Latest / The LIVING Room Podcast | Inside The WNDR Lab / A Neuroscientist Breaks Down GLP–1s, Genetics & the Real Science of Fat Loss | Zachary A. Knight

Transcript

A Neuroscientist Breaks Down GLP–1s, Genetics & the Real Science of Fat Loss | Zachary A. Knight · The LIVING Room Podcast | Inside The WNDR Lab

• 0:00
  Genetics loads the gun.
• 0:01
  An environment pulls the trigger.
• 0:02
  In the world we live in, many people have a genetic predisposition to gain weight, and they do, and they find it very hard to keep it on.
• 0:08
  Before they took the GLP ones, they would basically think about food more than they would have liked to.
• 0:12
  The concept of food entered their mind more frequently because they just were hungrier.
• 0:16
  And that noise is quieted for many people when you take these drugs.
• 0:19
  There's this disconnect between our perception of what we have the ability to control with willpower, and then what the data says over the long term, most people can actually do.
• 0:27
  At this point, they're forever drugs.
• 0:29
  If you go off any of these current drugs, you'll regain the weight.
• 0:32
  Because basically, what these drugs are doing is your body initiates a counter-regulatory response from keeping you at the lower body weight.
• 0:39
  One easy way to make sure that you're not overeating is just to make sure you're getting enough protein.
• 0:43
  A man can do what he wants, but he can't want what he wants.
• 0:46
  Meaning, we can decide what we're going to do in the moment, but what we want is sort of chosen for us by biology.
• 0:50
  If you could give three pieces of advice to anyone that is struggling with their body composition and trying to understand their hunger, their appetite in a way that is more manageable, what would those be?
• 1:17
  Today on the living room, I'm joined by Dr.
• 1:19
  Zachary Knight, one of the world's leading neuroscientists studying how the brain controls some of our most fundamental human drives: hunger, thirst, temperature, and homeostasis.
• 1:31
  Zach is a professor of physiology at UCSF and an investigator with the Howard Hughes Medical Institute, one of the highest honors in biomedical research.
• 1:40
  His lab has made groundbreaking discoveries into how the brain predicts and regulates our physiological needs, work that's reshaping completely our understanding of metabolism, behavior, obesity, and human performance.
• 1:53
  Today we're going to explore the hidden biology driving appetite, cravings, hydration, and energy balance.
• 2:00
  And we're going to do a deep dive into these GLP1 receptor agonists and their impact on modern health and longevity.
• 2:07
  I'm Chris Wharton and I am your host.
• 2:09
  Welcome, friends, to the living room.
• 2:12
  Zach, you are, and correct me if I'm wrong, widely regarded as one of the world's leading experts in the connection between physiology and behavior, and with a specific focus on thirst, hunger, appetite, and the regulation of temperature of body.
• 2:31
  That's right.
• 2:31
  Yeah.
• 2:31
  That's right.
• 2:32
  Why and how did you end up with that as your focus?
• 2:35
  How did you get here?
• 2:36
  Because I know you've had a bit of a different journey to your traditional researcher.
• 2:40
  Yeah, that's a great question.
• 2:42
  Um, so uh yeah, I actually traditionally I actually started off uh in chemistry, um, uh basically making cancer drugs uh uh and uh trying to understand the signaling pathways that go awry in that process.
• 2:55
  Um and uh uh, you know, uh basically developed some of the first mTOR inhibitors, actually, founded a company that that that uh that developed those into clinical compounds.
• 3:06
  Um but then you know around that time in my training, this is when I was getting my PhD, there was just this sort of world-changing technologies that were being developed in neuroscience that are really allowing us to sort of look into brain function in a way that wasn't possible before.
• 3:19
  Tools for for sort of monitoring and manipulating the activity of neurons with light.
• 3:24
  Um, and I just saw an opportunity to ask some of these basic questions about physiology uh using these new tools and finally get some sort of specific answers.
• 3:34
  And so in my postdoctoral training, after I got my PhD in chemistry, I switched fields to physiology to really sort of investigate how how these neurons in the brain that sense the internal needs of the body, right?
• 3:45
  Such as the need for food and water and warmth, how they um sense those internal signals and how they they use them to generate this motivation we have to pursue the things that our body needs, sort of the the origin of sort of this wisdom of the body.
• 3:59
  And so um, so it was really it was sort of seeing seeing how things were changing and realizing there was an opportunity to ask some new kinds of questions.
• 4:06
  There was a a huge amount of misinformation, particularly around hunger and appetite.
• 4:13
  Yes.
• 4:14
  And you know, we we were talking about this very briefly earlier that you know, I think it's around 70% of the US population now are considered overweight.
• 4:21
  I think of that, I think around 40% are considered obese.
• 4:26
  Um, a huge amount of increase in childhood obesity.
• 4:30
  And I think there is still a very big m misunderstanding around this concept of um discipline and motivation and appetite and hunger being a weakness, right?
• 4:45
  And what at a very high level, in a way that someone like me can understand, have you found that would contradict that?
• 4:54
  Sure.
• 4:54
  So yeah, so I think I think one of the things that's kind of fascinating about the regulation of body weight and how that then relates to things like motivation that you mentioned, is that right, we all have this experience, right?
• 5:03
  That you can decide at any given moment, I'm not gonna have that piece of cake, right?
• 5:07
  You have free will in that sense in the moment to make that decision.
• 5:10
  Yet, sort of on a longer time scale, we know very few people successfully lose weight and keep it off over an extended period of time.
• 5:18
  We know that that most clinical trials, or almost all clinical trials, of behavioral interventions, diets to cause people to lose a large amount of weight and keep it off, do not succeed.
• 5:27
  And so there's this disconnect between our perception of what we have the ability to control with willpower, and then what the data says over the long term, most people can actually do.
• 5:38
  There's this uh quote from philosopher Schopenhauer, it's it's that um a man can do what he wants, but he can't want what he wants.
• 5:46
  Meaning we can decide what we're gonna do in the moment, but what we want is sort of chosen for us by block by biology, right?
• 5:51
  By evolution.
• 5:52
  And it's very difficult to change those sort of those sort of innate uh desires and drives that that are so important, like eating, because they you know, we're programmed over millions of years of evolution.
• 6:03
  Now, what I think in the specific case of obesity that people find really hard to wrap their heads around is if what I'm saying is true, then how can it be possible that we've seen this explosion in obesity in the United States sort of since the 1970s is around when this started, and there's just been the steadily climbing rates of body weight, and then throughout the rest of the world as well.
• 6:23
  In that amount of time, you know, in that 50 years or so, you know, the only thing that's really changed is our environment, right?
• 6:30
  It's basically the the foods that we're surrounded by, the sort of infrastructure of transportation, other things, kinds of activities we engage in.
• 6:37
  So it would seem like like uh it has to be our choices that are controlling this, right?
• 6:41
  And therefore we should be able to change those choices.
• 6:44
  And um and uh we should all just be able to lose weight and keep it off just just through through willpower alone.
• 6:51
  And on a theoretical level, that is true.
• 6:54
  If we understood everything about the environment so that we could perfectly reverse it to get rid of all the things that are toxic to us, then maybe you could do that.
• 7:03
  But um, but we don't understand what all those things are and we have imperfect control over our environment, right?
• 7:09
  You're in a world that you cannot completely control, that you did not design.
• 7:13
  Um, and so and so many of this environment in which we find ourselves, um many, many people, most people find it hard to maintain the body weight that they would like to maintain.
• 7:24
  So I guess I guess then you know tied up then in this idea of of willpower and body weight is the idea of genetics, right?
• 7:33
  Because if it's not controllable by willpower, then the sort of default assumption then is is that it's well, it's something I was born with, it's genetic.
• 7:42
  And and there is a lot of evidence actually that body weight is extremely heritable.
• 7:47
  So if you look at twin studies, for example, studies where they've compared like monozygotic versus dizygotic twins, especially fraternal twins versus identical twins, and ask how similar are they in their body weight, you see that there's a strong genetic component that that that monozygotic twins are much more similar in their body weight than fraternal twins.
• 8:06
  And and in fact, it's one of the most heritable things we know about.
• 8:09
  So even in different environments, even in different environments.
• 8:12
  Um pretty much one of the only things we know about that is more heritable than body weight is height, right?
• 8:17
  Almost no disease is as heritable as body weight.
• 8:19
  And so there's a there's this question, you know, and I think this is this gets to the root of I think this question this you raised about about willpower and body weight, which is that if that's true, um uh then how can it be that there's been this explosion in obesity, right?
• 8:34
  Because there's been no human evolution in the last 50 years, there just isn't time for people to evolve.
• 8:39
  Um and and I think this gets to the root of what a lot of people find hard to understand.
• 8:42
  And I think I think the the way I like to explain this is that you know, any human phenotype, meaning anything about us, is always the interaction between genetics and environment.
• 8:52
  Neither ever acts in isolation.
• 8:54
  Yeah.
• 8:55
  Um, and so and so what presumably has happened as this environment around us has changed, as there's all this ultra-processed food, we've changed our activity patterns, all these other things, that has then interacted with elements, latent elements of our genome that existed at a previous time, maybe weren't that important because we didn't have access to easy high high calorie foods, et cetera.
• 9:17
  But now those, those, those latent elements of our genome are exposed and cause people to gain a lot of weight.
• 9:23
  So an expression that people sometimes use is um genetics loads the gun and environment pulls the trigger.
• 9:30
  Meaning uh genetics sets your propensity for anything, including weight gain.
• 9:35
  And then genetics exposes, and then environment exposes that that propensity.
• 9:39
  And so in the world we live in, uh uh, many people have a genetic predisposition then to gain weight, and they do, and they find it very hard to keep it off.
• 9:46
  So, how does, you know, if if I am that person, yeah, how do I know that I'm that person and that, you know, that there is obviously a tremendous amount of willpower involved in sticking to any of these long-term sort of sustainable lifestyle change, right?
