made in cardiovascular disease since that time. So I think the answer in how do you live longer with respect to cancer is engine is prevention person. Well, it's both right. It's so what can we do to prevent cancer and not smoking and being metabolically? Healthy our hands down the two biggest things that you can do and then the next step is, how aggressively can you screen and stack?
Levels of screening Technologies on top of each other. So that the way we kind of describe it to patients, is you want to think of like, the Swiss cheese approach, right? You want to be able to stack a whole bunch of things on top of themselves, so that you just get only one pencil can fit
through. Yeah, each method or technology in of itself, having gaps. But when you lay them on top of each other, hopefully, the remaining gaps are sort of allowable if that makes any
sense. Absolutely. And it's exactly that it's basically how do you use multiple Technologies to cover the
Blind spots of others,
I'm excited about Grail also, because it seems like, especially if scaled through alumina, the ability to have Grail widely distributed makes it just by definition more available. At least as one tool compared to say the MRI that we were referring to earlier which would appear to be site specific. I don't know.
Yeah, MRI is going to be far less scalable and frankly far more of a hassle. I mean if you've I don't know if you've ever had well, you haven't had one yet. We got to get you up
there. Yeah.
I've had for better, and For Worse, probably quite a few MRIs. Not always an ideal circumstances here, but this particular MRI not
yet. Yeah. So it's like, how do you drive the cost down? How do you improve the technology? How do you make the algorithm better? And better? And better? Because it is under all of this is a huge engine of machine learning. That makes it better over
time. So you mentioned in terms of prevention, metabolically healthy, is there anything you're excited about or would like to underscore that relates to?
Whipping metabolic health, or improving metabolic
health.
Always, I'd say exercise is so important, right? It can't be overstated. Its potentially one of the most potent drugs we
have, but all exercise is not created equal. I would imagine
correct. And this purpose. Absolutely. And so, I think of exercise is having four pillars. You have to be strong on each of those. So if you're strong in three but not in one, it's sort of like a table that has three legs and not one. It's still a reasonable table, but
It's not as strong as a table, with four legs and a table with two legs is pretty pathetic. And obviously a table with one leg is not a table. So the four pillars are stability strength, aerobic, efficiency, and anaerobic, performance. And I think that most people understand Loosely, what three of those
are, can you say those all one more time?
Sure, stability. That's the one that most people don't understand. We can talk about that in a minute strength, aerobic, efficiency, and anaerobic.
So I guess we can unpack all of them, but stability is the ability to safely transfer load from the outside world to the body, and vice versa, which sounds sort of like a soft explanation. An analogy that I really like using is that of a race car versus a street car. So what makes race cars? So unique is that and why by the way, a race car that's got half the power of A Streetcar will still knock it. Socks off on a
rack is because the chassis and the tires of the racecar are constructed in such a way, that every bit of that power is making it to the road. So the analogy I like to think of is that the tires of a race car or like our feet and stability, really does begin with defeat and most people myself included when I was starting had horrible, proprioception with our feet. You know we don't really know how to load our feet correctly and a lot of that comes from the fact that we wear shoes all day. Your hands and your feet are actually very similar and if you
What you can do with your hands, how easily you can move them around, spread your fingers sense, pressure in different areas. Most people can't do that with their feet and that comes to bite you. So as you think about how it moves up, the sort of chain a very common problem is, which I think accounts for probably more of the injuries that people experience is this pattern where the pelvis is tilted forward. The ribs are flared up, the erector spinae muscles in the back.
Back are sort of locked short. Meaning they're locked in concentric load and the hamstrings are locked long so they're locked in eccentric load. Yeah.
It's how someone who's quite lean from a body fat perspective can still look like they have a potbelly. That's right with that anterior pelvic tilt which actually
so you've asked me a question. I think I can answer this with there are really two things. I'm excited about that pertain to exercise and I'll go down this path and then we'll come back to the other one. What's the etiology of that position?
In which I was the king of that position, it's
probably what you mean by etiology like where did what drives that? Why would a person
show up with that posture of ribs? Flared up pelvis tilted, forward back tight hamstrings tight and
long besides wearing six-inch stiletto heels
which I never wore. I mean I wear them sometimes but I don't
often wear them. You're in good company, Jagger Hoover and all didn't, so it
probably starts with lousy.
Ian and I'm not exactly sure why that's the case. But I think somewhere along the way, we stopped breathing correctly into our abdomen, instead of breathing the way, we should breathe, which is the diaphragm should go down the abdomen, should come out, the pelvis should actually fill with pressure. We tend to breathe using X. So that's those are the primary muscles of respiration, is the diaphragm. We start using accessory muscles like the pack in the PEC minor? And we kind of lift the chest up. Those are very common pattern of respiration, and I think it's
That lifting of the chest that is, what's bringing the ribcage up. And when that happens, the body is a little bit out of balance. Meaning your center of mass shifts forward and the body senses that and in an effort to prevent you from falling forward, it's basically tightening. Those erector spinae muscles, it's pulling you into balance again, but in doing so it's creating this Downstream problem in the hamstrings, which is
they're locking. And if there's another thing I've become really obsessed with its hamstring control, which is different from hamstring strength. A lot of people, myself included, can have very strong hamstrings. I used to have incredibly strong hamstrings. If you put me on a machine and made me do something in isolation but you never recruit them is simple exercise. That demonstrate this which Beth Lewis had me do for the first time, maybe two and a half or three years ago, was you laying on your back with your knees up and your feet down. So you're sort of in a back position, knees up, you know, feet
The surface of the ground and without letting your back tilt into a huge Dome underneath it. So while keeping your lower back flat can you with one leg pull very, very hard back to your butt and feel your hamstring tense so that is a very specific manner of recruiting hamstring strength and believe it or not. I couldn't do that while keeping my back down, I would Arch like a cat if I tried to do that.
That there were many more of these types of exercises, but it was through this type of, very deliberate starting on my back and then learning to do hamstring recruitment while standing and while feeling pressure in my feet that really allowed me to get back to deadlifting with a feeling of safety that I've never really experienced because I used to deadlift so heavy when I was young and basically got away with using my back to deadlift which is obviously not what you want to do.
And I just started having nagging injuries as I got older. So by the time I was in my mid 40s, I'm dead lifting and it's like oh my SI joint would bug me and after I'd finish my back would just feel Tight Age sort of exposes your deficiencies and eventually everybody is going to sort of pay a price for this. Some people do these things naturally better than others so I think there are some people who can kind of go their entire life lifting heavy weights without having to pay much attention to this stuff. But you know I certainly wasn't one of
Them does that type of training that you're describing that progression can starting back from the foundation or the fundamentals. Does that have particular name?
There are a couple different schools of thought that have been implemented into this training. One of them being Dynamic, neuromuscular stabilization, or DNS, which is heavily focused on this ability to find the breath and generate. You know, this concentric abdominal pressure so creating a cylinder inside the abdomen, as opposed to, like an upside down triangle, where you have some
Up here, but none down here. And then another school of thought that's been heavily. Influential here is been something called postural restoration, Institute, or PRI. That's really the one that has focused on this idea of, how do you correct? What from the side looks like this, right? You know, sort of pelvis down ribs up and how do you fix that position? And again it's it's hard because it requires fixing everything from the feet, to the
neck, how much of a contributor if it.
I'll do you think extended sitting is to that configuration with the kind of flared ribs up and anterior pelvic tilt if any I think it probably
is and probably for a couple of reasons you have to sort of think about it is the positive and the negative, right? So one drawback of sitting is that you're not active, it's simply the removal of active time, that is a problem. And I think the other problem with sitting is it is simply harder to
An Irate intra-abdominal pressure, and it's easier to just rely on these accessory movements of respiration to lift up. So, I think I've said this once before, like, if I could bees are for a day, you know, I'd go back to kids when they're in school and, you know, have them in standing desks or squatting those would be your two positions, right? So you either your kind of squatting to do work or you're standing to do work, but you're not sitting in the types of chairs that we sit
in. I think I have an idea.
Before a complimentary short-form podcast for you which is just called Czar for a day. Five minutes. Five minute Commandments from Zara. Tia, yep. And more
Barefoot time, you know, with my first two kids I wasn't so aware of this when they were young and now with my youngest who's almost for, I study this guy like he's the master. His movement patterns are simply unbelievable, which of course, all four year olds should be
I just never noticed it before but the manner in which he moves and lifts himself and reaches for things and sits around it's incredible. It is such a spectacle to behold, you spend more time watching your children and that's, you know, DNS is modeled on exactly that, right? DNS basically says it grew out of something called the Prague school and Czechoslovakia which was originally
Looking at ways to take children with cerebral palsy and teach them how to move again by realizing that what CP had robbed them of was a lot of the developmental movement patterns that occur in the first two years of life. And once they started to realize, you could actually take these kids and retrain, their neurologic system to do things in a more functional way that you could actually do this as a form of rehab and then ultimately a form of prehab which is sort of how I like to think of it now.
I've seen I don't know how much of this is public, but incredible results from trainer. Also world record holder or former world record holder in Olympic weightlifting. Jersey, Greg, Iraq working with a number of clients or patients with cerebral. Palsy using very incremental
Movement Rehabilitation and training. I mean the before-and-after differences are staggering a nice piece to probably my ignorance of cerebral palsy but just never was even within my conceptual, schema that that would be possible. It's a very exciting to see. So, speaking of
exciting. Oh, so the other thing on exercise to get back to your question about the metabolic stuff is you know, about three years ago. I was becoming more and more
Interested in this idea of Zone to training which has a very technical definition and then we can explain proxies for it. But the definition of zone 2 is the highest level of output you can produce while keeping lactate below to millimole. So lactate is a byproduct of anaerobic metabolism. So when we're sitting here at rest are lactate levels, probably one if we're metabolically healthy, there are some people who sit around at rest higher than two
Anybody's done lactate testing knows, as you start, exerting yourself more and more, your lactate will rise and Peak levels in highly trained, individuals can reach above 20 millimole and that's accompanied by remarkable discomfort. Actually, I've always done lactate training when I was being an athlete which I haven't been in forever, but I was never focused on this aspect of it as always focused on something called lactate threshold and Peak lactate. So Peak lactate for me was kind of a marker of just how much pain I could endure.
Or and lactate threshold was a marker of the highest amount of output, I could produce for relatively short races short for me would be like half an hour or something like that. So knowing my lactate threshold was important for that stuff, but this Zone to stuff is way below that zone 2 is by definition. You're all day Pace. It's basically at a lactate level of to, you should be able to go all day. That's the level at which you do not net, accumulate, so you're producing, but you're not accumulating and so it's the rate.
Which clearance equals production and you stay at that level of 2.
Just a very quick note to say that we really nerd it out on Zone to training with Peter. We got deep into the rabbit hole. I got very very dense also actionable but I move to that section to the end of the episode. So if you want to check that out later, just continue listening. Now back to the show.
You mention fat utilization or the ability to use fat as a substrate, are there things and specifically, what's coming to my mind such as fasting or intermittent ketosis that help you to use fat. And such a way that it transfers to zoom to training. Is there any crossover I suppose?
Yeah, well there's no question that ketosis by its very definition is a nutritional state that forces.
Our body to utilize fat and depending on how much you're in taking some of that fat could be endogenous. So again, exogenous is the fat that you put in your body. So what fat you eat is exogenous the fat stores that we have are endogenous. There's a bit of a
I think just a misunderstanding around ketosis. I think a lot of people assume it is automatically a weight loss diet or a fat loss diet, but of course, that's not necessarily true. It's only a fat loss diet. If you use your endogenous fat
stores also, turns out a pound of fat as a lot of calories.
Yeah, so, you know, I could gain weight on a ketogenic diet. If I ate enough, the advantage of ketogenic diets for most people is that they're quite satiating. And you don't want to eat endless amounts in the way that if you went on.
All Dorito diet, which I've also pioneered got experience with the all Dorito diet and turns out you can eat a lot. The all licorice do I used to work in a video store when I was in high school called movies and Munchies?
Yeah. And,
you know, it was owned by my friends
to video store plus dispensary. Yeah. And they didn't,
they just didn't care how much I ate. Yeah. And I would literally eat the pound of Twizzlers like you
They came in that pound. Maybe I found it happens. Like the biggest bag of whose kids take
out like a Mugger with this bag of
Twizzlers. Yeah, exactly. Like it's a weapon and if any reasonable group of four people went to a movie they'd have a hard time, finishing one. But I would easily throw that down. Plus the really big bags of Doritos, plus a really big bag of popcorn plus God knows what else like that was routine for the
night. Just disgusting
easily for 5000 calories of junk food, three nights a week.
My estate. So we look at the opposite of that fasting. Has you have you changed your mind or had any insights since we last spoke? Come to any different conclusions related to fasting? Because you've done a lot of fasting. I mean, you have a lot of experience doing right? Fasts have many different lengths, including it without a note, the long as fast as that you've done, what we tend to tend to his. Yeah.
