 I have a lot to say so I'm going to probably talk really fast and I'm not going to tell you how I got interested in this or my history with the AHS but I will extend a great appreciation to the ancestral health symposium in society because of the opportunities and the encouragement and the mentorship over the past several years have really been formative and so thank you for that. Okay so here's a list of things I'm not going to talk about that could have to do with sleep related mismatches so I am going to talk about food and metabolism but there are so many things about the modern world that could have an effect that could be different from our adaptations to sleep including light and temperature and all kinds of things there's a review at the bottom. Metabolism is particularly interesting because there are bi-directional relationships so what we eat can affect how we sleep and how we sleep can affect how we process what we eat. So if we are looking for some kind of a mismatch we want to know if something might be interfering with what sleep is supposed to be doing but the problem is we don't really know necessarily what sleep is supposed to be doing. There are theories and some of them have very good support but it's definitely not settled kind of science so we have to do a kind of backwards inference and find out what happens when we don't sleep well and then infer from that what sleep might be trying to do. So one of the things that we do know is that sleep has a strong homeostatic regulation. There's a drive for sleep so we get enough and not too much and there's also circadian input to that but the homeostasis is very strong and one way that we can tell is because when you don't get enough sleep there's a sleep becomes irresistible basically after a certain point and the pressure for that builds up essentially linearly but it falls off faster than linearly and we'll talk about why. But we also want to know how we can compare sleep in some quantitative measures and the easiest way to do that the most straightforward thing is duration just how much time elapses between when you go to sleep and when you get up. But of course there's some subtlety to that because from the time that you go to sleep to the time that you wake up you might not be sleeping all the time either knowingly or non knowingly there could be efficiency that can be measured sleepiness in the daytime can also be a measure of how much quality sleep there was and that can be measured subjectively by asking people about it or in the lab by trying to get them to go to sleep and see how easy it is if it's easy then you were more sleepy. Stages I'll go into more detail but the basic idea is that we measure brain waves during sleep and so we can see different patterns that are occurring. So that's another way that we can compare different kinds of sleep. And of course circadian rhythms can encompass a lot of different things because we're looking at how our physiology is varying throughout the day in response to light and dark cycles. Talking about light and dark cycles having something to do with the earth rotating is almost archaic at this point but nonetheless light is one of the strongest cues for what our body knows how to do. But I won't really get to talk about that much today I'm going to focus on duration mostly principally because there are a lot of relationships between metabolism and duration and there's also an apparent paradox in that relationship and I just can't resist paradoxes. I'll also talk about stages because the duration can mask what's going on inside sleep so just like if you're interested in lipids you might not want to know just what your total cholesterol is but how the proportions of different sub fractions are changing. So there's a similar thing here. And I'm going to go over sleep stages really quickly just to make sure everyone's on the same page even though many of you probably know all this. So it's fairly easy to tell if an animal is awake versus asleep because of behavioral things like responsiveness but once we start looking at the EEG the differences start to appear that characterize more particularly. So the primary difference is between REM sleep which stands for rapid eye movement because that sometimes happens in that type of sleep versus non-REM. And in REM your brain is actually really active almost like you're awake except that your motor neurons are mostly disconnected probably so that you don't act out dreams. But because of that similarity to waking state it's sometimes called paradoxical. And these cycle throughout the night usually starting with non-REM. And then there's a further subdivision there are actually more and more subdivisions but this is as far as we're going to go but between deep and light non-REM sleep. So it's called deep because it takes more of a stimulus to wake someone from it. The main characteristic of it is that it has the slow wave sleep. And what's happening with that is that your neurons start to turn off all at the same time and that produces this high amplitude slow wave sleep. And it's called coordinated neuronal silencing. And this is a typical order but it doesn't always go exactly like