• 10:02
  To to exercise every day, to get enough sleep, to build human connection with other people, to manage stress, all of these things require effort.
• 10:09
  How do I know as an individual whether, you know, I am genetically predisposed?
• 10:15
  And this is just a lot harder for me because it strikes me that I think if we all think about our family and friendship group, there are certain people that you know seem to look at a dumbbell and get really strong and fit.
• 10:26
  And there are people that look at a donut and seem to put on weight.
• 10:28
  And like that, from what I'm hearing, is to some degree true, right?
• 10:33
  But how do you know?
• 10:34
  I mean, unless you have a rare monogenic obesity syndrome where you have one of these single gene mutations that that causes you to be morbidly obese.
• 10:42
  And there's, you know, about sort of 20% of people who, from a young age, are very overweight, have mutations in single genes that we know about that cause control body weights.
• 10:52
  They can actually do a genetic test.
• 10:53
  Yeah.
• 10:54
  And this is not this is not people who are overweight.
• 10:56
  This is people who have sort of syndromes from a young age where basically this person's extremely overweight.
• 11:01
  Very often they're in a single pathway in the brain that controls body weight, the melanocortin pathway.
• 11:06
  So there's just a handful of mutations that happen again and again in this pathway that in people with this sort of inherited obesity from a very young age, they're very common.
• 11:14
  Now, for most of us, it's not going to be something like that, right?
• 11:17
  And we know from human genetic studies that there's sort of over a thousand genes that have been implicated in body weight control.
• 11:24
  And so your predisposition.
• 11:26
  Over a thousand genes, your predisposition to body weight to a particular body weight and mind will be determined by the interaction between different alleles of these hundreds, thousands of these different alleles.
• 11:36
  And so it'll be very complex to decipher what the small contribution of each of those is.
• 11:40
  But I would say just from a practical perspective, I mean, there are a set of interventions that are pretty well known, pretty low tech, that you can do to try to improve your metabolic health and lose weight, right?
• 11:52
  Things, things like trying to eat more whole foods, um, you know, uh eat enough protein, which is important for lots of reasons because, you know, both because uh it's more satiating, but also because there's this idea of protein leveraging, right?
• 12:06
  Which is that basically it's the only macronutrient where if you don't get enough protein in your diet, you will then consume more of other things just to raise that protein up to a minimal level.
• 12:15
  So there's basically a an innate need to get a certain amount of protein, and people will overeat just to get that if their if their diet is sort of too.
• 12:21
  So just to be clear, that's the only of the three macronutrients.
• 12:25
  That's right.
• 12:26
  Yeah, so let me explain to you what I mean by that.
• 12:28
  So basically, um, you know, obviously we like sugar and fat.
• 12:31
  And so we'll eat sugar and fat just because we like them.
• 12:34
  But but there's evidence in all sorts of different organisms, including humans, that there's um that there's a certain amount of protein consumption that's actually defended by the body.
• 12:42
  Yeah.
• 12:43
  And um the the reason we know that is if we give animals that have a low protein diet, then they will overeat to in order to get that pro that their total amount of protein up to a certain minimal level.
• 12:54
  So they'll essentially become obese because they're trying to get that protein up to a minimal level.
• 12:58
  If we just increase the amount of protein, then they won't overeat.
• 13:01
  And humans do the same thing.
• 13:02
  It's called protein leveraging.
• 13:03
  And so one easy way to make sure that you're not overeating for some sort of solvable reason is just to make sure you're getting enough protein.
• 13:09
  Yeah.
• 13:09
  You don't need to eat extreme amounts of protein.
• 13:11
  You don't need to be eating protein bars or supplements or whey powder, any of that stuff.
• 13:14
  But you just need to make sure you're getting, you know, a reasonable amount of protein.
• 13:17
  Um but there's those kinds of things.
• 13:20
  It's it's it's you know, it's it's it's known that, you know, just tracking your activity, right?
• 13:24
  Tracking how much you eat each day can be really sort of eye-opening and teach you about wow, really eating this many calories and this this particular food has way more calories than I thought.
• 13:32
  So simply being mindful about that.
• 13:33
  I mean, one of the things we know about the small group of people who successfully lose a lot of weight and then keep it off for many years is that they really track their progress.
• 13:42
  They weigh themselves every day, they monitor everything they eat.
• 13:45
  So there are all of these sort of suggestions that you can employ to um to try to improve your metabolic health and lose weight.
• 13:51
  But for many people, um, if they even if they employ all of those things, they won't necessarily get to the weight that they want to get to.
• 13:57
  Yeah.
• 13:58
  But they'll find it extremely difficult to get to that weight.
• 14:01
  And then the question becomes you know, do you want to devote your whole life to being thin?
• 14:05
  Yeah, to what end are you doing?
• 14:06
  Exactly, exactly.
• 14:07
  And you have other activities in your life that you want your focus and energy and attention to be directed towards.
• 14:12
  And so that's when we start thinking about sort of other options.
• 14:15
  Yeah.
• 14:16
  So, so across that spectrum of different personas, different biology, genetics, even preferences, does this sort of law of thermodynamics apply to everyone every time?
• 14:30
  Right.
• 14:30
  And by that I mean regardless of how hard it is for you based on your biology and genetics, if you were to have a deficit of energy intake, i.e., eat less calories than you than you burn, will 100% of the people 100% of the time lose weight?
• 14:48
  Right.
• 14:49
  I understand that it's obviously very different in terms of level of discipline and effort for some people who have, you know, a worse deck, a worse deal of the hand, so to speak.
• 15:00
  But does that law still apply right to everyone every time?
• 15:03
  Yeah.
• 15:04
  I mean, physics applies to the entire universe as far as we know.
• 15:07
  So basically, the amount of, I mean, there's just three things happening.
• 15:10
  There's the energy you intake in eating, there's the energy you excrete, right?
• 15:15
  And then there is the energy that's burned.
• 15:17
  Yeah.
• 15:17
  Most of us harvest approximately the same percentage of calories.
• 15:21
  So there's there's very little fluctuation among most people unless you have some parasite or something, basically in that.
• 15:26
  So it really comes down to how much you consume and versus how many calories you burn.
• 15:31
  So, like an interesting sort of sort of anecdote about this.
• 15:34
  So, you know, it's actually very hard to measure food intake in free living humans.
• 15:38
  Yeah.
• 15:39
  Because just people just they won't tell you the truth.
• 15:41
  Yeah, either intentionally or unintentionally, they will not accurately record their food intake.
• 15:45
  So technologies were developed for measuring energy expenditure and freely living.
• 15:50
  When I say freely living, I mean at your house, not like in a lab, spending 24 hours in a lab.
• 15:54
  Um, were developed for measuring energy expenditure and freely living people long before uh food intake.
• 15:59
  And the one that that that um and I would say we still don't have great measures for for ways for monitoring food intake and people just in their everyday lives.
• 16:06
  But but the one of the techniques that that that that uh uh was developed is a thing called doubly labeled water.
• 16:11
  So you use that.
• 16:12
  Use that, okay.
• 16:13
  Yeah.
• 16:13
  So it's basically just a technique so you can monitor how much energy people are expending.
• 16:16
  It's expensive, but it's very accurate.
• 16:17
  And you know, the major result of the very first doubly labeling water studies was that everyone is lying about how much they're eating because basically it just like it was thermodynamically impossible.
• 16:28
  And I think uh it was a kind of a famous study, right?
• 16:30
  And that they did it for nutritionists as well.
• 16:32
  I think one of the like cohorts and they even underreported.
• 16:36
  Yeah.
• 16:36
  So it's just so so yeah, so I don't remember how we got on that.
• 16:40
  But anyways, yeah, that's so yeah.
• 16:42
  I think well, I think like when we are one of the most disheartening things about trying to either lose fat or build lean tissue is that you know we put a lot of effort into it, and maybe if we're not tracking it with real accuracy, and that can sometimes not be our own fault.
• 17:00
  It might be the technology we use or the labeling of the you know, um, the foods that we're eating, that's really disheartening.
• 17:05
  Yeah, right.
• 17:06
  When you like go to weigh yourself or have a scan and then you can see that you haven't made progress.
• 17:10
  And I think for us to create that long-term behavioral change, that lifestyle change, you need to see momentum, right?
• 17:18
  And you know, I think that's probably one of the reasons why these GLP ones have become so hugely popular because people are seeing results quick.
• 17:28
  Absolutely, yeah, absolutely.
• 17:30
  Let's move on to that because I know that is a question that you know everyone who is looking to change their body composition is thinking about, right?
• 17:39
  Because it seems that they've become remarkably popular remarkably quickly.
• 17:42
  Yeah.
• 17:43
  What's your sort of high-level perspective on using them as a as a tool for improving body composition in the people who are um clearly in very much need of doing that, but also in the people who are using them for other reasons?
• 17:58
  Sure.
• 17:59
  So generally I'm very positive on GLP1.
• 18:02
  So, you know, so I so I've worked in this field um uh of you know uh energy energy homeostasis and body weight regulation for some time.
• 18:10
  And I remember when I was starting in this area, and you know, basically the history of drug discovery for obesity was just a history of failures, right?
• 18:19
  We had things that that were pulled from the market one after another because they were toxic.
• 18:23
  We had things, and none of these things were really that effective.
• 18:25
  You know, you would get maybe five to seven percent weight loss, um, people couldn't really stay on them over the long term, things like stimulants that lost their effectiveness over time.
• 18:35
  Um, and so it was really the the idea was that this was, you know, something that I don't didn't think we would see something this effective, you know, in my lifetime.
• 18:42
  Or I say I was I was not certain that we would.
• 18:45
  And I think the GLP ones really caught a lot of people by surprise because, you know, they're not new drugs.
• 18:50
  And so, and so they've been around for around 20 years.
