John Newman - Ketone Bodies As Signaling Molecules

I'm a little different I'm a geriatrician some of the time at UCSF and I run a aging biology laboratory at the buck Institute the rest of the time so I love that DOM and Jeff we're talking about treating Navy SEALs and Army Rangers I treat your grandma but but we're all interested in nutritional effects on health and the mechanisms that mediate those things so I'm gonna I'm gonna expand on some of the topics that Dom started touch on about what we're learning about the new biology of ketone bodies and how that fits into the picture of mechanisms of nutritional interventions and and what that means for aging and disease I haven't written a book yet I have no disclosures and this is science this is going to be interesting and I think directly relevant translational science especially for those of you who are clinicians and are trying to figure out how to think about managing patients who are trying interventions like low carb diets or ketogenic diets or even these exogenous ketones so this is science if I know you guys aren't afraid of that after the the great talks this morning and talking there are lots of molecules and enzymes and pathways going on so we're going to do some of that too we're going to talk a little bit about ketone bodies in normal physiology which we've already heard a lot about and then focus on the new biology of signaling activities of ketone bodies and talk a little bit about how this could fit into actions in health and disease I'm gonna echo what Dom said although I actually am a doctor that kind of doctor but none of this is medical advice do not take medical advice from people wearing microphones on stages but I hope that you'll learn something from this that that will be useful for you in terms of practical questions like when you're thinking about nutrition interventions or even exercise interventions it's absolutely fascinating to me that we don't know what the right dose of exercise is and we don't even know how to measure it and the same is true for nutritional intervention so this may give you some thoughts on how you can quantify and define doses of lifestyle nutrition and exercise interventions and how to think about which elements of these interventions might be helpful for you or your patients to meet certain goals and where the science hopefully the translational science is going to be headed in terms of testing specific effects of nutritional intervention on conditions and health and disease and my own favorite aging so the first part ketone bodies are signaling metabolites and I've got in the sense in the last two talks that this is now becoming common wisdom I love that so how did I get interested in ketone bodies well just from the observation so remember I'm coming at this from the angle of a geriatrician who studies aging and aging physiology and mechanisms of aging and I've it's been really interesting to me actually throughout the day to day that I sort of existed in a in a parallel and very closely opposed universe to the obesity universe if you change the word obesity for aging in most of the talks today we talk about exactly the same stuff we talk about the same we talk about nutritional interventions like fasting and dietary restriction we talk about the same pathways we talk about insulin and igf-1 glucose signaling and fat metabolism we're really talking exactly the same language just with a slightly different emphasis so that's where I came from this the observation that the the interventions that have been known for the longest time to improve health and particularly aging in longevity in especially in the laboratory things like exercise interventions dietary restriction fasting and now carbohydrate restriction all share in common the production of ketone bodies our ketone bodies just a bystander in these interventions or do they actually have a mechanistic biological role you've already had an introduction of what ketone bodies are beta-hydroxybutyrate is the major ketone body that's that's induced when you fast or your exercise so most of the most of the extra ketone bodies that you generate are beta-hydroxybutyrate that's one reason I'm going to focus on beta-hydroxybutyrate so beta-hydroxybutyrate ketone bodies they're fasting fuel they're the way that your body mobilizes the energy reserves in your in your adipose tissue so that your heart and your brain your muscles can use it when there's not a lot of glucose around we've known that for a long time and that's extremely important but maybe this is interesting too that ketone bodies are also fasting signals and I'll show you how they bind to proteins inhibit enzymes and do other things that regulate broad cellular processes like tableaus 'm inflammation and that these signals may convey some of the biological effects of the conditions in which they're made of fasting and dietary restriction and exercise to kind of I want to tell you how I think about what a ketogenic diet is I think it's really important to remember as as we heard in the last talk that there is no Zee ketogenic diet the ketogenic diet is I think of it as part of a continuum of low carbohydrate diets where as you begin to restrict carbohydrates at some point you reach a threshold probably mostly determined by insulin levels where your liver starts to make ketone bodies it's not it's not a switch but it begins but it there's a threshold where that production starts and then as you continue to restrict carbohydrates