Yeah, I think that one thing that I absolutely learned through fasting is the enormous importance of strength training throughout a fast. It's very easy. You're going to lose muscle mass when you fast, you have to accept that. So, the question is, how do you minimize that damage? How do you lose as little muscle, mass as possible and strength training daily, during a fast has become an important part of that, but when you look at time restricted, feeding people, call it intermittent fasting. Although I don't, I don't like that term very much. I think time,
It makes more sense when you're just talking about, you know, 16 or 18 hours. I'm really starting to see a lot of people who do that excessively and who aren't necessarily training correctly, they lose weight, but they're losing muscle more than they would want to see. And we just had a patient who we did a dexa scan on last week and it was probably the first one we've done in 18 months on him and in that 18 month period, his body weight had not changed. Maybe he was a bit lighter.
Actually might have lost 4 pounds but his body fat was so high. I almost fell off my chair and he doesn't look chubby it speaks to how much muscle he's lost. So he his body fat went from about 18 percent to 30 percent yikes which was, you know, it's just a totally unacceptable amount of fat for someone his age and his visceral fat went up which I actually care more about than body fat. We can talk about that later but his visceral fat also went up. So you know this guy who
Religiously been doing his time restricted feeding every day, but he doesn't really lift weights, he walks and does some yoga and stuff like that, but he's not doing strength training. So I think in a person like that, there's a real downside to Too Much Time, restricted feeding, and even for myself, like, in the last four or five months. I've been, you know, I did a dexa back in January, and I haven't done one in years and from January to the last period that I had done a dexa. My body weight was almost identical
Nickel maybe I was two pounds lighter this year versus the last time, but my body fat was up. I think I went from 10 to 16 percent body fat. And again you can say well 16 is not the end of the world but you know that was a significant loss of muscle and gain a fat. I did wonder if that was just too much because I always exercise in the morning but then don't eat to exercise and then not provide yourself especially with when your strength training to provide yourself with any amino acids every single day to undergo muscle.
Synthesis. I think it's a little bit risky so I've been looking at other strategies around that. So for example, front loading the meal
question and then we'll come back to front letting those during that period of time. Were you doing? And I just I may be misremembering but one three day fast a month or one week long fast every quarter. What was the
frequency of the above? Yeah I probably spend maybe two years doing seven days, a quarter maybe a year doing of three days a month but in between it's also doing lots of time.
Stricted and honestly, I think the Daily Time restricted was a bit more the issue, you know, I think the three day fast a month with a lot of lifting. I didn't sense. I lost a lot of muscle during that period of time, but I think every day, exercising in the morning, not putting calories in until later in the day, it has to be taken in the context of an individual. So, if you're someone who's a hundred pounds overweight, or you have diabetes, it's a totally worthwhile trade-off to lose muscle mass because your
Losing more fat Mass along the way. Yeah, so you are going to technically get leaner with that approach, but when you take a relatively healthy and lean individual, one has to be a little bit careful and look for alternative ways to sort of get the benefits of that
fast. So you were saying something about front-loading
meals. Yeah. So I just find nowadays, although probably not tonight, I'm going to
eat almost certainly not tonight,
I'm going to eat a little bit more early in the day and a little less late in the day
so I'm gonna remain.
Not be some Mezcal involved, there will be. So we we won't take either of our Aura ring data as standard for this evening. I totally got caught up in my own fantasy, narratives Mezcal, so front-loading meals. Could you just walk back and it's in an
Ideal World? I think that the best way to do time restricted eating would be to eat a big breakfast. So would be to wake up exercise, eat a huge breakfast.
A huge. I don't mean gluttonous but I mean that's your biggest meal of the day. That's a I don't know. Like let's just put some numbers to it. You wake up at six, you work out from 7:00 to 8:30 at nine o'clock, you're eating your largest meal. You eat another meal at one o'clock, that is modest and you don't eat again. That would be a great way to do 16 hours of not eating a day, that's problematic for two reasons. The first is its socially problematic, it's really easy to not have breakfast because very few
People eat breakfast with other people, but dinner is our social meal. And for obvious reasons, it's just poses a difficulty to be the guy who never eats
dinner. This is a side effect. I've been at multiple dinners now, quite a few actually where you've been fasting and we've all been sitting drinking wine and just like past the cheesecake at the end and you take a big whiff and then continue, moving it along it's entertaining. But it is pretty
antisocial. Yeah, to be that guy to be that guy.
Yeah, drinking the soda water, and then the other thing is, I think for many people, it is hard to go to bed hungry and truthfully and longer fast, it gets easier. Because, you know, if you're fasting for seven days by the time, you hit that fifth day, you're a lot of your hunger has sort of dissipated, but 16 hours of not eating can generally pose some hunger. And for some reason, I just think psychologically in the evening we're a little less busy. So it's even more notice
Possible. Whereas if you're doing the traditional way that people think about, not eating for 16 hours, it's pretty easy to wrap yourself up and work in the morning skip breakfast and kind of delay, your lunch a little bit. So I don't know that I have a great answer for that other than I think people should be a little cautious and not just apply the same Hammer to every nail and kind of think about their own physiology a little bit and rely on these Technologies like dexa to make sure which again is so so readily available relatively inexpensive and provides
Both good information about body composition. And also, this thing of visceral
fat will come to the visceral fat. And just a second on the decks and note about, I don't want no a year and a half or two years ago. I recall a conversation with a dexa technician who said to me over the last 12 months, I've seen many cases of people coming in who are newly evolved out intermittent fasters
Who have had their body composition flip basically? I mean like I'm not necessarily flip, but they've had massive jumps in the percentage body fat and I put that on social as a as a note, not to say that all people who do time restricted feeding experience this and it was hilarious. And also frustrating to see how many religious zealots there are around intermittent fasting who were just like,
Thy tongue, you know, baby, but you said that, according to this Tech that they got better intermittent fasting.
Or well, they got worse, they got work, there are
many it met with what I'm
just. What's? Exactly? It's exactly compatible with what you're saying. Yeah, but there was a lot of resistance to the idea that that would even be possible. Which I which I found really interesting more social commentary than anything
else. I think it just speaks to sort of why I don't like talking about nutrition very much because it does lend itself to
To politics, not literally, but it's sort of the politics religion, ethos, which is whatever you're eating. Is, obviously, the only thing and I guess I just encourage people to be much more attuned to all of the tools, right? So caloric restriction, dietary restriction time, restriction, right? You've probably heard me go on and on about my framework, the 3 levers always pull one sometimes, pull to occasionally, pull three, never, pull none. So time restriction, what we're talking about
Drifting when you eat but otherwise not restricting. How much or what dietary restriction is restricting. Some of the content in what you eat. So not eating carbs, not eating wheat, not eating meat, is nothing like Doritos, right? Not eating sugar. Those are all forms of dietary restriction, and then caloric restriction, is restricting the amount. And so if you are never pulling one of those levers which means you're eating anything, you want anytime, how much whatever that's called the standard American diet.
So sad. Yeah, the sad and we've been running a very good natural experiment on that for 50 years and the data are in. So it turns out that less than 20% of the population, probably less than 10 percent of the population is genetically robust enough to tolerate the sad. So it's a great piece of data. Like there are people out there who can eat KFC, and Doritos and pizza anytime they want and they're generally, okay.
To A first order approximation, I would add that, we don't really know the answer this question because we don't have super granular data at the population level. But notwithstanding that, at least at the surface level, it appears that 10% of the population are largely immune to the sad, but for the rest of the 90% of us Schmucks, which I'm certainly in that camp, the sad is lethal. And so you've got to come up with a way to escape the gravitational pull of the sad. And that's why I think having these three levers at your disposal,
Ezel is the key. And yeah, I think that what happens is, people get so into the camp of their lever. Like it's all time restriction or it's all dietary restriction. Not too many people are in the all calorie restriction group, there's a whole calorie restriction society and there are. So there certainly are people that are in that camp, but it's usually the first two camps that have the most
salads leavers Sweden for the Canadian to come out. I love those levers and I'm sorry, I'm sorry, I'm sorry, sir.
So sorry, process process process. I also think I said bite thy tongue. I don't practice my older English much. I think it's thine tongue, but sure the internet will correct me.
Just a quick thanks to one of our sponsors and we'll be right back to the show. This episode is brought to you by athletic greens. I get asked all the time. What I would take if I could only take one supplement, the answer is invariably, athletic greens. I view it as all-in-one nutritional insurance, I recommended it. In fact, in the 4-Hour Body, this is more than 10 years ago. And I did not get paid to do so with approximately 75 vitamins minerals and Whole Food, sourced ingredients. You'd be very hard-pressed to find a more nutrient dense. And
A formula on the market. It has multi vitamins, multi-mineral, greens, complex, probiotics, and prebiotics for gut health and Immunity formula digestive enzymes, adaptogens and much more. I usually take it once or twice a day just to make sure I've covered my bases. If I miss anything, I'm not aware of of course I focus on nutrient-dense meals to begin with, That's the basis, but athletic greens makes it easy to get a lot of nutrition when Whole Foods aren't readily available from travel packets. I always have them in my bag when
And I'm zipping around right now. Athletic greens is giving my audience a special offer on top of their all in one formula, which is a free vitamin D, supplement, and five free travel packs with your first subscription purchase. Many of us are deficient in vitamin D. I found that true for myself, which is usually produced in our bodies from sun exposure. So adding a vitamin D, supplement to your daily routine is a great option for additional immune support support your immunity got health and energy by visiting athletic greens.com
Tim, you'll receive up to a year supply of vitamin D and five free travel packs with your subscription again. That's athletic greens.com /. Tim
Quick tactical question. And then I want to ask you about any research or studies that have been interesting to you, that have come out since we last spoke, is it effective or have you tested using small amounts of branched chain amino acids to mitigate the muscle loss? During what we would otherwise consider fasting? And does that also? If it has any effect lessen, the benefits of the
fast.
Depends on what you're doing the fast for. I think, if you're doing the fast for weight loss, then the answer is absolutely knock yourself out with branched-chain amino acids during strength training because from a caloric perspective, they represent such a visible. Yeah. Like, even if you were to double up on, you know, my favorite BCAAs which are bios deal, you know, your what are you going to get in there? 40 calories in two servings, right? So not an issue. If you're doing the intermittent fasting with
Call it the hope of achieving some amount of the early signatures of a toffee G. Then I would say that it probably is counterproductive because the amino acids that you use in exercise are exactly the ones that are the most potent stimulators of mtor. And the whole purpose of fasting, at least in the short term, is to give mtor arrest, its to take away that which it senses and it is the most potent sensor of leucine.
Which is the most important Branch chain
amino acid. Yeah, so if I could dumb that down for myself, if you are interested in the longevity benefits of fasting aside from just getting to healthy body composition, you should not take the branched-chain amino
acids. I mean, I can't say anything with certainty, but it seems counterproductive. Yeah,
got it. All right, studies. Any papers are studies that you.
Interesting. Oh my God,
it's in so many ways. There's a lot if you do. If you had to cherry,
pick a few, well, look, I think the recent New England Journal
paper, that you and I have talked about is very interesting comparing, Lexapro to psilocybin. I wrote about it recently and my little diatribe. Basically said I think the paper was in some ways. Misinterpreted it was positioned as a negative trial, though. I saw it as anything but a negative trial, maybe just keep going to be zoom out just for a
second and give people an overview of the
So the objective or the hypothesis of the
study of the question that was being tested was is an intermittent dose of pure synthetic. Psilocybin more effective, I think, is the way the question was posed, then the top-tier SSRI for patients with depression. So Lexapro is a relatively new SSRI very well tolerated. Hello, Prem yeah. You know, has
It does have sexual side effects, that's its most common side effect, that's true of other SSRI. Absolutely accessorize are known for having sexual side effects. Some of them also come with Incredible amounts of somnolence incredible amounts of weight gain. Like I'm no one's sleeping, sleeping us. Yeah, Lexapro seems to be relatively free of that for most people which is why it's kind of more of a go to drug comes in two doses, 10 and 20 milligrams, generally, most people need 20 if they're going to go to it, but usually start people attend.
20. This is a daily
today. We struggle, yep. Those participants are divided into two groups. One group is given Lexapro, let me think I believe that, they all started out at 10 milligrams for three weeks. And then we're increased to 20 milligrams for three weeks or maybe it was four plus four. I can't remember is relatively short study in the psilocybin group. The participants were give. Oh they whether it's in the side they were also given one milligram of psilocybin which I is an important point I should
make. And if that word is
unfamiliar to, folks of psilocybin is molecule found in selasa, be mushrooms. Also known as magic mushrooms. These are mushrooms that imparts psychedelic effects at a sufficient dose,
will come to talk about that. Do so the subjects were all recruited knowing that they would get psilocybin. No matter what because that was an important recruiting tool. People wanted to be in a study where they were going to get the psilocybin that has to be taken into account from the standpoint.
Point of patient selection. So every trial has to be thoughtful about what type of people it's selecting, and are they representative of the population? You're going to want to extrapolate your results to. So I flag this to make the point that when you have a patient population that says, I really, really want to get psilocybin. And you say, okay well you're not going to get necessarily the full dose, there's only a 50-50 chance. You're going to get the full dose but you're going to get some so you're going to get one milligram or 25 milligrams and we'll put in context with those.
Doses mean in a
second just to bracket one thing with makes this study and paper worthy of discussion is that it is a head-to-head comparison with lots of nuance, of course of psilocybin with. I think two or three sessions total in the intervention arm versus Lexapro. Very common SSRI, for major depressive disorder. Yep. Please continue.
