Journal Club With Dr. Peter Attia | Metformin for Longevity & the Power of Belief Effects
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Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I'm Andrew huberman and i'm a professor neurobiology and opened ology at stanford school of medicine. Today Marks the first journal club episode between myself and doctor Peter a tea or any of you that are not familiar with doctor Peter attia.

He is a medical doctor and md was an expert in all aspects of health and lifespan. He is the author of a best selling book entitled outlive, which is a phenomenal resource on all things health span and lifespan. And he is the host of the very popular podcast of the drive, where he interviews various experts in all domains of medicine and scientists as well.

Today, Peter, I hold our first online collaboration journal club. For those of you that aren't familiar with what a journal club is, a journal club is a common practice in graduate school and where medical school, whereby students get together to discuss one or two papers, to critique those papers, and to really compare their own conclusions of those papers with the conclusions of the authors and to highlight any key takeaway. Peter, I have been wanting to do a journal club together for a very long time, and we decided to do that journal club and to record IT for you.

So today you will be sitting in on the first huberman. A tea journal club, by the way, could just easily been called the a tea huberman journal club. And we will discuss two papers.

First, Peter is going to discuss a paper on metformin, which is a drug that many people are interested in for its potential role in longevity. I want to highlight potential there. He's going to compare that paper to previous findings on met forming.

And by the end of that discussion, he will advise as to whether or not he himself would take metformin, and whether not other people might be well advised or ill advised to take met forming based on the data in that paper end at this time. Then I present a paper which is about the palacio effect. I have to imagine that most of you have heard of the placable effect, but what's interesting about the paper that we discussed today is that IT shows that the placement effect can actually follow a dose response.

So it's not just all or none. IT actually is the case that you can scale the degree of placement effect depending on whether not you're thinking you're taking low doses, moderate doses or high doses of our particular drug. And the particular drug that discussed in the paper that I covered is nickey. So for those of you that are interested in cognitive enhancement by way of pharma logy, or Frankly, for people who are simply interested in how our beliefs can shape our physiology, I think you'll find that discussion to be very interesting.

So by the end of today's episode, you will not only have learned about two novel sets of findings, one in the room of longevity as IT relates to met formin, and another in the realm of nearby ology and placebos, or placable o effects, but you will also learn how a journal club is conducted. Think you'll see and observing how we pass these papers and discuss them, even arguing in them at times, that what scientists and clinicians do is they take a look at the existing p reviewed research, and they look at that peer reviewed research with a fresh eye, asking, does this paper really show what IT claims to show or not? And in some cases, the answer yes, and in other cases, the answer is no.

What I know is for certain is that by the end of today's episode, you will learn a lot of science. You will learn a lot about health practices, some of which you may want to apply or avoid, and you learn a lot about how science and medicine is Carried out. Before we begin, i'd like emphasize that this podcast, separate from my teaching and researchers at stanford IT, is, however, part of my desired effort to bring zero cost to consumer information about science in science related tools to the general public.

In keeping with that theme, like to thank sponsors of today's podcast. Our first sponsor is element. Element is an electronic drink with everything you need and nothing you don't. That means plenty of salt, magnesium in patashie, so called electronic and no sugar.

Now salt magnesium um and patasse are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electrical lights need to be present in the proper ratio. And we now know that even slight reductions in electronic light concentrations or dehydration of the body lead to deficits.

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Again, that drink element element dot com slash huberman. Today's episode is also brought to us by waking up, waking up as a meditation APP that includes hundreds of meditation programs, trainings, yoga eja, recessions and n sdr non sleep depressed protocols. I started using the waking up up a few years ago because even though i've been doing regular meditation since my teens, and I start doing yoga edra about a decade ago, my dad mentioned to me that he had found an APP turned out to be the waking up APP, which could teach you meditations of different durations.

And that had a lot of different types of meditations to place the bringing body into different states, and that he liked IT very much. So I gave the waking up up a try, and I too found IT to be extremely useful, because sometimes I only have few minutes to meditate, other times have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain body into lots of different kinds of states, depending on which meditation I do.

I also love that the waking up up has lots of different types of yoga media sessions. Those who you don't know, yogananda is a process of lying very still, but keeping an active mind. It's a very different and most meditations, and there is excEllent scientific data to show that yogananda and something similar to IT called non sleep deep breath or nsd r, can greatly restore levels of cognitive and physical energy even, which is to a short ten minute session.

If you'd like to try the waking up, you can go to waking up dot com slash huberman and access a free thirty day trial again, that's waking up dot com slash huberman to access a free thirty day trial. And now for my journal club discussion with doctor Peter at tea. Peter, so good to have you here.

So good to be here, my friend.

This is something that you and I have been wanting to do for a while, and it's basic, something that we do all the time, which is to produce the literature and fine papers that we are excited about for whatever reason. And often times that will lead to a text dialogue or a phone call or both.

But this time, we've opted to try talking about these papers that we find particularly exciting in real time for the first time as this podcast format, first of all, so that people can get some sense of why we're so excited about these papers. We do feel that people should know about these findings. And second of all, that is an opportunity for people to learn how to dissect information and think about the papers they hear about in the news, the papers they might download from pub met if they're inclined.

Also, just start thinking like scientists and clinicians and get a Better sense of what that looks like to pick through a paper, the good, the bad and the ugly. So we're flying a little blind here, which is fun. I'm definite excited for all the above reasons.

Yeah, now this is a uh, you and i've been talking about this for some time and um you know actually we used to run a journal club inside the practice where once a month one person would um just pick a paper and you would go through them kind of a formal journal club presentation. We gotten away from the last year just because we've been a little stretch, then I think it's something we need to resume because it's uh, it's a great way to learn and it's a skill.

You know, people probably ask you all the time because I know I got to ask all the time, hey, what are the do and dance of interpreting scientific papers? Is that enough to just read the abstract and you know use the answer as well? No um but the how to is is tougher and I think the two papers we've chosen today illustrate two opposite ends of the spectrum.

You you're going to obvious ly talk about something that we're going to probably get into the technical nature of the essays, the limitations at sea and the paper ultimately i've chosen to present. Although I apologized, i'm surprising you with this up until you a few minutes ago, is is actually a very straight forward, simple, epidemiologic paper that I think has important significance. I had originally gone down the rabbit hole on a much more nuance paper about at binding cassette in cluster's absorbtion.

But ultimately, I thought this one might be more interesting to a broader audience. But though I ve got to tell you a funny story, so I had a dream last night about you. And in this dream you were obsessed with making this certain drink that was like your alexa and IT had all of these crazy ingredient in IT supply, tons of supplements in IT.

But one thing I remembered when I woke up, because I forgot most of them, I was really trying so hard to remember them. One thing that you had in IT was due, like you had to collect a certain amount of deal of the leaves every morning to put into this drink. IT was like.

just sounds like something that I would do.

And and so, but here's the best part you had. You had like a thermos of this stuff that had to be with you everywhere, and all of your clothing had to be tailored with a special pocket that you could put the thermos into so that you were never without the special Andrew drink. And again, you know how dreams when you're having them seem so logical and real and then you wake up and you're like, that doesn't even makes sense.

Like, why would he want the farmers in his shirt? Like, I would warm IT up like you all these. But boy, IT was a realistic dream. And there were lots of things in IT, including do special do of the leaves every morning. I love IT.

Well, it's not that far from reality. I'm a big um fan of uba muti. I'm drinking IT right now and in its many forms usually the loose leaf I don't tend to drink IT out the guard my dad's argentine.

So that's where I picked IT up. I start drinking IT when I like five years old, older, Younger, which I don't recommend people do, is heavily cabinet. I don't drink the smoked versions either, folks. I think potentially cars in the genre.

But this mean you describe of caring alma thermic close to the body if you are ever in org, or if you ever spot grown men in a restaurant anywhere in the world Carrying a thermos with them and to their meals and hugging IT close, chances are they were gone and they're drinking your ba mote. They drink IT, usually after their meals supposed to be good die. So it's not that far from from reality. I don't Carry the thermos, but I do drink mute every day. And i'm going to start collecting, do off the leaves just .

a few drops every morning. Oh my, some other time .

we can talk about dreams. Recently i've been doing some dream exploration. I've had some absolutely transformative dreams for the first time in my life. One dreams in particular, that has that allowed me to feel something i've never felt before and has catalist ed a large number of important decisions in a way, no other experience waking or sleep has ever impacted me and this was drug free ETC ta um and do you think you could have had that dream?

We don't have to get in to IT if you don't talk about now, but was there a lot of work you had to do to prepare for that dream to have taken place?

Oh yes yeah um at least eighteen months of intensive um analysis type work um with a very skilled psychiatrist but I wasn't trying to see the the dream yeah and I was just I was at a sticking point with a certain process in my life and then I was taking a walk while waking and realized that my brain, my subconscious was going to keep working on this. I just decided it's gonna ep working on IT.

And then two nights later I travel to a meeting in usband. And I had the most profound dream ever, h, where I was able to send something and feel something i've always wanted to feel as so real within the dream, woke up, knew IT was a dream, and realize this is what people close to me that I respect have been talking about. But I was able to feel IT.

And therefore, 嗯， i can actually access this in my waking life that I was, I was, I was absolutely transformative for me. Um anyway, sometimes I can share more details with you or the audience, but for now, we should talk about these papers very well. Um who should go first?

I am happy to go first. This one, this this is a pretty story paper. So so we're going to talk about a paper titled we assessing the evidence of a survival advantage in type two diabetics treated with metformin compared with controls without diabetes.

A retrospective cohorts study this is by Matthew Thomas keys and colleagues. This was published a last fall. Why is this paper important? So this paper is important because in two thousand fourteen um ban ister published a paper that I think in many ways kind of got the world very excited about.

Metformin is almost ten years ago and i'm sure many people have heard about this paper even if they're not familiar with thit but theyve heard the concept of the paper in many ways. It's the paper that has LED to the excitement around the potential for gero protection with met form. And I should probably just define for the audience what gero protection means when we think .

probably also started to show up what metformin is just for the uninformed.

That's a great point. So i'll start with the the latter. So matt, former is a drug that has been used for many years.

Depends you know where I was first approved I think was in europe um but you know call IT directionally fifty plus years of use as a first line agent for patients with type two diabetes uh in the U S. May be forty plus years. So this is a drug that s been around forever trade name, a group of hage um or brand name.

And but as you know, to generate drug today, the mechanism by which mmt forman works is debated hotly. But what I think is not debated is the immediate thing that metformin does, which is IT inhibits complex, one of the medical ria. So again, maybe just taking a step back so that might can ria.

Everybody thinks of those as the cellular engine for making A T, P are the most efficient way that we make. A T P is through ox dated for for relation, where we take either acid pieces or a breakdown product of glucose once it's partially metabolize to piu vate. We put that into an electron transport chain. And we basically trade chemical energy for electrons that can then be used to make fast fates onto A D. P.

So now you think of everything you do eating is taking the chemical energy and food, taking the energy that in those bonds, making electrical energy in the might andria those electron's pump, a gradient that allow you to make ATP to give a sense of how primo l an important, this is, if you block that process completely, you die. So everybody is probably ard of soni, right? Soni is something that is incredibly toxic, even at the smallest doses.

Sanei is a complete blocker of this process. And if my memory search me correctly, I think IT blocks complex four of the matter country. I don't know you recall if a complex three year, complex four.

I know a lot about toxins that impact the nervous system, but I don't know a lot about Price. But if ever you want to have some fun, we can talk about all the dangerous stuff that animals make and insects make and how they kill you.

Yeah, like I I really gig .

out on stuff because allows me to talk about neuroscience. Animals and scary stuff is like combinations. So we could do that sometime for fun, maybe at the end, if we have a few moments.

So, so, you know, something like soni, that is a very poor inhibitor of this electron transport chain, will kill you instantly. People understand that, of course, I drop a sign, I, and would be dead literally instantaneously so metformin works at the first of those complex as I believe there are four of my memory source correctly four electron transport chain complexes and um but of course is not a complete inhibition of IT.

It's just kind of a weak blocker of that and the net effect of that is what so the net effect of that is that IT changes the ratio of dense monopoly ate to deny um what's less clear is why does that have a benefit in diabetics? Because what is unambiguously does is reduces the amount of glue coast that the liver puts out. So hpc glue cos output is one of the fundamental problems that's happening in type two diabetes.

You may recall, I think we talk about this increase podcast. You and I sitting here with Normal blood sugar, have about five grams of glue cos in our total circulation. That's IT five grams.