• 18:52
  Um, the first ones were approved, uh, mainly for diabetes or entirely for diabetes, the initial um approvals.
• 18:58
  And it's really slowly through clinical use that we've learned uh that these can be used for weight loss and how effective they can be.
• 19:04
  And then through progressive optimization of these compounds in the pharmaceutical industry.
• 19:09
  So, so you know, in terms of your, in terms of, you know, basically uh uh uh the feet the the the the the you know safety of these drugs, I would say that, you know, one, we have 20 years of clinical experience now with these compounds, so many millions of people.
• 19:23
  So we uh uh uh we really know something about long-term outcomes.
• 19:27
  The other thing I think that a lot of people might be don't appreciate about the way these drugs are developed today compared to say things that like fenfen that you might have heard of from 20 years ago or something, where there were these issues, because of those failures, because of those toxicities that happened, because some of those drugs are pulled from the market, you know, the FDA now requires large cardiac safety clinical trials for these for these GLP1 drugs, you know, 20,000 people, you know, institutions all over the world, it costs like a billion dollars to run some of the largest clinical trials, right, in in in in in medicine.
• 19:59
  And um these drugs seem to be very safe, you know, in these large clinical trials.
• 20:05
  Um, and not just safe, in some cases, they seem to have uh health benefits that we didn't even really expect, you know, and so as many people are aware, the the the the clinical trial for for semaglutide, which is ozempic, that that cardiac safety trial was published a couple years ago now.
• 20:23
  And they found that um as expected, uh basically people who took that drug they had fewer heart attacks, fewer strokes, fewer deaths for any sort of cardiovascular reason.
• 20:34
  Um but it seemed that for many of those people, um, the benefits of taking the drug appeared before they'd even lost a significant amount of weight.
• 20:41
  And there was no correlation between how much weight you lost and your protection from heart disease.
• 20:45
  Is that right?
• 20:46
  And and so and so one idea that's been emerging is that is that is that while there are undoubtedly big health benefits from losing weight, obviously, and these drugs are very effective in helping you do that, um, there are uh uh additional benefits, perhaps related to things like like inf suppression of inflammation that these drugs may be doing, operating through some of the same pathways that they control appetite, but then uh uh basically having other effects that that have other health benefits.
• 21:09
  Now, it's still early days.
• 21:10
  There haven't been a lot of clinical trials for these other kinds of indications, but um I think that's something people are very excited about.
• 21:16
  But what what makes the scientific community collectively think that that is beyond the fact that they are just consuming less calories?
• 21:24
  Well, I think as I sort of said, I mean, I think part of the part of the idea is that so yeah, so there's there's a couple ideas.
• 21:30
  So so if you look at sort of when the placebo and semaglutide groups diverge, right, in these trials, you seem to see the incidence of these cardiac events decreases before they've lost a large amount of weight.
• 21:42
  Yeah.
• 21:42
  And the and and the protection doesn't seem to correlate with how much they lose over the course of the trial.
• 21:46
  Now, one point which which you may may be might be making, which is a good point, which people argue about, is that is it simply that when you start taking these drugs, you experience an acute reduction in food intake?
• 21:58
  And just in this first Few weeks, like just having just having that there's sort a certain toxicity associated with just overeating on a short time scale, and you're correcting that.
• 22:07
  And that's the basis for this.
• 22:09
  And I think we still don't know the answer to that.
• 22:11
  It's it's hard thing to tell you.
• 22:12
  You would expect to see some of those markers improve with fasting.
• 22:15
  That's right.
• 22:16
  Right.
• 22:16
  That's right.
• 22:18
  That's right.
• 22:19
  But then I guess you would see some weight loss then as well.
• 22:21
  That's right.
• 22:22
  So so I think, you know, it's it's the jury is still out on that.
• 22:25
  But I think I think, you know, you know, I guess I didn't really talk at all about the effectiveness of these drugs, but I think um, you know, uh uh they are very effective, and we can talk about that.
• 22:34
  But but I think we safety is something where there were legitimately a lot of concerns.
• 22:38
  And I think now most of those have been put to rest.
• 22:41
  I mean, there are a lot of people experience nausea, um, experience constipation, various GI side effects.
• 22:47
  That's well known.
• 22:48
  Um, for many people, they go away over time.
• 22:51
  Um, and then the sort of dosing regimen for these drugs is such that uh you start off at a low dose deliberately to minimize the side effects and gradually increase.
• 22:59
  There are also newer generations of these drugs that seem to have some of those effects minimized because they have slightly different combinations of targets.
• 23:06
  We talked about that earlier.
• 23:08
  Um but but I think serious side effects are quite rare.
• 23:13
  I have three questions for you on this.
• 23:16
  The f the first being what is happening mechanistically in the brain that is then meaning that we don't feel so hungry all of the time?
• 23:26
  Because I'm assuming that is the you know the number one reason we're seeing that weight loss is that you know, over time the weight loss is due to consuming less calories.
• 23:34
  So mechanistically we must not be feeling as hungry, right?
• 23:39
  That or our appetite lowers.
• 23:41
  How's that happening?
• 23:42
  Yeah.
• 23:42
  So basically, um yeah, so so so these GLP1 drugs act primarily on neurons in the brainstem, in the most the most posterior part, the post back part of your brain, that are evolutionarily specialized for controlling basically food intake on the timescale of a meal.
• 24:00
  So these are these are neurons in the back of your brain that get input directly from the vagus nerve, which is the nerve that innervates your stomach and and intestines and heart, and sends signals from the body to the brain.
• 24:10
  And um, these neurons sense all sorts of circulating signals, uh, hormones, that are produced when you eat food and that cause you eventually to be sated.
• 24:19
  And what GLP ones are doing is just basically activating, sort of superactivating that pathway continually.
• 24:27
  Um so ordinarily when you eat, you would have a rise in these hormones and then a fall after a few hours, and then there was there'd be this cycle.
• 24:33
  And the the sort of thing that was the key advance that made GLP ones into effective obesity drugs was making drugs with this very long half-life.
• 24:41
  So, so for example, semaglutide, so you know, uh ozempic has a half-life of seven days.
• 24:46
  And so what you can do with a seven-day half-life is basically give someone a dose of one of these hormones from the gut, but at a level so that it's always very high, never decreases.
• 24:55
  And so just continually activating this break pathway in the brainstem.
• 24:58
  So it's as if you have or having the hormonal milieu of a post after a meal, sort of seven days a week, 24 hours a day.
• 25:05
  Right.
• 25:06
  Um, now I think it's a little bit surprising that you can actually do that.
• 25:11
  People seem to be fine and it just makes you less hungry, but that seems to be what the evidence suggests.
• 25:16
  Now, how that's working mechanistically in the brain, you know, that signal from the brainstem is then being propagated forward to all sorts of centers in your brain, including centers that you know process the reward value of food.
• 25:28
  And so, so you know, one of the things people find is just that that they find food less rewarding.
• 25:32
  Right.
• 25:33
  I mean, um, and and and then and the rewarding word value of it decreases faster during a meal.
• 25:38
  So one of the important most important things that controls appetite, this concept known as anesthesia.
• 25:44
  This is it's from like Cervantes' quote, you know, uh, hunger is the best sauce, right?
• 25:48
  So basically what makes food taste good is is when you're hungry.
• 25:52
  Right.
• 25:52
  And then as you have eat each bite of a meal, the hunger just goes down, right?
• 25:56
  That's anesthesia.
• 25:57
  And so, and so what what GLP ones do, one of the things they do is speed that up, right?
• 26:01
  And so basically, so that it just goes faster.
• 26:04
  Yeah.
• 26:04
  So basically your meal is shorter.
• 26:06
  Another important thing they do is Does that in some way take the joy out of eating for you?
• 26:11
  You know, I think there it doesn't seem to cause generalized anhedonia.
• 26:15
  And I think people still enjoy food, but I think they don't maybe enjoy it as much for as long.
• 26:19
  Sure.
• 26:20
  And so, and so, you know, um, I think it doesn't complete, you know, people who have completely lost or to a great extent lost the pleasure of food, you know, people who've lost their sense of smell and taste, they report really it's really unpleasant.
• 26:32
  Is food, the reward of food is one of the really important things about life.
• 26:35
  Sure.
• 26:35
  And so uh GLP ones don't seem to do that, but they definitely do, you know, I think accelerate this decrease when you're eating.
• 26:42
  And that's why you stop eating.
• 26:43
  Yeah.
• 26:44
  Right.
• 26:44
  Um That's why they work, right?
• 26:46
  Yeah, it's how they work.
• 26:47
  And so um uh, but the other, the other sort of thing they do is is is decrease the activity of these neural circuits that cause you to search for rewards, sort of foraging, to go out in the world and look for things, sort of wanting things.
• 26:59
  This is not when you're putting the food in your mouth, but this is when you're sort of motivated to go to the store to buy the sandwich because you're you're hungry, right?
• 27:06
  Dopamine?
• 27:06
  Yeah, which involves dopamine.
• 27:08
  And so they really tamp down those food-related dopamine signals.
• 27:12
  And this, I think, is the is the origin of a lot of what people say is this reduction in food noise when you're taking the the GLP ones.
• 27:18
  Lots of people report this.
• 27:19
  The idea that, you know, before they before they took the GLP ones, they would um, you know, uh basically think about food more than they would have liked to, right?
• 27:28
  The the concept of food entered their mind uh uh uh more frequently because they just were hungrier.
• 27:34
  And and and so sort of that that noise is quieted uh uh for many people when you take these drugs.
• 27:39
  Would I be right in then saying that's why people are reporting um less addictive behaviors in general?
• 27:45
  Yeah.
• 27:46
  Is that the same thing?
• 27:47
  Yeah.
• 27:47
  So there's an idea that that's that's the connection.
• 27:49
  And so and so it's still early to figure out sort of to demonstrate which of these addictive behaviors are really reduced by the GLP ones and which is more just sort of anecdotal.