Well, so to your point, the group that was in the
True psilocybin group received. I think it's just two dosas spaced out, three weeks apart of 25 milligrams of psilocybin, which depending on the variant of mushroom. So when you dry a mushroom out, its yield of psilocybin, pure psilocybin can be as low. I mean, I went and reviewed all the lid on this can be as low as 1 point, 7 percent can be as high by weight can be as high as even four or five percent. So the edible
Leti. Yeah. So that 25 milligrams was clearly a hallucinogenic dose. Yeah. So probably in the four to five gram of mushroom dose. So they used a number of. Well, there's one other point. I should explain about research. Generally, when research is done in a credible fashion, you have to call your shot before you do the study pointing to center field. That's right. You have to be able to not just say, I'm going to hit a homerun. I'm going to hit a home run over that wall and that's called your primary objective.
So, one of the things that is important to understand when you're evaluating research is, was it pre-registered? So when the study
I did they call this shot by thanking all the primary outcome. That's
right. And so in the United States, anything that's funded by NIH. For example, has to be pre registered on clinicaltrials.gov. So I would encourage anybody to go to clinicaltrials.gov and just start perusing. And what you'll see there is a list of all of these ongoing studies. I'll say, you know,
adhere and it's a template. So it always looks the same and it's very easy to navigate these things. You know, here are the investigators, here's the hypothesis, here's the experimental design, here's the inclusion criteria, the exclusion criteria here. The primary here is the primary outcome. Here are the secondary outcomes and it shows you all of that stuff. So you have to pre-register this, you have to State what you're doing. If you don't do that, it becomes very difficult to publish your work in anything prestigious. This, of course, was published in the hands-down. Most prestigious medical journal in the world, in England, Journal of Medicine. So they
Stirred around one type of survey, one type of depressive survey because unlike say, giving people drug to treat cholesterol where you have an objective metric, you can say, well, did it lower a poby or ldl-c or something like that? Here, you're relying on subjective outcomes because in such a short study, you're clearly not going to be able to follow people for wait. Was there less depression in this room was there? Less suicide in this group or something, you know, like a hard outcome, you know?
Did people have, you know, fewer absent days from work or something like that? And it's been a while since I wrote this, the primary survey that they used. I believe had nine categories or maybe it was 12. And the difference between the groups, the Lexapro group in the psilocybin group was not statistically significant. So both groups achieved an improvement in their depressive scores. I
think it was six and four points respectively, correct. I think it's a nine-point scale. Something like that. Yeah, you you
Out something very important and I guess we should just step back for a second. So the upshot and then let's come back to these questions. But the upshot summary of the study was what
there was no difference between psilocybin in this drug, it was positioned as a negative study,
got it. Meaning it, I mean, I don't wanna see failed because it's not really how science works, but that the intervention did not meaning, well psilocybin. In this case was not Superior
to. That's right, I said yeah. Yes,
tell her
Ty, that's right. All right. So, this is a topic that is endlessly. Interesting to me what we're getting into it. Just study design and really digging into the nuance and how beneficial it is to know how to read a study. And I mean, this will seem like a friendly plug, but I highly recommend people read a series of articles that you published, and they are called, what does it studying the studies
or studying studies studying studies to increase your scientific
literacy because
Going to get into some of the weeds. And I think it'll be. I, I hope it will be interesting to
people. And the other thing we're doing, if I can plug something and I don't know when we'll have this out yet, but we're creating a course, we're about a year ago, we started recording our weekly Journal are part of your monthly Journal Club. So every month inside our practice, we do Journal club, which is just like old school Journal club for anybody who's been in a lab. So one person will present a paper. Usually takes an hour to an hour and a half, and we get into a complete dissection of the
Paper and we do it in a really kind of methodical way and the topics vary greatly.
So, I highly recommend everyone do this. Honestly, witnessing the complete Mayhem, and confusion over the last year with respect to anything science-related. Certainly the most obvious of which being anything covid or vaccine related as has made it so clear to me that this is really, I mean, it's hard for me to think of something that is higher priority.
Yeah. And we just decided to do this.
In, you know, we've been doing Journal club inside our practice for years, but it occurred to me a year ago. Why aren't we recording this to later package, and put out there because nobody comes out of the womb knowing how to read science. Like we just have to accept the fact slightly learnt it, so it is a totally non innate thing. Evolution had zero desire to teach us this skill, so you have to learn it. And some of us were really lucky to be in Labs where people were really good mentors, and they, they,
Beat into you, how to do this. And again, the topics that we explore our, you know, the latest on semi glue tide which we'll talk about today. I think the role of testosterone replacement therapy in men with type 2 diabetes. A huge paper that came out recently, this topic. So it doesn't matter what the subject matter is. The process of thinking is actually
quite so, the process of thinking dissecting and skeptically but not necessarily cynically. Looking at the purported outcomes. I think is, is really
Important. So coming back to this paper, super prestigious Journal study comes out psilocybin versus Lexapro.
Negative study are negative outcome. Rather then we have this questionnaire, let's just call it. That is determining the results and the differences come back as statistically. Insignificant however, as you pointed out when you wrote about this, that doesn't necessarily mean clinically insignificant
depending or it is it mean that? It wasn't. So let's go back and explain what statistical significance is as well because now there's three points. You reminded me of something else that I think is worth.
Dating. How is the testicle significance determine? And what does it mean? We hear this term all the time statistical. Significance is basically asking a question. What is the probability that the difference? That's observed between these groups is by chance to answer that question. You have to know a priority how big an effect size you would expect to see between these two
groups, a priori meeting beforehand. You need to know what magnitude of difference expect to see between the two groups. That's right. And
that's
Really important because that determines What's called the power of your study,
part of the importance of guessing correctly. Maybe that's not guessing, but determining or speculating or guessing correctly, the magnitude of difference. Like the difference in effect size is because that also will determine how many subjects you need to
recruit, right? So there's something called a power table, which I think we include in one of the studying studies articles, which I remember when I got to the lab was one of the first things, my pie.
Principal investigator showed me he said this is going to be one of the most important tables you'll ever pay attention to. When you're doing research, it's a complicated table to look at but on the horizontal axis it has effect size of treatment, a on the vertical axis, it has difference between treatment a and treatment B. So this will be like, 10% 15% 20% that the. And then here it would be like,
Five, ten, fifteen twenty. So for example treatment a would yield if you predict it's going to be a 30% effect size versus a 40 percent effect size you go to 30 and 10. Does that make sense? Yep, you're the Baseline plus the Delta and then within each Square you typically have two options at either 80 or 90% power, obviously, 90% power means an even higher standard and it requires more samp like it has a greater sample size so it's very common.
In research to under estimate or overestimate, your effect size. And if you overestimate the effect size,
You can under power a study. And I think there's actually a pretty sizable chance that that happened here. Yeah. Because the power analysis suggested. They were looking for a 4-point difference on this scale. It came back with two. It came back with a little over two little over two.
Yeah. So
it's not surprising that, it came back, not statistically significant because they had engineered the number of
This happens to only be statistically significant if there is a difference of four points or greater. So on the one hand you would say, well that's really impressive. That was a very high bar. My question is, was it too high? A bar is 4 Points necessary. When you're really trying to do a study against the gold standard, it would be one thing if you were doing a study against a placebo, where you do want to set a very, very high bar. But this is akin to almost
like a phase 3 drug trial where you're trying to compare a new drug to an existing Blockbuster gold, standard drug, and simply being non inferior to it, and maybe even potentially better on some of the secondary metrics. As this one was, could be more than enough to advance clinical utilization and promulgate further studies. So that was one of my first concerns with this study was I don't think it was powered correctly because I do wonder if for was too high and
Back tation against this treatment of course other issues are was this study long enough? This was a relatively short study and it could have gone the other way. It might be that after a year. It flipped and Lexapro is hands down the winner and psilocybin. 's affect Wayne, we don't know. But again, that's another thing to be concerned with and then the point that you brought up which is a subset of what we were just talking about. His look, maybe a two and a half Point, increase is clinically really relevant and the other thing here
is I definitely want you to give
If you remember and they can be rough but some of the common themes of the question. That's
right. And that's, that's the final Point. Here is not all questions are created equal. So some of the questions on that scale are like are there times when you don't feel good about yourself versus there are days I can't get out of bed. Those are not the same question to me. Like, those are very different questions, a person who says, yeah. Like honestly more than fifty percent time. I don't feel good about myself. Clearly that's a
Woman. Clearly, that's something you want to address, but that's that person is probably a lot more functional than, than the person who says, I can't get out of bed.
Yeah. Or I think that, you know, the, another two examples to compare would be a
lot about suicidal thought as
well, right? Right. And, or I sleep 10 or fewer hours per day or 12, or more hours per day, and that might account for say, a two-point difference, on an individual questionnaire. But then another question, which was something like. I feel
So badly about myself, most of the time versus or on a daily basis versus say less than half the time, or something along those lines. And then, as you mentioned questions about, that could include suicidal ideation. So not all points are created equal, right? You know, another thing that's, you know, I wondered because I have in part helped fund research at Imperial College where this came out of and a bunch of other places and in conversations with a number,
Different neuro. Scientists they said well these are people are very experienced with designing studies and being published. They said, well, you know, there are times when you you have to choose between the primary outcome, measure, you think the establishment so to speak is going to most respect, or the primary outcome, measure that you think is going to move the most. And this could be a case and I'm not speaking for Robin or anyone else involved with the study. But this could be an example of picking what the
Shipment would have wanted to see and then having the secondary outcome measures move in some some very interesting ways that maybe in retrospect could have or should have been the primary outcome measure current. If you had more confidence in those to
begin with, do you know what the budget was for this
study for this study? I don't, but I'm glad you mentioned budget, simply because I think this underscores how important
Wouldn't at least in the u.s. because I'm involved with with Hopkins and UCSF and a number of other places. How important it is to try to open up state and federal funding for this type of research from NIMH and IH etcetera. Because right now it's easy for someone to say, well, that was stupid, why didn't they just have 50 people in each arm? And the answer is cost a lot of fucking money and it's hard to raise money in some cases. So,
I mean that was just the point I want to make but I don't know what the budget for this was.
I mean look I think net-net this study must be viewed as a very positive. Finding yeah because the side effect profile was obviously higher in Lexapro. So again people taking Lexapro or far more likely to complain of if they're males, erectile dysfunction, sexual malfunction, reduced libido, things like that. How we wouldn't want to explore this to the nth degree. I don't understand. And of course there's other things I want to explore like microdose.
Right. These were macro doses. So these are people taking full hallucinogenic dose every three weeks I believe and that's not necessarily an easy thing to do either. So we you know I'd want to understand what that's like versus what would taking a couple of milligrams per day which would be well below the threshold of perception or three times a week or something. You know, you hear a lot of anecdotal talk about those things being beneficial to people, I'd like to see that studied and in some ways that would be an easier thing to study because that's the other limitation.
Of this study, which must be noted, which is technically, it was not a blinded study. Yeah, it was a randomized study, but it wasn't a blinded study. There is no confusion about which group you were
in. This is one of the biggest challenges. I think there are ways to solve for it. That I find pretty compelling from a scientific standpoint, but it's very hard to Blind when you're using hallucinogenic. Much less sort of mystical experience level dosing of it's psychedelic.
It raises, you know, as you noted given the frequency of administration. So you have say, two sessions with psilocybin at clearly psychedelic doses. These would be, I would say, in most people sufficient to produce
some type of what you might call Mystical experience and their questionnaires. The Johns Hopkins has developed Roland Griffiths and Matt Johnson, and that team to measure mystical experience ego, dissolution sense of unity, Etc. But when you look at the results and we assume for the time being, even though I think people should look really closely at the appendices and the secondary outcome measures, let's say that their Breakeven. All right, this is a tie, but on one hand, as you said, you have more side effects, you have
Daily Administration. And then on the other hand, you have
Administration every three weeks and I think that were they too and they may still plan on doing follow-ups in other university studies, there's quite a bit of durability that scene with this type of administration of psilocybin. Even out to 6, 12 months, it raises some really interesting questions. The most obvious of which is how does this work? Because if the ssris are on some level, I do want to say suppressing symptoms may be masking.
Tendencies, I don't know the right way to phrase it but it is a maintenance drug. It's an ongoing Administration versus highly intermittent by what mechanism are. These changes taking place? Is it just flooding the brain with a compound that has about chemical effect? Or does it relate more to changing the content and narrative and sort of what work can be done in those sessions themselves? Raises a lot of interesting
questions. Yeah. And I think with MDMA, I think the
Answer is probably a bit more clear prior to MDMA s Resurgence and serious treatment for PTSD antidepressants, were the Mainstay of therapy for this and I think it was exactly what you said. I mean antidepressants for PTSD were a masking agent that had some efficacy but not tremendous efficacy. I think the runaway success we're seeing of MDMA for PTSD is clearly less about the chemical changes in the brain.
Result of the administration of the molecule and far more about this state of mind that it puts the individual in for the type of therapy that they need to do to go back and rectify, and come to grips with the traumatic event. And I think you're right. I think it's less clear here, but it also doesn't have to be one or the other. It's, yeah, certainly possible. Could be
both and there's been for those people interested in reading more. And I can link to these in the show notes for this episode, there has been some great New York Times coverage.