Think about how quickly the brain will go through that within minutes. So the only thing that keeps us alive is our livers ability to tie trait de out glucose. And if IT puts out too much, for example, if the glucose, if the glucose level was consistently two tea spoons, you would have type two diabetes. So the difference between being metabolite healthy and having, you know, profound type two diabetes is one teaspoon of glue cose in your bloodstream. So the ability of the liver to tamp down on high glucose output is important.

Metformin seems to do that. So can I just uh one question is IT fared um to provide this oversimplified summary of the biochemistry which is that when we eat, the food is broken down but the breaking of bonds creates energy that then ourselves can use in the form of atp and the matter country are central of that process and that metformin is partially short, circling the energy production process.

And so even though we are eating when we have met form in our system, presumably there is going to be less net glue, cose the bonds are going to be broken down. We're chewing, we're digesting, but less of that is turned into blood sugar. Blue coast.

Well, sort of I mean, it's not um it's not depriving you of ultimately storing that energy. What it's doing is changing the way the body um partisans fuel. That's probably a Better way to think about IT to be a little bit more accurate. So um for example, like it's not depriving you of the calories that are in that glue, cose that would be fantastic.

But that was was the alestra remembers alestra from the nineties alestra folks for those who they don't remember um by the way, if you ever ate this stuff, you'd remember because IT was the fat that was not easily digested IT had a in server analyst step plant fiber or something like that so he was being put into potato chips and what not and the idea is that people would would simply exclude IT um and I don't know what happened except .

that people got lost .

stomach aches. Only a physician because after all, Peter is a clinic for physician and empty and i'm not could find IT a um an appropriate term to describe.

Yeah when you have that much when you have that much fat mal absorption, you start to have accidents.

Well.

so that did the way, way with that product, right?

That of the dire industry was going to really take off. okay. That's why you don't hear about less dry.

So so we've got this drug, we got this drug metformin. It's considered a perfect first line agent for people, a type to diabetes. So again, what's happening when you a type to, uh, the primary insult probably occurs in the muscles.

And IT is insulin resistance. Everybody hear that term. What does that mean? Uh, insulin is a peptide IT bind to a receptor on a cell.

So let's just talk about IT through the lens of the muscle. Because the muscle is responsible for most glucose disposal, IT gets glucose out of the circulation. High glue cose is toxic.

We have to put IT away, and we want to put most of IT into our muscles. That's where we store seventy five to eighty percent of IT. When insulin binds to the insulin recept, uh, tyring kinds is triggered inside.

So just ignore that. But a chemical reaction takes place inside the cell that leads to a forest for relation. So h atp donates a group and a transporter.

Just think like a little tunnel, like a little straw, goes up through the level of the cell. And now glue cose can freely flow in. And sure, you've talked a lot about those with the audience.

We things that move against gradients need pumps to move them. Things that move with gradients don't. Glucose is moving with its gradient into the cell. IT doesn't need active transport, but IT does need the transport put there that requires the energy.

That's the job of insurance. By the way, I did not know that. I mean, I certainly know active and passive transport as a relates to like neurotransmitter or and iron flow. But I never heard that when instant bines to a cell, that literally all straws placed into the memory of the .

cause doesn't need a pump p to move IT in because there's much more glucose outside the cell than insect. So IT just, but the energy required is to move the .

to draw up to the cell.

So is so cool. So so what happens is, as a general shown minute, yale did the best work on illustrating this as the intra muscular fat increases. And I by intra muscular, I mean intraocular fat, uh, try asal and diaster glisters ize accumulate in a muscle cell, that signal gets interrupted, and all of a sudden are making these numbers up.

If you used to need two units of to trigger the little transporter, now you need three, and then you need four, and then you need five. You need more and more insulin to get the thing up. That is, the definition of insuing resistance.

The cell is becoming resistance to the effect of insurance, and therefore the early mark of instant resistance. The canary in the coal mine is not an increase in glucose. It's an increase in insulin.

So Normal glycemic with hyper insulin ia, especially post cranial, meaning after you eat hyper insulin ia is the thing that tells you, hey, your five, ten years away from this being a real problem. So fast forward, many steps down the line. Someone would type two diabetes has long passed that system.

Now, not only are the insulin resistant, where they just need a boatload of insurance, which is made by the pankau to get glue cose out of the circulation, but now that systems not even working well, now they are not getting glucose into the cell. So now the glucose level is elevated. And even though it's continually being chewed up and used up because, again, the brain alone would account for most of that glucose disposal, the liver is now becoming insulin resistance as well.

And now the liver isn't able to regulate how much glue coast to put into circulation and it's overdoing IT. So now you have too much glucose being pumped into the circulation by the liver, and you have the muscles that can't dispose of IT. And it's really a vicious, brutal cade because the same problem of fat accumulating in the muscle is now starting to happen in the pancras.

And now the relatively few cells in the pancras, called beta cells that make insulin are undergoing inflation tion due to the fat accumulation within the panky is itself. And so now the thing that you need to make more insulin is less effective at making insulin. So ultimately, way, way wait down the line, a person would type two diabetes might actually even require insula exogenous sly.

Could you share with us a few of the causes of type two diabetes? Insulin resistance mean that one that sounds like is accumulating too much fat.

yes. So energy imbaLance would be an enormous one. Inactivity or insufficient activity is probably the single most important. So when gerry german um was running clinical trials at yale, um they would be recruiting undergrads to study, obviously because you're typically recruiting Young people and they would not be doing these very detailed mechanistic studies where they would require actual tissue biopsy.

So you know you're going to buy open y somebody's quite recept and actually look at what's happening in the muscle. Well, I remember him telling this when I interviewed on my podcast. He said the most important criteria of the people we interviewed, because they were still lean, these weren't people that were overweight, but they had to be inactive.

You couldn't have active people in this study. So exercising is one of the most important things you're going to do to ward off insulin resistance. But there are other things that can cause instant resistance. Sleep deprivation has a profound impact on instant resistance. I think we're probably talked about this previously.

But if you you know some very elegant mechanistic studies where you sleep deprived people, you know you like them only sleep for four hours for a week, you'll reduce their glucose disposal by about half, which is I mean, it's a staggering amount. You're basically inducing profound insein resistance in just a week of sleep deprivation. Hyper cortisol ia another factor, and then obviously energy imbaLance. So where when you're when you're accumulating excess energy, when you're getting fatter, if you start spilling that fat outside of the subcutaneous fat cells into the muscle, into the liver, into the pancras, all those things are .

exacerbated IT.

Okay, so internet form in first line drug. So most of the drug, so every drug you give a personal type two diabetes is trying to address part of this chain. So some of the drugs tell you to make more insulin.

That's that's one of the strategy. So here are drugs like cl honey areas, they tell the body, make more insulin. Other drugs like insulin just give you more of the insulin thing.

Metford tackles the problem elsewhere. IT camps down glue cos by addressing the glucose to the h head glucose output channel. Glp one agonies or another drug, they increase insulin sensitivity initially, causing you to also make more insulin.

That's OEM. Ic.

yes. Yeah, yeah.

And is IT true that burberry is more or less the poor man's met form? And yeah, it's IT from a tree market. IT just happens to have the same properties reducing m tour and reducing the blood lue cose yeah and met forming.

by the way, occurs from a light like plant in france like that's where IT was discovered. So it's forming is also based on a substance founded nature.

So you you need a prescription for metformin. You don't need a prescription for burberry, correct? But we can talk about burbery norbit. Later, I had a couple great experiences with a couple bad experiences. interesting.

Burberry, yeah. So um maybe taking one step back from this. In two thousand eleven, I became very interested in metformin, personally just reading about IT, obsessing over IT, and just somehow decided, like I should be taking this. So I actually began taking metformin. I still remember exactly when I started.

I started in may of two thousand eleven, and I realized that because I was on a trip with a bunch of buddies, we went to the bert chair half way, a shareholder meeting, which is, you know, the buffet, uh, shareholder meeting. And it's kind of like a fun thing to do. And I remember being so sick the whole time because I didn't titre up the dose of metformin. I just went straights to two grams a day, which was kind of like the full dose. And we went to exec terisa .

of your approach to things.

Yes, I think that's safe to say.

Next time i'll give you a thermos of this, do that I collect in the morning. yes.

So I remember being so sick that the whole time we were in nebraska mahadua, I couldn't. We went to dairy queen because you do all the buffett things when you're there, right? Like, I couldn't have an ice cream at dairy queen and I could not so nauseous.

I would say if you've got met forming in your system, you're going so clearly metformin .

effect initially, which is a little bit of appetite suppression but regardless, that's the story on metformin there there a lot of reasons I was interested in IT um I wasn't thinking true gero protection that term wasn't in my vintage lar at the time. But what I was thinking is, hey, this is going to help you buffer, glue us Better. It's got to be Better.

And this was sort .

of my first four into .

you self experiment. Do you want .

to define protections gero from geriatric old protection? So protection from major. And when we talk about a drug like metford or rap maison or even ad, and are the things, the idea is we're talking about them as gero protective to signal that they are drugs that are not targeting a specific disease of aging.

For example, A P C S K nine inhibitor is sort of gero protective, but it's targeting one specific pathway, which is cardiovascular disease, and disliked dema. Whether the idea is a gero protective agent would target hallMarks of aging. There are nine hallMarks of aging. Pleased to ask me to recite them. I've never been able to get all nine straight, but people know what we're talking about, right? So decreased auto fogy, increased seneschals, decreased nutrient sensing or defective neutral sensing, uh, predial, ic instability, genomic instability, methods, tion, all of these things up genre changes.

Those are all about nine monarch .

of eight so a gero protective agent would target those deep down biologic pommard of aging. And in two thousand and fourteen um a paper came up by vanishing that basically got the world focused on this problem in the world of of anti agent. So what what ministry and colleagues did was they took a registry from the U.

K. And they got a set of patients who were on mat forming with tito diabetes, but only met format. So these were people who had just progressed to diabetes.

They were not put on any other drug, just meant forming. And then they found from the same registry a group of matched control. So this is a standard way that epidemiologic studies are done because, again, you don't have the luxury of doing the round ization.

So you're trying to account for all the biases that could exist by saying we're gonna take people who a look just like that person of diabetes. So can we match them for age sex? So see we conomo ic status um blood pressure BMI everything we can.

And then let's look at what happened to them over time. Now again, this is all happening in the future. So you're looking into the past.

It's retrospective in that sense. And so let me just kind of pull up the sort of table here so I can kind of walk through. And this is not in the paper we talked about, but I think this an important background.

So they did something that at the time, I didn't really notice. I didn't notice what they did. I probably did and I forgot. But I didn't notice this until about five years ago when I went back and looked at the paper and they did something called um uh informative censoring. So the way the study worked is if you were put on metformin, we're going to follow you.

If you're not on mt form, that we're going to follow you and we're going to attract the number of deaths from any cause that occur. This is called all cause mortality, or ACM, and is really the gold standard in a trial of this nature or a study of this nature or even a clinical trial. You want to know how much are people dying from anything because we're trying to prevent or delay death of all causes.

Informative censoring says if a person whose on metformin deviates from that inclusion criteria, we will not count them in the final assessment. So how are the ways that that can happen while one the person can be lost to follow up too, they can just stop taking their metformin three. And more commonly, they can progress to needing a more significant drug.

So all of those patients were excluded from the study. So think about that for a moment. This is, in my opinion, a significant limitation of this study because what you're basically doing is saying we're only gonna consider the patients who were on met format, stayed on met format and never progressed through IT, and we're going to compare those to people who were not having tied to diabetes.

So an analogy here would be, imagine we're going to do a study of two groups that we think are almost identical. One of them are smokers and the other are identical in every way, but they're not smokers. And we're onna follow them to see which ones get lung cancer.

But every time somebody dies in the smoking group, we stop counting them. When you get to the end, you're going to have a less significant view of the health status of that group. So with that caveat, the banisters study found a very interesting result, which was the crude death rate um was and by the way, the way these are done, this is also one of the chAllenges of epidemiology is the math gets much more complicated.

You have to Normalize death rate for the amount of time you study the people. So everything is Normalized two thousand person years. So the crude deaf rate in the group of people with type two diabetes who were on met formin, including the censoring, was fourteen point force.

A fourteen point four deaths occurred per thousand patient years. If you look at the control group, IT was fifteen point to. This was a startling result and I remember reading this in again, two thousand and fourteen and being like, holy crap, this is really amazing.

Is there um could you explain why? Because I I hear those numbers and they don't seem that striking the difference of about a year and a half now of course um a difference of about a year and half and lifespan is is well is remarkable IT doesn't .

even translate to that. So taking a step back die too. Diabetes on average will shorten in your life by six years. I see. So that's the actual difference between having title diabetes and not all commerce. But you're write this is not a huge difference, is only a difference of a little less than one year of life, three thousand patient years studied.

