 Thanks for being here everyone. It's great to be back. I was at AHS last year for the first time So I'm really excited to be back this year and have the opportunity to present topics so My talk of course is on nutrient sensing pathways to optimal health and resilience So my first question before I move on is who here has not heard of the topic of nutrient sensing? Quite a few of you okay So the goal of my talk is to kind of give you a broad overview of nutrient sensing and for those of you who have heard of nutrient sensing particularly in the Contextivity fasting etc Information to give you a broader sense of that and also I'm going to talk a lot about the microbiome and its role in nutrient sensing as well There's a lot of new information here So of course we we think of food as primarily sources of energy and building Body but then you also hear this term that's talked about a lot as for this phrase that food is information So when I first heard this particular term it kind of turned me off a little bit because it seemed very vague I didn't quite know what people meant by it other than sort of the intuitive sense that it's providing Some sort of information to the body and being a scientist or former scientist My question is always why is that what are the mechanisms behind that? So that really leads to the whole topic of nutrient sensing which is really key to understanding how food Building blocks informs the body in terms of its effects on health and disease But what are these nutrients sensing pathways and what does that term mean? So essentially nutrient sensing pathways are nutrient signaling pathways cell signaling pathways They detect nutrients from the diet Or products from the diet from these nutrients Involves receptors that can involve other components. So that's one of the key things Cell signaling pathway is some sort of receptor or sensor And then they relay these signals along cell signaling pathways to inform So that has to do with its effects on health and disease That's typically by modifying gene expression or enzyme activity and things like that So they're very specific pathways that are responding these two things are really key in terms of that information aspect because a lot of these Products produced from nutrients are actually activating these signaling pathways. So there's specific pathways specific And there they go by many names. There's different types. You'll see nutrient sensors energy sensors Metabolite sensors and even some of the taste receptors play a role in this Receptors bitter taste receptors in particular throughout the gastrointestinal tract All right, so the big question is why are these important? Why are we talking about them? several reasons so they have been linked to Changes in these signaling pathways have been linked to chronic diseases and in particular aging and longevity Then this is kind of a particular area of interest of mine because this is sort of an in-between layer between the nutrient sensing and how it affects health and disease is a lot of these effects are mediated through Interactions between the gut the immune system the brain and metabolism and you'll see this again and again coming up in some of These studies that I'm citing that they have effects particularly in these areas And so you'll hear a lot about the immune system being related to chronic diseases through inflammation The gut is central to so many diseases nervous system microbiome and they're all interconnected and Nutrient sensing is part of the way in which that's connected. I Just talked about the role of the microbiome and health and disease. So we will be focusing on that So this is a figure I like to use in some of the courses that I teach in other presentations So there's a sort of general idea that chronic disease results Of course from the interaction of the environment in particular diet and our genes and physiology It turns out that the microbiome plays a really critical role here because a lot of those dietary nutrients and dietary factors are Basically having an effect on the microbiome and then the microbiome in turn then produces things that affect our physiology So you really have to think about these two pathways now. It's not just food affecting our physiology directly It's food going through the microbiome as well and then affecting our physiology And again, as I mentioned, this is largely through these systems, although there's others involved as well as including adipose tissue muscle tissue, etc. And They're also really important Understanding them is important for understanding all these debates that are going on kind of the never-ending debates about Diet and macronutrient ratios and is high protein good as low protein good high fat what type of fat, etc And so a lot of that can kind of be distilled out by understanding these pathways So macronutrient ratios as I mentioned quantity and quality Understanding the effects of different fasting regimens And it's also relevant to precision and personalized nutrition Partly because of the effects of the role of the microbiome. We know that's very individualized Gene differences between individuals as well and of course differences in the environmental inputs All right, so I want to talk a little bit about the evolutionary context here So basically just kind of a