that. So here is more detail. It's a hypnogram showing that the stages of sleep in a healthy person as we go through them. And you can see that it varies throughout the night. And the important things that I wanted to highlight is that slow wave sleep almost exclusively happens in the first half of the night. Here it's not shown at all in the second half but definitely happens there too but it's less. And then REM happens mostly in the second half of the night. So stage three and stage four, they're just arbitrary cutoffs for the amplitude of those waves. And so I'll just show you one more detail. So here's another hypnogram and I've circled stages three and four. And this is partly derived from these wave analysis. And you can see that the three and four are arbitrary cutoffs. But you can also see that the most of the intensity it's called of the sleep happens in the first half of the night. So when we look back at our sleep homeostasis and you look at that drop off that's nonlinear, that corresponds to slow wave activity. And that's one of the reasons that we associate sleep homeostasis with slow wave sleep. Okay, so slow wave sleep is really important for a lot of things. Even in metabolism, we have associations between, for example, BMI and slow wave sleep and insulin sensitivity. There's a lot more been studied cognitively because we know some of the mechanisms of how slow wave sleep influences our cognition. But we also see associations in various contexts where if there's cognitive decline, it appears that having more slow wave sleep is somehow protective of that. And because of that, there is an interesting paper from a couple years ago that I read where their idea is what if we try to enhance slow wave activity as a way to improve cognition, could that help? And so one of the ways that they talked about was that if the energy use in your brain goes up, that enhances slow wave sleep. So this picture, process S is just another word for homeostatic sleep as opposed to process C, which is circadian. And so if you had used more energy in your brain throughout the day, then you've got this steeper curve and more slow wave sleep associated with it. It also turns out that fasting and ketogenic diets increase slow wave sleep. And that might also be through brain energetics. And I wrote a paper describing some of the properties of ketogenic diets and how they affect sleep, including this slow wave activity, if you wanna read more about that. An interesting thing about humans is that compared to other primates, we seem to sleep more intensely. And the reason that we think that comes from looking at data about comparing primates and different characteristics of their sleep. So one thing that we've noticed is that our sleep duration is shorter, it's the shortest. And our REM proportion of all of our sleep is the longest. And not only do we follow those end points, but the researchers here did more analysis, spasian analysis, to argue that it's not just that we're at the end, but we're actually outliers. So why does that matter for sleep intensity? Well, if your sleep is shorter, but your homeostatic drive, you're finished sleeping, then that suggests that you were able to get all of that sleep homeostasis taken care of in a shorter time. So that would be more intensity. And similarly, I didn't mention this, but REM is often generally, at least proportional to the amount of slow wave activity. And so if we have higher proportion of REM that suggests at least that the sleep that we were doing in the non-REM portion was more intensely done. So that's the basic argument for that. So their idea about why that would happen is they say, well, humans must have had this really strong selective pressure for shorter sleep. And I'm sure that's true, but I think that all animals would have strong selective pressure for shorter sleep because it seems like it's a big advantage. Whenever we're talking about an evolutionary advantage, we have to have a strong selective pressure, but we also have opportunity. So I'm guessing that maybe we had more opportunity, something about, well, I really am partial to the unified hypothesis that Mickey Bendor was talking about with fat usage, but it could also just simply have been more cognition, which also uses more brain energy. Okay, so what are other things, other ways in which eating can affect sleep? I'm sure you've all experienced having a great big meal and then feeling very sleepy afterwards, and there is a reason for that, and it's not just the turkey tryptophan thing. Generally, the amount that we sleep is directly correlated to the energy that we got from all of our meals that were contained in that day. And that used to be thought to be macronutrient specific, but it seems to be just sheer amount of calories. In addition to that, it's also the case that when people and animals are gaining weight, they tend to sleep more. So that's been shown in lab induced weight gain and also in recovering from anorexia. And conversely, people who are losing weight tend to sleep less. I'll mention that at least in one of these studies, this effect didn't happen until fat stores were depleted. And maybe that makes sense