• 27:59
  Right.
• 27:59
  Yeah.
• 28:00
  Um, I think, you know, even though the the the the the large clinical trials haven't been published yet, I think there's a general consensus that it there these drugs are going to show um uh benefits in alcohol use disorder, right?
• 28:11
  Well, it makes sense, right?
• 28:12
  Like if your if your um ability or or desire to search for reward from food is dulled, it would make sense that the same applies for alcohol.
• 28:23
  And I think alcohol is you know, it's another ingestive behavior.
• 28:26
  Yeah.
• 28:26
  Alcohol is also caloric, right?
• 28:28
  It's caloric, just like food.
• 28:30
  Um, so there's lots of reasons to think alcohol is a special case.
• 28:33
  And really, and almost everyone reports it just produced desire to drink.
• 28:37
  Um, and and so there's lots of reasons to think that yeah, these drugs are really suppressing alcohol consumption, and and that's what we'll see when the data comes out.
• 28:44
  Um, you know, some of these other things, you know, it's being tested for opiate use, for uh stimulants, for other kinds of things, for gambling.
• 28:52
  Some of those things I think we'll see how general that is.
• 28:55
  It might be that some people experience that, but but maybe how general that is is not clear yet.
• 29:02
  Do we have um enough long-term data to know what the real impact this is gonna have on lean tissue is, on muscle mass?
• 29:12
  Because obviously, go back to that law of thermodynamics, if you're in a consistent calorie deficit, that is catabolic.
• 29:19
  You're gonna break down lean tissue as well as fat.
• 29:21
  Yeah.
• 29:21
  Right.
• 29:21
  And you know, we often say that muscle is the currency of longevity.
• 29:25
  Sure.
• 29:26
  And so, as we are, no, certainly with people that are considering or are already taking um one of these in their 50s, 60s, and beyond, how do you see that playing out?
• 29:39
  Because that could be catastrophic for some people.
• 29:41
  Yeah.
• 29:42
  So yeah, it's a great question.
• 29:43
  So I, you know, I think um it's it's something that's become a concern because most people by now have seen someone lose a lot of weight on one of these drugs, and they've seen they basically obviously also at the same time lose a lot of muscle mass.
• 29:56
  And and it can be kind of scary to see someone become so skeletal, especially for an older person where you're already losing so much muscle mass to begin with, and you don't want to accelerate that process.
• 30:05
  Yeah.
• 30:06
  Um, you know, I think that the the consensus is that this isn't any special effect of GLP1s.
• 30:12
  It's simply the effect of losing weight.
• 30:14
  And so basically, if you lose weight, and particularly if you lose weight rapidly and you don't do anything to prevent the loss of lean mass tissue, meaning you don't eat a high protein diet, and most importantly, you don't engage in resistance training, then um, almost everyone, if they just diet, they're going to lose muscle mass.
• 30:31
  And and you know, there isn't a lot of signal that people are losing muscle faster on the GLP ones than if they just dieted.
• 30:38
  There might be a subtle effect with semaglutide, but with some of the others, it doesn't really seem like there's any difference at all.
• 30:42
  My my devil's advocate argument there would be if I am just using willpower to eat less, yeah, my desire to eat enough protein will still be there.
• 30:55
  Whereas if I'm using a GLP one and that is blunted, that that desire to eat, is it not just then harder for me to actually hit that protein target or even to motivate myself to exercise?
• 31:07
  Do we have any data on that?
• 31:08
  Yeah, it's a good question.
• 31:10
  Um well, I I haven't seen any clinical trials that that combine these drugs with um specific strength training regimens or dietary regimens to prevent lean muscle loss that any longer trials that have looked at that.
• 31:21
  Yeah.
• 31:21
  I'm sure they're coming.
• 31:22
  Um Lee Schaumfeld is doing one right now.
• 31:26
  Um but um uh, you know, I I think you're right.
• 31:30
  You might be right.
• 31:30
  I mean, it might be that, you know, you know, it's just harder for some people that under the to eat, you know, a complete diet uh when they're taking these drugs.
• 31:38
  And on the other hand, the counter-argument might be that, you know, you know, because they're taking away this food noise, because you have to exert so much energy and focus to lose weight when you're taking these drugs, then that kind of frees up some of your mind and your attention to do these other things.
• 31:51
  I would think it almost might be easier.
• 31:53
  Yeah.
• 31:53
  I mean, definitely many people do start.
• 31:55
  And also I think just the experience of losing weight, um, you know, in many ways can make it more more rewarding to go to the gym, right?
• 32:01
  You know, if if basically if you're actually seeing progress.
• 32:04
  So um, you mean yeah, you get some traction and then you uh you're motivated to continue doing it, right?
• 32:09
  Yeah.
• 32:10
  Huh.
• 32:10
  So let me ask you a question then.
• 32:12
  Yeah, right.
• 32:13
  Your one of your parents or grandparents is considering someone more senior in your life who really does need to hold on to that lean tissue, right?
• 32:26
  We've seen some frightening statistics with people in their 70s, 80s, anything over 60 who are falling and breaking a bone, not recovering, right?
• 32:34
  Um, because they haven't got that robustness in their, you know, uh musculoskeletal system, who is not morbidly obese, who's considering taking GLP1 for an aesthetic purpose because they want to get a bit leaner or look a bit better, sure.
• 32:50
  Do you what do you tell them?
• 32:52
  What's your advice?
• 32:53
  Yeah.
• 32:53
  Oh, that's a okay.
• 32:55
  So um I would say that well, I would say that the the taking a low dose of a GLP one for aesthetic reasons, um it's unlikely to have uh a major acute adverse effect, but you could cause this body recomposition that could be could be you know bad.
• 33:14
  And so and so and so it really depends for each individual on the risk reward and your stage in life, your willingness to do the work in order to maintain the muscle mass that you need.
• 33:24
  Um it's a hard, it's a very individualized thing.
• 33:26
  It would be hard to say.
• 33:27
  I think generally, you know, you know, I'd be a little bit hesitant to take it just for aesthetic reasons.
• 33:33
  Um, but you know, I mean, most people seem to tolerate extremely well.
• 33:37
  So, so so I think that you know at this stage the risks, risks seem to be minimal.
• 33:43
  But um I guess it's a trade-off, right?
• 33:45
  Like and and I I suppose there's no reason that you couldn't do one then the other.
• 33:51
  Like if you if you did want to lose some weight and then build some lean tissue, could you then just stop the GLP one and then focus on building like a a sensible calorie surplus without putting on the fat.
• 34:03
  Yeah, I guess.
• 34:04
  Are these forever drugs, would you say?
• 34:06
  It's pretty clear that that if you go off any of these current drugs that that you'll regain the weight or most of the weight, most people will.
• 34:12
  Um, because basically what these drugs are doing is, you know, when you when you lose weight, basically your body initiates a counterregulatory response to try to force you to gain the weight back.
• 34:21
  And this happens in everybody.
• 34:22
  It doesn't matter if you're ordinarily lean or you're or or you're or you're you know genetically overweight, whatever weight is your sort of comfortable weight, when you start going below that, you'll you'll notice that that your hunger increases and your energy expenditure goes down.
• 34:36
  Um and there's variation between people, but the numbers that you know are quoted from clinical studies are that for about every kilogram of body weight that you lose, so for about every two pounds, um, you have a decrease in your energy expenditure by 30 calories a day and an increase in your appetite by 100 calories a day.
• 34:55
  Um now there's variation between some people, some will have less, some will have more, but on average, that's the response.
• 35:00
  That's 130 calories a day if you if you yeah.
• 35:03
  And so um uh and so over time that quickly adds up and then you will regain the weight.
• 35:08
  Yeah, like a pound in 30 days, probably.
• 35:09
  Yeah.
• 35:10
  32 days.
• 35:11
  Yeah.
• 35:11
  And so there's so what people think the GLP ones are doing is essentially um uh uh acting as a constant push that fights back against that counter-regulatory change.
• 35:20
  And so they're they're essentially this force that is keeping you, that is opposing that counter-regulatory change and keeping you uh at the lower body weight.
• 35:26
  And as soon as you relieve that, then you just sort of go back to to where you were comfortably before.
• 35:31
  Is that do you think we have a soul for that?
• 35:33
  Like, do you think there are, I know there are um we talked very briefly earlier about um these double and triple agonists, like variations of these drugs.
• 35:43
  Where do you see that going over the next sort of five years or so?
• 35:46
  Yeah.
• 35:46
  So it's an interesting question.
• 35:48
  So, so um uh, you know, there are new newer drugs coming.
• 35:52
  So it's uh you know, the GLP ones have just caused an explosion of interest in the pharmaceutical industry and obesity.
• 35:58
  And so, you know, you know, 10 or 15 years ago was really a wasteland.
• 36:01
  Everyone was exiting the area, and now almost the entire industry is all in on obesity drugs.
• 36:06
  And and lots of these are are essentially variations on GLP1 drugs.
• 36:09
  So taking the core GLP1 component, this hormone GLP1, and then adding additional properties to it, to call it GLP1 Plus, by adding additional hormones to it to sort of uh generate a sort of a customized metabolic profile.
• 36:23
  So one of the ones, you know, I think the the most effective drug that that's currently available of this class uh is this drug uh terzepatide, which is also known as Munjaro or ZEP bound for obesity.
• 36:35
  Um that's actually already a GLP1 plus.
• 36:37
  So that's the GLP1 agonist, which all these drugs have, and then has the second hormone, GIP, GIP.
• 36:44
  Um, and what GIP does is another hormone like GLP1 that comes from the intestine.
• 36:49
  It basically acts in the brainstem to suppress nausea.
• 36:52
  So you essentially have both the the uh uh the weight loss from the GLP1 and then this anti-nausea effect from the GIP.
• 36:58
  And so that would be a double agonist.
• 37:00
  That's a double agonist.