quick definition of these nutrients and some pathways is that they're largely conserved pathways So they go way back evolutionarily even to bacteria and yeast to some extent that promote homeostatic adaptive responses to nutrient quality so type Quantity the amount as well as the variability over time To specifically promote survival and resilience under these varying conditions That's kind of released the title of promoting optimal health and resilience This is an overwhelming slide basically the only reason I'm showing it here is Really for two things. So one is to show you can see there's three boxes essentially So on the left is C. Elegans drosophila mouse And some of these other pathways even have been detected in yeast for example And you can see that the pathways it just sort of visually as you look through it There's a lot of similarities and they're almost identical in some ways So these some of these pathways are really well preserved Evolutionarily suggesting they have a critical role and it makes sense because they're helping the organism to Recognize the food that's coming in and how to respond to it And it basically just gives you kind of an example of a typical signaling pathway as well that typically starts Not always but often starts with receptors on the cell surface that are detecting what's in the extracellular space or coming from the blood And then basically transduces that signal all the way down into the nucleus to get this gene expression response That's kind of a typical pathway All right So there's a few studies that I wanted to highlight here as well And just some basic statements from them not really going to go in depth in the studies just to kind of give you a sense of some of these conclusions So this is a paper that was published just a few years ago by Mark Mattson So it's essentially kind of a review opinion paper summarizing some of these concepts Humans and their predecessors evolved in environments where they were challenged intermittently with food scarcity Accordingly cells and organ systems acquired and retained Molecular signaling and metabolic pathways. So there's this largely these nutrient sensing pathways Through which the environmental challenges enhance the functionality and resilience of cells and organisms One such adaptation is the metabolic shift from the use of glycogen stores in the liver Muscle cells to the mobilization of fatty acids in adipose cells and their conversion to ketones Which is a topic of the last talk in this room an Alternative cellular energy substrate another interesting adaptation suggests suggested by studies of animal models is that cognitive function and Stress resistance improve in response to intermittent fasting. So the general idea here. It's not really something that's proven Is that when food is scarce? If all of a sudden we had low energy and we weren't able to perform and our brains weren't functioning That would be a really a big challenge to finding food So evolution sort of selected for our ability to be able to function well Under these sort of extreme conditions so that we can continue to survive. That's kind of the general idea behind that Now I'm going to go through a few nutrient sensing examples just to give you an idea Some of these may be more familiar to you other ones are examples I want to present to kind of give you an idea that this topic is much broader So essentially for nutrient sensing we have types of sensors that can detect the energy mediators The key energy mediators including ATP and NAD Carbohydrates particularly in terms of glucose Acids from protein fatty acids as well as bile acids that are released in response to fat in the diet Biodineutrients turn out to be a really interesting category I'll go through some examples there where they can stimulate a variety of pathways that are actually activated by other factors Probably mediate a lot of the roles of fatty of phytonutrients in health Micronutrients, I'm actually not going to go through examples here just because it's a short talk There's some really interesting example that have been coming out about receptors that can detect things like zinc and B vitamins and then have responses And of course microbioma tablates, which we are going to talk a bit about The kind of a summary table on some of these energy sensing Pathways, so if you see on the left the column is sensor pathway And on the right is the nutrients from metabolites that they essentially detect and then respond to So we have AMPK, which is adenosine monophosphate kinase sirtuins basically they detect some of these energy mediators like the Relative to AMP ratios NAD plus as well as certain phytonutrients actually can I'll show some examples of that that can activate AMP The insulin IGF pathway, which primarily can detect indirectly through insulin levels of glucose Well as to some extent amino acids and then mTOR, which probably a lot of you have heard of as well Can detect primarily amino acids particularly leucine, but then also glucose these pathways are really highly interactive and sort of interconnected Which gives the body a lot more information in terms of inflexibility in terms of how to respond to these and then something that's relatively new In terms of another pathway that responds to amino acids in particular methionine