because if your body is still detecting that there's plenty of energy available, then if it has to do with the detection of energy, then maybe it doesn't happen until that begins to be a scarce resource. So I don't know about the study at the bottom with obese people losing weight, they should still have lots of access to energy. But maybe there was something about the way their diet was constructed that the fuel partitioning was different. I don't know, that's just speculation on my part. All right, and this is actually particularly relevant for REM sleep, actually. And one of the reasons that we know that if you look at the anorexia study that I mentioned, people with anorexia tend to wake up a lot in the latter half of the night, and of course that as we saw was where REM sleep is happening. But if you think about it more generally, whenever you curtail sleep, since we have slow wave sleep is associated with that need for sleep, that usually takes priority. So sleep curtailment almost always disproportionately affects REM. Okay, so in addition to this kind of evidence, there's also mechanistic evidence that links sleep and satiation and satiety. They actually have circuits in common. And I just wanna recognize that measuring satiation isn't just about appetite hormones. It's definitely the case that if we do something and something like ghrelin goes up, we should expect hunger to go up. But that is not the same as measuring appetite. But of course, sorry. Appetite, satiation is really difficult because it's a subjective thing. And so we like to rely on these proxies. There's a definition that I really liked from this paper from Nicolaitis where he says, satiation is a progressive reversal of pleasant feelings toward nutritional cues. And eventually it's replacement by increasing unpleasantness. I like it because it lays bare that it's not trying to pretend that there's something really easy to measure here. It's really what we're trying to get at is this feeling. And it also leads us away from definitions that might say something about physical fullness because as I'm sure many of you have experienced, you can be completely full and still be getting pleasure from eating. But by this definition, you couldn't be getting pleasure from eating and be satiated. Okay, so he and his colleague Evan went on to make a hypothesis. They called the ischymetric hypothesis from the Greek, ischyros from power. And it's really quite simple, as simple as that definition. It says hunger comes from inadequate energy, which is fairly obvious, right? But they're talking about cellular energy. And then the reason that they could even say this and have it mean something is that prior hypothesis, hypotheses were really focused on trying to figure out some specific nutrient effect where they're trying to find one metabolite that could be the key to regulating appetite. So for example, glucostatic or lipostatic. And they weren't trying to say that these hypotheses were wrong, but that they were insufficiently general. And if we want to know what hunger is about, it has to be about energy. And so we're talking about ATP turnover specifically. So one way to measure that that they tried to do is to look at metabolic rates. So by this definition, you would think that if your metabolic rate is going down, that means you don't have enough energy and so you should be hungry. And if it's going up, then you should be satiated. And I just want to draw your attention to the top two lines, which are total metabolic rate and locomotor free metabolic rate. This is in rats. And if you just look at total metabolic rate, as the time is leading up to their meal to when they decided to eat, total metabolic rate is going up, which would seem to contradict the hypothesis. But if you take away the motor activity that's happening there, the metabolic rate is going down exactly until they eat. And then it starts going up again until they get back to baseline. And then they stop eating. So it fits very nicely with that hypothesis. And they argue that that's causal. But still, that is a cellular thing. And so if we want our pleasantness definition, we have to get somehow to the brain from the cells. And basically, you either have to have some kind of signal that's generated from ATP generation itself or the energy itself. And I think that the basic idea is that the brain is running a kind of surrogate or simulation. The brain has access to nutrients that are coming through and can itself generate energy and thereby infer what's happening to the rest of the body. And so that happens in the hypothalamus. These are some regions that are involved. And the hypothalamus can directly detect what's going around and do that kind of simulation and take in signals and integrate it. So one of the signals could be AMPK, which takes information from ATP and ADP and AMP. And the ratios and decides whether we're in a state that's low energy or high energy. And the interesting thing about that is that AMPK and how active it is is deeply connected to sleep. So when we're awake, we're in an active AMPK situation. And when we're sleeping, it's inactive and we're more anabolic. So that fits. Adenosine