But but but I but the point here is you .

would expect the people in the metformin group to have a far worse outcome, I E, to have a far worse crude death rate. And the fact that IT was statistically significant in the other direction, and IT turned out on the what's called the cox proportional hazard, which is where you actually model the difference in lifespan. The people who took metformin and had diabetes had a fifteen percent one five fifteen percent relative reduction in all cause death over two point eight years, which was the media duration of follow up.

That thing to be the number that makes me go wow yeah right that um because you could you repeat those numbers again .

yeah so fifteen percent reduction in all cause mortality over two point eight years.

not a big deal .

IT is and again, there's no clear explanation for IT unless you'd believe that meet former is doing something beyond helping you lower blood glue cose, because the difference in blood glucose between these two people were still in favor of the non diabetics. So again, the proponents of met form in being a gero protective agent. And I put myself in this category at one point.

I would put myself today in the category of undecided, but at the time, I very much believed this was a very good suggestion that matt forman was doing other things. You mention the couple already. Metformin is a weak k inhibit of m tour. Metformin reduces metformin potentially camped down on sentence cells and their secretary products. You know there are lots of things meant form could be doing that are off target and IT might be that those things are confirming the advantage.

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So fast forward until a year ago. And I think most people took the manisty's study as kind of the best evidence we have for the benefits of metformin. And i'm sure you've had lots of people come up to you and ask you, should I be on mt. Form and should I be at form? I mean, I probably get asked that question almost as much as I asked any question outside of do I mean, people definitely want to know if you should be consuming you but but after that.

it's meet form. Rush off the leaves has to be while viewing morning sunlight.

So okay, so let's so let's kind of fast forward to now the paper that I wanted to spend a few more minutes.

and thanks for that background. I still dazed by the insertion of the draw by way of of insulin. I I don't think I ever heard that described. I need to I need to go get a Better .

textbook. It's a pretty short straw.

is a little a to give people centre. Why am so dazed? I am always fascinated by how quickly, how efficiently and how specifically biology can create these little protein complexes that do something really important. And you're talking about an on demand creation of of a portal, right? And these are cells engineering their own machinery and real time in response to chemical signals.

And it's great. Yeah but i'm i'm sort of arrest on my neuroscience but an action potential works in reverse the same way like you need the p gradient to restore the. A to restore the gradient but once the action potential fires, it's passive outside right?

Yeah so what peers referred to is um the way that neurons become electorally activists by the flow of irons across the that from the outside to sell the inside the cell and we have both active conductance ces me they're trigger by electrical changes in the gradients, a changes in electrical potential um and then there are passed gradient where things can just flow back and forth until there's a baLance equal inside and outside to sell.

I think it's um what's different is that there's a movement of a lot of stuff inside of neurons when neurotransmitters like dope of new baLance. So it's reception and then a bunch of it's like a bucket or gay that gets kick off internally. But it's not often that you hear about receptors getting inserted in this very quickly.

Normally to go through a process, you a transcribing genes and making sure that the specific proteins are made and then IT. Those are long, slow things to take place over over the course of many hours or days. What you're talking about is a real on demand insertion of a channel, and that makes sense as to why that would be required. But is just so very cool, cool.

So keys and colleagues came along and said we would like to redo the entire band istar analysis. Um and I think their motivation for IT was the interest in this topic is through the roof. There is a clinical trial called the time trial that is, I think pretty much funded now and maybe getting under way soon. The time trial, which is an important trial, is going to try to ask this question prospectively and through random assignment.

So so this is the targeting aging .

with at four uh is probably the senior P I on that um and I think in many ways the banisters study along with some other studies um but of lesser significance, probably provided some of the motivation for the tame trial. So they said, okay, look, we're gona do this. We're going to use a different code of people.

Um so the first study that we just talked about, the banisters r study used uh I believe IT was like roughly they sampled like ninety five thousand subjects from the U. K. biobank.

Here they use the larger sample. They did about half a million people sampled from a uh a danish health registry. And they did something pretty elegant. They created two groups to study.

So the first was just a standard replication of what bannister did, which was just a group of people within, without diabetic that they tried to match as perfectly as possible. But then they did a second analysis in parallel with discordant twins. So same sex twins that only differed in that one had diabetes and one didn't.

I thought this was very elegant because here you have a degree of genetic similarity and you have similar environmental uh uh factors during childhood that might give you you allow you to see if there's any sort of difference in signal. So now turning this back into a little bit. A journal club.

Virtually any clinical paper you're gonna read, table one is the characteristic tics of the people in the study always want to take a look at that. So when I look at table one here, you can see it's, and by the way, just for people watching, this were going to make all these papers and figures available. So if you're don't, will have nice shown notes that'll make all this clear.

So table one in the key's paper shows the baseline characteristics. And again, it's almost always going to be the first table in the paper. Usually the first figure in the paper is a study design.

It's usually a flow chart that says these with the inclusion criteria. These are the people that got excluded. This is how we randomised IT at a and you can see here that there are four columns.

So the the first two are the single tins. These are people who are not related. And then the second two are the twins who are matched.

And you can see, remember how I said they sampled about five hundred thousand people. You can see the numbers. So they got, you know seven thousand eight hundred forty two single tns on met form in the same number.

Then they pulled out, matched without diabetes on the twins. They get nine hundred and seventy six on mat forming with diabetes. And then by definition, nine hundred and seventy six code wins without them.

And you look at all these characteristics, what was their age upon entry? How many were men? What was the year of indexing when we got them? What medications were they on? What was the highest level of education marital status at setter up? But one thing I want to call out here that really cannot be matched in a study like this.

So this is a very important limitation, is the medication. So look at, look at that cAllander. Notice how pretty much everything else is perfectly matched until you get to the medication list.

Ah it's all over the place.

Yeah, it's just it's not even close there there. No, we're near matched. right? Another words just to give you a couple of examples right on the and let's just talk about the single terms because it's basically the same story on the twins.

If you look at what fraction of the people would type two diabetes are on lipid lowering medication, it's forty five point six percent versus fifteen point four percent in the matched without diabetes. It's a three x difference. What about anti platelets therapy? Is thirty percent verses fourteen percent? Anti hypertensive sixty five percent or sixty three percent for thirty one percent.

because people have one health issue and are taking that form and are likely to .

have other health ish. exactly. So this is, again a fundamental flaw of epidemiology. You can never remove all the confounders.

This is why I became an experimental scientist. Yes, that we could control variable ables.

That's right. Because without random assignment, you cannot control every variable. Now you'll see in a moment when we get into the analysis, they go through three levels of corrections, but they can never correct this medication.

One to just keep done about your mind. okay. So the two big things that we're done in this experiment or in this survey or study to differentiate IT from banister was won the twin trick, which I think is pretty cool.

The second thing that they did was they did a sensitivity analysis with and without informative censoring. So one of the things they want to to know is, hey, does that really matter if we don't count the meat form and patients who progress? So um so let's see kind of what what tranced ribs so the next figure figure to about me, the next table, table two walks you through the crude uh mortality rate in each of the groups.

So the most important row, I think in this table is the one that has crude mortality per thousand person years. Now you recall that in the previous study, in the banisters study, those were on the ballpark about fifteen per. okay.

So let's look at each of these. So in the um single the single time with without. So the non twins who were not diabetic IT was sixteen point eight six.

And could you put a little more contact on what this thousand person years what IT is are talking about pulling the lifespans of of a bunch of different people until you get to the number one thousand? Yeah because you're Normalizing not so it's not who's gona live with thousand years because um you essentially taking so you've got some people that are going to live seventy six years, fifty two years, ninety one years and you're pulling all of those until you hit a thousand and then that becomes kind of A A it's like a Normalized division. You're basically like so let's say the the control group um you're asking if there were a thousand person years available to live, how likely is that that this person would .

live another yeah. So a couple of ways to think about. So taking a step back, we always have to have some way of Normalizing. So when we talk about the mortality from a disease like cancer in the population, we would we report IT as what's the mortality rate per and it's typically four hundred thousand persons.

okay. That's a much more intuitive way to express .

IT IT is but the reason we can do IT that way is because we're literally looking at how many people died this calendar year and we divided by the number of people in that age group. So it's typically what you're doing when you look at aged groups in buckets of like decades. So that's why we can say the highest mortality is like people ninety and up.

Even though the absolute number of deaths is small. It's because there's not that many people there, right? The majority of deaths in absolute terms probably occur in the seventh decade.

But as you go up because the dome intor is shrinking, you have to Normalize to its, we just Normalize to the number of people. Here are all the people that started the year. Here are all the people that ended the year.

What's the death? Y why are these done in a slightly more complicated way? Because we we don't follow these people for their whole lives, are only following them for a period of observation, in this case, roughly three years.

So to say something like, you know, we have a crude death rate of five deaths per thousand person years. One way to think about that is if you had a thousand people and you followed them for one year, you'd expect five to die. If you had five hundred people and you follow them for two years, you expect five to die. If you have a thousand people and you follow them for one year, you expect five to die. Those would all be considered equivalent mortalities.

great.

Thank you for clarifying that. No, no, this stuff is, I mean, like I find, I find epidemiology when you get in the weeds is way more complicated than following the basics of experimental stuff where you just you get to push all this stuff into the garbage bin and just say, we're to take this number of people, we're going to exclude this group. We're going to rana ize.

we're going to see what happens. Yeah, that's what like the paper will talk about next. yes.

So when you adjust for age, and I don't show IT in this table, it's only in the text when you adjust for age, a very important check to do is what is the crude death rate of the people on met formin who are not twins versus who are twins.

Now in this table they look different because it's twenty four point nine three for the meat forming group and twenty one point six eight for the twin group in that on metformin, when you adjust for age, they're almost identical. IT goes through twenty nine, twenty four point nine three to twenty four point seven. One other point i'll make you for people who are going be looking at this table is um you'll notice there are parenthesis after every one of these numbers.

What is that what is that offer in there? those. Emphasis is are offering the ninety five percent confidence interval. So for example, to take the number you know twenty four point nine, three is the crude death rate of how many people are dying who take metformin.

What is telling you is we're ninety five percent confident that the actual number is between twenty three point two three and twenty six point six four. If a ninety five percent confidence does not cross the number zero, it's statistically. significant. okay.

So the first thing that just jumps out at you, I think when you look at this, is there is clearly a difference here between the people who have diabetes in those who don't IT complicates the study a little bit because it's basically two studies in one but you're comparing um ninety five part me uh twenty four point nine three to sixteen point eight six at which by the way, remains after age adjustment. When you go to the twin group, it's twenty four point seven three to twelve point nine four. So just .

assume after that, what you're describing to understand correctly is this crude deaths per one thousand person years. Let's just talk about the single thing that is sixteen point eight six. So sixteen point eight six people die.

Some people prithi. How can point eight six of a person die? Well, is not always whole numbers, but there's there's a bad joke to be made here. But I just call .

IT seventeen hundred twenty five.

right? Seventeen deaths per thousand verses twenty five depth. You and the twenty five is in the folks that took mp forming. Now that to the naive listener to me means, oh, you know that form and basically kills you, right, not faster or you know you're more likely to die.

But we have to remember that these people have another they have a major health issue that the other group does not have. But because people weren't assigned drug or not a sign drug IT wasn't plasma drug IT. Lets look at people taking this drug for a bad health issue and compare to everyone else.

That's right. So now you have to go into and i'll just start to skip the next figure, but the next figure is a caplin mor curve. I I think it's actually worth looking at IT because show up in all sorts of studies.

So if you look at figure one, it's a caplin mie curve, which is a mortality curve. So you'll see these in any study that is looking at death, and this can be prospective randomised, this can be retrospective, but these are always going to show up. And I think it's really worth understanding when a cap on my curve shows you.

So when the x access is always time and on the y access is always the cumulative survival. So it's a curve that always goes from zero to one, one or one hundred percent and it's always decreasing monotonic ally, meaning IT can only go down or stay flat. IT can never go back up. So that's what accumulative uh, mortality curve looks like.

Now we're looking at you're starting at alive and you're looking how many people die for every year that passes. That's right.

And in each curve, there's one on the left, which is the matched single hence, and there's one on the right which are the discordant twins. You have two lines. You have those that were on mat forming with type two diabetes, and you have their matched controls in this figure. The matched controls are the darker lines and the people with type diabetes on matt form, that's the lighter line. You've also notice, and I like the way they've done IT here, they've got shading around each one.

And we should mention for those they are just listening that in both of these graphs the um downward trending line from the controls. So again, non diabetic not taking metformin is above the line corresponding to the diabetics who are taking metformin. Put crude the people who are taking platform and that have are dying at a faster rate for every single year.