levels Which is also relevant of course to the the whole methylation Transulfuration pathway So basically it's been shown recently that methionine restriction can mimic aspects of caloric restriction And that's largely through effects on this Transulfuration pathway and result resulting in a higher production of hydrogen sulfide which is usually thought of as a toxin But in this case physiologically can mediate the effects of caloric restriction on longevity There's a few more studies. I want to go through with regard to these energy mediators So this one's titled AMPK as a pro longevity target a number of dietary genetic and pharmacological interventions including dietary restriction and The drug by guanide metformin so many of you've heard of metformin is kind of a caloric restriction memetic Can extend healthy lifespan and reduce the incidence of multiple chronic diseases? Many of these interventions recurrently involve a core network of nutrient sensors So that's the point I just emphasize AMPK mammalian target of rapamycin or mTOR the insulin insulin like growth factor signaling pathway and the Sertuans so those are basically the ones I had in that table. This is reinforcing that they really highly interact another article on AMPK AMPK activation Protein potential for boosting health span AMPK activation is suspected to mediate some of the health protective effects of long-term calorie restriction Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP Generation most notably metformin which we just talked about and berberine an example of a phytochemical phytonutrient Can be employed as AMPK activators and hence may have potential as calorie restriction and medics for extending lifespan There's there's a lot of other studies that really gets interesting when it comes to metformin and berberine They also not only stimulate AMPK, but they have similar effects as well on the microbiome And there was a recent paper suggesting that at least some of the effects of metformin in relation to improving diabetes as well as in relation to lifespan and animal models Basically is through the microbiome as well But more about that This is just kind of a quick sort of set of studies I pulled from PubMed recently to give you lots of additional examples of phytonutrients Phytochemicals that have been shown to activate AMPK and have a variety of potential health effects mostly shown from animal studies So you can see the top rosmarinic acid from rosemary mediates mitochondrial Biogenesis and insulin resistant skeletal muscle through activation of AMPK The second one is strawberry consumption improves aging associated impairments mitochondrial biogenesis again functionality through AMPK Bicoline, which is a really interesting one that seems to have some very potent neuro protective effects polyphenols on and on so we see compounds from olive As well as quercetin polyphenol rich propolis extracts strengthen intestinal barrier by activating AMPK So again, there's kind of these connections between gut health these pathways immune system Abelism etc, and we'll see that it again throughout this talk All right, so let's talk a little bit about protein restriction So it's a little bit the opposite of the topic a couple days ago in Chris Masterjohn's talk about higher protein intakes So now we're looking at sort of the other end of the spectrum that a lot of studies have shown that the benefits of caloric restriction Are largely due to restriction of protein and in particular acids So they go on to say many of the effects of dietary restriction our link to amino acid and protein availability sense by these nutrient signaling pathways Protein restriction can have profound effects on health and longevity But excessive restriction is detrimental particularly in the very old. So again, we we have to be very careful It's not something that works for everyone in every condition Especially it's been shown in the elderly Investigation of the mechanisms that modulate nutrient sensing pathways is important to understand how regulation of protein intake can optimize health span and longevity. So this is really emphasizing the role of these nutrient sensing pathways in protein restriction The quick little study that emphasize they actually looked at the comparison So I mentioned there's the mTOR pathway that can sense amino acids that mostly responds to leucine Which is a branched chain amino acid and then there's an Sulfuration pathway that mostly responds to restricting methionine. So in this mouse study They compared those two pathways and they're restricting They wanted to see which one had sort of the greatest effect. So you can see here They say the effects of methionine restriction in rodents are well established It leads to decreased body fat and body fat mass improved glucose homeostasis and extended lifespan Despite increasing energy intake Leucine restriction replicates some but not all these effects in summary Leucine restriction is effective at improving metabolic health, but methionine restriction produces stronger effects Suggesting that that transulfuration pathways a little bit more important. So they're really kind of Pathways out quite a bit now A little bit more on the energy pathways. It takes two to tango NAD plus and sirtuins in aging longevity control The coupling of nicotinamide