Of the phase 3 trials related to mdma-assisted psychotherapy includes stories from subjects to very compelling, read the results are really pretty staggering and raised a lot of, a lot of exciting questions for me about the future of treating mental illness, or psychiatric disorders. And I also want to give just a shout out to Rick Perry in Texas who has been recently, very public about
Exploring.
Psychedelic compounds as possible, treatments for things like PTSD among veteran, populations, and other subpopulations, that I think is a very, it's very courageous and very justifiable stance to take. So, I was very excited to see that, especially in the great Republic of Texas in which we said, let's write any other studies that come to mind, or you mentioned a poby. I'm wondering if you have any thoughts on a poppy that you'd like to share
Yeah. Certainly as it pertains to things where I'm evolving my thinking,
I'm and what is a
puppy? Yeah, it's probably worth explaining that before we do anything else. So most people have heard of cholesterol and most people are used to seeing a blood test where you would see your total cholesterol LDL HDL if the lab is half, decent, it would actually say LDL - see HDL - seen on HDL - see, vldl - see what does all that mean? So that means l
L, cholesterol or the cholesterol contained within LDL HDL. Cholesterol is the cluster, all contained within LDL. So why do all these things even exist? So every cell in our body makes cholesterol, it's an essential molecule for life. So if you don't have cholesterol, you're not going to live more than a few seconds. In fact, you'll die in utero if we're going to be blunt. So every cell makes this thing, it makes up the cell membrane of every cell so it allows membranes to have fluidity and have Transporters sitting across them. It's also the
Backbone for many of the hormones we make now the problem is cholesterol is not water-soluble. So when you have something that's not water soluble that needs to be transported through the body, which this does because as I said not, every cell makes enough of it to meet their own needs. So there are net exporters and net importers of cholesterol. You have to have a system that can move it around but just like if you tried to pour olive oil into a glass of water, you would quickly realize they don't mix and similarly, you
Can't just move cholesterol through the bloodstream, the way you can move things, like, glucose, sodium, potassium things that are water soluble. So glucose just travels through the bloodstream on its own as does a ketone body for example, but triglycerides, you know, have to be bound things that are fat soluble have to be bound. So, mother nature invented something called A lipoprotein which is a spherical thing that on the outside is water-soluble and on the inside house.
Has has these water insoluble or what we call hydrophobic things, namely cholesterol, Ester and triglycerides. And these lipoproteins exist in two broad families and the families are defined by the protein signature that wraps around them. So the two families are the apob family and the, a Poe, a family. Technically, there's a subclass of the ape OBS. There's an APO be 100, and in apob 48. But for the most
For anybody that's talking about a poby is referring to a poby 108. Bobi 48 is only something called the chylomicron. That is a very short-lived lipoprotein that gets fat out of your gut. So, let's put that guy aside for the moment. Unless anyone wants to come back, and we'll do the advanced course on the
weekend. Okay. Advanced course for the middle chlorines and nerds out there. All right, then,
so, you're a poby family consists of very low density lipoprotein.
Or vldl intermediate density lipoprotein, or IDL low density lipoprotein or LDL and LP little a who is the worst actor of the bunch? Which is an LDL with another special lipoprotein wrapped around him called an ape OA, or in a polite, but protein little, a not a PA. I should be really clear. It's a polite protein. Little a, you have to specify little late to not confuse it with the a Poe, a family, the a Poe, a family, is the lineage of the high density.
Lipoproteins most people know that HDL, good LDL bad, but that's a little overly simplistic. What we really mean to say is that hdls do not cause a thorough sclerosis ldls do, but it turns out ldls aren't the only thing that causes atherosclerosis anything within APO, Beyond it causes
atherosclerosis, and just to just to just for the, for the listeners atherosclerosis, meaning the build-up of plaque within the
Cardiovascular system. And I think it's the, it's the mm deafening or it's the
inflammatory disease of arteries that ultimately results in plaque formation. And in the worst case scenario results in rupture of this plaque that leads to an acute thrombosis or an acute occlusion. And if it occurs in the wrong spot that can be fatal, instantly fatal got so vldls stick around for long enough. That if you have too many of them, they are atherogenic. Ideals are not really.
Problem, because they just don't last that long. So, the transit from vldl to IDL. And then ideal to LDL is so quick that the ideals are kind of irrelevant ldls, of course, are the majority of your apob concentration, unless you also have a lot of insulin resistance where you might have high vldls or if you have a genetic condition that predisposes you to have too many of those, the ideals we can we don't really worry about those. The ldls are the Lion's Share of your a poby & about 1 in 8 to 1 in 12 people.
I'll also have a very genetically high level of LP little a and that also represents part of the apob concentration. So, apob is a far superior measurement to ldl-c when trying to predict cardiovascular risk. So it is hands down the best biomarker we have for cardiovascular risk because it is the total concentration of all particles capable of inducing atherosclerosis. Now after sclerosis is multifactorial, so lots of things drive it.
Inflammation plays an important role and metabolic Health plays, a super important role, but we understand that lower apob is better where I think the data are becoming more and more clear is how low you can push this thing without unwanted effects and how much more benefits you can get. There's always a concern I think and understandably. So that, if you lower a poby, you're lowering cholesterol. Because if you have fewer of the particles,
That carry cholesterol, you have less cholesterol floating around the blood. But what most people don't understand is that that's sort of like saying. I'm going to reduce the number of cars traveling over this bridge. Does that necessarily mean you're reducing the number of cars in the city not necessarily. So most of the cholesterol in your body is not in the lipoproteins. Rummaging around through your veins. Again, most of the cholesterol is
Still sitting inherently in the sells itself. So if you took a person's total cholesterol and it was 200 milligrams per deciliter and you lowered it total cholesterol. By the way, at this point, I assume is straightforward to explain. It's the sum of all the cholesterol and all the lipoproteins. So, the vldl ID L LD, L LP little a and HDL. If you bash all of those particles and take out all the cholesterol, that's what your total cholesterol is. If you took that number from 200 to 100, you would say, God, that's a 50% reduction in your
Cholesterol. No, it's a 50% reduction in your serum cholesterol which might be like a five to ten percent reduction in your total body cholesterol. So that's one thing to keep in mind, everything to keep in mind is we are born with very, very low levels of cholesterol. So in a child, the apob concentration is probably in the ballpark of 30, 20 to 30 milligrams per deciliter. By the time we're
adults a level of 80
milligrams per deciliter would
But you at the 20th, percentile meaning, 80% of people would have a higher number than 80. What's the upshot of this? The upshot of this is there is no upside to having more a poby the upside is in having that number be lower and lower and lower. But until recently it wasn't clear how low you could drive it and there was a type of drug that was developed about 1718 years ago but it became clinically available. I shouldn't say it actually has probably started development in about oh five
Five so-called 16 years ago, hit the market in 2014 or 2015, the class of drug called pcsk9 Inhibitors and they work in a manner that's distinct from all previous drugs, that lower cholesterol, they work by inhibiting A protein that degrades LDL receptors on the liver. And by inhibiting this thing that degrades them, you get more of the LDL receptors on the liver. It pulls more of the apob bearing particles out of circulation mostly which are
All
particles, but also some LP little a particles with these trials. We see people achieving levels of apob in the 10 to 30 range with no side effects, no consequences, furthermore. These drugs were developed when populations of people were identified, who naturally had mutations in pcsk9 that rendered their pcsk9 ineffective. So this was basically a drug that was designed to mimic a genetic mutation found in people who
who over the course of their lives have no increased risk of any disease and simply have a decrease in the risk of cardiovascular disease. In fact, the risk of cardiovascular disease is virtually
non-existent yes because silly question. How does one find people who have such a mutation to track them?
Well, it started with the opposite. So there's a condition called familial hypercholesterolemia or FH for short, which are people who have very high levels of cholesterol and very high levels of LDL.
DL cholesterol and by extension, very high levels of apob and they're pretty easy to spot, but it's a definition that is based on phenotype, not genotypes, which is genetic condition, but it's one phenotype, but 3,000 or more genotypes, meaning there are thousands of different genetic mutations that lead to that. I think it was in the late 90s, one of those genetic Pathways was identified as a hyper functioning pcsk9.
A nine. So a group in Toronto, identified pcsk9 and realized that these people had a hyper functioning version of this protein and it was constantly degrading, LDL receptors. And so they just couldn't clear the apob out of their circulation and that's why they had sky, high LDL and total cholesterol. When that population was identified, the question was asked, which is, is there a counterpart to them? And it turns out to be really easy to identify them, because
As they're the opposite. These are people who don't take any medicine to lower their cholesterol and they have levels like, infants. And I remember actually reading that paper when it came out and being blown away and actually thinking there's no way they're going to be able to do this with a drug, but it turned out, it was actually pretty druggable, it wasn't that hard to do. And in many ways, it's a much cleaner drug than say a Statin like statins, which are despite all the public Mayhem around it, in the religious polarizing debates, Ronstadt and statins are
a really safe drugs, 10% of people have unwanted side effects and shouldn't take them, but they're very well, tolerated, drugs, and in my mind, that's kind of a miracle. When you consider what they do, which is, they inhibit cholesterol synthesis. And when you think about how important cholesterol synthesis is, it's kind of amazing to me, that that works without killing people. My hypothesis for this, by the way, is that statins occurred in nature. So, the first statins were really copying something that was found in nature called red yeast rice.
And as a general rule, I think things that came from nature, tend to be a little safer, psilocybin rapamycin metformin, some of my other favorite drugs, but this the method of by which the pcsk9 works is just elegant, because it's really just targeting one protein with a, you know, with an antibody that makes it harder for the LDL receptor to break
down. Are there any benefits to lowered or low a poby?
Outside of cardiac risk. Lowering cardiac risk. Yeah. There actually isn't a cardio. Yeah, the
avascular. Yeah and that's sort of, I mean I think we've known for a while that it also poses a benefit with respect to Alzheimer's disease for sure. And that's one of those things where I think one needs to be a little bit careful about never confusing population data with individual data and it's why I think population data are fantastic but every patient has to be completely assessed as an individual. So
Population-based data for as long as we've had statins, we've known that lower apob or lower LDL. See means less risk of Alzheimer's disease and if you think about some of the paths, by which people get Alzheimer's disease, there's clearly a vascular path. So, Alzheimer's disease is not a disease, just in the same way. Cancer is not a disease singular, its many diseases, not just tissue type, but even within tissue type, you know, within breast cancer. For example, you have different receptor profiles.
The same with in lung cancer. So or even just the mutation can render to cancers completely different animals. And similarly Alzheimer's disease is a collection of lots of diseases with a final common pathway, but you can get there metabolically, you can get there through a vascular path, you can get there through an inflammatory path. There might even be an autoimmune path there. The vascular path is a big path in my opinion and therefore anything that improves micro vascular Health which statins do should improve.
The risk of Alzheimer's disease. So there was something called the mendelian randomization that was published. I think like, literally a week ago and I'll explain what I mendelian
randomization. This is yeah. Gregor Mendel.
Yeah. So I guess I should explain what it. Mr. Is first Mr.
Is mendelian.
Randomization correct is a very elegant tool that allows us to try to infer cause
when an experiment is not done, this is a profound idea. Because when you just observe things without doing an experiment, which by definition means randomly, assigning treatments, are assigning treatments to randomly separated groups, which is the only way to eliminate all bias. There are other biases that can creep in, which we could mean, which are actually discussed in the studying studying section. I won't go into like performance bias and other things like that. But for much of the
Kids were interested in, you can't do that. You have to rely on natural experiments. So what Mr allows you to do is identify genes that are responsible for the traits at hand and not responsible for other traits and do, basically a model of, what does that genetic trait tell you when its present or not present? So, the the idea is
In an NMR analysis. You're basically assuming that genes can occur randomly which of course they can and you're then looking at what is the outcome from that. So for example, in the case of a poby you would look at genes that are determining a poby level and there are many genes that play an important role in understanding, how high or low, a person's apob is and these genes are set, right? It's sort of like you get the gene, you get you know, you're not going to change the Gene and it's not subject to
Your behavior, whereas so many other things like what you eat is a behavior that can also impact your apob. It's how do you strip that affect out the healthy user bias. All of the things that are are problematic when trying to infer this and the Mr. Demonstrated quite clearly that lower a poby is synonymous with improved all-cause mortality. Cardiovascular mortality, and even mortality associated with diabetes and things like that.
To me the most interesting finding in there was the all-cause mortality on the one level you could say. Well, that's not surprising, given the cardiovascular mortality as the greatest cause of mortality in the developed world. So, if you take a big enough chunk out of that, you should improve all-cause mortality but nevertheless that study combined, with a number of other very large cardiovascular trials, namely Fourier, Odyssey improve. It every trial has to have a cool name, just demonstrate this effect where lower is better, the lower
LDL goes where the apob goes, the lower the risk
goes.
Let's jump to rapamycin since you mentioned it and you can give a very quick idea on what rapamycin is. But since we last spoke more bearish, more bullish and why I'm a bowl. Yeah. Dogecoin and rapper hands. All
right, so what is Rabbi the way I mean I know I know what the diamond hats thing is, but what is it? Where did it come from? No idea.
No idea where Diamond hands comes
from.