is also such an accumulator. So I have to confess, I have a professional crush on adenosine. I wouldn't do a whole talk on it if I could. It's involved in how ketogenic diets work therapeutically. It's involved in sleep. It's involved in language processing. And it's involved in coffee. So what more could you ask for? But adenosine is an accumulation of, it's an ATP breakdown product. So unlike AMPK, which is more of a moment to moment what's happening, it accumulates. And for that reason, it's considered a mechanism of sleep homeostasis. So it has all these properties we would want for a sleep factor. It builds up during waking. It dissipates during sleep. And it's associated with slow wave activity. So for these and other reasons, Nikolaitis made this prediction where he says, whenever a neuro substance is shown to induce satiety, it may also be somnogenic. And it should also increase the background metabolic rate. And conversely, whenever a neuro substance is shown to be a rexigenic, it should also promote wakefulness and at the same time, decrease metabolic rate. So we'll come and look at that prediction again later. But I mean, basically what he's saying is that these are concordant states, being awake and being hungry. So let's look at the other direction. What happens when we manipulate sleep duration? How does that affect our metabolism? Duration is a bit tricky because there are three things that could be conflated. And I want to make sure that we're paying attention to which ones. So we could have acute sleep deprivation. If you don't get enough sleep one night, what are the effects that happen after? If you do that night after night, it accumulates. And then there are long-term associations, which we might try to infer are the same as accumulation over a long time. And they may or may not be. But a lot of places are mixing up these ideas. And so I want to be clear about it. I'm going to skip this distinction about those. And this is a piece of a graphic that I saw going around. And so what it says is, three to four hours, something, something, insulin resistance, obesity. And so when you see something like this, it makes a claim about sleep duration. I want you to ask yourself, what do they mean by sleep duration? So obviously, no one's going to get obesity from one night of short sleep. That one turns out to be a long-term association. Insulin resistance turns out to be an acute effect. It happens right away. One night of short sleep will cause temporary insulin resistance in fat tissue. And I'm going to skip that one. And here are some associations between obesity and sleep duration. So it seems like a shoe-in, right? If the long-term associations between short sleep and obesity are strong, and we've already got the acute explanation of insulin resistance happening, then it sounds like short sleep makes you fat in the long term by insulin resistance, right? I'm not sure that that's exactly right. We know a lot about sleep deprivation, at least in rats. And what happens is, after a couple of weeks of sleep deprivation, they die. And we know a lot of things that happen robustly along the way. So the first thing that happens is they get a drop in core body temperature. And the response to that, presumably it's a response to that, is a huge mitochondrial uncoupling, which generates heat. But it also takes a lot of energy. So they're expending lots and lots of energy. So you can see in this canonical experiment where before the rats died, their energy expenditure went up more than double. And they cannot eat to keep up with it. They have hyperphagia, and they eat and eat and eat, but they will lose weight while this is happening. But that doesn't seem to happen with humans. So we don't have as much experimental data. We can't bring humans to the brink of death and see what happens. But we shouldn't. But we do know that some of these metabolic effects seem to be quite different, at least. We don't seem to get the higher energy expenditure, at least not in many of the studies that we've looked at. But we definitely do get hyperphagia. So we eat more when we're sleep deprived. We don't have more energy expenditure, so of course we gain weight. And this might be partially explained by a decrease in leptin and an increase in ghrelin, which also happens with rodents. It might also be partly that most of our studies are about sleep restriction and not total sleep deprivation, because we just can't do that for very long. But when we have looked at that, some of the studies, at least, do show a reduction in core body temperature. So in this graph, just look at the solid line. And you can see there's a circadian effect, but the trend is going down. So maybe that will eventually have an effect. So this is Peter Dubromilsky, and he's a brilliant thinker and one of my favorite blog writers. He's a retired veterinary anesthetist, and he's been writing a lot about metabolism for many, many years and more recently about ROS, and even more recently a lot about uncoupling. And because of that, because I had this sort of paradoxical thing between rats and humans, I asked him if he would talk to me about what he thought might be going on. And