you make more and more ketone bodies but it is a kind of gradual dose response curve so I think of it as parts of the same different parts of the same continuum and that's true in the in sense of other biological effects too and I'll show you an example of that in a moment this is data from mice just to illustrate the point that as you as you gradually restrict carbohydrates in the diet of a mouse you can go pretty far actually you can you can have a mouse eating only 15% of its calories from carbohydrates and still really not making meaningful ketone bodies any any more than it would in a normal diet but then you start to see an increase and the increase is gradual and accelerates as you reduce the carbohydrates further and further to to nothing so there's not a switch threshold but ketone body production is very sensitive to relatively small amounts of carbohydrate and you get the the most in mel studies from nothing at all this is how I think about the mechanisms of what do ketogenic diets do and you could actually put you know low carbohydrate diet at the top of this hierarchy but fundamentally ketogenic diet has a couple of key components one of them is carbohydrate restriction in order to reduce insulin levels to the point where you reach that threshold where your liver starts to make ketone bodies that's the ketogenic state and that's the second characteristic and then the third characteristic are the ketone bodies themselves that are floating around all of these are biologically active and all of these have health effects walking down that chain and ketone bodies themselves I think of their actions as separate into energy functions as a fuel as a as a as the fourth food group is Dom said being burned to generate energy and tissues and then signaling functions this new area that we don't understand as well but where beta-hydroxybutyrate acetoacetate and other ketone bodies have these effects on cellular processes in addition to their energy functions so that's how I think about the hierarchy of mechanisms how trying to figure out if there is a phenotype that you observe on a ketogenic diet what is the mechanism is a really complicated question and this is how I think about how you might go about trying to answer that understanding that it'll be different for different phenotypes for different conditions for different diseases in some carbohydrate restriction might be really important and insulin might be critical in others it may actually be a direct action of a ketone body I do think that ketone bodies in some contexts at least have additive effects or at least the key genic state has additive effects over just carbohydrate restriction I'm going to show you a bit of aging data as an example of that so my group with Eric Burdon at the Gladstone now at the buck institutes along with a group at UC Davis led by John Ramsey both just finished a mouse longevity study of low-carbohydrate ketogenic diets and we we tried to use we both try to use those two comparisons in in the best controlled way we can so they're exactly the same diets in every way that we could control except that we lowered the carbohydrate content almost all the way but not so far that the low carbohydrate diet produced in the ketone bodies and then we lowered it to nothing and that was the ketogenic diet so almost exactly the same except for that last bit of carbohydrates and then production of ketone bodies and the data showed that the key genic diets in yellow on the left and in red on the right improves survival of these mice in John Ramsey study it was more towards the latter half of life and my study was more in the mid life surviving into old age but they both improved survival and they both improved survival a little bit more than just the carbohydrate restriction alone which is just a suggestion that the ketogenic part of that that last step of carbohydrate restriction added something on top of the low carbohydrate but just the carbohydrate restriction alone had important physiological effects probably a lot of that related to insulin but maybe there's something related to the ketone bodies too how I got into this scientifically working with Eric Burdon was on the tail end of a study that discovered a new signaling activity of beta hydroxy butyrate that inhibits a class of enzymes called deacetylases so our gene expression is controlled in an important way by the proteins around which our DNA is wrapped so our DNA is usually very tightly wrapped around these proteins those proteins have called histones have tails and those tails can get modified in various ways which affect the interaction of the DNA with the protein around which it's wrapped a set elation is one of the most important modifications and morissette elation or less acetylation has huge effects on gene expression and there's a whole panoply of enzymes that control this very carefully how much Isetta Latian there is where it is and taking it on and putting it on taking it off so it turned out that beta hydroxy butyrate binds to and inhibits certain of the enzymes that regulate this Isetta Latian like a drug and if we looked at this with purified enzymes we could show a nice linear correspondence between more beta-hydroxybutyrate causing more inhibition of these deacetylases and then to make a long story fairly short we found that inhibiting deacetylase enzymes change the histone acetylation at the promoters of certain genes regulated their expression and those genes included genes involved in the