• 37:01
  And that's already approved, and it's it's currently the best-selling drug in the world.
• 37:04
  So basically, it's I think it passed uh I think it that reached that status a couple months ago.
• 37:09
  And so um uh uh and so that's very successful.
• 37:13
  Um that's made by Eli Lilly, and they have a compound in late-stage clinical trials now in phase three.
• 37:18
  It'll probably be available to the public in 2027.
• 37:22
  Um, uh that's a triple agonist now.
• 37:24
  That's now three compounds, three three hormones in one.
• 37:27
  Uh one is GLP1, which causes the suppression of appetite.
• 37:31
  One is GIP, which suppresses again this nausea.
• 37:34
  And the third one is this hormone glucagon.
• 37:37
  And um, what glucagon has been shown to do is it acts to just increase your resting energy expenditure, meaning you just burn more calories at baseline doing nothing.
• 37:47
  You don't have to exercise, it just increases your metabolism.
• 37:50
  That does this primarily through effects on the liver, we think, just increasing the baseline metabolism and also the the heart.
• 37:55
  And so, um, and you know, to give you some perspective, you know, the sort of the the first real GLP one that was widely used for uh uh um obesity, uh well, I actually say the first one was lyriglutide, and that causes something like 9% weight loss.
• 38:10
  Lyriglutide, most nine of most people have have never used or heard of lyriglutide.
• 38:15
  But then osempic, which is semaglutide, um, that causes something like 16% weight loss on average in people for clinical trials where they take this drug.
• 38:25
  This drug I talked about, this dual agonist, terzepatide slash munjaroze bound, that causes about 21% weight loss.
• 38:34
  This new drug that'll be approved probably next year, uh terzepitide, um, uh retitrutide, um, the triple agonist, that causes around 28% weight loss.
• 38:44
  So we've been slowly sort of over the last 20 years working our way up until now at 28% weight loss.
• 38:49
  It's just like um, you know, that's like bariatric surgery.
• 38:51
  That's like these stomach surgeries people have.
• 38:53
  So it's just an incredible amount of weight loss.
• 38:55
  Now, for all of those drugs, you need to continue taking it because for any of them, they're operating by the same mechanism of delivering a hormone uh at a high dose continually.
• 39:05
  There are strategies being developed to try to get past that.
• 39:09
  So you can make the change either permanent or semi-permanent.
• 39:13
  And there's a lot of uncertainty about first, is that even a thing you want to do?
• 39:17
  Right.
• 39:17
  Because like because like I would, I personally would think that you know the safety margin that has to be incredible, right?
• 39:23
  Because then, you know, you're making irreversible change to your brain, basically.
• 39:27
  Um, uh, one way people are trying to do that is by using gene therapy to deliver GLP1s to various tissues, such as the pancreas.
• 39:35
  So essentially you would get, you would, you would, you would produce basically ozempic naturally yourself, and just like then one jet one ejection and then you're done.
• 39:43
  So there are people doing that.
• 39:44
  There, there are clinical trials investigating that.
• 39:47
  The other strategy people are taking, um, uh, which is not quite permanent, but it's definitely long-lasting, is um uh by just extending even further the half-life of these drugs.
• 40:00
  So, you know, you know, the current drugs have a half-life of about a week, which is about the longest you're gonna get with a peptide.
• 40:06
  So these are peptides.
• 40:08
  Um, but there are some compounds, including one uh from Amgen that is in late stage clinical trials called uh meritide, that's now an antibody.
• 40:18
  So this is an actual antibody.
• 40:20
  You get an antibody infusion rather than inject a peptide.
• 40:22
  Um, it's a GLP1 receptor agonist.
• 40:25
  It also modulates GIP.
• 40:27
  So, like like Moonjaro is that bound, it's a dual agonist.
• 40:30
  And for that one, um, you initially only need the antibody delivered once every month.
• 40:37
  And then some of the early clinical trials suggest that you can even then remove it.
• 40:41
  And then for several months at least, people maintain the weight.
• 40:45
  So it's either because the antibody has a long half, just a particularly long half-life, or some people think something about the mechanism of action is just causing longer lasting changes in the brain.
• 40:54
  Now, that mechanism is never going to give you lifetime, right?
• 40:56
  Yeah.
• 40:57
  But you're you're getting to the point then where maybe someone goes into the doctor's office every six months, gets an infusion, and you know, basically Can I ask you?
• 41:05
  I think, you know, when we hear as consumers, when we hear about products that you might need to take forever, yeah, that are worth billions of dollars, that are the things that are the highest sold drugs in the world, crazy numbers from pharmaceutical companies, there is an obvious and fair, I think, degree of skepticism, right?
• 41:25
  When something seems too good to be true, yeah, it usually is.
• 41:29
  And I think we're we're all a bit tired in general of a lot of overreaching and grandiose claims and you know, hyperbole in our space, we're seeing a lot of sort of celebrity biohackers and physicians that are um, you know, I think giving very broad advice across very complicated verticals.
• 41:49
  Sure.
• 41:49
  You know, is there anything?
• 41:51
  I don't want to get you in trouble here, but is there anything that you are seeing that you know you think is a little bit of an overreach in general that we're getting uh with regards to these drugs, but also with regards to like the the um management of appetite and hunger in general that you think is a little too early to be saying, you know, I'm I'm just acutely aware that we don't know everything about everything, right?
• 42:16
  And aging is no different.
• 42:18
  Yeah, sure.
• 42:18
  I well, so I mean, there has been this explosion over the past few years in this concept of consumers just purchasing peptides basically and treating themselves for diseases.
• 42:31
  And and and so, and I think a lot of it was driven by the GLP ones, basically, even though some people don't understand as we were saying that the GLP ones are peptides, right?
• 42:40
  In fact, they're sort of the the most successful peptides.
• 42:42
  Yeah.
• 42:43
  Um uh and and so I think the reason this has become popular is because there's there's something about so you know peptides compared to a lot of other pharmaceuticals, they're just relatively easy to make because the chemistry uh is kind of automated.
• 42:58
  And so you can just, you know, you don't have to be some expert chemist with develop some whole new process to make a bunch of peptides, right?
• 43:04
  This can be done in just factories that that maybe have a slightly lower standard, a slightly level of of investment.
• 43:10
  And so, you know, as a research scientist, that's what I do research in the laboratory with mice and rats and things.
• 43:16
  There are these companies that we've used for decades, right?
• 43:18
  That we just order peptides from them because we use peptides in science, right?
• 43:21
  I mean, we inject them into the brain or whatever.
• 43:23
  And and they exist to sell, to sell peptides to the scientific community.
• 43:28
  For research purposes.
• 43:29
  For research purposes, right.
• 43:30
  But but now people have realized, well, I can just go to the same company and buy it for research purposes, where the research purpose is to inject it into myself.
• 43:36
  Yeah.
• 43:36
  And and and you know, it's you have to be careful, right?
• 43:39
  Because, you know, you know, you know, the compounds that were produced by Eli Lilly and Novo, they go through extremely um uh uh careful uh uh safety testing, right?
• 43:47
  Impurity testing, and they have to be manufactured under good manufacturing uh uh criteria.
• 43:52
  And so you just know there isn't a contaminant in there because the FDA creates these high standards and these are real companies.
• 43:58
  Um, you know, there's not the same level.
• 44:00
  of of of uh care for uh these uh research peptides for good reason right because they're not supposed to be going into people yeah and um no i mean some of these companies that they'll often you know send their peptides out for third party testing and so you can see there's like safety there's there's not safety but there's there's um there's mass spectrometry reports saying this is the real stuff so at least you know it's not nothing right it's the real thing but but it is a little bit dicey right and I think I think you know the reality probably is for the GLP ones that are FDA approved, because they are pretty safe and because they're not so complicated to make, most people are probably getting the real thing and they're probably going to be fine.
• 44:35
  Yeah.
• 44:35
  But what it's what it's what it's sort of engendered then is this explosion in just all sorts of peptides that just basically many of which are barely studied in the clinic and there's one clinical trial or a few clinical trials 20 years ago but reported some interesting effects.
• 44:49
  Maybe the peptides weren't pursued further by the pharmaceutical industry because they saw some hint of some side effect that maybe they knew that was this is going to be a bad road if we continue down.
• 44:57
  But you know you read the the the phase two study from 10 years ago and it doesn't mention that really and so so so you know influencers and and and and just and sorry yeah.
• 45:06
  Are you bullish on them in general?
• 45:08
  Should they be you know assuming that you could have these purity checks like mechanistically are you bullish on some of these other peptides well because it sounds like kind of appealing to people right like anything that's gonna get you a better result in less time.
• 45:23
  So so I definitely I'm definitely in favor I mean I view this as technological progress and I'm very in favor of technological progress and I also view it as like an issue of freedom and I'm very in favor of people having the freedom to do what they want to their bodies.
• 45:33
  So I don't have any problem with either of those things.
• 45:36
  I do think though for a lot of these things, you know, they just haven't been studied.
• 45:40
  So you're basically you're you're just you're just you don't know right you don't know what's going to happen.
• 45:44
  I mean so you know one one that's very popular uh is this compound melanotan.
• 45:50
  And um it's it's long before GLP1s were widely used by people, there was another pathway that people studied for the regulation of obesity.
• 45:58
  It's called the melanocortin pathway.
• 46:00
  And it's actually we were talking about the genetics of obesity earlier this is the pathway that's mutated in all those people with those syndromes.
• 46:06
  And so it was a very logical candidate for to to make obesity drugs to target this pathway.
• 46:11
  And there were some some some early failures and one of them was this peptide melanotan which does target this pathway and uh it um causes some weight loss but also has some other side effects some blood pressure effects other things.
• 46:26
  Another side effect it has because this melanocortin receptor in your brain that controls appetite there's another form of it in your skin that controls pigmentation if you take this peptide you get sort of a tan, right?