Examine the two lines, do not overlap. Gh accept. At the beginning when everyone's alive, it's like a foot race. We're based the people with met forming and diabetes are falling behind and dying as they fall.

That's right, and i'm glad you brought up a good point. It's not uncommon in treatments uh, to see captain mr. Curves cross. They don't have to it's not a requirement that they never cross. It's only A, A, A requirement that they're montoni ally decreasing or staying flat.

So i've seen cancer treatment drugs where they have like two drugs going head to head in a cancer treatment and like one starts out looking really, really bad. But then all of a sudden that kind of flattens. Well, the other one goes bad, and then I actually crosses and goes underneath.

But that's not the case. Here is to your complaint, the people with diabetes taking metformin in both the match single tins in the discordance are dropping much faster, and they always stay below. And I was just going to say that the shading is just showing you in ninety five percent confidence in able.

So you're just hooding basically error bars along this. So if this were experimental data, if you were doing an experiment with a group of mice and you are watching their survival and you you know what you you'd have error bars on this, which you're actually measuring. So this is because you have much more data here. You're just showing this in this bash.

For those that haven't been familiar assist, it's no problem. Area bar is correspond like if you are, you just going to measure the heights of a room for of tenth graders, there's going to be arranged, right? You have the very tall kid and the and the very a shorter kid and you know the short kid and the medium kid.

And so there's arranged this can be an average I mean and then they'll be standard deviations and standards irs. And um uh so these confidence intervals just get give a sense of how much range of some people um die die early. Some people die late within a given year.

They are going to be different ages. Um so IT these are bars can account for a lot of different forms of variability. Here you're talking about the variability is how many people in each group die. We're not tracking one diabetic taken metformin verses a control I I should have asked earlier. But well.

and it's also a mathematical model at this point. Two, that's smoothing IT out has noticed it's running for the full eight years even though they're only following people for you know typically, I think the medium was like three or four years at a time. So they're using this quite complicated type of mathematics called the cox proportional hazards, which is what generates hazard rate shows.

And basically, any model has to have some error in IT. And so they're basically saying this is the error. So you could argue, when you look at that figure, we don't know exactly where the line is and there, but we know it's in that shaded area. If sort of one of the point in if those shaded areas overlapped, you couldn't really make the conclusion. You wouldn't know for sure that one is different from the other.

Yeah that's actually a good opportunity to um to uh raise a common myth which is a lot of people when they look at paper, let's say a bar graph um and they see these era bars and they will say people often think, oh, if the area bars overlap, it's not a significant difference but if the area bars don't overlap, meaning there's enough separation, then that's a real and meaningful difference and that's not always the case. IT depends a lot on the form of the experiment.

Um I often see some of the more robust twitter battles over you know how people are reading graphs and I think it's important remember that um you run the statistics, hopefully the correct statistics for for the sample um but determining significance whether or not that the result could be due to something other than chance, of course your confidence in that increases as IT becomes typically p values p less and point point zero zero zero zero one percent chance that it's do um chance right so very low, probably less. Some point of five tends to be the kind of gold standard cut off. Um but when you're talking about data like these, which are repeated measures over time, people are dropping out literally um over time, you're saying they've model IT to make predictions as to what would happen. We're not necessarily looking .

at the raw data point here. Yeah the raw data was in the previous table that's now taken and run through this cox model and it's smooth debt IT. And to your point about the bargrave s yeah, I think the other thing you always want to understand is just because something doesn't achieve statistical significance.

The only way you can say it's not significant is you have to know what IT was powered to detect um in statistical power is A A very important concept that probably doesn't get discussed enough uh but before you do an experiment, you have to have an expectation of what you believe the differences is between the groups and you have to determine the number of samples you will need to assess whether or not that difference is there or not. So you use something is called a power table and you you would go to the power table. So if if you're doing treatment A S S, treatment b and you say, well, like, I think treatment a is going to have a fifty percent response and I think treatment b will have a sixty five percent response.

You literally go to a power table that says fifty percent response, fifteen percent difference. That gives you a place on the grid. And I want to be ninety percent sure that i'm right.

So ninety percent power. I'm being a little bit so who's going to be a statistician listening to this? Who's going to want to kill me? But this is directionally the way we would describe IT. And that tells you this is how many animals or people you would need in this study. You're going to need one hundred and forty seven in each group. And by the way, if you now do the experiment with one hundred and forty seven and you fail to find significance, you can comfortably say there is no statistical difference, at least up to that fifteen percent. There may be a difference at ten percent, but you weren't powered to look .

at ten percent yeah and very important point that you're making. Another point is just a more general one about statistic. In general. The way to reduce variability in a data set is to increase sample size. And that kind of make sense, right?

If you if I just walk into a tenth grade measure height, I by the first three kids that I see, and I happened to look over there, and it's the three that all played in the volleyball team together. I my sympathized is small and unlikely to get a swed representation, in this case, taller than average. So increasing samp size tends to decrease variation.

So that's why when you hear about a study IT from the U K biobank or from you know um half a million danger citizens, like for instance in this study that those are enormous samples. zed. So even though this is a not an experimental study, it's an epidemiology observational study. Um there's tremendous power by way of the enormous number of subjects in in the time.

the way that epidemiology will make up for its deficit. So you could never do a random hied assignment study on a half a million people. You so so epidemiology makes up for its biggest limitation, which is IT can never.

Compensate for inherent biases by saying we can do infinite duration if we want, like we could. We could survey people over the course of their lives, and we can have the biggest sample size possible because this is relatively cheap. The cost of actually doing an experiment where you have tens of thousands of people as prohibitive.

And and if you look at the women's health initiated, which was a five years study, I don't know what was at fifty thousand women. I mean, that was a billion dollar study. So this is, this is the balancing act between epidemiology and analyzed prospective experiments.

And so they both offer something, but you just have to know the blind spots of each one. So let's just kind of wrap this up. I mean, I think, h, let's just go a table for which I think is the most important table in in here, which now lays out the the final results in terms of the hazard ratio.

So this is this is the way we want to really be thinking about this. So again, hazard ratio um these are important things to understand. A hazard ratio is a number, and you always subtract one from the hazard ratio.

And that tells you if it's a positive number, it's a number, sorry, it's a number more than one. You subtract one, and that tells you the relative harm. So if the hazara is one point five, you subtract one point five is a fifty percent increase in risk um if the number is negative, you may recall on the banana sture paper the hazardous was twenty eight five.

So it's nothing when so that means it's a fifteen percent reduction in relative risk. And here you can see all the hazard ratios are positive. So what is telling you here is, and I want to walk to this because there's a lot of information packed here.

You've got single tins, you've got twins. They're showing you three different ways that they do IT. They do an unadjusted model. If you just look at the single things with and without meat form and you make no adjustments, the hazard ratio is one point for eight, meaning the people on metformin had a forty eight percent greater chance of dying in any given year. Then there are non diabetic counterpart.

The only reason of smiling is not because I enjoy people dying quite to the contrary is that um this is novel for me that i've had some of democratic studies before. It's not Normally where I spend the ventures ity of my time but up until now I was thinking, okay, people taking matt form and are dying more than those that aren't. I just and I just relieved to know that I wasn't looking all this backwards.

You so they're dying more. But of course, we don't have a group that's taking that form and who doesn't have diabetes and we don't have a group um who uh has diabetes and um you know is taking mta form and plus something on. So again, where we're only dealing with these constrained yeah others .

opposition armed to this study that i'm not getting into because IT adds more complexity, which is they also have another group that got diabetes takes metformin and take so phoning your reas, which is are a bigger drug and those people die even more oh so which again speaks to the point right? The more you need these medications, they're never able to errors the effect of diabetes.

But in this case, IT seems that they might be accelerating, possibly accelerating death due to diabetes.

Possibly, we could never know that from this because we we don't see we would need to see diabetics who don't take metformin, who take nothing. And I would bet that they would do even worse. So my intuition is that the metformin is helping, but not helping nearly as much as we thought before.

So my point is they make another set of adjustments. They say, okay, we will look in the first one. In the unadjusted model, we only matched for age and gender.

Okay, that's pretty crude. What if we adjust for the medications there on the cardio accused psychiatric pommers mads and marital status? I don't know why they threw marital status in there.

but they did. I don't know, maybe being married, unmarried didn't.

i'm sure, but IT just seems like a random thing to throw in with all their meds. I would have personally done that adjustment higher up. But nevertheless, if you do that, all of a sudden the, uh, hazard ratio drops from one point four eight to one point three two, which means yet you still have a thirty two percent greater chance of dying in any given year.

All right. What if we also adjust for the highest level of education, along with any of the other covariance? Well, that doesn't really change IT at all. IT ends up at one point three, three or a thirty three percent chance increasing .

that OK always knew that more school wasn't .

going to save me. It's not doing jack. So now let's do IT for the twins.

If you do the twin study, which you could argue is a slightly pure study, because you at least have one genetic and environmental thing that you've attached, the unadjusted model is brutal. Two point one five at one hundred and fifteen percent. Think about this.

These are twins who in theory, are the same in every way. That one has diabetes in one dozen, and the one with diabetes on met forman still has a one hundred and fifteen percent greater chance of dying. Then the non diabetic cochin, when you make that first adjustment of all the medals and marital status, you bring IT down to a seventy percent increase in risk.

And when you throw education and IT goes up to an eighty percent chance of risk. Now they did this really cool thing, which was, they did the analysis on within without censoring. So everything I just said here was based on no censoring.

Tell me about censoring. Censoring is when you stop counting the met form and people who have died. okay.

So in the single tim group, when you unadjusted and the reason i'm doing the unadjusted is that where they did the sensitivity analysis, I don't think IT really matters that much. You just have to draw line in the same somewhere. You'll recall that that was a forty eight percent chance of increased mortality.

All cause mortality. If you stop counting, if you, if you help me, if you don't sensor meaning, if you include everybody, including when people on met form with diabetes die, if you sensor them, IT comes down to one point three nine. In other words, this is a very important finding.

IT did not undo the benefits that we saw in the banister study. Bannister saw a fifteen percent reduction in mortality when they censored. When keys censored, IT got Better, but not that much Better. IT went from forty eight to thirty nine percent in the twins. IT went from one hundred and fifteen percent down to only ninety seven percent.

So in some ways, this presents a little bit of enigma because it's not entirely clear to me, having read these papers many times, exactly why bonus's found such and outlined like such a different response. There's another there's another technical detail of this paper, which is they, you can see on the right side of table before they did something called a nested case control. But you'll see, and I was gna go into a long explanation of what nested case controls are.

It's another pretty elegant way to do case control studies where you sample by year and you, you, you sort of Normal, you don't count all the cases at the end. You count them one by one. I don't think it's worth getting in two hundred because IT doesn't change the answer.

You can see IT changes IT just slightly, but IT doesn't change the point. The point here is the key's paper makes IT undi ably clear that in that population there was no advantage offered by met forman that undid the disadvantage of having type two diabetes. This does not mean that metformin wasn't helping them because we don't know what these people would have been like without metformin. IT could be that this bottom of fifty percent reduction in relative mortality to where they have been. But what IT says is in the way this is what you went have expected, this is what you would have expected ten years ago before the banisters paper came out or maybe .

even before met forman was used because in some ways it's saying, um what is the likelihood that sick people who are on a lot of medication are gone to die compared to not sick people who aren't on a lot of medication you want you know it's not quite that simple and in the sense that as you said, there are ways to um trying isolate the form and contribution somewhat um because they're on a bunch of other meds and presuming that was done and analyzed in other figures, say where they they can sort of train, they can never attach the results specifically to metformin, right? But there must be some way of waiting the percentage that are on psychiatric meds or not on psychiatric medas a wait to teeth out whether not there's actually some contribution performance to this result.

Well, that's what they're doing in in be in the in the partial adjustment is they're actually come they're actually doing their best.

say drug all the way through high blood pressure.

non high blood pressure, smoking non smoking .

the way they would do that um by saying, okay, mary, not mary, that's why that's a simple one.

Um are you on lipid lowering? mads? Yeah no OK you are not, you are not. And then comparing .

those group up, yeah OK so no, no differences jumping out that can be purely explained by these other variables. Yes.

although again, this is this is a great opportunities to talk about why, no matter how slick you are, no matter slick your model, as you can't control for everything, there is a reason that, to my knowledge, virtually every study that compares meat eating to non meat eaters finds an advantage amongst the non meat eaters. And we can talk .

about all span advantage, yes.

and we can. Our disease you know incidents are studies and yeah might be tempting to say therefore eating me is bad um until you realize that IT takes a lot of work, not eat meat. It's a very, very significant decision that a person for most people is a very significant decision a person makes and for a person to make that decision.