antioxidant defense response probably a lot of other genes too in a lot of different contexts but that was the one thread that we pulled out of this and that was published about five years ago now histone acetylation deacetylases have really interesting roles in regulating aging in in yeast in the yeast and flies and worms that aging scientists like to study but I want to also point out a couple of human examples of their roles in age-related condition and diseases that we know that deacetylases and histone acetylation is important in age associated cognitive decline and also in in age associated heart failure diastolic heart failure pressure overload heart failure so some interesting hints that this regulation of deacetylases could have implications for chronic diseases of aging that's not the only way that beta-hydroxybutyrate regulates gene expression just last year Yin mingzhu who is a fantastic mass spectrometer estat the University of Chicago who studies these little things that get attached to histone tails found that one of the things that gets attached to histone tails is also beta hydroxy butyrate it directly binds to those histone proteins and we have no idea what it actually does there but all we know is it's there and if you fast a mouse and fasting turns on expression of a whole bunch of genes involved in fat metabolism then you find this beta hydroxy Butera layin at the promoters of those fat metabolism genes and again we have no idea what it's doing there this is kind of cutting-edge topic for research but probably has something to do with regulating gene expression you've heard a bunch already about the infamous ohm so this is another signaling activity at beta hydroxy butyrate what is the infamous ohm it's this sort of signal integrator inside of immune cells inside of macrophages and other immune cells that helps that cell decide whether to become inflamed when it senses damaged so the cells sense damage and maybe that's bits of DNA it's bits of mitochondria it's its reactive oxygen species maybe it's amyloid in the brain and then the cell decides whether that's sufficient to turn on an inflammatory response if it is then the inflammasome assembles from a whole bunch of little tiny subunits since this gigantic complex which then turns on the expression of inflammatory cytokines especially Iowan beta one example of this is uric acid crystals activating infamous ohms and triggering the inflammation associated with gout and deep dixit at yale as you already heard today did some really interesting work over a couple of papers showing that beta hydroxy butyrate inhibits and beta-hydroxybutyrate itself inhibits the assembly and then activation of these infamous ohms and there reduces inflammation in various states including particularly looking at of rat model of gout I know that he's interested now in more translational studies looking at ketone bodies in beta hydroxy butyrate and gout in people but this is not just about gout inflammation of course but the nlrp3 inflammasome specifically have been implicated in a variety of diseases of aging I guess I should today I should call these diseases of obesity too and and all of which have potential applications for signaling activities at beta-hydroxybutyrate beta hydroxy Barre is also a receptor for a couple of cell surface or sorry a ligand for a couple of cell surface receptors one of them is called hcar - it's a really interesting receptor which is expressed in lots of cells all around our body beta hydroxy birria is probably the primary ligand for it it does a bunch of different things it's how beta-hydroxybutyrate reduces lipolysis from adipocytes and i'll return to that in just a second as may be part of a kind of self regulatory mechanism to reduce its own production but this receptor also regulates inflammation and also regulates neuron function in different tissues there's another receptor FFA r3 which maybe is most interesting for probably mediating the reduced sympathetic tone that you see in fasting so in in certain neurons beta-hydroxybutyrate inhibiting this receptor reduces sympathetic tone and then lowers heart rate in in laboratory mice FFA r3 does a bunch of other stuff related to metabolism inflammation where the role of beta hydroxy be raised a little bit more shaky not clear if it's turning on or turning it off but this is a particularly interesting bit of data and then just a couple of months ago we have a new signaling activity of beta hydroxy butyrate a new protein which it binds to this time a protein that stabilizes RNA molecules so remember DNA is transcribed RNA is translated to proteins so the stability of RNA how long it hangs around there is an important regular of gene expression - so beta-hydroxybutyrate binds to this protein hnr and pa1 and thereby stabilizes allows that protein to stabilize the transcript of another gene called act 4 which is one of the genes that Shinya Yamanaka found to be important for turning cells into stem cells it's a it's a quiescence factor or a stemness factor but the point of this study was that by turning on this stem cell factor it reduced senescence especially in endothelial cells and vascular cells so the the bit on the right here dark spots are senescence cells along the aorta of a mouse and showing that increasing levels of beta-hydroxybutyrate reduces that senescence senescent cells are cells that are damaged not enough to kill themselves but enough to shut down and then turn on inflammatory response so this is