adenine di-nucleotide NAD plus breakdown of protein desolation Is a unique feature of the family proteins called sirtuins This intimate connection between NAD plus and sirtuins has an ancient origin And provides a mechanistic foundation that translates the regulation of energy Metabolism into aging and longevity control in diverse organisms. So effects longevity Just one more on the whole sort of energy regulation pathways So there of course been a number of studies on fasting because long-term caloric restriction Of course is harder to maintain even long-term protein restriction potentially is hard to maintain So many of you are probably already aware of something called fasting mimicking diets FMD And which is what they're looking at in this study here Bimonthly FMD cycles started at middle-age extended longevity Lowered visceral fat reduced cancer incidence and skin lesions Rejuvenated the immune system and retarded bone mineral density loss in old mice FMD cycles promoted hippocampal neurogenesis lowered IGF levels and pK activity Elevated neuro D1 and improved cognitive performance. So many many benefits across the board of this type of fasting And then they go on to say so that part of the study was looking in at these effects of mice This is looking at the effects in humans as well in a pilot clinical trial Three cycles decrease the risk factors biomarkers for aging and then they lose several Well, but the idea is that it's consistent with promoting health span in humans as well And I'm not going to really go in any depth on ketones But there are some links with the whole ketogenesis Aspect to this as well ketone bodies have been shown to also go act partly through signaling pathways Studies Not as recent as some new research that just came out this past week showing that Ketogenic diets in mice can extend longevity. So there's a lot of accumulating research again that Ketosis also kind of figures in the whole thing All right, so we really looked at the first Three or so of the different types of nutrients that can be sensed in this list So now I'm going to go through a few more examples of these other categories so there's a whole category of Sensors that are called G protein coupled receptors So I'm just going to talk a little bit about those because these are important for fat sensing for phytonutrient sensing and Sensing of the products from the microbiome So they say nutrition in the gut microbiome regulate many systems So right there is kind of summarizing one of my key points that again that it's nutrition and the gut microbiome that we need to take into account Including the immune metabolic and nervous systems I'm emphasizing that there's really these three systems that they affect in particular We propose that the host responds to Deficiency or sufficiency of dietary and bacterial metabolites in a dynamic way to optimize responses and survival The family of G protein coupled receptors term to meta metabolites sensing GPCRs Bind to various metabolites and transmit signals that are important for proper immune and metabolic functions I'm going to go into this one here But basically it's talking about there's a subset that respond to fatty acids So again that pertains to the debates about the effects of fats on our health We actually have these specific receptors for different types of fats. There's a set of receptors that respond to the long chain Fatty acids a set of receptors that respond to medium chain and Another set of receptors and some of them are kind of cross over a bit to the short chain fatty acids that are produces produced by the microbiome example of some of those receptors you can see just a short list here some of these Pregluceride metabolites as well as bile acids, so that's part of the picture when we're assessing the effects of fat on Health is the effects on bile acids as well You'll see that one listed last lithocolic acid is detected by a receptor called TGR 5 Another figure from a recent publication that kind of summarizes a couple aspects of diet In relation to things that are modified by the microbiome So at the top you see fiber on the left and in the second column are the metabolites So those are the short chain fatty acids Acetate propionate and butyrate the receptors that are known to interact with them and then the Physiological aspects and health aspects that are related to that Second group here is tryptophan tyrosine metabolites. So there's another way in which specific amino acids can affect our health through the microbiome Those have the whole tryptophan metabolism story is really really fascinating and be an hour plus lecture on itself But there's effects on the intestinal permeability and effects in relation to all kinds of aspects of health as well and This is an interesting study I just came across again kind of illustrating that phytonutrients can really play a role in activating a variety of different types of Receptors in this case all spice and clove as a source of triterpine acids activating the gpr receptor tgr5 That's one of the bile acid receptors. So interestingly enough And we know that that is a plays a critical role in metabolism as well as the immune system So yet Can affect our health Targeting gastrointestinal and nutrients sensing mechanisms to treat obesity Gut hormones have important