And they probably have a very high conviction about the benefit of that to their health. And IT is probably the case that they're making other changes with respect to their health as well that are a little more difficult to measure a million other problems with that. I picked a silly example because the whole meat discussion .

then gets into, well, you, when we say eating me, what do we mean to you? I, you unt with your.

how do we get into all those things? But my point is it's very difficult to quantify some of the intangible differences. And I think that even a study that goes to great length as this one does epidemic gc ally to make these corrections can never make the corrections.

And so. For me, the big takeover of this study is one this makes much more sense to meet in the banisters paper, which never really made sense to me. And again, I was first critical of the banana sture paper in two thousand and eighteen, about four years after comment.

That's about the time I stopped taking metformin by the way, I stop taking a for a different reason, which we can talk about in the sec. But um that was the first time I went back and said, wait minute this information, this informative censoring thing is that's a little fishy and I think we weren't looking at a true group of real typed de diabetics. Now that said, maybe IT doesn't matter.

In other words, maybe and even even the key's paper doesn't tell us that metformin wouldn't be beneficial because IT could be that those people, if they were on nothing as their matched cohorts were on nothing, would have been dying at a hazard ratio of three. And this brought IT down to one point five, in which case you would say there is some gero protection there. IT is putting the breaks on this process. All of this is to say absent a anomie control trial, we will never know the answer .

as there remise control show, not image.

not when IT comes to a hard outcome. Now there has been in the itp, so the interventions testing program, uh, which is kind of the gold standard for animal uh studies, which is run out of three labs. So it's it's an nih funded program that's run out of three labs.

They um they basically test molecules for euro protection. Um the I T P was the first study that really put a rap of my on the map in two thousand nine. That was the study that's fortutiously demonstrated that even when ravi zing was given very, very late in life, IT was given to sixty months old mice. It's still afforded them a fifteen percent uh lifespan extension has a somewhere .

that you been done in humans. I means hard if you can't really control with rappids .

um but when the I T P studied met forman IT did not succeed so the there have not been that many drugs that have worked in the I tp. The I tp is very rigorous, right? IT doesn't using in read train of mice.

IT is done concurrently in three labs with very large samples zing. And so when something works in the itp, it's pretty exciting. Rap izon has been studied several times.

It's always worked. Another one we should talk about IT. A subsequent time is seventeen alphaeus dial. This continues to work in male mice, and IT produces comparable effects to rapidly, doesn't make female rice. But this is alpha net beta. So this is seventeen alpha astro dia, not beta astro dia, which is the astrology that we all that is by available .

in all and just as a ref side, thank you. And I basically agree that unless it's a problem males were taking post purity um should try and have their estrogen as high as possible without having negative system logy because of the importance of the libido for brain function to sue health health crushing ater gen and raising testosterone one is just silly right there's let's just leave raising testosterone out of IT.

But many of the approaches to raising testosterone that are psychologic and nature also raised emergent a lot of people trying push down on another gen. And that is, again, unless people are getting a hydrogenic effects like gonna, massive or other issues is the exact wrong direction to go. You want estrogen.

Estrogen is a very important harmon for men and women that's can ega loser. And s gt. Two inhibitor, also very successful in the itp. But again, interestingly rap up metformin t so metford has failed in the p so you .

no longer take a metformin five years ago. Later you .

and .

you .

go to the day, queen. Now finally the nazi a went away after a few weeks or months maybe um but once I got really intellect testing I noticed how high my lactate was a at rest so arresting faster lack ate should be in a healthy person, should be below one, like somewhere between three point six milmo. And only when you start to exercise should like to go up.

And in two thousand eighteen was when I started blood testing for my zone too. So previously, when I was doing zone to testing, I was just going off my power meter and heart rate. But this is when, this is after I met inigo some alone, and I started like wanting to use the late thresh to two million mal as my as my determination of where to put my voltage on the bike. And i'm like doing finger pricks before I started, I like one point, can be one point.

Ran flare up the back of the no.

that would put me a lot higher where.

but but in the generous gear fit?

No, but but, but that's when I started doing a little digging and realized, oh, you know what? This totally makes sense. If you have a week, might a on real toxin what you going to do? You're gna shun t more glue cose into piovano more piotr intellect.

I'm anna roy.

So, and then my zone, two numbers just seemed off my life.

Could you feel IT sorry and know but you feel that in your body because maybe now i'll just briefly described I took burbery um I um during the period of maybe somewhere in the two thousand and twelve two thousand and fifteen stretch.

I don't tell you well, tell you so I was and I still am a big fan of temps, a slow hydrate because I like to me and vegetables and starch as i'm on the war um and I found that I worked very quickly, got me very lean. I could exercise, I could think I could sleep all you know a lot of my rationale for following one eating regiment or another. What I need is to enjoy myself but also have mental energy.

Mean I sleep garbage you know um so I found the slow carb died to be um which was in the four. Our body to be a very good plan for me is pretty easy. You drop some things like bread at that are you don't drink calories, i'm except after a resistance training session sea but one day a week you have this so called cheap day and on the g day, anything goes. And so I would, you know, cross once, and then i'd alternate a sweet stuff, and then I go to piece. And by the end of the day, you don't want to look at, I am of food at all.

So the only modification I made, the sound diet for our body thing was the day after the cheat day, I wouldn't need, I was just fast and I had no problem doing that because he was just basically well, since you said, uh, what was that in? Uh, I do not have that but since you said that I I won't up the anti here but i'll least mature anal severity comment by saying I had, let's just call IT profound gastro distress after eating like that the next day, the last thing you wanted do is eating food. I was just hydrate and often times to try and get some exercise um and what I read was that burberry poor man's metformin could buffer blood glucose and in some ways make me feel less sick when ingesting all these calories and in main cases, spiking my blood sugar and insulin.

Because you're having ice cream, you know you know, etta and indeed, IT worked. So if I took burberry and I don't recall the milligram count, and then I eat, you know, at twelve donuts, I felt fine. IT was as if I had eating one donut.

wow. I felt sort of OK in my body and I think much, much Better now presently because it's buffering the Spike in blood cheer. I wasn't crashing in the afternoon nap and that whole thing and .

you remember how much you are taking.

I think this a couple hundred milligrams. So that sound about right um right yellow capture um I forget the source. In any case, one thing I noticed was that if I took burberry and I did not in just a profound number of carbo hydrate, very soon afterwards, I got brutal headaches.

I think I was hyper light simic. I didn't measure IT, but I just thought I had headaches, I didn't feel good, and then I would eat a pizza or two and feel fine. And so I realized that burberry in was putting me on this, you, a lower blood shatter state. That was the logic anyway.

And IT allowed me to eat these cheap foods um but when I cycled off of the the four up because I I don't follow the slow club guide more although I might again at some point when I stop doing those cheap days uh I didn't have any reason to take the burberry and I feared that I wasn't interesting enough carbo hydrates. Tes, in order to really justify I trying to buffered my black lue costs. Also, my blue host tends to be.

did you ever, did you ever try a car?

Bos, no, what is that?

So a car. Bois, another glucose disposal. Yeah so it's actually a drug that but IT works more in the gut and IT just prevents luco s absorption.

A A car bus is another one of those drugs that actually found a survival benefit in the itp and IT was a very interesting finding because the the thesis for testing in the ig pie's, a very clever system. Anybody can nominate a candidate to be tested. Then you know the panel over their reviews IT and they decided that this is interesting. Go go.

And that so when I think David Allison nominated, uh, a car board to be studied, the rational was IT would be a chloric restriction memetic because you would literally just fail to absorb, I don't know, make up some number, right, fifteen to twenty percent of your carbo hydrates would not be absorbed and therefore you the mice would effectively be calorically restricted. IT was past them out. That's right.

And what happened was really interesting one, the mice lived longer on a carbs, but too, they didn't wait any less. So what if they lived longer, but not through calorie restriction? That's interested, yes. And the speculation is they live longer because they had lower glucose and what insein.

And I don't want to send us down some rabid holes here, but there are all sorts of interesting ideas about um for instance, that some forms of dementia might be so called type three diabetes and diabetes of the brain and so things like bring met form and lowering blood lue cose key generic tides at that. I might be beneficial there. I mean, there's a lot to explore here and I know you ve explored a lot of that on your podcast.

I've done far less of that. But well, at least IT seems that we know the following things for sure. One, you don't want insulin too high nor too low.

You don't want black luck s too high nor too low. If the buffering systems for that or disrupted, clearly, exercise, meaning regular exercise, is the best way to keep that system in check. But in the absence of that tool, or I was said in addition to that tool, is there any google disposal agent? Because that's what we're talking about here. Net form in burbery, a carbo set at sea that you take on a regular basis because you have that much confidence in IT.

The only one that I take is an S T two invita. Um so this is a class of drug that is used by people with type two diabetes but which I don't have. But because of my faith in the mechanistic studies of this drug, coupled with its results in the I T P, coupled with the human trial results that show profound benefit in non diabetics taking IT, even for heart failure, I think there's something very special about the drug. actually. That was another paper I was thinking about presenting this time maybe .

will do that the next time but but you believe in color restriction as a way to extend life or are you more of the do the right behaviors um and that discovered in your book outlive and elsewhere on your podcast and buffer blood glue cose is do you still obviously you believe in buff ing blood blue cose in addition to just doing all the right behaviors.

but I think you can uncouple a little bit the buffing of blood blue coast from the chloric deficit. So um I think you can be in a reasonable energy baLance in buffer k glue cos with good sleep pygmy lots of exercise and just thought for eating uh without having to go into a calorie deficit.

So you know it's not entirely clear if profound chloric restriction would offer a survival advantage to humans even if IT we're tolerable to most, which is not right. So for most people, it's just kind of off the table, right? Like if I said under you need eat thirty percent fewer calories for .

the rest of your i'll live thirty .

percent four years yeah there's just not many people who are willing to sign up for that's what kind of a mood point um but the question is, you know, do you need to be fasting all the time? Do you need to be doing all of these other things? And the answer appears to be outside of using the my tools to manage energy baLance.

It's not clear right? And energy baLance probably plays a greater role in glucose homeostasis then from a nutrition standpoint than the individual constituent of the meal. Um now that's not entirely true.

Like I can imagine a scenario where a person could be in negative energy baLance eating twice bars all day and drinking you big gulp s but I also don't think that's a very sustainable thing to do because if by definition, i'm going to put you in negative energy baLance consuming that much crap, i'm going to destroy you like you're gna feel so miserable you're going to be starving, right? You I can be social eating pure garbage. And being in chloric deficit, you're going to end up having to go into choric access.

So that's why it's interesting thought experiment. I don't think it's very practical experiment for a person to be generally social and energy baLance. They're probably eating about the right stuff. But I don't think that the specific macro s matta, as much as I used to think.

i'm a believer in getting most of my nutrients from on processor minimally process sources simply because IT allows me to eat foods I like yeah and more of them and I just loved I I so physically enjoy the sensation of chewing that all just cucumber slice is for for fun yeah right. You know that I mean, that's not my only form of fun.

Fortunately this is an amazing paper um for the simple reason that IT provides a wonderful tutorial of the benefits and drawbacks of this type of work. And I think it's also wonderful because we hear a lot about mat form and rap mize and and. These anti aging approaches but was not aware that there was any study of such a large population of people. So it's very pretty interesting.

yeah. So I think IT remains to be seen if and my patients often ask me he should I be on met form? And I give them a much, much, much, much shorter version of what we just talked about.

And I say, look if the tame study, which should answer this question more definitively, right, this is taking a group of non diabetics and random zing them to plus bo versus performing and studying for specific disease outcomes. If the tame study ends up demonstrating that there is, uh, a gero protective benefit of metformin, I i'll reconsider everything. So I think that we just have to, I think, all walk around with an appropriate degree of humility around what we know and what we don't know. But but I would say right now, the epidemiology, the animal data, my own personal experience with its impact on my late production exercise performance, we could there's a whole other raby hole we could go on another time, which is the impact on hyperdrive phy and strength, which appears to be attenuated as well by metformin. Um you know, I still prescribed IT to patience all the time of the instant resistance for sure is still a valuable drug, but I don't think if IT is a great tool for the person whose influence sensitive and exercising a lot.

I can help but ask this question, do you think there's any longevity benefit? Two short periods of color c restriction you so for instance, I decide to by the way, I haven't done this, but let's say I were to decide to you fast into a one meal, a type thing where i'm going to be in a slight lord deficit you know five hundred two one thousand calories for a couple of days and then go back to eating um the way that I before that short color c restrictions slash fast.