another yet another way that beta-hydroxybutyrate might regulate inflammation particularly in an aging context so you've already seen this nice figure showing this is just one half of how I think about the signaling functions of beta-hydroxybutyrate these being direct activities where beta-hydroxybutyrate is really acting like a drug directly binding to something and inhibiting its activity or activating it there's another whole set of signaling activities which are indirect as I as I think of them they're the result of metabolizing beta-hydroxybutyrate into energy through a selca way and this have changes in a sort of Kawai abundance changes in the NAD balance and things like that and I won't talk about those today so putting it all together there's a variety of ways that beta hydroxy butyrate can regulate inflammation through the inflammasome gene expression through RNA stability through beta hydroxy B relation through deacetylase and abyssion and inflammation of metabolism both through cell surface receptors all of which have really interesting implications for metabolic disease diseases of obesity and aging and I'm talking mostly about beta hydroxy butyrate I think at this point we probably know the most about signaling activities at beta hydroxy butyrate but as Dom alluded to we're finding similar things for acetoacetate and even as I learned from Dom for acetone so all of the ketone bodies have seem to have some degree of direct signaling function acting like endogenous pharmaceuticals so beta-hydroxybutyrate is fasting fuel but is also a fasting signal how does this fit into aging is this a strange thing and I just wanted to tell you that this is actually a great example of of what we find with with a lot of metabolites in an aging context this is the link it's a great example of the link between metabolism and aging so in the in the aging world I'm gonna show you some kind of cartoon versions of signaling pathways they might hearken you all the way back to undergraduate biochemistry where you think about how signals from the outside will get into a cell so you can have you know channels that let molecules through you can have receptors that molecules bind to and then these go through amplification steps kinase cascades where one one enzyme activates a whole bunch of others or second messengers you make a whole bunch of a small molecule and then that small molecule activates a whole bunch of other things but ways to amplify the signal to get eventually the effect you're looking for in the case of pathways that modulate aging these are usually various forms of cellular stress response you know etaf adji and and protein quality and things like that what's interesting about aging is that many of these second messenger molecules that amplify signals are boring old metabolites that we all learned about in undergrads that have just canonical simple roles in helping us to use energy so nad a MP s adenosylmethionine a subtle Kawai you know the kind of fundamental currency of energy in the cell that gets burned in the TCA cycle a subtle Kawai but remember I mentioned a set elation on the on the tails of those histones around which DNA is wrapped this is probably the the best-known example of how these little metabolic molecules have entire secret lives as signaling metabolites so a subtle Kawai is a substrate for protein acetylation which is a a widespread and hugely important way of regulating protein function including the proteins that control our gene expression nad is now problem may be better known as a substrate for of enzymes called sirtuin deacetylases a long wish being electron-carrier that helps us to process the energy released from glucose and the TCA cycle so this is this is kind of standard now I think we're learning more and more that more and more metabolites have these sorts of signaling functions and this is the this is how metabolism and aging are linked and maybe it's how metabolism and obesity are linked to so if BHB beta-hydroxybutyrate a really interesting molecule could we put it into a pill and would that give us some of the same biological effects of a ketogenic diet so this is getting a little bit speculative but I just wanted to give you some tools to to know how to think about the things that patients might come to you with so first of all there is no ketogenic diet in a pill ickey genetic diet is of course a very complicated intervention that does a whole bunch of things in the body and I kind of laid out my my outline for you of how I think about those mechanisms so if you think about how to pull off I that you need to first figure out what's the actual active component in whatever condition or phenotype you're looking at and then you can maybe figure out how to bypass the that's the sledgehammer that is the the carbohydrate restriction and connect diet and and design more precise therapies but there is no one key genic diet in a pill that will work for everything but at least for some of the things that key genic diets do ketone bodies are probably important and now we're starting to have some tools in which we can parse this out mechanistically so cute ketogenic diets in a pill so just to remind you beta hydroxy butyrate is the think of it as the circulating it's the the ketone body that travels it's the one that goes around your blood gets taken up by tissues that need energy it's converted to acetyl acetate inside of cells both as the last step before it's produced and the first step before it's burned