• 46:36
  So you basically are losing weight at getting a tan very popular for this for this reason.
• 46:41
  But you know it was abandoned for a reason because there's some concerns about you know safety.
• 46:47
  And so and so you wonder, you know, if lots of people start doing this, what is the frequency which they're going to have you know cardiovascular effects five, 10, 20 years down the road that maybe you know, you can't even be traced necessarily to that they were buying this peptide from this source.
• 47:01
  And so and so I think you have to be careful.
• 47:03
  But but I I I think the the thing that I'm optimistic about is that I think what the GLP ones have shown is that um you know there's a big market out there for people who want science-based approaches to improve their health.
• 47:16
  Right.
• 47:16
  I mean many people who are taking GLP ones now are are not clinically obese, right?
• 47:23
  They could benefit from losing some weight to be fitter, healthier, but they're also probably not in the same category as the people who were usually originally tested in the clinical trial.
• 47:31
  Right.
• 47:32
  But they're with to be clear like is life changing for right absolutely absolutely but those people are benefiting as well right and so and so and I think and I think many of those people you know it's not being covered by their insurance because they maybe don't they don't have a diabetes diagnosis.
• 47:47
  They're not obese um but they're just willing to pay for it because basically of the incredible effects it's having on their life.
• 47:54
  And so I think what that has sent a signal you know to to the pharmaceutical industry in general just that there's this huge world of US consumers and maybe other places as well that um are hungry for science-based approaches to enjoy and market.
• 48:07
  Yeah yeah and so for for someone who is you know a little um skeptical about taking something like that or they you know don't feel they really need to or that you know kind of fairly happy with their body composition are there any like simple hacks that you can point them to that can help manage appetite and just the regulation of appetite in general because I think there's a a whole market of people who are you know always trying to be mindful not to put on body fat but are kind of happy where they are.
• 48:38
  Yes.
• 48:39
  So like like non-pharmaceutical approaches yeah there are.
• 48:42
  And and we we talked about some of them earlier I can go through them uh in more detail.
• 48:45
  I think there are a number of things associated with your diet that you can do to basically you know to to to sort of maximize the satiety that you get per calorie so that you can eat fewer calories and um uh be more sated and eat less.
• 49:02
  Um a lot of this can just be summarized as eating more of a whole food diet.
• 49:06
  So so and and the the exact reasons that whole foods are more satiating than processed foods are complex, but a big part of it is just their volume.
• 49:15
  So if you look at you know basically something composed of you know just vegetables and a piece of fish and something versus the same number of calories in a highly processed form, it's just much more dense in the highly processed form.
• 49:26
  And one of the things we know is that a big way the gastrointestinal tract senses how much you've consumed and makes you say it is volume.
• 49:32
  And so if you can can just eat these these foods that have lower energy density, there are a larger volume, you will tend to consume less.
• 49:41
  Eat your broccoli kids.
• 49:42
  Exactly I mean there's protein as well right the the there's a thermic effect of like different macros there's a different cost to break them down right that's right.
• 49:51
  So so protein is good for a bunch of reasons.
• 49:53
  So getting enough protein is important because um uh it's more satiating in general than than fat and sugar because of this effect you just mentioned the thermic effect of food so basically um it just takes more energy to break down fat uh protein and convert it into fat that you would store than just to store fat directly and so and so there's an added benefit from that.
• 50:15
  Also we we talked about this idea of protein leveraging the idea that people almost all animals want to consume a minimum amount of protein and so if you're not hitting that minimum amount then you might overeat just for that purpose.
• 50:28
  So those are some ideas.
• 50:30
  There's I think one area where there could be more more more scientific work is you know just this idea of comparing different foods really empirically and looking at the satiety per calorie in a very rigorous way.
• 50:41
  There's a study that did this uh maybe like 10 or 20 years ago just took like 50 foods and um uh gave people a fit a fixed amount of that food a certain number of calories and then came back several hours later and gave them a test meal and asked okay how much do you eat now and measured empirically for X number of calories of this versus this uh uh what is the most satiating okay I'm curious do you do I don't know if you know the study but uh what would you guess if you had to pick a food that you would think is the most satiating I would have said some kind of lean meat.
• 51:13
  Okay.
• 51:14
  Well yeah or just maybe not lean meat, uh a a protein.
• 51:18
  Yeah.
• 51:19
  So so I think lean meat scored well but they weren't near the top or they weren't the top.
• 51:24
  Um one one protein basic or one one uh food basically blew everything else away which is boiled potatoes.
• 51:31
  So potatoes basically are just incredibly satiating.
• 51:35
  And at first when I saw this I I thought you know I thought you know kind of like it's like uh people find this hard to believe it's like it's carbohydrates like potatoes taste good.
• 51:42
  But then I tried it like try like consuming like a thousand calories of potato it's like impossible right I mean it's just they're so heavy like the amount the volume of potatoes is just absurd and it just kind of sits in your stomach and so it just has a strong effect of basically they have to be boiled asking for a friend.
• 51:58
  Well well so so I think I think the reason that the they test boiled potatoes is because like if you fry them or something you have to like thousand calories pretty easily yeah yeah but you know you would never eat a thousand calories of potatoes.
• 52:08
  500 calories of potatoes would just be absurdly satiating right that's a whole meal.
• 52:11
  And so um I actually tried this after I read the paper because I didn't believe it and it's real.
• 52:15
  And so um so so I think there is actually an area where where actual studies like that that get much more granular into different kinds of things could be very useful to design the perfect diet so that you know you you can you can just consume these these optimally satiating foods.
• 52:29
  But uh I don't know that that hasn't been done yet.
• 52:32
  Is there is there any um sort of robust research to support the idea that you know people who are just fidgety tend to burn more calories like this concept of neat this non-exercise activity thermogenesis right that you know the people that we typically see in over the years I've seen who remain incredibly lean but aren't necessarily doing a ton of actual like structured exercise and aren't even all that good at managing their nutrition, but they just move around a lot and it might be like tapping their foot or standing up at a desk.
• 53:05
  You know, have we got good data to support that being true.
• 53:08
  It's an interesting idea and I have not aware of any data on that.
• 53:13
  I mean the thing I am aware of is that is that one hypothesis and this is still a little bit controversial about why it is often difficult to lose weight with exercise.
• 53:22
  So exercise can make you fitter, it can help you build muscle but most people don't lose a lot of weight when they start exercising is that there's this idea of conservation of energy expenditure.
• 53:30
  So basically if you do a bunch of exercise every day what will then happen is some of that fidgeting and stuff will decrease and then basically there will be a little bit of a compensation and so you don't get the full the full amount that you that's one hypothesis.
• 53:42
  Some people don't believe that so it's sort of controversial.
• 53:44
  But um I have not I have not seen a study that measured that I should look into that.
• 53:50
  I'm one of those people I think okay yeah I can't sit still whatever.
• 53:54
  Okay.
• 53:54
  It's kind of frustrating for everyone around me.
• 53:56
  Let's switch gears a little bit because I'm I'm mindful that that is not the entirety of your research and there's two other pieces I wanted to pick your brain on one is um hydration and thirst.
• 54:07
  Yeah right um I think one of the easiest hacks that there is to improve our overall health and the way that we feel day to day is is being hydrated.
• 54:16
  And I think I suspect a lot of people go through their days being under hydrated.
• 54:22
  Yeah.
• 54:22
  Am I right in that hypothesis or is that well it's well yeah so so the scientist to me would say that's hyperbole.
• 54:31
  I think that the I think that I do think that you know you know there probably are some benefits to to sort of forcing yourself to drink a little bit more water than you necessarily feel that you need.
• 54:42
  But the reality is that in most people and healthy people especially people who are younger the system that generates thirst is just incredibly sensitive.
• 54:51
  So um you can exp so you know this sensation of thirst, this idea that I need water that is sensitive to a 1% change in the osmolality of your blood.
• 55:00
  So basically the purpose of thirst is to prevent your blood osmolity from increasing because that's dangerous.
• 55:04
  So we know from studies where they've just infused salt into people's veins and then ask when do you feel thirsty?
• 55:08
  It's a 1% change.
• 55:10
  So so it's just like you you it's so important for survival that you immediately feel thirsty.
• 55:15
  Now could there be benefits from being slightly overhydrated for maybe feel a little bit better?
• 55:21
  Is that 1% value chosen evolutionarily to make you perform the best at your job or is it so that you you know survived in the jungle and so so that that there's an interesting question there.
• 55:30
  But for general health probably drink when you're thirsty is is fine.
• 55:34
  So there's this I think common misconception then that by the time you're thirsty it's you've left it too late.
• 55:40
  And that's not true.
• 55:41
  No that's not true.
• 55:41
  I mean I mean you don't want to be extremely thirsty right and you want to be like yeah I'm starting to get thirsty okay I'm gonna drink something but why when and again asking for a friend here why when you've had a lot of alcohol the night before right you can wake up in the middle of the night and it is an insatiable thirst but you quench it the moment you start drinking rather than you know I'm assuming the water hasn't had yes time to then be like absorbed or used in any fashion but you immediately that's got to be some kind of mechanism of your brain right yeah so that that's something we've studied in my lab.
• 56:14
  And so um and so uh yeah the idea is that yeah exactly as you said so you know your thirst is quenched immediately upon drinking water.
• 56:22
  But but basically you know it takes tens of minutes for that water to go into your gastrointestinal tract, be absorbed into your blood and uh correct the uh the changes in in the osmolality of your blood that initially made you thirsty.
• 56:34
  And this is actually one of the things we we sort of figured out a couple years ago in my lab by recording uh from the activity of the neurons in the brain, in this case in a mouse, the control thirst and just asking what happens when um uh an animal drinks.
• 56:47
  And what you see is that there are receptors in the oral cavity that become activated as soon as sort of the the the water uh enters the mouth that then are transmitted in seconds back to the uh uh to these thirst centers in the brain to basically quell their activity and then the the way that a person decides the way you decide how much to drink is is these neurons in the brain are measuring on the one hand the state of your blood.