Is there any benefit to IT in terms of cellar health? Can you also reset the system? Is there any idea that the the changes, that clearing of sentence cells that we hear about on topic that we you know that in the short term you can clean a lot of benefits and then go back to to irregular pattern of eating and then periodical, you know, once every couple of weeks or once a month, just being fast for a day or two. There are any benefits to that, that the purely in the domain of longevity, not because there's a discipline function there, there's a flexibility function, there's polling insula sensitivity function, but there any evidence that I can help us live longer?

I think the short answer is no um for two reasons. One I don't think that, that duration would be sufficient if if one is gonna that approach. But two, um even if you went with something longer, like what I used to do, what I used to do, seven days of water only per quarter, three days per months.

So I was basically always like to be three day fast, three day fast, seven day fast. Just imagine doing that all year. Rotating, rotating, running for many years. I did that. Um now I certainly believed and to this day I would I have no idea if that provided a benefit.

But my thesis was the downside of this is relatively circumscribed, which is profound misery for a few days and um what I didn't appreciate the time, which I obviously now look back at and realized his muscle mass lost. You're it's very difficult to gain back the muscle cumulatively after all of that loss um but my thought was exactly as you said, like there's got to be a resetting of the system here. This must be sufficiently long enough to trigger all of those systems.

But you're getting at a bigger problem with gero science, which i'm really hoping the epi genetic field comes to the rescue on IT has not come close to IT to date, which is we don't have biomarkers around true metrics of asian. Everything we have to date stinks. So we're really good at using molecules or interventions for which we have biomarkers, right? Like when you lift weights, you can look at how much weight are lifting, you can look at your dexia can and see how much muscle mass you're generating like that.

Those are biomarkers. Those are giving you outputs that say my input is good or my input needs to be modified. Um when you take a sleep supplement, you can look at your eight sleep and go, oh my sleep is getting Better like there's a biomarker um when you take metformin, when you take promising, when you fast, we don't have a biomarker that gives us any insight into whether or not we're moving in the right direction.

And if we are, are we taking enough? Just don't know. So I I, I often get asked, like what's the single most important topic you would want to see more research dollars put to in terms of the space? And it's unquestionably this as unsexy as IT is. Like who cares about biomarkers? But like without them, I don't think we're going to get great answers because you can't do most of the experiments you and I would dream up.

Got IT. Well, i'm grateful that you're sitting across the table for me telling me all this and that everyone can hear this but again, we will put a link to the paper is pure that Peter just described and for those of you are listening and not watching um hopeful ly you are able to track the the general themes and takeaway and IT is fun to go to these papers is here these big stacks of numbers and and IT can be a little bit overwhelming but my additional suggestion on parsing papers as notice that Peter said he spent he read IT several times unlike a newspaper article or or A A instagram post with a paper or not necessarily going to get IT the first time. You certainly won't get everything so that I think spending some time with papers for me means reading IT then reading IT again a little bit later and tell me.

yeah it's just about to say what's your because because I kind of have a way that I do IT. But i'm curious to how you do IT like if you if you're captain of pair for the first time, what do you have an order in which you like to go through? Do you want do you read IT sequentially? Or do you look at the figures first? I mean.

how do you how do you go through IT? Yeah unless it's an area that I know very, very well where I can you know skipped to some things um before reading at the whole way through um my process is always the same. And actually this is fun because I used to teach a class when I was a present U C C ago um called neural circuits in health and disease.

And IT was an evening course that grew very quickly from fifty students to four hundred plus students. And we would do exactly this. We would past papers. And and I had everyone ask what I called the four questions, and wasn't exactly four questions. But I have a little three by five card next year, or a piece of a main nap by eleven paper typically.

And when I sit down with the paper, I want to figure out, what is the question they are asking? What's the general question? What's the specific question? And I write down the question then, what was the approach you? How do they test that question? And sometimes I can get a bit detailed and get into to chemistry and they did you know P C R for this.

It's not so important of for most people that they understand every method, but IT is worthwhile. D that if you encounter a method like pcr or um your commodores phy or F M R I, that you at least look up on the internet what it's purposes okay, that will help a lot. And then I was what they found.

And there um you can usually figure out what they believe they found any way by reading the figure headers, right? What you know figure one. Here's the head that typically if it's an an experimental paper IT will tell you what they want you to think they found.

And then I tend to one another conclusion of the study. And then this is really the key one and this is the one that would really distinguish the high performing students from the others. You have to go back at the end and ask whether or not the conclusions, the major conclusions drawn in the paper are really substantiated by what they found and what they did.

And that involves some thinking and involves really, you know, spending some time thinking about what what they identified. Now this isn't something that anyone can do straight off about, is the scale of that you develop over time. And different papers require different formats.

But those four questions really form the cornerstones of of teaching undergraduates and I think graduate students as well of how to read a paper. And um again, it's something that can be cultivated and it's still how I approach paper. So what I do typically already title abstract. I usually then will skip to the figures and see how much of that I can digest without reading the text, and then go back and read the text.

But in fairness, journals, great journals like science, like nature, often times will pack so much information in the soul internals to into each figure, and its coded with no definition of the acronyms that almost always i'm into the introduction and results within a couple of minutes wondering what the hell acronis is had acronym and it's it's just, yes, just wild. How much how much more in clatter there really is. I can't remember.

Was you or was that our friend paul county when he was here? Um who said that? Oh no, i'm sorry, he was neither IT was cheer of the logic stanford uh, doctor jeffrey golden k who has a guess on the podcast recently who off camera I think IT was told us that if you look at the total number of words and terms that are physician leaving, medical school owns in their mind, and their vocabulary is the equivalent of like two additional full languages of fluency beyond their native language.

So you're try lingual at least. And I wanted you speak a language rather than english corner. okay. So at least trial will and probably more so no one is expected to be able to party. Newspaper is the first time through without you know substantial training.

Yeah no. I I I think that's that's a great format and you're absolutely right. I have a different way that I do IT when i'm familiar with the subject matter.

But as what I got ah well, again, if i'm reading papers that are something that I know really well, I can basically clean everything I need to know from the figures and then sometimes i'll just do a quick scheme on methods but I don't need to read the discussion, I don't need to read the intro. I don't need to do anything else. If it's something that I know less about than I usually do exactly what I say, I try to start with the figures.

I usually end up generating more questions like, what? what? What do you mean? what? What is this? How do they do that? And then I ve got to go back and read methods typically.

And one of the other thing is worry worth mentioning is a lot of papers these days have information that are not attached to the paper. So um you're amazed that how much stuff gets put in the supplemental section. And the reason for that, of course, is that the journals are very specific on the format and length of a paper. So a lot of the times when you're submitting something, you know like if you want to put any additional information and there I can't go in the main article that has to go in the supplemental figure. So even for this paper, there were a couple of the numbers I spot IT off that I had to pull out of the supplemental paper, for example, when they did the sensitivity analysis on the censoring verses not on censoring, that was in a supplemental figure that was actually not even in the paper represented.

Well, should we paving to this other paper? Yes, it's a very different sort of paper. It's an experimental paper where there's a manipulation.

I must say, I love, love, love this paper, and I don't often say that about papers. I'm so excited about this paper for so many reasons, but I want to give a couple of copy outs up front. First of all, the paper is not published yet.

The only reason I was able to get this papers because it's on bio archive, there's a new trend over the last, I i'll say, five, six years of people posting the papers that they've submitted to journals for pure review online so that people can look at them prior to newspapers being too reviewed. So there is a strong possibility that the final version of this paper, which again, we will provide a link to, is going to look different, maybe even quite a bit different than the one that we're going to discuss. There are couple of things that make me confident in the data that we're about to talk about.

First of all, the group that publish this paper is really playing in their White house. This is what they do, and they publish a lot of really nice papers in this area. I'm not going to miss pronounce um her for his name, but I think it's child c guo at um who's at the icon school of medicine mount sn I runs S A laboratory their studying addiction in humans and um the first of author of the paper is over perl um this paper is wild and i'll just give you a couple of takeaway first as a bit of a hook tolly entice people into listening further because this is an important paper.

This paper basically addresses how our beliefs about the drugs we take impacts, how they affect us at a real level, not just at a objective level, but at a biological level. So just to back up a little bit, a former guest on this podcast, doctor ali chrome, um whose name is actually a lecrone, but he goes by alicran talk about f effects. Belief effects are different than placebo effects.

Placebo effects are really just category effects. It's okay. I'm gone to give you this pill, Peter, and i'm going to tell you that this pill is molecule x five nine and five two and that is going to make your memory Better. And then I give you a memory test, right? And your group performs Better than the people in the control group who I give a pal to.

And I say this is just a placebo or the other variants on this where um people get a drug and you tell them it's placebo, they'll get a placable, you tell them it's drug, it's it's a binary thing, it's an honor. And often you're either in the drug group of the placebo group and you're either told that you're getting drug policy and we know that placebo effects exist. In fact, one of the cruel ones, I was never the subject of this, but there was kind of a law in high school that know kids would do this mean thing.

It's a former buying. I really don't like IT where you know they get some kid at a party to drink alcohol free beer and then that kid p was start acting drunk, then they go gotcha you know he does even have alcohol in IT now that's a mean joke um and just reminds me of some of the the the horse of high school that writing go very often which I also don't suggest but no IT it's a mean joke but IT speaks to the placement effect right and there's also a social context effect. So political effects are real um we know this belief effects are different.

Belief effects are not a or b and placement or on placebo. Belief effects have a lot of knowledge to enrich one's belief about a certain something that can shift their psychology and physiology one way or the other. And I think the best examples of these, really of these belief effects really do come from ally chromium lab in the psychology department at stanford.

Although some of this work he did prior to getting to stanford, for instance, if people are put into a group where they watch a brief video, just a few minutes of video, about how stress really limits our performance. So let's say, IT archery, or at mathematics, or at music, or at public speaking, and then you test them in any of those domains or other domaines. In a stressful circumstance, they perform less well.

okay? And we know they perform less well because we're by virtue of a heightened stress response, you can measure heart, right? You can measure stroke volume of the heart. You can measure preferred blood flow, which goes down when people are stressed, narrow ing a vision eta.

You take a different group of people and randomly assign them to another group, where now there, being told that stress enhances performance IT mobilizes resources that narrows your vision, such that you can perform tasks Better and Better, and their performance increases above a control group that receives just useless information early, as useless as that relates to the task. So in both cases, by the way, the groups are being told the truth, stress can be depleting or can enhances performance. But this is different than placebo because now it's scaling according to the amount and the type of information that they're get IT.

And and can you give me a sense of magnitude of benefit or detriment that one could experience in a situation like the .

one you just describe? Yeah so it's it's striking the opposite direction. So the stress gets us worse to um let's say I think that if we were to just put a rough percentage on this, there would be some power between ten and thirty percent or performance in the control group and stresses enhancing is approximately equivalent improvement.

So there are an opposite. Even more striking is the the studies that um Alice lab did um and others looking at. For instance, you give people a milk shake, you tell them into high calorie milk shake as a lot of new trends and then you measured grown secretion in the blood.

And glen is a marker of hunger that increases the longer instance you eaten. And what you know is that suppresses glin to a great degree. And for a long period of time, you give another group shake.

You told me to low calorie shake that has got some nutrient in IT, but that doesn't have much fat, not much sugar at seta. They drink the shape, less vaLance suppression, and it's the same shape and it's the same shake. And satire lines up with that also in that study.

And then the third one, which is also pretty striking, as they took hotel workers, they give them a short tutorial or not, informing them that moving around during the day and vacuum and doing all that kind of thing is great, helps you lower your BMI, which is great for your health. You give, you incentivize them, and then you let them out into the wild of their everyday job. You measure their activity levels.

The two groups don't differ. They're doing roughly the same task, leaning down, cleaning out trash cans. That guess what? The group that was informed about the health benefits of exercise lose twelve percent more weight compared to the other group.

and no difference in actual movement.

Apparently not.

Now, how could that be? I mean, literally, this was Sparked by, in alley's words, you know, this was Sparked by her graduate advisor saying, what if all the effects of exercises are policy ba, which is not what anyone really believes, but is just such a you, I love that annual that ali told us, because IT just really speaks to how, like, really smart people think that you sit back and they go, yeah, exercise, obviously, as benefits, but like, whatever a lot of the benefits that you tell you yourself, it's good for you. And the brain can actually activate these these mechanisms in the body.

And why wit that be the case? Because the nervous system extends through both. So so i'm for so interested okay, so fast war to this study, which is really about belief effects, not placebo effects.

To make a long story short, we know that nickey vapor smoke dipped or snipped or these lows in pouches or taking in capture form does improve cognitive performance. I'm not suggesting people run out and start doing any those things. I did hold episode on nickelodeon.