for energy and then the other ketone body is sometimes lumped in with acetone which is a spontaneous breakdown product of acetoacetate and gives you that that fruity breath so could you just eat beta-hydroxybutyrate or acetoacetate you could try well I guess you can I think we all got a packet for that not exactly though the the obstacle is that these are small molecules that are organic acids and they're small molecules that are food so we'd be talking about eating them in you know meal level quantities and they're rapidly metabolized so you'd wind up having to eat an awful lot of an organic acid or an awful lot of salt if you try to neutralize it as a salt but this is one way that you can do that you can create ketone salts with sodium or other other ions to balance out the the acid the trick though is if you're talking about a meal level quantity so say a hundred grams a beta-hydroxybutyrate which is about 400 calories that'd be a small lunch that would include about 20 grams of salt because this is such a small molecule and and something about a you know quarter of the weight of that is the sodium that's a lot of sodium for a small lunch it's the equivalent sodium content of about five liters of normal saline so probably you don't want to do it every day and remember I'm coming at this from the angle of you know aging and chronic disease and you know things that we might do for for months or weeks and months and years but this is not hopeless so first of all there are some very clever and sophisticated ways you can try to balance this out to reduce the sodium content use other ions and maybe you know mix in other things so some very clever ways that you can you can modulate this a little bit but the real hope I think comes from thinking about this in a signaling function so yes it's a nutrient but it's also a drug and that drug has effects on its own and maybe that drug and we don't know this yet maybe that drug has outsized effects beyond the amount that you're actually burning for energy so there's a couple ways to think about from these signaling functions how beta-hydroxybutyrate might either inhibit or potentiate its own actions so we already know from from binding to a particular receptor on adipocytes that beta-hydroxybutyrate inhibits the mobilization of lipids and that helps to put a tamper at least somewhat on its own production it's a bit of feedback inhibition but there are also examples emerging from the study of signaling activities which look more like feedback activation if beta hydroxy butyrate changes gene expression in a way that enhances fatty acid metabolism and it might actually promote its own synthesis or promote the synthesis of other beta-hydroxybutyrate from other lipid precursors as long as you have lipid precursors around so maybe this is a biochemical basis for this idea of mixing beta-hydroxybutyrate salts perhaps a little bit of that with other with other dietary lipids even long-chain fatty acids to provide some substrate for BHB to use we don't really we haven't done the where I haven't seen the experiments to really show whether this is is what's happening in our bodies but this is one idea that maybe there's a chance that small amounts of ketone bodies could have larger effects on metabolism so ketone salts are one strategy for exhaustion Eschete owns another are quitar beta-hydroxybutyrate precursors so molecules that are metabolized to beta-hydroxybutyrate in the body one example of this is the alcohol precursor butanediol which Don mentioned briefly a little while ago so this is this is metabolized this looks just like beta hydroxy butyrate except it's an alcohol instead of an acid and it's turned your liver turns it directly into beta hydroxy butyrate using the same enzymes that you use to metabolize ethanol so that's very nice and very clever another another group of molecules I think about as precursors are are these medium chain triglycerides so what's different about medium chain fatty acids medium chain triglycerides two things one is the way that they're transported from the gut to the liver which is more direct than for long-chain fatty acids but the more important one is how they're transported into mitochondria once they get to the liver so for long-chain fatty acids insulin inhibits that transport and this is one reason why you don't make ketone bodies if there's a lot of insulin around but medium chain fatty acids use a different transporter to the mono Kandra which is not insulin sensitive so they can enter the mitochondria and then the mitochondria figures it has to figure out what to do with them and generally turns most of them into ketone bodies so there is a so that's the biological basis for the ketogenesis so to speak of medium chain triglycerides you can also combine these things and this is the world of ketone esters so trying to get around the organic acid nature of bate hydroxybutyrate or acetoacetate by linking that to other molecules and so sort of shielding the acid part of it so the most the most commonly studied ketone ester so far developed by Richard Veatch and Kieran Clark and the only one that's as far as I know that you is is available to the public is a combination of this alcohol precursor butanediol plus beta hydroxy butyrate and you can see you sort of flip the butanediol around and just dock them together so that's an ester you can make an ester with just about anything so you can combine these and all sorts of interesting combinations you also heard about