his main insight for me was to think about it from the ROS perspective. So that's what I did. So let's talk about ROS just a little bit. So it's a normal product of ATP generation. And it generates lots of signals that are used throughout the body for many things. So it's not all bad. You don't want too much, but you want enough. In this graphic, it's from a paper that's talking about the role of ROS in satiety. And it's showing when glucose metabolism is high, so is ROS. And that produces satiety in this complicated way. They have a corresponding one for hunger that talks about lipid metabolism and ROS going down, which is it's skipping a step. So actually, when you burn fat, it creates more ROS. But there are reactions to that that then bring it down. So actually, fat metabolism generates so much ROS that that's thought to be why we don't use it in the brain. So the brain famously can only use, for example, glucose and ketones and maybe some other things, doesn't want to use fat. And one of the ideas about why that is is because we generate too much energy in the brain too fast to deal with all of that oxidation. And also, our brains are made out of this very vulnerable, polyunsaturated fatty acids. OK, so there's a nice paper here about how uncoupling is a response to dealing with all this oxidative stress and the various evolutionary strategies that might have happened, including uncoupling, including burning fat in the peroxisms and other things. But one interesting thing to note is that recovering from ROS is thought to be, at least by some people, what A or the function of sleep is. So there's this nice paper last year where they took fruit flies and deprived them of sleep. And the ones that they gave antioxidants to didn't die, which is really quite amazing. And then there is a whole theory about how ROS is the modulator. So sleep clears it, and it is an instigator of sleep. It's what makes you tired. So just notice that that fits Nikolaitis' prediction. It's something that induces satiety. It's somnogenic. And if you bring in the uncoupling effect, then it could increase background metabolic rate. But that part is a little bit murkier. So we have many different uncoupling proteins. In fact, all eukaryotes have uncoupling, even plants. And they're different in different species and in different tissues. And UCP1, which is the one I think we know the most about, is only in brown adipose tissue, especially for thermogenesis and has really high uncoupling power. UCP2 actually is for glucose sparing. And UCP3 is for enhanced fat metabolism. And there's some more information about that. I'll skip. So if we go back to this question of why do humans get fat with sleep restriction, one possible kind of answer is, well, we have different proportions of uncoupling proteins. And so when our uncoupling proteins are stimulated, compared to rodents, we just won't get as much actual uncoupling. So we won't get that energy expenditure advantage, we're just left with the hunger. In addition to this, and I don't have time to really get into it, but another thing that Peter Dubromilski and I talked about was that what he's seeing, at least in the polyunsaturated fatty acids context, is that if you have some excess of ROS, the first response is insulin resistance. And that functions to reduce the amount of energy that's coming into the cell. And so that can be a reducer of additional ROS. And then only when you get a lot more does uncoupling start to really become the dominant response. And so if we're looking at maybe the human studies are more about sleep restriction, then maybe we've really only gotten to the insulin resistance part and haven't gotten as far into it to get an energy expenditure benefit. I guess you could call it a benefit. And then if you put those together, maybe there is some kind of a mismatch there where you have a concordance between short sleep and a low glucose situation. If you've got this ROS and you've got insulin resistance and then you add glucose on top of that, then you've got a mismatch in metabolic states. So maybe that could explain why humans are getting fat with sleep restriction compared to rodents. So given all these things, I think these are the three potential mismatches for sleep and metabolism that I have thought about when going through this material. One is that we could be getting less slow wave sleep stimulation, and that could be from a change in diet or it could be change in some of our activity that doesn't have anything to do with eating or even cognitive, but that could affect our sleep. Maybe we're having more exposure to oxidation, but without getting the extra sleep that would normally take care of that. And so if we as a species are used to having a certain amount of sleep that might have been dependent on a lower amount of ROS. And then finally, the thing that I just mentioned where maybe there's just a mismatch between having short sleep and having a higher glucose diet at the same time instead of having the short sleep go along with lipid metabolism. And that's all I have. Let's open the microphones for questions. Is there any difference in what you have presented here in regards to