I was like, did I miss that somewhere in my, in my real in
your and your econ classes? Yeah. No, I don't think so. Okay, so what is
rapamycin? So rapamycin is a drug that is a naturally occurring anti-fungal agent made by a bacteria that was discovered on Easter Island back in the
1960s. Otherwise known as Rapa Nui. Right
Rapa Nui is the correct name for Easter Island and the bacteria streptomyces.
Hydroscopic asst, which was discovered there by a group of explorers. Explorers may be the wrong word but people doing sort of medical prospecting a group from Montreal. I believe in call it 1966, they took a bunch of soil and dirt back from Rapa, Nui to the lab in Montreal, where it's sort of sat there unattended to for about five years chemist. A very astute chemist by the name of Sir ends Seagal right now. Yeah, he
started to Steven Segal, no difference.
And no pony tail, unfortunately. So surrendered. Some really interesting chemistry isolated the compound and noticed it had these really remarkable properties, which was it was the most potent antifungal agent he had ever seen or the world had ever seen. Frankly, at the time. As his son Ajit tells the story who have gotten to know a little bit. He felt he had basically come onto the biggest Blockbuster cure for athlete's foot. The world was ever going to know and right about that time the company he
I worked for closed, its Montreal headquarters actually laid many people off ordered the destruction of all non-viable compounds and shipped him off to New Jersey. In one of the greatest acts of scientific fortuity. He did not follow orders and he instead stuck, said rapamycin into a little mini freezer that he and his family transported to their new home in New Jersey, they kept it in the freezer for
Years until ultimately another drug company, purchased the company, he worked for and the new management said, hey, anybody working on anything interesting. He said I'm working on this thing interesting that I haven't looked at in a few years and they said bring it out. Must have been an interesting
lawyer conversation based on the not following orders.
Yeah, continue. Yeah. So out came rapamycin, which he named meissen and my sin is typically the suffix I guess that we use or what's the what's the second part of a word Cox?
Chuckles. Yeah, for antimicrobial agents and of course, wrap a, as a tribute to the Rapa Nui
like azithromycin correct. It
quickly became clear that this had remarkable anti proliferative properties so it could stop things from proliferating. So that was obviously a big knot
of just fungi,
right? Exactly and in particular it was very effective at making a certain type of lymphocyte which is a white type of white blood cell, not proliferate. And it then basically,
Down the path, eventually Pfizer than bought Amorous, which was the company that bought his previous company. Whose name, I don't even remember at this point, Pfizer ended up pursuing this and it was FDA approved in 1999 for treatment of organ transplantation. So patients that have an organ, transplanted have to be put on a really heavy regimen of drugs to suppress a part of their immune system called the cellular immune system that will attack a foreign organ.
That's what is that called? Host graft
no graft-versus-host is
Ali. When the organ, usually. It's in the case of lymphoma or leukemia when someone has a bone marrow transplant and The graft, what they've been transplanted attacks, the host I say yeah, this is this is really hosts versus graph. We don't usually call that that. Yeah. But traditional sort of you know rejection actually I did a really cool podcast on the topic of organ. Transplantation history with a guy named Chris on and day and it's I mean I know this subject well, but having a discussion with Chris really opened my eyes to just what a beautiful story it is and
The big breakthroughs were with drug development and how you know at one point it was like all you could give people was prednisone and you couldn't save anybody and then you had other drugs like cyclosporine that were introduced. But then you get into this third generation of amazing drugs like rapamycin that took organ preservation to a to a higher
level. Now you're not swapping kidneys. How do you know? Well, at least not since the last time you sold one. Yeah.
Wanna settle a bad. But why would you take rapamycin? I know I'm skipping ahead a little bit but let's
say yes, let's skip ahead. So so 99, this drug comes on the market for organ rejection. And about 12 years later, a study, gets published by Rich Miller, Randy, strong, and colleagues, as part of What's called the interventions testing program, or the ITP, which is an amazing NIH funded program that tests molecules that are believed to
Have a shot at enhancing longevity and it does so in her really, really rigorous way, probably the, most rigorous way we can test small animals. I've interviewed Rich Miller as well. Probably, one of my five favorite podcast in terms of like nerding out on all of the molecules that can potentially impact longevity and rapamycin was in many ways the poster child for the ITP program because first of all it's hard to get anything to live longer. Second of all, when they were making the
For the rapamycin to feed the mice and these were very special mice. These were not your typical crappy lab mice, that have no bearing whatsoever to real animals. These are a very special type of mice that are much more, akin to real animals, and that's a very important distinction, between what happens in 99% of meiosis research, which is almost in applicable to humans. And it's why so many drugs that get tested in these, be six, mice and things like that.
That show some marker of success and they become wild failures beyond the mice, but this was different. They had trouble getting the formulation to work. And by the time, they finally did the mice were, like 20 months old, which means they're almost at the end of their life. They're like 70 year old, 65 year, old mice and they contemplated just scrapping the experiment, but they were like a screw it, let's just run it late. So they started feeding the treatment group with rapamycin and the placebo group.
You get to continue eating their regular ciao because it was oral Administration. Yes, it was the rapamycin was mixed into their ciao and lo and behold the rapamycin group despite initiating treatment. So late in life, had a staggering Improvement in life span. There's been so many it PS that have replicated this. I don't want to misquote it but it's something to the effect of like a 17 or 19 percent Improvement in the males and the females and 11 to 12 percent in the males. And remember the ITP used a very rigorous way of assessing
This which is they're taking a look at total life, not just remaining life. It's an even higher bar to clear. How much lifespan elongation happens. They, of course, immediately went. And repeated the study administering, the dose when they were younger and saw an even greater response, this has been repeated over and over and over again. And to my knowledge, there is not a single animal study that has tested this hypothesis. That has not found on this result. That's wild, which again is very unusual.
Yeah,
it's just replicated over and over and
over its replicated non-stop. What is also interesting is when looking at other markers other interesting, things such as vision and hearing and other markers of Health span, we continue to see improvements in these things for Animals as well. And as I think we even spoke about before the guy named Matt caber line. Who I'm just interviewed for a second time for the podcast has been studying this in companion, dogs, and looking at
Function because as you know, basically two things kill companion, dogs primarily, heart failure and cancer. And so the question is, what would you be able to do to mitigate especially heart, failure, congestive. Heart failure in dogs, especially large dogs, which are more susceptible to this. And again, the results, though, the research is limited because there's not an enormous interest in funding This research and it's expensive to fund research in dogs that live so long. It's all pointing in the same direction. So when you
Contrast, metformin and rapamycin. You have the opposite thing. Right? In metformin. We have tons of human data that are not randomized, but are suggesting in cohorts that metformin is also protective but in a subset of people that have diabetes so it's not as clear. How protective metformin will be in people that do not in the ITP metformin did not succeed. In other words, metformin did not extend life in the mice when given a loan when it was given with rapamycin, it did. But you could argue that was all the rapid my
And I'm more bullish on Rapa simply because I'm, you know, I've been taking it. Now, for three years outside of getting here dog, whistles outside of the Apple saucers which are the most annoying side effect of them. Those are those little mouth little mouth sores you get canker sore? Yeah, yeah. I don't get them de novo but if I like if one of my kids headbutts me which they do at an alarming frequency and my if I break a piece of my gum like it's going to be an app that's all sir.
Sir. Hmm. Although I was it called again abscess? All sir abscess. Yeah a pH th OS hoof.
Yeah, yeah, nasty. Last it doesn't sound fun. Is that the only documented in healthy normals? I don't know who would fund This research if anyone would or I don't know what I guess. I don't even know what the measurements the metrics
would be, but well, that gets to the problem. We don't have a meaningful biomarker of Aging. Yeah. I mean that's. The biggest
I'm in aging research, today hands down. Nothing else matters. Yeah. When you don't have a really good biomarker for aging,
We're sort of sitting around twiddling, our thumbs pontificating doing studies, that look at things that aren't that interesting or things that are interesting but are like first order second order, you know, but we just we can't see the whole polynomial, right? Like if you think back to it I got a Taylor series is in Calculus. If you're trying to use a polynomial to estimate sine X, the first order term is x, equals y, like that's interesting for about that much. But, you know, when you really want to know, x, minus X cubed over,
3, factorial, plus x to the 5, over 5, factorial. Like when you want to really start figuring out the shape of this thing, you've got a you're just going to need better
tools as we're talking about rapamycin. I think naturally a lot of people listening will think of Life Span. It's a term, they're more familiar with and you start to finish. What do you clocking in in terms of years and then there's Health span? And, you know, I took a note as I always take notes during these conversations about the vision and the hearing, so, I'm 40, guess my memory is also going 43 and
And recently had a not quite an Audiology test. I mean, it wasn't as quite basic hearing, test done and seem to have some minor hearing loss in the higher. Ranges, on one side. Could have been some of the ambient noise in the room. I don't know, I'd like to try to replicate it but could one make a compelling argument that rapamycin could improve restoring that
Of
hearing or is that too much of
a stretch? It's just too soon to say. I think it's certainly plausible but I think it's too early to say, I mean, we've seen that in animals now we've seen that in animals, but I don't know if that's going to translate to
humans as up in seen in multiple
species. I've only seen it in mice in mice. Yeah,
these are kind of the feral mice versus the like, Holstein cows of -,
to be honest with you, I don't remember what mice were used in that study, but it's quite possible. They were your garden-variety genetically. Not so interesting mice, got it.
You've hinted at or outright identified, a big challenge, which is how do you study a drug in healthy people. And, by the way, a drug that has a little bit of a bad rap. Immune suppressing, drugs? Don't have people very excited and until 2014 until Christmas Day, 2014 or Christmas Eve day. I didn't think of this as very interesting. So in 2011, you have the first ITP published and it's like, wow, that's cool. But I used to give this to kidney transplant.
Asians, I'm not taking that and then you had Joan manic was the lead author on a study that came out at the end of 2014 that looked at a rapamycin derivative called everolimus and it was given to 65 year olds in. The following fashion were four groups, a group that was given a placebo, a group that was given one milligram every day, a group that was given five milligrams once a week and a group that was given 20 milligrams once a week. And they were given this for a period of eight weeks, I believe and
Then they were taken off everything for another period of I believe six weeks and they were challenged with a flu vaccine and then look to see who mounted the best immune response and counter to what you would expect. The people in rapamycin developed a better immune response, which flew entirely in the face of what one would have expected the group getting 5 milligrams. Once a week, they had the best response in the fewest side effect. So the 20, we probably don't want to go down this path, is just more complicated.
There are two complexes of mtor. There's this that we talk, we got to talk but I'm tour. How does rapamycin work right? It it works by inhibiting. Something called mtor, the mechanistic target of rapamycin. We
could also refer people to our conversation with David
Sabatino, slowly back on Easter
Island, back on Easter Island. So long story short, there was a trip, it may or may not have involved some wine to Rapa Nui to Easter Island and one of
Our trip. Mates was David sabatini, who Q? Peter
was the first person to identify how rapamycin worked in
mammals. Yeah. So we talked about that quite a bit in that episode. So I think let's refer people to if you just search Tim Ferriss show Easter Island. I can't imagine. There are many results and you will see an amazing Crow arm displayed by another one of our trip mates, which happens to just be an artifact from a weird.
MX shot. But we did use that photo just just to shape his nuts a bit. So let's see.
Yeah. So let's just wrap it up by saying that the five milligram do seem to be The Sweet Spot once a week at produced all the benefit without the side effects. 20 produced a similar benefit but had too many side effects.
Do you no longer take Metformin? I do not. Hmm. Interesting, what were some of I know you referred to was his last name, Matt, Chamberlain, maybe it wasn't Matt, Matt cable. And I know something Miller. Oh Rich Miller rich.
Miller, what are some of the other candidates that are most interesting to you in terms of pharmacological interventions? That might extend lifespan or
healthspan? There are several others that were found to have significant lifespan enhancement. Repeatedly one is acarbose which is a favorite of our mutual friend,
Kevin Rose.
So the way the I TPS work is really cool. Anybody can suggest a compound
So it's basically like, you know, it's like a crowdsourcing thing where you can decide, like I want to know if this molecule has a benefit and as long as you can write the proposal, which contains the rationale for why if they buy it, like they're going to study it. So acarbose was suggested because the idea is acarbose prevents the absorption of starch. So if you eat a pizza, you can have half of it, leave your body, basically, without being
absorbed, footnote for Kevin think the ratio of donuts,
Beer to a car bus does matter. Probably at
some point. Oh sure. Yeah. And you can only take so much acarbose. I mean it is a little hard on your gut because it's in the gut that it's preventing the absorption and the thinking was will acarbose. If it's eliminating a reasonable fraction of your glucose is going to be a caloric restriction mimetic or a CRM as they call them. So let's see if that works and it turned out acarbose
did work, but
interestingly the animals who live longer weren't any lighter?
And didn't have any lower levels of average glucose than their shorter-lived counterparts. So whatever acarbose was doing to extend life. It wasn't through making, you eat less or making you way less or making you even have a lower hemoglobin A1c. It almost assuredly worked by the only other thing it did, which was lower the spikes and peaks of glucose. It blunted those. So it spreads out the speed with which glucose is hitting you. But lowers the spikes,
are you
Or bullish on acarbose then metformin.