Livery device often will kill you some other way is bad for you. But IT causes visual construction, which is also not good for certain people. But nickel is cogniac enhancing. why? Well, you have a couple sites in the brain, namely in the base of four brain nuclear mesas, in the back of the brain structures like local as russia.

But also this, what's called is got a funny name, the peduncle t time nucleus, which is this nucleus in the, in the, the ponds, in the back of the brain, in the brain stem, that sends those little acts on wires into the foma. The Philomena is a gateway for sensory information. And in the film, as the visual information, the auditory information, IT has nicotine ic receptors. And when the peduncle ponder nucleus releases nickey or when you in just negative what IT is IT increases the signal to noise of information coming in through your senses. So the fidelity of the signal that gets up to your cortex, which is your conscious perception of those senses, is increased.

And how much endogenous marketing .

do we produce um well it's going to be a seto calling binding .

to a eto Colin recept right of which there are at least seven and probably like .

fourteen subtypes but um so they're called nicotine nic recept tors in an annoying way in the same way that can abode e recept tors are called can abode receptors but then everyone thinks, oh you know those receptors or are there. So because we're opposed to smoke pot or those receptors or are there because were reposed to and just niki, no, the drugs that were used to study, that's right, very exactly. Receptor was name after the drug.

And so the important thing to know is that whether or not to basel four brain, a purdon q upon time nucleus or a locust, is that, at least in the brain were not time about muscle, where I see the calling does something else via cnc cept. There in general, just tends to be a signal to noise enhancer. And so for the non engineering types out there, no problem signal to noise.

Just imagine i'm talking right now. There's last static in the background. There are two ways for you to be able to hear me more clearly.

We can reduce the static or I can increase the fidelity, the the volume and the clarity of what i'm saying. okay. Um for instance and that's really what I see to calling does.

That's why when people smoke a cigarette, they get that boost of nickey and they just feel clear IT really works. The other thing that happens is the film ious sends information to a couple of places. First, what sends information to the reward centers of the brain, the new olympic reward pathway that releases depine.

And typically, when nick oti is increased in our system, dopamine goes up. That's one of the reasons why nicki is reinforcing. We just like IT, we seek IT out. If you done beautiful experiments with honeybees, even where you know you put nickey on certain plants or IT comes from certain plants in their forage, there are more you get the of them kind of like buzz that was upon um in any event, there is also an output from this thing. The follow us to the venture media prefrontal cortex, which is area of the forebrain that really allows us to limit our focus on our attention for sake of learning, which allows just to pay attention. This is the circuit.

You talk about this in your fantastic podcast on stimulus.

Yeah yeah. So A D H, typically A D H drugs. So things like at or all via math theefe demand for that matter. Riddle in yeah why it's .

counterintuitive that a stimulant would be a treatment for someone with difficulty focusing.

Yeah, in Young kids who have difficulty focusing, if you give them something they love, they're like a laser. And the reason is that venture medial prefrontal cortex circuit can engage us when the kid is interested and engage. But kids with A D, D, adhd tend to have a hard time engaging their mind for other types of tasks, and other types of tasks are important for getting through life.

And IT turns out that giving those stimulant drugs in many cases can enhance the function of that circuit, and IT can strengthen so that ideally the kids don't need the drugs in the long run over. That's not often the way that IT plays out. And there are other ways to get at this.

And there's now a big battle out there. You know, is hd real? Is that not real? Course, it's real. Does everybody need A D H. D? mads? no.

Are there other things like nutrition, more play time outside IT set, or that can help improve their symptoms without drugs? yes. Is the combination of all those things together known to be most beneficial? yes.

Or the dosage is given too high and generally should be titrated down. Maybe some kids knew a lot. Some kids need a little. I probably just gained in lost a few enemies there. So the point is that these circuits are hardwired circuits.

Sorry, one of the question here um if my memory search correctly doesn't negative potentially have a coming effect as well and that seems a bit counter intuitive to the focusing. One is IT a dose effect or a timing effect?

How does that work? Yeah, it's a dosing effect. So the interesting thing about nicky is that IT can enhance focus in the brain. But in the periphery, IT actually provides some muscle relaxation. So it's kind of the perfect drug if you think about IT again.

Um IT was also reflecting on this how when we were growing up, people would smoke on plane, that a smoking section on the plane, you know people smoke all the time and now hardly anyone smokes before the obvious reasons but yeah IT provides that really ideal baLance between being alert but being mellow and relaxed in the body. So um hence its reinforcing properties. Okay, this study is remarkable because what they did is they had people come into the laboratory.

They gave them a vapor pen. These are, these are smokers. So these are experience smokers.

Typically, there's a wash out before they come in, so they're not smoking for a bit, so they can clear their system of negative and they measured typically it's a couple of days. Yeah, which you must be miserable for those no nothing. They must be dying.

And I wonder how many cheat? They measure, measure and measure carbon ox measure is so they a good job. So then what they do is they have them rape and they're raping either a low, medium or high dose of negative. The doses is not really matter because tolerance varies at sea. And then they are putting them into a functional magnetic resonance imaging machine.

So where they can look at it's really blood flow is really human dynamic response for those who they want to know is the is the ratio of the oxy to the blood because when blood, blood will flow to neurons that are active to give IT oxygen and then it's d oxygen ated. And then there's a changing what's called the bold signal. So FM, when you see these like hot spots in the brain, is really just looking at blood flow.

And then there are some interesting physics around and i'll I get this wrong, but i'll taken an attempt at IT so they get beat up a little bit by the physicist engineers. Remember the right hand rule, right? okay.

So do I have this right? Uh, correct. Um the right and rule. If you put your thumb with your first with your index finger in middle inger, you're thun facing up.

I think that the fmb represents the charge, the direction of the charge, right? And then isn't the electro magnetic field, is the downward facing figure. And then it's to have that right? Um have to look at, okay, what someone will look IT up. But what you do is when you put a person's head in this big magnet and then you pulled the magnet, what happens is the oxy and d oxinate blood IT interacts with the magnetic field differently, and that difference in signal can be detected. And you can see that in the form of activated brain areas.

Yeah I mean M R I all works by on detection. So prisoned bly there's a difference in the proton signal when you have high oxygen versus low xxxx concentration.

Yes that's right. Um and they'll do is i'll pulse with the magnet because my understanding is that um and this is definitely getting beyond my expertise, but that the the spin orientation of the protest and it's going to relax back at a different rate as well. So what by the relaxation at a different rate, you can also get um not just resting state activation.

I go look at a banana, what areas of the brain light up. We can look at connectivity between areas and how one areas driving the activity of another area. So very, very powerful technique. So what they do is they they cook him on the scanner. And then you're .

like this because are the limitations of fmri in terms of, I mean, how fine is the resolution? I mean, where are the blind spots of the technique?

So resolution you can get down to sub centimeter. They talk about IT always in these paper as of boxes, which are these low cubic things um um you sub sub centimeter but you're not onna get down to millimetre OK um there are a number of will come down that maybe we won't go into now that have been basically worked out over the last ten years by doing the following. You can't just give somebody a stimulus compared to nothing.

I'll just tell you the experiment IT was discovered, for instance, that when someone would move their right hand because even when you're in the the MRI and just went for one of these recently for clinical, not a problem, but just for a diagnostics, and you're leaning back and you and you can move your right hand a bit, and they would see in an area, motor cortex lighting up. But what they noticed was that the area corresponding the left hand was also lighting up. So what you really have to do is you have to look at resting state. How much are they lighting up, just right. And then so now you'll always see resting state versus activation state.

Yeah, wasn't through a really funny study done as a spook maybe a decade ago that put a dead salmon into an MRI machine and did an like they did an fmri of a dead salmon that demonstrated like some interesting signal.

We got to find this one for for .

the show notes.

We should do one of these wild papers once there's there are papers of, you know, people putting, don't do this, folks putting elephants on d that we're published in science and things like like crazy experiments, which should definitely crazy experiment's journal club.

Um in any event, you can get a sense of which brain areas are active in when with fairly high spac resolution, fairly high and pretty good temporal resolution on the order of hundreds of million seconds. Not but it's not all all through fast because a lot of neural transmissions is happening on the tens of milliseconds, especially when you're in talking about auditory processing. okay? So they put people into the scanner and then they give them a essential task that's designed to engage the salome's known to engage the salome's reward centers and the venture medial prefrontal cortex.

And it's a very simple game. You're like this because you have a background in finance. You let people watch a market, you know, okay, here's the stock market or you can say that the Price of peace IT doesn't really matter.

IT goes up, that goes down and they're looking at swingle line, then IT stops and then they have the option, but they have to pick one option. They're either going to invest a certain number of the hundred units that you're given them or they can short IT. They can say it's going to go down and try to make money on the on the prediction, it's going to go down.

You could explain shorting Better than I could for sure. So depending on whether not they get the prediction right or wrong, they get more points so they lose points, and they're going to be rewarded in real money at the end of the experiment. So this is going to engage this type of circuitry.

Now remember, these groups were given a vate pen prior to this, where they've wiped what they were told is either a low, medium or high dose of nicki. And they do this task. The goal is not to get them to perform Better on the task.

The goal is to engage the specific brain areas that are relevant to this kind of error and reward type circuit. And we know that this cast does that. So that includes the film is that includes the miss olympics reward pathway and doping IT includes the venture media.

Prefrontal cortex, first of all, they measure nickey in the blood. They are measuring how much people vpc. They were very careful about this.

One of the nice things about the vate pen for the sake of experiment, you're not recommending people, vae, but they can measure how much naki is left in the vate pen before after they can measure how long they inhaled, long they healed in lot that you can do. That's harder to do with a cigarette. okay? They measured people's belief as to whether or not they got low, medium and high amounts of dictating.

And they were told, they were told they got.

this is a low amount of medium amount or high amount. And then, of course, they looked at brain area activation during this task. And what they found was very straight forward. Sorry.

they were all given the same amount.

Yes, this is, this is the sneak I was going to offered as a punch lying. But that's okay. No, I think that the cool thing about this experiment is that the subjects are unaware that they all got the exact same amount of relatively low nickey containing the pen.

So they based, and they are measuring IT from their bloodstreams s so they all have fairly low levels of, but one group was told you got a lot. One group was told you got a medium amount, and the other was told you got a little bit. Now a number of things happen, but the most interesting things are the following.

First of all, people's subjective feeling of being on the drug matches what they were told. So if they were told, hey, this is a high amount of niki like that feels like a high amount of icing and these are experience smokers. If IT was a medium amount, like Better feels like a medium amount for a low amount, they think that was a low amount.

Now that's perhaps not so surprising that you're just tricking people that's possible. But if you look at the activation of the Thomas in the exact regions where you would predict a seto coin transmission to impact the function of the sales of these include areas like what's called the central media nucleus of attribute urian nucleus, the names that really don't matter. But these are areas involved in attention, its scales with what they thought they got in the vet pen.

Meaning, if you were told that you ve got a low amount of nicotine, you got a little bit of activation in these areas. If you were told that you got a medium amount of negative, and that's what you've ipad, that you had medium amounts or moderate amounts of activation. And if you were told you you got high amounts of continue, got a high degree of activation and the performance on the task believe not scales with IT someone.

So keep in mind, everyone got the exact same amount of dictating in reality. So here, the belief effect isn't just changing what one subjectively experiences. So oh, this is the effect of high nick or low IT actually changing the way that the brain responds to the belief.

And that, to me, is absolutely wild. Now there are couple of other things that could have confounded this. First of all, IT could have been that if you believe you've got a lot of nickey, you're just faster or you're reading the lines Better or your response time to hit the button is quicker.

You know I tell you have a drug that's going to improve reaction time. You might believe that about nicki. And so you're r on the trigger and you're getting they have a different activation as more activation um there could be rule that out. They also rule out the possibility how do they rule that out by looking at rates of of pressing and there nothing any sensory areas of the brain that would represent that kind of difference. They don't see that.

The other thing that um is very clear is that the connection between the filament and the venture media preferences cortex that pathway scales in the most beautiful way such that people that were told they had smoked a low or taped a low amount of naked teen got a subtle activation of that pathway. People that were told that they got a moderate amount of sixteen got a more robust activation of that pathway, and the people they were told that they got a high amount of nickey in the vate pen saw a very robust activation of the files to the eventual prevented critical pathway. Of course, this all happening under the hood of the skull simply on the basis of what they were told and what they believe.

And technically, the MRI is showing the activation of those two areas. And that's how you can infer the strength of that connection.

That's right. There's a separate metic called the future tensor imaging, which was developed, I believe, out of the group in minnesota. Minnesota has a very robust group in terms of neuroimaging um that can measure activation in fiber pathways. This is not that, but you can look at the timing of activation and is unknown what we call mona atic pathway. So we haven't talked so much about figures here, but um I guess we were gona look at any one figure um and I can just describe IT for the audience that's not paying, doesn't have the figure in front of them.