accommodations of acetoacetate and butanediol earlier today all of these are ketones esters so ketone esters like ketogenic diet is a class description there's lots of different ways to make a ketone ester I just think of a ketone esters anything that has a ketone body acetoacetate or beta hydroxy butyrate which is ester linked to something else in order to shield that organic acid so the way that ketone esters work is they're really just payloads their delivery molecules so you have enzymes called ester raises all over your gut and in your blood that will cleave this molecule at its ester bond so it's an ester just so that it's safer to eat a bunch of it but then as soon as it gets into your body it's split into its constituents and so in the case of the Veatch clark ester those constituents are a beta hydroxy butyrate and butanediol and then the butanediol will be turned into more beta hydroxy butyrate in your liver now one thing to keep in mind is that B chain dial as an alcohol and alcohol is an almost necessary component of one of these esters so when you split the ester you'll generate an acid beta hydroxy butyrate or acetoacetate and then whatever you've hooked them to will be in the form of an alcohol so your liver has to process that alcohol it's not ethanol but it's some form of an alcohol and since weird again talking about you know meal level quantities it's it's not a lot of alcohol but it's it's something so these alcohols are metabolized by the same enzymes that we used to metabolize ethanol and if you're talking about say 30 grams of a ketone ester that's the equivalent of metabolizing about half of a drink so and 30 grams is I think what people have settled on as a reasonable single dose of a key to an ester so as a single dose depending on your metabolism that's probably fine it's definitely something to think about if you're doing dose after dose especially of a long period of time so I thought I'd briefly talk about what we know about these exhaustion is ketones ways of delivering beta-hydroxybutyrate directly in both rodent and human studies and the slides are available so you can look at this in more detail on your own most of the studies and rodents have used the this Beach chloric ester butanediol and beta-hydroxybutyrate and show an interesting interesting set of metabolic changes as well as as as Dom summarized earlier a variety of interesting anxiety and memory effects including in Alzheimer's models I do some work on looking at the mechanism of ketogenic diets and alzheimer's models - in people most of what we know is through the study of free ketones esters anyway is through the study of elite endurance athletes there is a little bit of literature about medium chain triglycerides going through a couple of small clinical trials in patients with Alzheimer's disease which was quite fairly promising in small phase one in two studies but wound up with a not so promising larger phase three study that it should be published soon but most of what we know about ketone esters is in the context of young people taking them just one you know one at a time and for exercise performance there's not much if any literature right now on the use of exogenous ketones in older adults and people with chronic diseases or for the treatment of diseases except for a a case study of using one of the ketone esters in a colleague of Richard Beaches who had Alzheimer's disease but that's the only person that I know so far who's who's been published to take a ketone ester in the hope of treating a chronic disease but these studies are underway and I think we're going to start to see them pretty soon and then start to see more and more of them so I know there's a lot of interest in studying sahjhan as ketones in neurodegenerative diseases but also in heart failure and diabetes and other conditions so what is all this complexity mean for how to think about ketone bodies and ketogenic diets just a couple of examples of how these signaling activities contribute to plio tropic effects on phenotypes like obesity and metabolic disease so for example there are several mechanisms that we can guess through which beta hydroxy butyrate might affect metabolic disease I already mentioned a couple like effects of beta hydroxy butyrate on the expression of genes involved in fat metabolism we know that certain deacetylases have roles in regulating insulin sensitivity h3 in particular controls gluconeogenesis we know that the nlrp3 inflammasome can regulate inflammation in a dipa site or sorry in in macrophages in adipose tissue and we know that inflammation in adipose tissue is an important mediator of metabolic dysfunction and then there are also potentially effects through the through some of these cell surface receptors on mobilization of fatty acids and again regulation of inflammation especially in macrophages so all of these mechanisms might be relevant in different degrees to effects of beta hydroxy butyrate on obesity and metabolic disease and similarly for in the kidney there are at least three mechanisms through which beta hydroxy butyrate may be renal protective in certain in different contexts so our own study looking at expression of antioxidant genes from beta hydroxy butyrate an interesting study of beta hydroxy butyrate regulating prostaglandin production and maybe that's through one of those cell surface receptors we're not sure and then a very recent study of beta hydroxy butyrate protecting the kidney in a rodent model of hypertensive hypertensive