No, I don't think so. I would still probably put metformin as a more interesting agent. I mean acarbose, first of all is just not an easy agent to take. Yeah I mean unless you like diarrhea when they were those Giardia is also a caloric restriction abetik so and honestly monthly doses of typhoid fever. Yeah exactly. Right. I'm always one I'm just one grd about away from Bowl way. I'm still more.
Optimistic about metformin, but also metformin is more of a mystery. In fact, our other mutual friend from Easter Island, nav. Cendol this is one of the things that he works on eccentric, row arms. Yeah, and I'll be having nav back on the podcast, probably an early 22, novice fantastic. When there's some killer work that he's doing on the mechanisms of metformin and we'll dive back into that. But there is another drug that I think is super exciting that was recently published in the ITP called kanaga Flows
In.
Wolf connector
flows, and Nega, Flows In spelt actually as it sounds with a
c and it is a class of
drug known as an sglt2
Inhibitors. Rolls off the tongue. Yeah,
the sglt2. I and it's a more elegant version of acarbose working in the kidney. So the kidneys kind of a cute organ cute in that, it's really smart. I think Evolution figured out that it would be too difficult.
Cult to know all the things that are bad for you. But it's really easy to know all the things that are good for you. So the way the kidney works is it gets it obviously a staggering amount of your circulation like 25% of your cardiac output is passing through your kidneys with every time your heart pumps and the first pass of the kidney is to take everything in your blood and dump it out. So it's sort of like, saying I'm going to clean my drawers by throwing everything on the floor and then only putting back in my drawers.
The things that I want and because again, it's easier to know you need glucose, you need potassium, you need magnesium. You need sodium that it as opposed to this talks in might that might appear a hundred years from now a million years from now. So in the reabsorption process, can I go Flows In blocks the reuptake of glucose. So you end up peeing out a lot of glucose. So this drug obviously was introduced to treat people with type 2 diabetes and it showed remarkable.
Table efficacy in doing that.
So in a healthy subject you would be presenting the sort of traditional old-fashioned symptoms of diabetes. Yeah though not quite to
the extreme extent because it's sort of gradient driven. So in the traditional Osler sense where you know, literally diagnosis of diabetes was made by tasting the urine and seeing how sweet it was those were patients that were presenting with you know, wildly uncontrolled diabetes with a
Cosette like 800 milligrams per deciliter, you know, they're about to have a
coma. I first learned to a diabetes was when I was in Japan as an exchange student. And it's told Noble, which is sugar urine disease, and you, it's really obvious in the characters. I've no idea what I have diabeetus, you know, I heard it on the oatmeal course.
Interesting, because I'm guessing nobody in Japan actually has diabetes.
Yeah, I included a day when, you know, if people eating like rice with mayonnaise. Yeah, slightly more when you were there. Yeah, there's
probably just like
Five people with diabetes have very few. So can I go Flows In basically blunts this reabsorption of glucose, very successful drug for the treatment of diabetes. And also, in people with diabetes is showing better effects when it comes to heart failure, better effects when it comes to mortality, this is really, in my opinion, a first line drug for any patient with diabetes, and it does not cause hypoglycemia. So if a normal person takes it, they're not going to have a
Is drop in blood sugar, so it is also blunting the spikes, but it also seems to lower the average as well. So con Agra Flows In extended the lives of mice in the ITP. I don't remember the exact numbers. It wasn't quite as diabetic or
so. No, no, no, no. These
are perfectly normal mice. It wasn't as big, an effect as rapamycin, but it was bigger than most other things. There haven't been that many successes in the ITP, obviously most drugs fail, but the successes like rapamycin 17 Alpha.
- estradiol kanaga flows in a car Bose. Those are, you know, some of the big successes and of course they get tested over and over again to make sure they weren't one. Who's these
Seventeen, something? Rather? You just my
17 Alpha. Estradiol was a very
interesting molecule teen Alpha
estradiol, which is not the estrogen. It's not normal estrogen, which is beta estradiol. And 17 Alpha estradiol, only improved lifespan of male mice, it had no impact on female mice, the thinking being that it's
Mimic the estrogen protection benefits in a male, but not in a female because they already had
estrogen. Yeah, that's super
interesting. Yeah, that's not a molecule that to my knowledge is even in clinical trials, like, I don't even know if there's an IND for that molecule that it's even I don't know what farm is doing with that
information. How did that get submitted for the ITP? Yeah, it's funny. I asked Rich about that accountant. Just backyard chemist. He was like yeah, it was, it was an inherited, a bunch of oil money here.
I want you to
make. No, it was effectively someone who had been studying this molecule and thought, like I wonder if this would be interesting for the hypothesized mechanism that it would offer some of the protective benefits of estrogen, what was out the feminizing effects, right? So it doesn't have the sexual characteristics of estrogen. So the question is, because if you gave a male, a whole bunch of estrogen, you're not going to make them live longer. Yeah. Because whatever benefits come from, it are going to be offset by a bunch of
negatives. Just to scratch my own inch and curiosity. Here's Ken someone with enough.
Money, just push whatever they want through the ITP to get something tested or like, what combination of factors lead someone to be able to take a candidate or something? They think, is promising like a 17 Alpha. I just read about
money. I think, honestly, it's just about having the time. Like there's a candidate drug that I'd like to put on and I just haven't had the time to write a proposal, so maybe in a couple years old when I finished the book and a few others, all objects are time. Yeah, there is a candidate that I think would be
Arresting. So now it's just having a good scientific case for it. Yeah. That's fascinating,
huh? Should we do some stupidity? I think absurd things anything particularly ridiculous that you're doing these days or enjoying?
I think with the lockdown with the whole covid thing. I've never spent more time at home and it's been amazing. Like, it's been a huge dream come true. It's just take the most antisocial person in the world and allow him to never have to go out.
And that's been, I think really great for my family on some levels but also its mean that they it meant. They had to put up with more of my stupid jokes and the like just the dumb things that I think about. So one of the things that I have been really harping on and just drives my wife nuts is, you know, when you eat a banana at the very bottom there's that little nubbin. Yes. You know the little parts. So I am convinced that the nubbin is like lethal. Like, if you eat a knob and
you're going to die
and
And so, I'm the nubbin police of our house because a lot of times, you know, how you can never finish bananas, like you buy them, you buy like 10 and you might eat three, but then seven are going to go bad. Yeah. So we peel the bad ones and put them in the freezer to make smoothies later on because we always add, you know, frozen fruit to make my protein shakes or whatever. And when I do it, I'm really careful to never put the nubbin in. I peel it, but I keep the nub in, in the peel and it goes in the trash. But when my wife does it,
She just left. These are nothing in, so I'm like, of course,
I don't care, but I act like I care and I'm like, babe, are you serious gettin up in here? Like there's people in the house. They could eat this. Like, do you
understand the nubbin is literally the third leading, cause of death worldwide,
not in the developed World here. It's like the fifth leading cause of death, but when you average it out across the globe, third leading, cause of death. Now bite us now itís. So and it just doesn't get old. And I think the more bugs her the funnier it is to me and the same with my daughter.
Just endless eye rolls and the Netherlands. They don't buy it. They really think they claim that you can eat a knob in and nothing
will happen. To depends on your toe Pacheco to love and ratio in the house. I think it pretty heavily weighted in the former. All right, what else do we have? On any of the three categories? Really, if there's something that jumps out where you're like this is really
For any reason pulling my attention.
Let me look at my list here and see what else. Oh, I know something else. I've changed my mind
on. Yeah, I'm way way, way more bullish
on sauna than I have ever been before. I used to be in the camp of sauna feels great. It maybe even helps you sleep a bit better but that's probably about it. There's no way you're going to really live longer because you're in a sauna. Well truthfully we don't have really great.
Active data or sir? I should say. We have good prospective better. We don't have good randomized data. I think this is one of those things where the burden of evidence in the non randomized data is so strong.
It's becoming hard to ignore. So, most of the research on this subject has come out of Finland and
the sauna lava is, yeah,
and so there's the obvious issues with this, right? The people who can afford to sauna are by definition going to have more time on their hands. More disposable income, probably more education, like all of the standard things on top of that. If you're going to choose to sauna because you believe it's healthy, what else are you doing? Because
You believe, it is healthy, I mean, right? So if the data showed that Sauna versus non sauna was like a five percent Improvement in mortality, it would be hard to get that excited about it. But when you look at the largest published series on this, you see a benefit in all-cause, mortality a relative risk reduction of 40%, and an absolute risk reduction of like 18%. Those are
those are high numbers. Those are
Oculus numbers. And that's when you are comparing someone, who likes on has four to seven times a
week. I was going to ask you. So what's the dosing frequency? The yeah. What's the disagree with seeing? What do you believe? The minimum effective dose to be kind of like the zone to training, you describe what it is and then you said bath let's see how we can. I do for times
45 just to get to the punchline. I think based on the research, the Meed is for sessions, 20 minutes, 80 degrees
Celsius
four sessions tops, 20 minutes, Addie degrees Celsius, you have your
Fahrenheit. What's the conversion there? I shot about a
hundred and seventy-five
Fahrenheit hundred. Seventy-five Fahrenheit. Got it.
Dry wet,
those much more literature on dry. You noticed, I actually had a call with a patient this morning. In this topic of saunas came up and she asked if she could substitute steam rooms and such and I said we just don't know because we don't have the data. So you know the precautionary principle would say, if you have access to a dry sauna, that's where we have Reams and Reams and reams of data. So it's probably where it goes. But look, if you think about what the mechanism of action is, yeah, I
was going to ask you next. Is that heat shock proteins, is it?
He gets many things, I think its heat shock proteins. I think that's nitric oxide. I think it's literally vascular tone, right? Reduction in blood pressure increase in heart rate and cardiac output. So there's a bit of an exercise benefit. I think bdnf has been measured. I can't recall. That could be another potential benefit. So my guess
is that you didn't have brain-derived neurotropic Factor. Yeah,
I think it's probably half a dozen things that are all moving in the right direction as funny. When I have done some sauna Inge, I've done lactate check.
It's in there to see if it gets me to Latin Zone to it's not a pure exercise mimetic because it doesn't even get me to the level of his own to work out at least when it comes to a pure ATP uptake or ATP production standpoint. But yeah I've become really optimistic on this and I think it's very promising and I think it's again it's the challenges is how scalable is it, right? Like it's not as it's not that easy to
do. I would imagine also contraindicated for a lot of folks.
Yeah, yeah, I suspect if you're really far down the line of your health is suffering and your, you know, particularly old or something like that or your heart's a little more frail. Yeah, this might push you a little bit beyond. So again it speaks to sort of prevention and and hopefully with covid kind of winding its way down and enough. People getting vaccinated people can get back to Jim's where saunas are and things like that.
Yeah, amazing. Preferred method for Zone 2 training. Seems like you do most of your work on a bike.
I do I like the bike. It's just my body is so
More efficient on a bike than anything
else. Give preferred stationary bike or do
you? I do I ride my bike. Like my road bike on something called a wahoo kicker. Walk of kicker is awesome. Like hands
down. If someone doesn't have a road
bike, then I my favorite stationary bike is the
Kaiser deck haisa and I don't think that's actually death. But a Sosa Ka is er
yeah Ka is
er I believe
All right.
And I think Kaiser makes such a fantastic spin bike.
You want to do one more change your mind about, or one more excited. You can dealer's Choice.
Yeah, I'm pretty excited about glp-1.
Agonists, tell me to. I don't even know what that means. Tell me Peter, alright, so
glp-1 agonists glucagon-like peptide one, they also go by glp-1 Ras. So,
Kagame like the peptide 1 receptor Agonist. Okay, so glucagon is a hormone it's made by the liver, sort of opposes the action of insulin. It's a hormone that produces satiety and can regulate blood glucose
levels regulate. Meaning it's catabolic
lowers lowers blood glucose? Yeah, it secretes insulin actually results in secretion of insulin to lower blood glucose so got it. These are a group of drugs that have been around.
And for quite some time also a high choice in people with type 2 diabetes, a trial came out. What I say 2014 showing that one of these drugs was actually also pretty good for weight loss in non-diabetics.
It didn't get a lot of traction. The effect size was was reasonable, but it wasn't great. I looked at it quite a bit because I remember the time I had a patient whose weight was really recalcitrant, it just wasn't clear what it was going to take to help her lose weight and I certainly am not a fan of stimulants for weight loss drugs. Like Phentermine can be somewhat effective but they can also have their side effects and be somewhat habit-forming and we had sort of
noodled this and eventually we ended up trying this drug. It didn't really have that much of an effect and I kind of sort of put it aside for a while until about six or seven months ago. I was talking to someone who had an early line of sight into a trial that was going to be published and they said, you know, they'd been using it. Clinically a newer version of this drug is called semi glue tide. The trade name is ozen pick and they said yeah you got to see what this drug can do.