roles in the regulation of appetite and glucose homeostasis Understanding how macronutrient sensing in the gastrointestinal tract modulates gut hormone release They reveal novel pharmacological or dietary approaches to metabolic So this is really emphasizing the role of the gut as an endocrine organ And of course microbiome is right there and we'll be talking about that in just a second But this is one of the reasons why the gut is so important For overall health is it sort of acts as a nutrient sensor in addition to everything? We're all on signaling to the brain What's coming in? Influenced satiety and energy expenditure, etc So this is bringing in a little bit more of the microbiome aspect microbiota gut brain access modulator of host metabolism and appetite So it's kind of the other side of the Slide that I just showed each bacterial species within the gut aims to increase its own fitness habitat Survival by specific fermentation of dietary nutrients and secretion of metabolites Many of which can influence host appetite and eating behavior directly by directly affecting nutrient sensing and appetite and satiety There's lots of evidence for example that butyrate can affect this group of hormones that are produced by the gut called in Cretans One PYY, etc that have roles on insulin metabolism have roles on satiety Sort of set of pathways now and connections that are being mapped out between the microbiome the gut and all these different Act with the brain This is really leading to a new paradigm overall for the gut microbiome Partly illustrated in that figure where I showed diet Genes and microbiome the microbiome is an important nutrient sensor that mediates many of the effects of diet on health and disease and of course for better or worse So of course, that's a really key aspect to understanding the impacts of a bad diet versus good diet Is all these different effects that they can have on these different receptors and then how that gets relayed through the brain immune that microbiome actions There's a little bit about evolutionary mismatch, which of course is a key theme overall in ancestral health Regarding particularly the microbiome nutrient sensing. So this is kind of a complicated figure from one of the References that I cited but they kind of sum up nicely this idea of mismatch to some extent so you can see up here in the upper left We have the sad Western diet Hygiene excessive hygiene antibiotic use that are affecting microbiome composition Leading at the bottom of the figure to dysbiosis intestinal permeability and it LPS basically getting into the system Changes in the prevalence of these short chain fatty acids in the next column along with omega-3 fatty acids and these tryptophan Metabolites that I mentioned which are a really key aspect to what the microbiome does and all these different conditions that are affected potentially Deceptors and pathways that may be involved in that so again kind of connecting the dots here to Explaining this mismatch between what's coming in the effects on the microbiome and then how that gets translated into these altered signals That basically are no longer consistent with optimal health All right, so these are basically my take-home points In terms of optimizing health and resilience So of course There's lots of data to show that fasting potentially in long-term caloric restriction or protein restriction to some extent Most of that's coming from animal models Not so much human studies But that is consistent with increased health span and potentially even increased longevity So I think there's a healthy discussion to be had around That versus sort of like high protein intake etc and the Instances where you'd want to basically take that approach. So the anabolic sort of versus catabolic considerations Bidoneutrients play a role in so many ways. We know they're antioxidants. We know that they're anti-inflammatory But now we're starting to see that they also Specifically activate many of these pathways. So we're really starting to understand We also know that phytonutrients in particular can help balance the microbiome and counteract to some extent dysbiosis because they tend to Reduce the incidence of potentially harmful bacteria and then they tend Generally considered beneficial bacteria, so there's lots of different roles that phytonutrients play Micronutrients I didn't really go into but just keep in mind that there are pathways that can sense some of those And really the bottom line is the implications for improving health by basically targeting the microbiome and then these systems that it's connected with In terms of trying to get the effects that we would like to have in terms of changes in health So I think there's so many of these connections that we see kind of independently in this system really sort of ties a lot of that together in terms of how Microbiome affects our health how the immune system affects our health in relation to diet Really fascinating area of research, but it's also pretty overwhelming when you dive in it becomes alphabet soup of Receptors and pathways, etc. All right, so that's what I wanted to say today So if you like more information my website particularly for practitioners on the microbiome. I have a few courses translating microbiome information for clinicians microbiome