The let's see at the most but the most important figure is figure two members that i'd like to read the titles of figures, which is that the belief about nicotine strength induce a dose dependent response in the sellers basically if you and figure to b um can tell you if they believe that they got more nickey, that's a that's essentially the response that that they saw. So if you look at a start panel e, if you look at the belief rating as a function of the estimate influence of of what how much activation there was, it's it's a mess when you look at all the dots at once. But if you just separated out by high, medium and low, you run the statistics.

What you find is that there is a gradual increase, but a legitimate one from low to medium to high. In other words, if I tell you this is a hypos of nickey, your brain will react as if it's a hypos of nicotine. Now what they didn't do is give people zero.

There's a control that's missing.

yes. So what they didn't do is give people zero nickey and then tell them, uh, this is a high amount of negative sort of the equivalent of the cruel high school experiment no alcohol, but the kid act drunk. Now in the in the high school example, it's unclear whether not the kid actually felt drunk or not um it's unclear whether or not they had been drunk previously if they even know what I would be like to feel drunk and that there's the social context what I find just outrageous and outrageously interesting about this study is simply that what we are told about the dose of a drug changes the way that our physiology response to the dose of the drug.

And in and in my understanding, this is the first study to ever look at dose dependence of belief effects, right? To really and and why would that be important? Well, for almost every study of drugs, you look at a dose dependent curve, you look at zero low dose medium, those high dos, and here they they clearly seeing a dose dependent response simply to the understanding of what they expect the drug ought to do. In other words, you can bypass pharmacology.

Someone right now look at figure to be and my reading this correctly. So it's got a four bars on there. You've got the group were told they ve got a low dose, the group who was told they got a medium dose, the group that was told they had to hide dose and then these healthy controls, who presumably were nonsmokers, we were just put in the machine.

That's right. Yeah yeah.

This is measuring parameter estimate. What is that referring to? Um they are built to play the the the the trading game.

The premier estimate is the is the activation um reward related activities from an independent almas mass, right? So what they're doing is they're just saying if we just look at the elements.

what is the level of activation I see? So this suggests that the only statistical difference between the low and the high.

that's right.

and nobody else was statistically different.

But that's not the whole story. No, that's not the whole story. So when you look at the output from the film is to the venture media preference to cortex, that's where you start to identify the is that figure for that is, yes.

So this is where you see so figure for b if you look at preedy estimates. So this is the deal of activation between the fulness and the venture medio preferences cortex. And it's called the instructed belief. You can see that there is a low, medium and high scatter of of dots for each, and that each one of those .

is significant. So isn't IT interesting that at the Thomas, which is an you're you'll immediately appreciate my stupidity when IT comes to neuroscience, which is more proximate to the nicki mi or the the nickey, what do you call the nicking eto calling reception? You have a lower difference of signal strength. And somehow that got amplified as IT made its way forward in the brain. Yeah.

that surprise you. IT is surprising and IT surprised them as well. The interpretation they give again, as we're time about before, important to match their conclusions against what they actually found, which is what we're doing here.

The interpretation that they give is that IT doesn't take much nick tonic recept occupancy in the fairness to activate this pathway. But they too were surprised that they could not detect a raw difference in the activation of the us. But in terms of its output to the pronto cortex, that's when the .

because show that figure for b is more convincing than figure to because even figure to e if you read the fine print, the r the correlation coefficient is only two, seven. It's not that strong, right? It's weak.

So at the Thomas, it's kind of like, yes, there might be a signal. By the way, this goes back to our earlier discussion. There could be a huge signal hearing. We're under powered. How many subjects were in this this you wouldn't .

have a lot of subjects in this experiment is no you and this just speaks to the general chAllenge of doing this work. It's hard to get a lot of people in and through the scanner.

It's expenses.

It's expensive. We have to I should know this, but we can we can go back to the but you .

can sort of just look at the number of dots on here. I mean, it's in the low tens, right? It's like forty, thirty, something like that. It's not. So it's possible.

But yeah.

you do with a thousand people, this could all be statistically .

significant, right? If so, they talk about this. You based on this, we estimate that an end of twenty and a sample size in each belief condition, the final sample would provide ninety percent powers to detect an effect of this magnitude and an alf of point zero point five and a two tailed test OK.

So that's then referred to what we just talked about, which is we believe at ninety percent confidence to get an alpha of point of five, which means we want to be ninety five percent, we need sixty people, twenty per group, right? yeah. But if the difference is smaller than what they expected, they'll miss out on some of the significance, which that looks like they're missing between the .

medium and high group. You and I too was surprised that um they did not see a difference in the between the medium in the high group um but they did in the output of the film as I was also surprised that they didn't see a difference. This is kind of interesting in its own right. IT figure three talks about the belief about nickey strength, did not modulate the reward response.

the dopamine response. How was that measured just in F.

F, M, R, exactly? If you look at figure three b, other people can see basically, oh yeah, what you'll see is that there is no difference between these different groups um in terms of the amount of activation in these reward pathways if people got a low, medium or high amount of nicotine. Now that actually could be leveraged, I believe if somebody were trying to quit nickey, for instance, and they were going to do that by progressively reducing the amount of nicot that they were taking, but you told them that IT was the same amount, went from one day to the next, you could widder IT down to presumably to a low amount before taking IT to zero. And if they believed IT to be a greater amount, then IT might actually not disrupt the reward pathways meaning they would feel um presume ly they'd feel rewarded by whatever nicking they were bringing in.

What would be your prediction if this experiment were repeated? But IT was done exactly the same way with non smokers who well .

one thing that sort of um interesting you asked about our potential sources of artifact problems with that from mari. One of the chAllenges that they know in the study was you have to stay very still in in the machine but the subjects were constantly caughey because their smokers. So okay, so presently the data would be higher fidelity.

So I chuckling at that one, but I I was like how to read that one twice. So I know make sense that their smokers are coffee that can stay still. So movement artifact um but in all seriousness, I think that for people that are naive to nicot, even a small amount of nickel is likely to get this pathway activated to such a great degree or like the first time effect of .

pretty much any drug. But I wonder if they would be more or less suspect ble to the belief system.

Yeah, that's a really good question, right? Because they have no prior to compare IT.

they have no pleasant, they have no experience to compare IT to with respect to the obviously beneficial effects of negative that the smokers are well used to.

So this is the poor kid that got duped in the thinking that on alcohol, beer was at alcohol, though there actually the winner. We know, because I didn't up. So an alcohol, alcohol bad for you. So in the end that the kid wins and the other one's lose poetic justice. But um that kid having never been actually drunk before, presumably I would .

feel like more .

cept more potential as well. So you know my glee for this experiment is not or this paper rather is not because I think it's the ball and all or it's a perfect experiment. I just think it's so very cool that they're starting to explore dose dependence of belief because that has all sorts of implications.

I mean, um use your imagination, folks, whether not we're talking about um a drug, we're talking about a behavioral intervention, we're talking about a vaccine. And i'm not referring anyone specific vaccine. I'm just talking to vaccines generally.

I'm talking about psychoactive drugs. I'm talking about um illicit drugs. I'm talking about anti depression. I'm talking about all the sort of drugs were talking about before met four minutes that just thrown arms around all of IT. What we believe about the effects of a drug personably, in addition to what we believe about how much we are taking and what those effects ought to be, clearly are impacting at least the way that our brain reacts to those drugs.

Yeah it's very interesting. And me, when you consider how many drugs that have preferable effects um or preferable outputs, begin with central issue. So again, I think the G L P one eg and are such a great example of yeah yeah you know I don't think anybody fully understands exactly how they're working, but it's hard to argue that they're impacting that. The G L P one analogues is having a central impact with something in the brain that is leading to a reduction of appeal.

We believe that yeah yeah. And I think the most data point to different areas of the hypothalamus that are related to society. You have that that is at least possible.

Yeah, I mean, you there is no quicker way to make a mouse over eat or after eat than by leasing a type of films, depending on where you do so. So personably ly, these drugs work there. But again, IT speaks to, like, what do you need to believe in order for that to be the case?

Have they done placable trials there where people get something and they're told, I mean, of course.

those drugs have all been tested via placebo and the placement groups don't do anywhere near as well. That's how we know that there is activity of the drug. But again, there, you know, that's a little bit different than being told you are absolutely getting IT right because in the R, C, S, you're just told you might be getting IT, you might not be getting IT.

So it's not quite the same as this experiment. This experiment is is one level up where you're being called no, you're absolutely getting IT. You're just getting different doses .

of IT yeah to take this to maybe the adhd realm, let's take a kid has been on adhd mets for a while and the parents, for whatever reason the physician decide want to back on the dosage um but if they were to tell the kid is the same dosage they've always been taking and it's had a certain positive effect for them according to the results, at least in this paper a which are not definitive but are interesting.

The lower dose maybe as effective simply on the basis of belief and and this is the part that makes IT so cool to me is that and it's not a kid tricking themselves or their parents tricking the kid so much as the brain activation is corresponding to the belief, right? So that's where this this is why? Because it's done in the brain.

I think we can um you know I gets of these kind of abstract, nearly mystical but not quite mystical aspects of a belief effects which is that you your brain is a prediction making machine it's A A data interpretation machine. But it's clear that one of the more important pieces of data are your beliefs about how these things impact you. Ah so it's not that this bypasses physiology. People are deluding themselves. The salomon is behaving as if it's the high dose when it's the same dose as the low dose group.

Wild yeah I mean think I think of the implications, for example, blood pressure, right like we don't really understand essential hypertension, which is the majority of people walking around with hy blood pressure is unclear ideology um so what's the people being treated? How do we know that the belief system about IT can be changed? And yeah this is this is I don't know, this is my opening.

Yeah it's call stuff and ally chrome, is that on to another really cool stuff? Like, for instance, just to highlight where these belief effects are starting to show up, if you tell a group that the side effects of a drug that they're taking are evident that the drug really works for the purpose that they're taking IT, even though those side effects are kind of annoying, people report the experience is less awful and they report more relief from the primary systems that they're trying to target.

So I believe about what side effects are can really impact how quickly and how um compatible but we feel about how quickly a drug work, excuse me, and how compatible we feel that drug is with our entire lives. So when if we call them something else like not side effects but like didn't benefits for something, it's kind of crazy. You don't want to lie to people obviously, but you also don't want to send yourself in the opposite direction, which is reading the list of side effects of a drug and then developing all of those side effects um when and then maybe later coming to the understanding that some of those were raised through belief effects.

Um we d definitely see that that's the nosebleeds CT, right that's the one we see a lot uh with all sorts of drugs and it's tough because you know how do how do you know which is which and um I think there are some people who are really impacted by that and that makes me very difficult for them to take any sort of pharma logic agent because they basically they can help but incur every possible side effect. Is that is that true that medical .

students often will start developing in the symptoms of the different diseases that they're learning about actually? Well, you know.

I tell you, I do think that in medical school, you start to you start to think of zebras more than the horses all the time. You know like, you know i'm referring to, right? You know you see foot from you, you see who print. You should think of horses. But of course medical students, you only think of the ebra. There are some runny things in medical school like there are certain conditions that you spend so much time thinking about that you have a very warped sense of their prevalences uh you in medical school there's this condition called sarcodes is like we I feel like we never stopped talking about sarcoidosis ve seen like three cases in my life right? Like it's just not that common.

Does that provide a great teaching tool? Something I don't know.

I just some of the things I don't no, uh, how much time did we spend talking about cats and verses? This is when people embro logically have a reverse rotation and everything in their body is flipped. Literally everything is flipped, so their heart is on the right side, their livers on the left side, their pendexter on the left side like and so i'm not making .

this as common as this.

I've never seen IT O.

I was in about boxing, in the liver shot, like, so you could easily be going for the .

wrong side of the body, I swear a god. Like, as a medical student, if you were told someone had left, cited lower quadrant pain, to which the answer is almost assuredly that they have diverticulitis. You'd think they could have a pdc. Tis in the context of cats and verses like the fact that I would even register in the 他 and things that I could possibly be。 But yes, you just have a totally warp sense of what's out there.

Well um this has been peer pleasure for me. I don't know about I don't know about our listeners but for me this is among the things that I just delight in and and even more so because you're the one across the table for me teaching me about these incredible findings, the gap in those findings, which are equally credible because they equally important to yeah.

so do this again in Austin.

absolutely next time on your home court very .

well and bring a little bit of that do if you've got IT oh yeah.

yeah. I bring a low.

medium and high, low.

medium and high. Thanks, Peter.

You're the best. I sir.

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