The drug the dose that's given for people with diabetes is one milligram once a week, so it's an injectable drug. So it's it comes in a little pain you you know shoot it in your gut or your leg once a week 1
milliliter muscular or
subjects a few tiny, tiny little insulin syringe and he said yeah, but when we push people up to two-and-a-half milligrams, the weight loss is comical. This is not just people with diabetes. This is anybody. And then sure enough there was a study that was published probably a couple of months ago. Looking at
It's Emma, glue tide in overweight and obese, people without diabetes. And the weight loss was through the Moon. I mean it was, you know, we're talking like 20 percent weight loss, holy shit, completely durable as long as you're on the drug. So then it begs the question what happens when you come off the drug? We haven't seen fully what that looks like yet. I mean I think we need to see what those studies look like. I mean my thinking of this we've now put a lot of patients on this drug. I'm a lot is relative but you know maybe
12:15 patients. We've put on this drug, some people can't tolerate it because of the nausea, so nausea. Yeah, I mean, that's definitely one of the side effects. Then
is it administered once a week. Once a week. Is the nausea transient or is it?
Yeah, tends to fluctuate. So, if you inject it on a Sunday and then, you know, usually by the next Saturday, the symptoms are gone. But then, when you hit yourself on that Sunday Sunday, Monday, Tuesday, you'll be a bit more nauseous now. Again, that's so it's transient across the week, but it also seems to be transient over time. So the, the
the dose in this study was two point four milligrams. So, you know, two and a half times higher than you're doing it in people with type 2 diabetes. But you don't start people at that dose, you'll start them at half a milligram for a few weeks, then one milligram then one and a half then 2 etcetera. But basically we haven't seen any patient who can tolerate the drug that does not lose weight
have any cycled off in which case I mean obviously Behavior matters a lot and calories matter a lot. But yep do you see
A greater. No, don't do it, no State otherwise
and they don't seem to regain all the weight they lost. Now my biggest concern, I was so fascinated by this before the study came out. We actually did a whole Journal Club just on this study and when stupidly nerdy on this drug, the biggest concern I would have is is a drug that lowers glucose but raises insulin, such a good idea and also it flies in the face.
Face of how you would lose weight in that situation, right? It seems to not be entirely clear, why would that result in weight loss? Unless the increase in insulin, along with the glucagon-like peptide are reducing appetite. But what we've discovered in experimenting with a lot of our patients by experimenting, I mean just doing a lot of blood tests before. And after is while it, probably slightly increases your fasting insulin level, it's also clearly increasing muscle insulin sensitivity because post
And you'll insulin levels seem to be down and I would bet though it was not done in this study postprandial, meaning post meal after meal. I would bet that if they had looked at 24-hour insulin secretion, which you can do by collecting 24 hours of urine and measuring c-peptide, which is an another exist in a one-to-one ratio with insulin. Because when insulin comes out, it's a prohormone. And then it gets cleaved into insulin and c-peptide, so you should have one c-peptide for every insulin. So if you measure the urinary amount,
Of c-peptide. You know, how much insulin was secreted? I'm really disappointed that study didn't do that, but my guess would be that. They saw 24-hour c-peptide go down, even as resting insulin went up, okay. Which would
mean and well, please correct me if I'm over simplifying this, but that on if you look at the average it is not net-net leading you to increased insulin levels. That's right. Yeah, that's so interesting. Now when you see 20 percent reductions,
Talking about body fat or body, weight,
or body weight? Wow, Yo body
weight. Yeah. Wow.
So, you know that's and that's easy there. You'll
see more. Yeah. These are an obese
people. Yeah, we've even put it, we've even had patients who are not even wouldn't be classified as obese just slightly overweight, you know, a 200 pound person but in three months is a hundred and eighty pounds and effortlessly at 180 pounds, right? Like they've literally reduced their appetite and they've improved their insulin sensitivity and glue.
Kostas and that's where other
interventions failed. So it's not I mean I know we're not blinding this or anything with patience, but you don't think that that you attribute that predominantly to this this drug not too.
Say changes in eating or other habits?
Well, they have changed their eating, but I think it's in response to the drug. Yeah. Right. So I think the drug is working, centrally peripherally. I think it's working on the fat cells. I think it's working on their brain. I think it's working on their muscles. I think it's doing a lot of things and it's still early days. But I mean, this is a promising drug in my opinion and I think there's some people who think that you shouldn't need a drug to help you.
And if you need a drug to lose weight, you're somehow a bad person or something like that, but, you know, I just, I just think categorically that's just such a simple-minded view of the world, right? Like we live in a world with technology and just as you don't rub two sticks together when you want to have a fire if a Zippo lighters available to you. If you have tried every dietary strategy imaginable and your metabolism is not, you know, moving in the right direction, why shouldn't we explore other ways to kick-start bad? And the other thing, by the way, as I think you can take these things for a few
It's come off them and see if you have formed new habits in the interim. I also think they'll be in my mind, a model for cycling. Three months on three months off three months on three months off again we want to make sure that that doesn't cause some recalcitrance to the medication or something like that, but I think this is exciting. I think this warrants a lot more follow-up, but what it's saying is that things that improve diabetes also improve health and nothing does that more than exercise and nutrition. That's the
Do you have it? But not everybody can do enough exercise and the right nutrition with enough, he's to get the benefits. So the more tools we have in our tool kit that go outside of that, the
better they get Peter always, so fun to hang. And I want to underscore to me how exciting and interesting it is for people listening
To strive to increase their scientific literacy and you have your series of Articles which will put in the show notes. There's a book that I enjoyed tremendously called bad science by Ben, goldacre, I believe is an MD and enjoyed that so much that had a few excerpts from that book, put into the appendix of the appendices of for our body because I wanted to provide some Basics. Are there any other resources or recommendations?
for folks, who
Want to improve their ability to separate fact from fiction. Hype from reality when it comes to headlines, media studies. And so on. I mean, not not to get to Peter, T level. But to get to the point where they just have a better ability to separate signal from noise with this kind of thing.
You know, there's a good newsletter that I subscribe to out of the University of Indiana, it's called the metabolomic sand.
Dexter metabolism and energetics, like a Weekly Newsletter that comes out on Fridays and it's, you know, it's pretty detailed but one of the sections is always headline versus study. And that's that's always a cute one because every week you get to see, they just pick one example. Because, of course, there's a billion examples every week of how the headline says something and it turns out to have nothing in common with this study. Now, that's not exactly the question you've asked, but it is a good illustration of just how if you read something in the media.
Idea you should just assume it's being taken out of context and it's incorrect. And unfortunately, I wish I had better answers
on well, it'd be like if you saw a headline said, eating nubbins increases risk of colorectal cancer by 100%, but if the chance is 1 in 10 billion people on, it goes to 2 and 10 billion people it's rating doesn't mean you should pay attention to,
it's right and it's great to discredit your nubbin. That's a great example of always knowing absolute risk versus relative risk. That's exactly. That's exactly like the kind of stuff we
About in studying studies, is never pay attention to relative risk, without knowing absolute risk, as well, and things like that. So
yeah, Peter I think it might be time for us to prepare for our prandial adventure. That's probably not the way he's to have our meal to have our Taffer
are pre prandial. Exploration are
pre-printed oil, exploration of various various cacti is is it gonna be considered a cacti all I guess. What is Miss Cal actually made from? Is it agave?
I noticed like a keyless fire in your mouth, but that doesn't tell us much about the Botanical Origins. I know. So the toll is different. Have you had such tall as a side note. It's plant, or I should say, it's a bet. Also, it's a beverage, maybe it isn't the plan, but it's only found in a few parts of Texas and Mexico, and it's sort of in between
Tequila and
mezcal. Speaking of Texas, can I tell you the only thing so far about Texas. I'm not fond
of scorpions in your kitchen at. Yeah, I've only found that whisks that was this morning in my household, took care of. It was fine. It's the
cactuses when I'm out in the bush. So when I was out, hoping you doing out in the bush. Well, when I was out doing that precision shooting couple months ago,
they were like training for your counter-sniper
operation. That's right. So we had like, maths down
A ground and we're laying on our mats and we're shooting off in the distance and I vaguely remember someone saying stay on your mat.
Oh God. Yeah.
So at one point I'm like loading my magazine and I kind of rolled off the mouth
and you know
loaded it and was shooting and then like
that day we're driving home. And I'm like, why does my butt
hurts so
much? And why does my
leg hurts so much? And you know, by the time I got home, I realized I was just full of these little micro
Dolls. And I mean, this is how, you know, your wife really loves you because like, I had to give her a set of tweezers to literally start yanking these needles out of my butt and my leg and I actually still have some there. 3 months later. I still, I can still feel some of the ones that broke beneath. And and so I'm going on this hunt in about three weeks and it's my first time hunting access to your here in Texas. And one of the things that the guy who's taking me said is
You got to make sure your shoes like the cactus is 103 or but you're
not going to wear your ninja socks for this one. Yeah. No this will not be a Barefoot. Huh. But aside from the cactuses man. Yeah yeah. All good. In the Republic of Texas I have a shirt maybe I'll get you one of these you might have seen it. It says has a big flag text and flag on it and says most likely to succeed. They sell those at the airport in Austin for those who are interested. Well, Peter off to dinner, we go. Thanks.
Again, is there anything that you would like to mention before we close? Of course, people can find you Peter, Atia? MD will basically take them to everything. I would imagine that's the website that's Twitter, it's Instagram. That's Facebook, also YouTube. So you've been very consistent with how people can reach you. The podcast is the drive, which as mentioned is a weekly Deep dive podcast, focusing on all of the nerdy subjects.
That I find so fascinating the Peter and his guests, know so much about anything you'd like to add to that.
And I would just say that some decaffeinated brands of coffee or just as tasty as the real thing. You know what they're our friends is, what movie is that
from? I don't get the reference but it's that. Is that Real Genius? I think it's really Jank cuz I Real Genius. You know, I'll give you a bit of Austin trivia. We were gone all over the show here, but there is a food truck here in Austin, which I had been told by a former professional.
All tennis player I had to try it had the best chicken wings. And for me, the chicken wings, in general, are kind of like the pistachios of the foul family. They're just so much work and you don't get much out of it. Turns out Tommy want wingy, which is the name of this food truck has incredible chicken wings. They're delicious. I don't know what anabolics they give these chickens but they're enormous you can have a full meal and Tommy want wingy. Whereas you Tommy want wingy? Do you know he's actually at
It gets Cosmic Cafe. They may have multiple locations. Do you know what reference Tommy want? Wingy is from.
Well, it's not the donger need
food. That's Sixteen Candles. Tommy. Boy, Chris Farley, Tommy want. Wingy the diner scene. It's
funny. I've seen that movie a hundred times. How have I missed that? Oh
yeah. Where he's talking about his sales process and he convinces them to the the waitress to fire up the kitchen after they've closed.
He grabs I think it's like a muffin and he's like, let's say that's my Prospect and he walks through this entire thing will link. Will link to this video
in the show notes
so that first for people who want to send to guest, Chris Farley plus Zone to training Plus rapamycin in one place. This is probably the only site on the internet that will have all of those in one set of show notes, and Peter, thanks for taking the time, man. Thanks man.
So does that training fall into the aerobic efficiency category? Exactly efficiency. I don't want to take us off of where we are too much, in the sense that at want to create a breakaway, but could you just briefly explain what efficiency means within the aerobic efficiency and then come back to the zone to training.
Yeah. It comes down to basically substrate usage. So in a robic activity, you can use glucose or fat
Those are basically the two fuels that the body with oxygen can turn into ATP. So, aerobic, most people will recognize means with oxygen and anaerobic means without oxygen. So when you're not demanding, much energy of yourself and energy, of course we talked about is ATP. So ATP is the currency for energy. When your body isn't demanding much energy,
you can make ATP using
glucose or using
A fatty acids and it's a similar process, but obviously different because they're different molecules. So glucose gets turned into something called pyruvate. And that happens in this cell, but outside of the mitochondria, and then the pyruvate gets shuttled into the mitochondria where it undergoes a process known as the electron transport chain, where a whole bunch of chemical reactions occur. That basically generate a gradient of electrons in the inner membrane
Mitochondria, that's ultimately used to produce carbon dioxide and water and a boatload of ATP with fatty acids. It's a little different fatty acids. Get broken down into smaller chunks of fatty acids that have two carbons called acetyl Co a and the acetyl COA is get fed into the mitochondria and undergo the same sort of process. So what's nice about that is you have the ability to use both fuels but when energy demands start to climb. So when
You are asking more of yourself when you're now running or when you're walking up a flight of stairs or doing anything. That now the body saying, hey I need more and more ATP. That glucose system is the first one to Cave. So the glucose system when you turn the glucose into pyruvate it basically says I don't have enough oxygen to run this through the mitochondria to do what I need. I'm going to instead turn pyruvate into lactate which yields some ATP but a pittance compared to what it could do.
So, pyruvate into lactate will generate 1/16 the ATP that it would, if it went into the Krebs cycle, which is horrible, but it's like any port in a storm. It's like, I don't have a choice as a side note, everybody tends to think that lactate is what causes the soreness when you're doing that. It's actually not the lactated energy, it's the hydrogen ion that accompanies the the lactate because lactate is acidic. So you don't actually feel anything from the lactate and lactate itself is actually a pretty remarkable fuel the brain. There's emerging evidence
That the brain actually likes lactate as a fuel and the liver can turn it back into glucose pretty easily. But nevertheless it's inefficient, it's a horrible way to turn your hydrocarbon into ATP and it does come with this problem of being self-limited. So the efficiency speaks to a longer you can use the mitochondria the better and this Zone to characteristic is really one of the most remarkable ways to separate and differentiate people with different degrees of metabolic efficiency. So
Go son, Milan and George Brooks, did a study that I talked about at length and one of the
amas. Do you say Cesar? Millan, I'm Kettle, the dog trainer with the names again in ago,
okay? Son Milan and George Brooks gotta and it goes been a guest on my podcast as well. They did a study looking at three cohorts of people professional cyclists, fit people and people with type 2
diabetes.