• 57:09
  And so they're measuring how dehydrated you are.
• 57:11
  And at the same time they're getting this signal that's coming through your throat basically of thirst of water consumption.
• 57:17
  And they compare those that volume to the volume you need and then basically when they're in equal you sort of your thirst is quenched.
• 57:24
  And so um uh and so there are a lot of sort of uh uh interest or there's several sort of interesting sort of uh aspects of everyday experience that are explained by this observation so one is just the idea that you know we tend to experience cool things as more thirst quenching right you put ice cubes in your water you drink you eat some ice you know some ice cream that feels kind of thirst quenching right um if you're in the hospital and they can't give you lots of fluids because you're about to undergo surgery or something they might give you ice chips to suck it.
• 57:55
  And the idea behind all of these things is that when you drink water, one of the things it does is it tends to cool your throat because because uh basically water is almost always colder than your body.
• 58:06
  And so one of the signals that your brain uses to track the volume of water that's going through your throat is the temperature.
• 58:12
  And so if you just artificially cool it then you can sort of a little bit trick the brain into thinking I've consumed some water.
• 58:18
  That's that's one of the reasons people put ice cubes in their drinks.
• 58:21
  And so we've done experiments like this in in rodents where we've shown for example we can record the activity of these neurons in the mouse's brain that control thirst.
• 58:28
  And then we can put sort of a cold piece of metal on the mouse's tongue.
• 58:32
  And we can see when we touch the cold piece of metal to the mouse's tongue, the activity of these thirsty neurons goes down and then we take it away and they go back up.
• 58:38
  No way.
• 58:39
  So so so yeah so so I think that's you know does does the same thing apply for food right in that not the temperature but like sometimes when you're feeling really hungry and you you you start eating you feel satiated before you've even Yeah absolutely absolutely I mean similar similar sorts of things start to happen for for food.
• 58:57
  I mean in some in some sense they have to happen for both eating and drinking due to the simple fact that the digestion and absorption of nutrients or water is slow, right?
• 59:06
  They're delayed they're delayed by tens of minutes from when you start because just for for food, I mean if you eat a fatty meal it can take three hours for that to leave your stomach and slowly enter your bloodstream.
• 59:16
  So if you had to wait for um for uh uh uh basically uh all of that metabolism and digestion to happen before you knew how much you ate you would just chronically be overeating but we do do that right sometimes I mean I certainly do.
• 59:31
  Well I don't think you eat continually for three hours or no but like I think I've on more than one occasion and more than one occasion this week have I continued to eat and then I've felt too full because I didn't stop in time.
• 59:47
  Like is there some is there some truth to the fact that we should stop eating before we feel full?
• 59:52
  Well I do think I I do think there might be some value to to slowing down your eating and so that these gastrointestinal signals have time to be generated.
• 1:00:02
  I don't I I you know I think these systems are pretty efficient.
• 1:00:06
  So so you know um uh I don't know that's gonna make a huge difference but I think I think there there there there could be some value to that I I I know there are some studies of of sp of basically the pace of eating and how that affects the amount that people eat and it's sort of there's evidence on both sides, but I don't think it's a huge effect either way.
• 1:00:22
  So the idea that we should chew our food more is a Well again it's like all a lot of these things so so there probably is a real thing there.
• 1:00:31
  Yeah.
• 1:00:31
  I mean we definitely in my lab we study this in rodents we study how these orosensory cues promote satiety and they they are they they do.
• 1:00:39
  And so chewing your food in principle will have that effect.
• 1:00:43
  The challenge is because consumption of food and water are so important for survival because they've been under such strong evolutionary pressure the system is redundant.
• 1:00:52
  And so if you just try to fool you know in the same way that if you put a cold piece of metal on your tongue it might feel a little thirst quenching for a few seconds but then your brain's going to figure out you didn't drink any water, right?
• 1:01:01
  Yeah and so so you might get a little bit of a satiation effect that's short term.
• 1:01:05
  But then when the nutrients eventually don't come to your intestine, your brain's going to figure it out and you're not gonna really really over the long term change how much you eat under most conditions.
• 1:01:15
  So so has has studying this changed the way that you eat has it changed the way that I eat or your relationship with food.
• 1:01:25
  Well I think it's giving me an appreciation of why it's so difficult because you're essentially trying to fool a system that has been fine-tuned throughout evolution not to be fooled because it was so important for your survival.
• 1:01:38
  So you know one of the one of the uh uh uh early experiments from my lab that I think uh surprised a lot of people in the field was we we looked at some of these neurons in in this case in the hypothalamus in this brain in this in the structure that uh the base of the brain that contains these sort of very ancient neurons that um uh uh sense cues from the body hormones from the body and regulate appetite they're critical for hunger and um it it had been thought for a long time that the way these these neurons work it is uh just by sensing these hormonal signals gradually fluctuating the activity so you have more more hunger when you haven't eaten in a while and then when you have eaten basically these hormones rise and then the the activity of these neurons falls gradually um but we sort of technology was developed around the time that that that I started my research in this area so that we could record for the first time the activity of these neurons in a rodent in a mouse and just see what they do.
• 1:02:34
  And so the big surprise was that what we found was that when my graduate students, Yi Ming Chen, did these experiments he went, made a mouse hungry gave the mouse food and then asked you know what do these neurons do when the hungry mouse starts eating and we expected they would gradually decline as the mouse eats.
• 1:02:51
  But what he found was that that he discovering this we gave the mouse the food and then the moment that the mouse sees the food the neurons are inhibited and then they stay inhibited throughout the entire meal.
• 1:03:01
  And I remember him running into my my office and saying Zach this is so weird that the neurons are inhibited immediately even before it takes the first bite I said that can't be the case go back and repeat the experiment.
• 1:03:10
  But then he he repeated several times and uh we found that was actually the case.
• 1:03:15
  And and and what he eventually showed by changing the kind of food or the accessibility of the food or how hungry the mouse was in measuring this inhibition that happened when the mouse saw the food was that we we sort of demonstrated that what these neurons at the base of the brain were doing was predicting how many calories the mouse was going to eat in the forthcoming meal.
• 1:03:34
  Essentially the mouse looks at the food and says about this hungry and that looks about this palatable and it's accessible and I've had this food before.
• 1:03:41
  And so and within just a few seconds it knows with a great degree of accuracy how many calories the mouse is going to eat you know in the next 30 minutes.
• 1:03:49
  And so one of the lessons I took from that was this is a mouse, right?
• 1:03:52
  It has a tiny little brain, right?
• 1:03:53
  It can't it is a very limited computational capacity and it's able to perform this incredible calculation in seconds and the the mouse presumably has no sense that its brain already knows what it's going to do over the next 30 minutes.
• 1:04:03
  And so you know presumably our brains are doing something similar but even much more sophisticated.
• 1:04:07
  And so I think I think that you know if you have a bit of humility then about uh uh trying to do simple things like chewing your food and spitting it out and thinking that that's going to you know you know fool this system.
• 1:04:17
  So it's not that simple.
• 1:04:19
  It's not that simple.
• 1:04:20
  Over millennia.
• 1:04:21
  Can I ask you a question that I get asked a lot and that is there seems to have been this very rapid rise in companies selling electrolytes or any kind of like um hydration powders to go and drinks any value to those in your opinion?
• 1:04:40
  Well so when you drink you drink to replenish not just the body of water but also to to reestablish the sodium basically the the osmolites in in the appropriate concentrations and so um and so yes uh uh uh in principle that is valuable I think in reality unless you've been engaging in in high intensity exercise and have lost a lot of salt um you don't need that under most circumstances in most circumstances water is fine um but uh you know I think for athletes and under conditions of you know high athletic performance that can definitely make a difference or if you're a 40 year old that has the bladder of an 80 year old well um it feels like a good hack for me yeah I mean there's nothing there's no harm right I mean you have kidneys and they're very efficient and so if you if you consume a little bit extra of these osmosis they're just going to be filtered out.
• 1:05:33
  Good sense and so uh so but um I mean I drink a lot of Gatorade and things you know and especially the zero calories light though yeah Gatorade light yeah zero Gatorade zero um whenever I work out that's what I drink I don't often often it's resistance training and I don't work out hard enough that I actually need any additional electrolytes but I just like it.
• 1:05:50
  So there's no harm in doing that.
• 1:05:51
  But um Zach, you um another sort of body of your research focuses on the regulation of temperature of the home Of our body, right?
• 1:06:02
  Can I ask you that given that again, there's just been this explosion in interest in these um eustress protocols, things that like uh like infrared saunas and coal plunges and things like that.
• 1:06:14
  One, do you do them yourself?
• 1:06:17
  Two, do you think they're valuable tools?
• 1:06:20
  And we spoke about this earlier, as addition to majoring in those major pillars that we know work.
• 1:06:25
  Yeah.
• 1:06:25
  You know, do you think there's value to them?
• 1:06:27
  Well, based on your research and what what you're saying, I would say that no, I don't do them.
• 1:06:33
  Um, you know, I I'm not sure I can tell you based on our research, actually how valuable they would be.
• 1:06:39
  Because, you know, a lot of what we're studying is this basic homeostatic response.
• 1:06:43
  How do animals maintain their body temperature?
• 1:06:46
  And I think what you're seeing there with these kinds of things is these very secondary effects of that homeostatic response, then having effects on other tissues in ways that aren't maybe the major effects of these things.
• 1:06:57
  And it's it's just very hard then to extrapolate from a basic science perspective how that might affect a person, have small changes in athletic performance or things like that.
• 1:07:04
  So in that case, I think it really comes down to what the human evidence is.
• 1:07:07
  And I I don't have any deep insight into that mechanistically.
• 1:07:11
  Yeah.
• 1:07:11
  So I can't give you more information.