kidney disease through the nlrp3 inflammasome so inflammation probably inflammation and repair all potential molecular mechanisms that could mediate renal protective effects of beta hydroxy butyrate so all of this complexity also means that the biology is complex and the effects on people are complex and may be hard to predict we had a great example of that this morning in the very in the relatively straightforward idea of how much blood sugar goes up after you eat a food and you can imagine predicting how different people will respond to ketone bodies all the information I just gave you should make you think that that's going to be very complex and difficult to predict because you're not just talking about their ability to metabolize these exogenous ketones or their ability to generate ketogenesis or on a ketogenic diet you're also now wondering about their the state of their deacetylase genes and their gene expression their epigenetic states and their nlrp3 and their infamous ohm how active their macrophages are all of which have both genetic and epigenetic contributors so this is unfortunately this is the normal state for studying aging and metabolism that there is a huge component of individual variation and I just want to show you a bit of mouse data since I'm mostly a mouse biologist that was a real relevation for those of us who studied dietary restriction and aging so dietary striction we've known for 80 or 90 years if you feed a rodent less they're usually live longer it works in most strains but these guys did the really cool experiment of taking a couple of strains of mice interbreeding them in ways to generate some genetic diversity not nearly as much as we have but at least some and then dietary restricting them all it turns out that dietary restriction and then looking at lifespan dietary restriction extended a lifespan of some of them these are the bars on the left side of each of each graph but actually in many strains dietary restriction made them live shorter actually shorten their life span a huge genetic diversity and you can just think of how much more complicated we are than mice so precision medicine and really understanding the genetic and epigenetic basis of how a person is going to respond to these large-scale interventions is is the future and finally thinking about these signaling activities might give us some tools to actually be able to quantify what is the dose of a diet or exercise that you need to achieve a certain end so maybe if beta hydroxy butyrate binds to proteins maybe you can measure that maybe that's a good measure of exposure to beta hydroxy butyrate and maybe you could use that as a threshold for when someone has had enough or you could look at downstream biochemical effects like activation of infamous ohms or expression of certain genes but these might give us hard quantifiable things to be able to tailor treatments to individuals with a certain certain goal in mind so what I'd like you to remember as you leave here into camp for the cocktail hour that beta-hydroxybutyrate is a nutrient and and makes ends and it's used for energy but also has drug like signaling and fog signaling activities I want you to remember this hierarchy of ketogenic diet mechanisms I showed you of how to think about what a ketogenic diet is actually doing to create a phenotype I told you a little bit about a taxonomy of exogenous ketones so you can know how to think about what is a ketone salt what is a ketone ester and then finally I think that BHB signals will help lead us towards new clinical applications give us some ideas of what diseases or or syndromes or clinical problems might be most amenable to treatment with key genic diet or ketone bodies and help us to guide making those therapies precise and individualized so thank you for your attention [Applause] we do have time for questions you can jump right in that was excuse me yes really a beautiful story and I'm just curious about the beta-hydroxybutyrate mutilation of histones and probably other proteins I don't know how wide it's been looked looked at but obviously if that's happening in a dynamic way there has to be a deacetylase and we have this or two Infirmary we have the non nad dependent deacetylases has that been figured out yet no one has it so great question and we should talk later about that this is a very active area of study so I mentioned a set elation and beta-hydroxybutyrate actually just about any metabolites you can think of that's hooked up to an acetic away at some point in its life in the cell we now know binds to proteins and modifies proteins and affects function and we know some of the enzymes that and so anything that's important functionally there'll be enzymes that take them on and enzymes that take them off sirtuins we're learning our class of enzymes that seem to have adapted to removing many of these different modifications we don't know if any of them remove beta hydroxy be relational at ends I'm does that we also don't always know what enzymes put these modifications on in some cases it seems like much of that is non enzymatic which can still be regulatory because it's it's a function of of the energy state of a cell if there's a lot of succinylcholine or a lot of a selca way around that says a lot about the state the cell is in but we don't know what if there is an enzyme that attaches beta-hydroxybutyrate specifically yet well that was going to be my second question because my guess is it probably is non enzymatic because