Just real quick. How do they Define fit? I don't remember exactly. But it would be like people who exercise a
certain number of hours a week who were pretty fit. These were people that were probably exercising 10 hours a week or something to that effect. So not just
kind of like we can tell hours a week is non-trivial. No, not at all right. And what they looked
at was what were their lactate curves on a bicycle. And at what point did they reach that to millimole level? You know, it's just a staggering.
So all of them would ultimately achieve High, lactates admittedly, very different powers that fit our you are, the more power you generate. Before you hit that Peak lactate, the people with type 2. Diabetes were reaching this critical Threshold at something in the vicinity of eighty to a hundred Watts. So 80 to 100 Watts on a bike. If you don't know what that feels like, it's hard to explain what that would. I wish I had a good conversion for what that feels like. That's not
A lot of effort because for someone who spends any time around slight incline. Yeah flat ground. No wind going 13 or 14 miles an hour. Got it maybe less which amounts to about 1.2 watts per kilo because you always want to normalize these things to body weight. So, 1 Point 2 watts per kilo. One watt per kilo in that vicinity, the reasonably well-trained person was hitting that number at closer to a hundred and fifty to a hundred and seventy Watts. Putting them pretty comfortably in
The 1.7 1.8 watt per kilo range. So, you know, significantly higher than people type 2 diabetes, and the professional cyclists were hitting that Mark in the vicinity of three hundred and twenty three hundred, and sixty watts, and of course they're even lighter. So they're hitting that. Number at
a staggering 4 watts per kilo. What was the total duration of the assessment? It's typically done on like a ramp
test. Where your quickly quickly.
A changing you typically do long ramp. So 15 minutes check lactate 15 minutes, check lactate or 10 minutes would be about the
minimum. Do you think those results would have looked different head? The muscle groups involved, been different? Had it been like a hand bike or something like that? I guess I'm wondering if there's any localized effect just given the training of the
cyclists. Yeah, it's possible. And certainly, there's a, you know, the efficiency that comes from doing the thing that you're being tested on.
Typically lower body exercises or the way to do this, because we have so much muscle mass there. When we have patients do their Zone to, we basically recommend three things, a bike rowing machine or a treadmill are probably the best ways to get that. And it doesn't have to be running. I mean, when I do
to get you in to assess, or to also train
both both. Yeah. Because it does need to be pretty steady state hiking up and down steep climbs tends to not be a great form of training for this. That's another
Type of training. But when you're coming in and out, and in and out of Zone 2, it's not the same as sort of planting yourself. They're staying there, and forcing your mitochondria, to
adapt to it. That was actually going to be my next question. So, what is the adaptation that one hopes for what is actually happening to the body when you do effective Zone to
training? So you're increasing the ability of the mitochondria to utilize the substrate, you're increasing the ability of the
Soul to actually take in more oxygen. So it's really funny when you compare a really fit person to a really unfit person. And so think about something like a VO2 max test. Everybody's breathing, the same amount of oxygen. So, let's imagine for a moment that you are the fittest guy in the world and I am not, we're both sitting in this room. We're both breathing in 21%. Oxygen, if you then put us on a bike and make us go as hard as possible. And measure how much.
It's oxygen is coming out. You'll notice that much less oxygen is coming out of you than me. So the difference is you're able to use more oxygen than I am and that is probably not mediated at the level of your lungs. That's probably more mediated at the level of your muscles. Now there may be some differences in the lung as well. This is not an entirely settled question but there's undoubtedly a bigger Delta at the muscles. So that's a big part of it as simply being able to
Lies more oxygen. The other thing is perhaps increasing the density of mitochondria. So simply having more mitochondria in the muscle will allow for more of that substrate to enter the mitochondria versus outside. And then of course there are Transporters and the Transporters determine a little bit of how the body can sort of utilize lactate. Keep it in this cell versus recycle it and get it out of the cell quicker from a training standpoint. The good news is
All of this stuff is trainable but it does require deliberate form of training and one thing I don't think we know yet. But it's looking like, the minimum effective dose is probably about 3 hours a week, ideally delivered at sort of 45 to 60 Minute intervals. I've asked in ago about this specifically, you know, would just as a thought experiment would doing a whole bunch of 15 minutes sets a week, be sufficient. His view is it would not be that it probably needs to be at least.
Five minutes per session. So you could do say for I do for 45s these days as my zone 2 protocol at times I've done more, there's times I'm doing for 60 Minutes sessions a
week and those should feel if I'm remembering correctly from what you said earlier those should not feel agonizing know. These should be kind of sustained All Day hike type of I know hike isn't exactly perfect but assuming it's a
Say flat ground constant load. This should be something you could sustain for much longer than say 45
minutes. That's right. And not all of our patients want to use a lactate test so I lactate test myself every time I do a Zone to test
so I have someone like you Peter, right? Right. So for
three years, I have every session I've ever done recorded by power, heart rate lactate, all of that stuff because you do see variation, by the way. So a given power, doesn't always keep me at the same Zone to
Well, I slept the night before my state of hydration, what I've eaten will all Impact this,
but how are you tracking? Whether you are in zone 2 or Not
by poking my finger and say yep, I'm using that. Okay? So when people don't want to do that, what do we recommend? What we recommend figuring out what your Zone to heart rate is because you can track heart rate, really easily.
So, rectal probe, most of the time
exactly now, that's for temperature. So,
so heart rate hands on how long it is, right? So hot. Yeah.
Just sitting right here on the vena cava.
So with heart rate
you want to give somebody a starting point. So one option is you tell people to do a little bit of lactate testing, maybe test yourself. Once a month, figure out what your heart rate is. And then going forward, just rely on heart rate for people who never, ever, ever want to poke themselves or just are insulted by how expensive these stupid things are, which they are really stupidly expensive. Like the lactate meters, 250 bucks but the strips are four dollars a piece.
So now which is just so aggravating because you know, these things cost about 12 cents to make. We usually use two ways of estimating. One estimate is a hundred and eighty minus your age, which I think is the low estimate. So a 50 year old, you'd start them at about a hundred and
thirty hundred and thirty what beats per minute beats per minute,
another way to estimate it is if you know your maximum heart rate. So this is usually for people who exercise quite a bit with a heart rate monitor and they know what their true
maximum heart rate is. So let's say a person's out there and they can say they say, you know what, I can achieve a hundred and seventy eight beats per minute. Just before I feel like I'm going to Keel over. That's your max heart rate. I usually start people at about 78 percent of Max heart rate. Now again, the next thing we layer on that is the sort of the litmus test of, how do you feel? Are you able to almost carry out a conversation when you're doing the activity? And the answer should be.
Yes, but I don't really want to that's about The Sweet
Spot. It's a strained conversation but you could do
it. Yeah. Like yesterday, I was doing my zone 2 and my dad called, and I'd missed a bunch of his calls. Normally, I don't answer the phone when I'm on the bike, because I have a fan that is blowing air on me so much and it's so noisy but I answered the phone anyway. So you know, I talked to my dad for five minutes which mostly meant. I let him talk and I was kind of like grunting a little bit. Yeah, uh-huh. Yeah. Okay yeah, but I wouldn't want to do this.
My bike for his own to like this would be a bit more than I'd want to do and if you can't talk at all, which you wouldn't be able to talk. Of course, if you're doing like a zone 5, then you're obviously going to
hard the long-term benefit just to reiterate, the long-term benefit of doing Zone to training for say, a minimum effective, dose of three hours per week is what. And when can someone expect to start to see adaptations that are
beneficial?
Well the ladder is a good question because it probably depends on from where you start with someone who's starting out really metabolically broken, which by definition is what type 2 diabetes is. That's the most extreme example, we have of completely broken metabolism, right? So a complete inability to partition fuel, almost a complete inability to burn fatty acids, which again, gets back to your question about efficiency and efficient engine should be able to run on two fuels. It should be able to run on glucose and I should be able to run on fat. A broken engine can only run on the short-term fuel, which
Glucose. That's a brutal cycle to be in. If you can only run on glucose, you're going to be in a tough situation because we can store such a tiny amount of glucose relative to fat. And you're going to be at the mercy of fluctuating glucose levels constantly. Whereas, if you can rely on fat, you're better off. I've seen people make adaptations to this. I would usually say, it takes three to six months, to start to see some adaptations. I guess over the past two and a half years.
Is my zone. 2 power has gone up by
25% power measured but in blocks. Yeah. And to be honest, it's still below what it was.
Nine years ago or seven years ago when I was training as a cyclist. So even though I didn't think of this type of training as a cyclist, I would do these types of workouts as an important part of my overall training and I was just infinitely fitter back then. So my zone to back then was probably 40 Watts higher than it is. Now although my zone 2 is probably 40 Watts higher now than it was two and a half years ago.
Hey guys, this is Tim again just a few more things before you take off. Number one, this is five bullet Friday. Do you want to get a short email from me and what do you enjoy getting a short email for me? Every Friday is that provides a little more soul of fun for the weekend and 500, Friday's a very short email, where I share the coolest things I've found or that I've been pondering over the week, that could include favorite new albums that have discovered it could include gizmos and gadgets and all sorts of weird shit that
I've somehow dug up in the the world of the esoteric as I do it could include favorite articles that I have read and that I've shared with my close friends for instance and it's very short. It's just a little tiny bite of goodness before you head off for the weekend. So if you want to receive that check it out. Just go to four hour workweek.com. That's 4-Hour. Workweek.com all spelled out and just drop in your email. You will get the very next one and if you sign up,
Hope you enjoyed.
This episode is brought to you by Aura. Oh, you are a, it is the only wearable that I wear on a daily basis, or is the company behind the smart ring, that delivers personalized sleep and health insights, to help you optimize just about everything and I've tried every device out there that you can imagine. This one really makes the cut. I've been using it religiously for at least six months now and I was introduced to it by dr. Peter atilla's also vetted just about everything with Advanced sensors.
Four packs state-of-the-art heart, rate, heart rate, variability HRV, super important to me temperature activity and sleep. Monitoring technology into a convenient, non-invasive rang, its tiny. It weighs less than 6 grams and focuses on three key, insights sleep Readiness and activity. So I can use it to help Focus my attention on the type volume intensity of exercise that I should do in a given day. I use it to determine how certain types of alcohol at different times of the day affect my sleep.
Beep, which they do and I can see all of that in graph form. Trended over time, there are tons of actionable insights that have come from using this ring for me. They have a number of incredible people on their team. Dr. Matthew Walker, the professor of neuroscience and psychology at UC Berkeley and also author of why we sleep. The mega-hit is or as Chief science advisor, as just one example, the aura ring is one of the most accurate wearables available because it measures your vitals directly from your
So it's not deducing that for making a best guesstimate based on a bunch of other things and trying to triangulate compared to a medical grade. Electrocardiogram, the ordering is 99.9% accurate for resting heart rate, and 98.4% accurate for heart rate, variability. And I work with HR be doctors and they recommend that I use the or array. So, try yourself. It is super cool, and super practical very actionable. The aura ring comes in two Styles. And
Three colors, silver, black, and matte black. I use matte black for $299, you can give or get the gift of Health by visiting aura, ring.com that. So you are a are ing.com. Again, that's fora ring.com. This episode is brought to you by eight sleep. My God, am I in love with eight sleep? Good. Sleep is the Ultimate Game Changer more than 30 percent of Americans struggle, sleep. And I'm a member
That sad roof temperature is one of the main causes of poor sleep, and heat has always been my Nemesis. I've suffered for decades tossing and turning throwing blankets off putting the back on and repeating Ad nauseam. But now, I am falling asleep in record time, faster than ever. Why? Because I'm using a simple device called the Pod Pro cover by a silly. It's the easiest and fastest way to sleep at the perfect temperature, it pairs Dynamic cooling and heating with biometric tracking to offer the most advanced.
Last. But most user friendly Solution on the market. I pulled, all of you guys on social media, about best tools for Sleep, enhancing sleep. And eight, sleep was by far and away the crowd favorite and people were just raving fans of this. So I used it in here. We are, add the Pod Pro cover to your current mattress, and start sleeping as cool as 55 degrees Fahrenheit or as hot as a hundred and ten degrees Fahrenheit. It also splits your bed in half so your partner can choose a totally
Different temperature. My girlfriend's runs hot all the time. She doesn't need cooling. She loves the heat. Then we can have our own bespoke temperatures on either side, which is exactly what we're doing now, for me. And for many people, the result 8 sleep users fall asleep up to 32 percent faster, reduce sleep interruptions by up to 40% and get more restful sleep. Overall, I can personally attest to this because I track it in all sorts of ways. It's the total solution for enhanced recovery so you can take on the next day, feeling
Refreshed. And now my dear listeners. That's you guys, you can get 250 dollars off of the Pod Pro cover. That's a lot. Simply go to eight, sleep.com Tim or use code Tim that's a tall. Spelled out. TIG HT, sleep.com Tim or use coupon code. Tim TI m, 8, sleep.com Tim for $200 off your pod, Pro cover.