• 1:07:13
  So I have to keep doing them maybe.
• 1:07:15
  Um okay, next question for you.
• 1:07:17
  This is a big one.
• 1:07:19
  If if money were no object, if you had unlimited resources, is there one like real true north big picture question that you'd like to answer?
• 1:07:30
  Oh wow.
• 1:07:32
  Unlimited funding, unlimited unlimited headcount.
• 1:07:40
  Um an alternative to that would be, you know, are there hypotheses that you have that you haven't got around to studying?
• 1:07:52
  You know, are there things that you're looking forward to studying and questions that we just don't know the answers to?
• 1:07:56
  Yeah, I mean, I think I think, you know, there are.
• 1:08:00
  I think that, you know, when I think about the sorts of if I'm just thinking of this question of unlimited money, what would we?
• 1:08:05
  I think, you know, in this field of obesity and bodyweight regulation, the real limitation is that we can do very sophisticated experiments in rodents now and we can really control every parameter and and monitor uh their brains at the same time, understand what's happening in the brain.
• 1:08:21
  But translating that to people is still challenging.
• 1:08:24
  One because just ethically and scientifically, we can't do those kinds of experiments in people.
• 1:08:28
  But even more basically than that, just the simple nutrition science and simple physiology science that you could do on people, if you could do sort of long-term laboratory-based experiments on people, have not been done because they're too expensive.
• 1:08:42
  I'm thinking about the work of people like Kevin Hall, for example, at NIH, or he was at NIH, you may be familiar with.
• 1:08:47
  He does these beautiful studies where, you know, he uh you know takes people into the hospital for for you know four weeks or something, feeds them different diets, and then measures sort of what happens uh to both to their food choices and to their metabolism on that timescale.
• 1:09:02
  And I think the reason a lot of these questions in nutrition and and and metabolism and obesity are just so unresolved at the human level is because we just cannot do the right experiments.
• 1:09:11
  And some of them they ethically can be done.
• 1:09:13
  They just would require large inpatient, long-term clinical trials so we could really monitor exactly what people were eating and then get some real longitudinal data on like what's happening.
• 1:09:24
  I think we could then put to rest all sorts of questions in nutrition if we could just do that.
• 1:09:27
  But they're just it seems to be an area where an actual and it's you know, it's not an infeasible amount of money, right?
• 1:09:33
  But but um, you know, it's an area where a large but practical investment could actually really answer finally a lot of these questions.
• 1:09:42
  And so in the absence of that, we just end up doing all this correlative stuff that is kind of hard to know what it means.
• 1:09:46
  Or, and so so that would be in this field where I would say if you had to make a big investment, you know, and I say that I'm saying that, you know, that's not what I do, right?
• 1:09:54
  What I do is mostly neuroscience in the brain.
• 1:09:56
  Uh, but I think there's an area where we have the technology now, we can we can answer the question.
• 1:10:00
  We we just sort of don't need that scale of investment at this time.
• 1:10:03
  I think it's really the people doing the clinical work that need that scale up.
• 1:10:06
  Well, we were discussing this off camera briefly earlier.
• 1:10:09
  I think that's one of the challenges we face in aging research in general, um, but science in general, is that you know, we can do a pretty good job of testing these things in animal models, right?
• 1:10:20
  But that sort of bench to bedside piece is is difficult to bridge.
• 1:10:24
  Right.
• 1:10:24
  And so I think, you know, at times as consumers, we're left with unanswered questions or we're being misled by headlines that appeared to be very promising.
• 1:10:33
  And we used rapamycin earlier as an example.
• 1:10:36
  You know, miracle molecule extends lifespan by 50%.
• 1:10:40
  Anyone reading that article would say, uh, I should be taking this.
• 1:10:43
  Right.
• 1:10:44
  Right.
• 1:10:44
  But the reality was it did in some mice.
• 1:10:47
  And some of them went blind and got cancer, right?
• 1:10:49
  So I think we're still some way off being able to say all of these things are safe and effective.
• 1:10:54
  Um but it's still there are some promising geroprotectors that we're seeing and different tools and technologies.
• 1:11:01
  And so I think if we had more funding.
• 1:11:03
  Yeah.
• 1:11:04
  I mean, I think I think one of the maybe the differences between longevity, which you're talking about, and then some of the sort of basic nutrition stuff is I think these kinds of studies will just are will not be feasible for longevity, right?
• 1:11:14
  You just can't take people and just control their lives for 50 years, no matter how much.
• 1:11:18
  But I think actually the timescale that you would need to say, as we talked about earlier, finding this optimal diet so that you could then lose weight and maintain weight, that could be done, right?
• 1:11:26
  You could do it a year-long or six-month-long inpatient trial in principle, um, really systematically.
• 1:11:32
  That is a no-brainer and should with that there should be a collective agreement to get that solved for, because we see a lot of discourse, like even with in high science, right?
• 1:11:42
  Some of the best nutrition scientists in the world completely disagree.
• 1:11:46
  That's right.
• 1:11:47
  That's right.
• 1:11:47
  Absolutely.
• 1:11:48
  Absolutely.
• 1:11:48
  So so I think, you know, it's kind of annoying for the rest of us.
• 1:11:51
  I know.
• 1:11:52
  It's yeah, no, I mean, there's yeah, there's these bitter arguments between the you know, carbohydrate insulin people and the energy balance people, and and it's just these are testable things.
• 1:12:02
  It's just expensive because it involves lots of people over, you know, sort of a longer period of time, but not an impossible amount of money.
• 1:12:09
  Is there um we we again we were talking about this very briefly that when you're a young scientist or young in any profession, in fact, you feel like you know everything about everything.
• 1:12:22
  And then that the older you get and the more you do, you realize you know nothing about anything, or less than you thought.
• 1:12:28
  Is there anything that you were like steadfast believed 10 years ago that you've since disproved?
• 1:12:34
  Oh, yeah.
• 1:12:35
  I mean lots so many things, almost everything.
• 1:12:37
  I believed.
• 1:12:38
  I mean, I don't know where to begin.
• 1:12:40
  Um uh something that you really truly believed in, though, and you were kind of shocked that disprove your own hypothesis.
• 1:12:46
  I mean, I guess that's the point of science, right?
• 1:12:48
  Yeah.
• 1:12:48
  I mean, I mean, I would say, you know, most of the most interesting results from my lab have been exactly that.
• 1:12:53
  Um, there have been cases where, you know, there was a model uh of how physiology works based on sort of indirect experiments, uh, you know, manipulations where some hormone was manipulated, and we just sort of imagined what might be happening in the brain.
• 1:13:07
  But no one had ever actually looked to see what is the brain really doing because it just wasn't possible, the technology didn't exist to monitor it on that timescale with that resolution.
• 1:13:16
  And what we found in every case, basically, is that um when we actually look at what the brain is doing, it's doing something that is much more clever and subtle than our imaginations were up to the task of sort of imagining, right?
• 1:13:28
  And so I told you the story about the mouse that can predict in a few seconds how much it's going to eat over the next 30 minutes.
• 1:13:33
  But we see that kind of thing again and again.
• 1:13:35
  And I just think it's because, you know, it's just biology is this wonderful complexity, right?
• 1:13:39
  And uh we tend to think of about things as, you know, as humans in this very simple linear way.
• 1:13:44
  And then that's not necessarily how evolution happened.
• 1:13:47
  And and so, and so whenever we get get new approach new approaches and we can look for the first time, just observe how is the thing working, we always find that.
• 1:13:55
  And so that's sort of I've made my career doing that.
• 1:13:57
  So that's basically continually being being sort of uh uh surprised.
• 1:14:01
  Yeah, yeah.
• 1:14:02
  So, Zach, last question for you, and then I'll I'll let you go.
• 1:14:05
  Um, if you could give three pieces of advice to anyone that is struggling with their body composition and trying to understand their hunger, their appetite in a way that is more manageable, what would what would those be?
• 1:14:20
  Sure.
• 1:14:20
  Um easy one to finish.
• 1:14:22
  Well, the first thing I would say is track your progress.
• 1:14:24
  It's very hard to improve something you're not measuring.
• 1:14:27
  And so record your food intake, record your body weight at regular intervals.
• 1:14:31
  That'll help you understand the scope of the problem and what steps you need to take to improve it.
• 1:14:36
  Um uh the second step I would say is really focus on um focusing your diet around high satiety whole foods.
• 1:14:44
  Um try to minimize the consumption of processed foods, get enough protein, uh, eat some of these foods like potatoes that we talked about that are really satiating.
• 1:14:53
  Um and then, you know, I think um the third thing I would say is that because willpower is in limited uh uh supply for all of us, try to do things that restructure your environment so that you can minimize the amount of willpower you need to basically achieve your goals.
• 1:15:12
  So don't have things around the house necessarily that are going to be bad for you.
• 1:15:15
  You know, don't put yourself in situations where you're going to uh say be really hungry and have no way to get something healthy to eat.
• 1:15:21
  Plan ahead.
• 1:15:22
  That alone can, I think, be a change to your environment.
• 1:15:25
  And we talked about how it's these changes in the environment that uh have driven a lot of this obesity epidemic.
• 1:15:31
  That's an element of your environment that you can control and that that you can then make it much easier on yourself.
• 1:15:36
  Don't rely on just willpower alone, just counting on sort of steel knuckling it through it.
• 1:15:40
  Those are my three pieces of it.
• 1:15:41
  I think one thing as well that you touched on earlier, which I think is a good addition to that, is is you know, don't be so hard on yourself because to what end are you doing it for?
• 1:15:49
  And I think you know, we don't all have to look like a you know a cover model or the snapshots that we see on the Instagram highlight reels, right?
• 1:15:57
  And I think knowing more about how this is affecting our brains and our behaviors is fascinating stuff.
• 1:16:05
  Zach, it has been an absolute privilege.
• 1:16:08
  This was fantastic.
• 1:16:09
  Thank you.