increase in obesity and all the factors that go into it? When sleep duration is adequate, but sleep architecture is not, such in the case of narcolepsy in IH. Yeah, that's a really good point. And one of the most prevalent sleep problems is obstructive sleep apnea, which causes intensive fragmentation and is also highly associated with obesity. So, yeah, duration, it masks all of those things. That's a really good point. Yeah, on one of your slides you mentioned wide directional. I think chronic pain interferes with sleep, which leads to insomnia, fragmented sleep, and narcolepsy. So when I treat chronic facial hair and neck pain, so we always evaluate the pain and the sleep. So we find a lot of interaction between the pain and sleep coexist between the patients. So what I like, what you mentioned, thank you. Yes, absolutely, if you're in pain, you can't sleep as well, and if you don't sleep as well, it can lead to worsening of your symptoms. Definitely. It's a bad feedback loop. Thank you. Thank you. Hi, this is just sort of an observation. You talked about the rats had increased activity, and I was thinking, most parents know if you miss the window, when to put your children to bed, they have increased activity. And I, you know what I mean? Yeah, I thought about that. I thought you were gonna say if you missed a snack. But I guess it's the same thing. If you missed that moment, then they get hyped up. I wondered what you think about that. That's an interesting idea. I hadn't thought about that, but maybe, so the cue to sleep has come and you haven't taken it, and so you're gonna go into a different, I think the increased activity is probably explained by, you know, you need to eat, so now you're gonna start looking for food. I think that would be the exploratory behavior, would be the explanation for that. But it fits with what you're saying. Need an idea. Great talk as always, Amber. Thanks, Dave. So this obviously is something that I couldn't help but think about it in the context of especially since you've been researching it a lot. I'm very interested in sleep eating, where often it comes up that people, and almost invariably they're in a terrible metabolic state, but where it's almost as though they are being awakened by their hunger and then feel that they have to eat in order to get back to sleep. Did you have any opinion on that? Yeah, I do. So there's two things that can be meant by sleep eating. There's actually a disorder where people eat in their sleep and they don't know that they're doing it. It can be very dangerous because you consume things that aren't necessarily food. But then there's getting up to eat or eating late at night and that can be a self-perpetuating problem. So if you're eating is actually another really strong circadian cue. And if you're eating late at night, well for one thing you're gonna wake up and not be as hungry. So then you're gonna wait so that's self-reinforcing. But another thing that it does is it creates this mismatch between your circadian rhythm, what it's expecting with respect to your sleep cycle. And that will also lead to insulin resistance and glucose intolerance. You may sort of refer to it just now, but you were talking about as people lose weight and gain weight, so the shift in their eating, I mean in their sleeping. And I was wondering, maybe like the exploratory behavior you were talking about, but a lot of people report during fasting that it disrupts their sleep. And I'm wondering if that's just sort of a cortisol surge, but some people do multi-day fasts and so on. And you've always read like how for a second night or whatever there's disruption in sleep. And if you observe that or have some insight into that. Yeah, I'm not sure what exactly the hormonal activation mechanism would be, but it's definitely the case that when you're fasting, your sleep duration gets shortened, especially if you don't have a lot of adipose tissue, because again, if you have a lot of fat there, the energy should actually be supplied. But if it's not being supplied, then yeah, a lot of people report insomnia with fasting in particular. Hi Amber, thanks for a great talk. I wanna preface my question with just brief personal insight. So I'm way more hypersensitive to hunger, interfering with my sleep than anyone else I know. And as a result, I get modestly fat as a result of avoiding insomnia because my appetite isn't, if I'm not regulating my food intake, my appetite's not perfectly regulated to prevent me from insomnia. And so if I do get insomnia, I get more fat because then I overeat. And so I think the imprecision of that backup mechanism of trying to get the food that you should have eaten the day before has to be part of why people get fat from not sleeping. But so that's sort of a preface to what seems like a simple thing emerging here to me. So if ATP is a signal in the brain to go to sleep and if calories drive ATP in the brain, then if you're not sleeping and you become, since the transport of food energy into the brain is dependent on its concentration in the blood, then wouldn't insulin resistance in adipose tissue and hyperphasia be two really simple ways to increase the concentration