it's probably not connected to acetyl it to the to the co a component rather at least not in the nucleus yeah we actually don't know yet that we don't know that yet either what's the mechanism even for non enzymatic attachment beta-hydroxybutyrate this is very kind of it's incredible that simple questions like this are unknown in cutting-edge in 2018 wonderful conclusion to an exciting session David Ludwig from Boston oh you and others in the session have emphasized that ketogenesis is a highly regulated biochemical pathway and one jumps over biochemical regulation with caution is there many examples in which unexpected and in some cases catastrophic especially long term consequences could occur so in the normal state high ketones is associated with low carbohydrate both intake and circulating levels of glucose just a very rare exceptions I guess very high amounts of MCT you know could put that put could could alter that giving exogenous ketones changes that now it's true as it was emphasized earlier I think by Dom or Jeff that ketones can suppress gluconeogenesis and so you don't get very high levels of both but if you're eating a high carbohydrate diet with a fair amount of protein and you're not oxidizing it you know that gluconeogenic substrate is going to build up in a state of high ketones I've heard anecdotal reports of people taking ketones on a high carbohydrate diet and feeling like an overwhelming burst of energy but almost adversely so like they couldn't sit still could we be setting ourselves up for overtaxing metabolic pathways that have acute benefits but long term adverse consequences I absolutely and I'm glad you brought up the idea of having caution when you're bypassing normal metabolic regulation and I absolutely echo that and agree with that and I'm gonna return to something I mentioned about how the signaling activities of beta-hydroxybutyrate might regulate its own synthesis the idea that there could for example be feed-forward activation of ketogenesis is interesting for the idea of maybe small doses could have biological effects it's also caution raising for the that you might reach a threshold where an overdose becomes a real possibility and the dangerous possibility because you've you're doing this this this element beta-hydroxybutyrate signaling and and ketosis in the absence of what normally is the rest of the regulatory network in the context of fasting or carbohydrate restricted diet so I think there is absolutely reason to be cautious about how we try these things and use them and really try to stay on top of our skis so to speak in terms of how we're advising the public and using them to I think that one of the I so clearly I'm a fan of the exogenous ketone idea from a biological and medical perspective I think one of the needs in that field besides testing exogenously tones in the setting of older people with chronic diseases and maybe with not the perfect metabolism of a marathon runner I think is also really carefully studying the effects of higher doses and the effects of longer term use just to really know what we're dealing with I absolutely agree or when in doubt we could also just stick with the ketogenic diet absolutely absolutely mine sort of comes off of that but the much more simple question for people that have relatives loved ones with early mild cognitive impairment if you had a relative starting that would you suggest a ketogenic diet for them is it too early to actually say that or can we just start doing that to family members and see some results so I stay over my skis and I'll tell you why specifically in the context of Alzheimer's disease or early stage dementia but but first that this is an active area of clinical investigation and for example there is a randomized controlled trial underway and I know one of the investigators at Wake Forest who is who's running this of a ketogenic diet in early Alzheimer's disease so I think in the context of Clinical Investigation that's a great idea in terms of you know what I would ask you ask my grandmother do it I have a hard time doing that in part because geriatricians are naturally very cautious people because we know how easily older adults can be hurt with the best of intentions and how fragile they can be in certain ways so I really don't want my older adults losing weight I I don't want them having GI symptoms that could that could even be a delirium trigger besides affecting their their weight maintenance and and other things so I would be very cautious about that given that we don't really have great data to say that we know it's a good idea yet but it's clearly a good enough idea to study yeah and I hope that there's more clinical investigation along that route so we could we could talk for an hour about geriatrics oh maybe we'll talk over cocktails about that but when I so the older adults that that I would worry more about what's a good way to say that if you have to put your medicines into a paper bag when you go see the doctor that's probably a good sign definitely if you've lost track of the number of chronic diseases someone has diagnosed you with definitely a good sign if you need help doing things day-to-day and that's sort of the bread and butter of a geriatric practice that's definitely a good sign but ages ages not a number age is about about your function about how you act

Channel: JumpstartMD

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Id: NmdBhwUEz9U

Length: 44min 40sec (2680 seconds)

Published: Wed Jan 30 2019