mastery comm my fishing consulting practices prime health span I Find me on Facebook or feel free to like as well. So thank you so much appreciate it. Hello. I really like the Signaling view on this and is really great segue I Recognize there's a lot of complexity here, but just to check my understanding. It seems like they're they're at least a general level They're signaling for Nutrient High nutrient Environment and a low nutrient environment and so protein would be signaling that you're you're getting enough nutrients But it seemed to me and this ties into some things about bitter plants that I've been reading recently It seemed to me that a lot of the phytochemical Signals that you were demonstrating Seem to be more in line with the showing that there's a poor nutrient environment And that therefore they are signaling in a sense starvation. Is that is that an accurate? Assessment. Yeah, it's not really known There's certainly Hypotheses I've come across that are similar to that that they potentially are sensed as Toxins, you know by the liver and basically the body tries to get rid of them pretty quickly Once they enter the system So there is a lot of evidence that the body doesn't necessarily recognize them as something that's healthy and beneficial and does try to get rid of them And then that may be reflective of as a total speculation, but basically in a nutrient poor environment where other resources around that they have to resort to Sources that are not calorie dense like certain plants and so they're over consuming these phyto nutrients that is interpreted by the body in the context of Yeah, that's definitely consistent with it. Yeah, I recognize it's conjecture, but it's a just so story that I like Thank you My question is just about fasting and whether there is a particular length of time That you need to fast to get these particular benefits some of the benefits for example the slide that I show where there's Hippocampal neurogenesis and things like that is the fasting mimicking diet and typically those Depend on two things at least in humans They seem to depend on and also rodents on fasting for several days like three to five days But also on the refeeding phase as well so that's one big difference between fasting and caloric restriction where you just sort of Restriction calories across the board the idea of one of the Sort of benefits behind the fasting mimicking approach is that you have this refeeding phase that's stimulating regeneration For stimulating these pathways. I'm actually off the top of my head. I don't remember kind of the typical Timeframes for those a lot of these studies were done in sort of calorically restricted rodents that were done You know, those are long-term experiments. Okay. All right. Thank you Thanks for that talk. It was really great. I Don't remember the details, but it was some time in the 40s. They did a metabolic ward study with children some of them had deficiencies and You know, it was an ad libitum thing. They could eat whatever they obviously it was healthy foods And they were you know, the kids would scurvy would gravitate towards the vitamin C containing foods and Brickets would you know gravitate towards the vitamin D contained sort of The body was sensing deficiencies and That are really, you know, the behaviors and food choices were you know Fact that I wonder, you know, that's something you could comment on So in terms of act like activating these specific pathways Or yeah, I mean, I guess it it works in both directions if your body's looking for a nutrient They're obviously your sensors somewhere that Right Yeah, there's multiple levels to that. I'm not as you know, certainly not an expert on sort of the brain reward system aspect to all that but Particularly in terms of the microbiome There's a lot of speculation that the composition of your micro microbiome may have an effect on that too in that And if you have a certain prevalence of certain types of bacteria That they may produce because we know that the microbiome can produce potentially neuroactive compounds And other compounds that can affect the brain and that may be able to affect that whole sort of food Ford food seeking system. So that's one aspect, but they also have an effect on the gut which has a much better Establish effect on satiety and hunger So it's entirely possible. I haven't really come across too many studies that address that specifically that if you're lacking Amino acids in your diet, for example, or any of these specific amino acids that that stimulates Thank you. Cool. Thank you for your talk In fasting in humans, is there any speculation or data looking at the use of things that may upregulate AMPK during that time like green tea and maybe Burberrying on the day that you're doing the fast. I Have not seen any studies sort of on combining those So I can't really speak to that. I would assume there may be some additive effects Trying to think if I have come across any information related to that where they've done both of those at the same time I'm sort of this is again just sort of a guess But I'm guessing if you do have a sort of a high phytonutrient diet That may kind of prime your system to be able to handle fasting better. That'd be an interesting thing to sort of Explore more, but I again, I have not studies on that