of food molecules in the blood? Therefore they're transporting to the brain to increase ATP. And wouldn't that simply be a homeostatic loop to make you go to sleep when you didn't get to sleep? Yeah, actually that's a really good idea. So if I'm understanding you correctly, I think you're saying that the response to being tired is to boost that signal of being tired. Well, you didn't sleep and so the brain somehow knows that you need to sleep and so you do more of the stuff that would make you sleep. Yeah. Yeah, I like it. It's interesting when you mentioned about the insomnia could predispose you to being fat. I mean that's even a simpler explanation than any of this is just you're awake longer so now you've got more exposure to the food environment. I tend to not like the, because it's their explanations but I mean that can accumulate. Thank you. Right, I guess nobody on that side. Great talk, Amber. So let me throw out a situation where I have a friend who has about the same body mass as me. Low carb diet, similar activity. I sleep like a baby. He has terrible insomnia. So you can't look at carbs or fat. It's a very similar situation. What else would you look for in the diet or activity according to your theory that might help him with his insomnia? Oh, that's a good question. I mean there are certainly lifestyle factors like things like light and temperature that I said I wasn't gonna talk about but there's also things like things that could be affecting sleep fragmentation like the obstructive apnea. Nocturia is something getting up in the night to go to the bathroom will disturb you. Yeah, that's definitely part of that, yeah. Or anxiety, if he's got a lot of stress and every time there's just a brief awakening you start to perseverate on something that can. But any intervention relating to energy management that might help? I know some people say that you could take something small to eat to get yourself to sleep. I'm not sure that that's really a great solution. Melatonin actually works really well for getting to sleep although in the night it doesn't necessarily help you stay asleep, it's found. In the daytime if you're a shift worker and you want something to help you go to sleep melatonin will both shorten sleep onset and reduce awakenings. But apparently in the night it only helps with onset and not with staying asleep. Thanks. Melatonin helps. Melatonin is both an osteoporosis. It's true, that study that I mentioned with Adrosophilia melatonin was one of the ones they used. Good, oh sorry. Quickly, thanks Amber. In terms of I guess personal experience I've noticed that I have had to sleep a lot more when I was much more unhealthier. So in relation to that could it be possible that when you're unhealthier you're suffering from metabolic syndrome you have sleep apnea that the quality of sleep which you touched on earlier in your presentation about like the length of deep sleep and the amount of REM you're getting that because people are unhealthier that their sleep is lacking in quality. So therefore they're needing to sleep more as opposed to kind of a hormonal explanation. It could be that. You might also put it down to ROS. So if you have a lot of inflammation or healing as I like to call it going on or if you're working out a lot you're generating a lot of that so that would be a not unhealthy way that could increase your sleep duration. Right, thank you. Sure. Hi, could you speak to the appetite dysregulation relative to Grelin and leptin and fragmented sleep like that balance that is that something you're involved with or curious that you wake you know if you're not sleeping well you're always hungry and you're not being satiated as well because of the Grelin and leptin. Is that like- Yeah, that's a thing. So I mean short sleep duration could be simply not having enough sleep opportunity but if your sleep efficiency is low because of things like fragmentation it's gonna look a lot like as if you didn't like somebody I was just talking to said he's in bed for eight hours but his or a ring tells him he's only sleeping for six. So the amount of time you're in bed might not correspond to the amount of sleep you're getting and then you're gonna be in that hunger situation. Okay, this is the last question and we go to break for lunch. Hi Amber, thank you for the excellent talk. I found something fascinating about the link between ketogenic diet and the increase in like slow wave sleep. I saw there was a study up there and also the fact that you found when people first started losing weight they'd actually have a decrease in sleep. Whenever I get into a ketogenic state and I track my sleep with Aura I do find that like my deep sleep is longer like it gets increased but I actually sleep overall less. And so I just want to get a thought so that makes sense. Like it's always happened. Yeah, that's exactly consistent with the studies. So it's kind of the best of both worlds. I mean, I like sleeping but I also like to do other things. So if I can decrease the amount, if I can decrease the amount of time I have to be in bed for the same benefit then that's great. Awesome, thank you. Thank you and we're on now break. Thank you.